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Multiple evanescent white dot syndrome | Multiple evanescent white dot syndrome (MEWDS) is an uncommon inflammatory condition of the retina that typically affects otherwise healthy young females in the second to fourth decades of life.
The typical patient with MEWDS is a healthy middle aged female age 15-50. There is a gender disparity as women are affected with MEWDS four times more often than men. Roughly 30% of patients have experienced an associated viral prodrome. Patients present with acute, painless, unilateral change in vision.
Presentation
Patients commonly present with acute unilateral painless decreased vision and photopsias. Presentations like central or paracentral scotoma, Floaters and dyschromatopsia are less common. An antecedent viral prodrome occurs in approximately one-third of cases. Myopia is commonly seen in patients.
Eye exam during the acute phase of the disease reveals multiple discrete white to orange spots at the level of the RPE or deep retina, typically in a perifoveal location (around the fovea). Optic disc oedema may also seen occasionally.
Cause
The etiology of multiple evanescent white dot syndrome is currently unknown. However, it is associated with the Pfizer vaccine according to the Jerusalem Post, August 4, 2021.
Diagnosis
Visual field abnormalities are variable and include generalized depression of visual field, paracentral or peripheral scotoma and enlargement of the blind spot.
Fluorescein angiography of the eye reveals characteristic punctate hyperfluorescent lesions in a wreath-like configuration surrounding the fovea.
Indocyanine green angiography reveals hypofluorescent lesions in a greater number compared with other studies.
Fundus autofluorescence (FAF) has been shown to be a noninvasive method to demonstrate the subretinal spots in MEWDS.
Treatment
MEWDS is a self limited disease with excellent visual recovery within 2-10 weeks. However residual symptoms including photopsia may persist for months.
== References == |
Chordee | Chordee is a condition in which the head of the penis curves downward or upward, at the junction of the head and shaft of the penis. The curvature is usually most obvious during erection, but resistance to straightening is often apparent in the flaccid state as well. In many cases but not all, chordee is associated with hypospadias. This is not the same condition as Peyronies disease, which involves curvature of the shaft of the penis most commonly due to injury during adult life.
Signs and symptoms
It is usually considered a congenital malformation of unknown cause. Since at an early stage of fetal development the penis is curved downward, it has been proposed that chordee results from an arrest of penile development at that stage.The curvature of a chordee can involve
tethering of the skin with urethra and corpora of normal size;
curvature induced by fibrosis and contracture of the fascial tissue (Bucks fascia or dartos) surrounding the urethra;
disproportionately large corpora in relation to the urethral length without other demonstrable abnormality of either; or
a short, fibrotic urethra that tethers the penis downward (the least common type).Severe degrees of chordee are usually associated with hypospadias, but mild degrees of curvature may occur in many otherwise normal males. When the curved penis is small and accompanied by hypospadias, deficiency of prenatal androgen effect can be inferred.
Cause
A chordee may be caused by an underlying condition, such as a disorder of sex development or an intersex condition, or from a complication of circumcision, though some medical professionals do not consider it to be true chordee because the corporal bodies are normally formed. However, not all congenital chordee includes abnormal corpora, and case reports of damage to the corpus cavernosum from circumcision are noted in the literature; particularly as a complication of local anesthetic.
Treatment
The principal treatment of chordee is surgery in infancy, usually by a pediatric urologist. With chordees caused by circumcision, the preferred method of surgical treatment is a z-plasty. The preferred time for surgery is between the ages of 6 and 18 months and correction is usually successful.
References
== External links == |
Seminal vesicles | The seminal vesicles (also called vesicular glands, or seminal glands) are a pair of two convoluted tubular glands that lie behind the urinary bladder of some male mammals. They secrete fluid that partly composes the semen.
The vesicles are 5–10 cm in size, 3–5 cm in diameter, and are located between the bladder and the rectum. They have multiple outpouchings which contain secretory glands, which join together with the vas deferens at the ejaculatory duct. They receive blood from the vesiculodeferential artery, and drain into the vesiculodeferential veins. The glands are lined with column-shaped and cuboidal cells. The vesicles are present in many groups of mammals, but not marsupials, monotremes or carnivores.
Inflammation of the seminal vesicles is called seminal vesiculitis, most often is due to bacterial infection as a result of a sexually transmitted disease or following a surgical procedure. Seminal vesiculitis can cause pain in the lower abdomen, scrotum, penis or peritoneum, painful ejaculation, and blood in the semen. It is usually treated with antibiotics, although may require surgical drainage in complicated cases. Other conditions may affect the vesicles, including congenital abnormalities such as failure or incomplete formation, and, uncommonly, tumours.
The seminal vesicles have been described as early as the second century AD by Galen, although the vesicles only received their name much later, as they were initially described using the term from which the word prostate is derived.
Structure
The seminal vesicles are a pair of glands in males that are positioned below the urinary bladder and at the end of the vasa deferentia, where they enter the prostate. Each vesicle is a coiled and folded tube, with occasional outpouchings termed diverticula in its wall. The lower part of the tube ends as a straight tube called the excretory duct which joins with the vas deferens of that side of the body to form an ejaculatory duct. The ejaculatory ducts pass through the prostate gland before opening separately into the verumontanum of the prostatic urethra. The vesicles are between 5–10 cm in size, 3–5 cm in diameter, and have a volume of around 13 mL.The vesicles receive blood supply from the vesiculodeferential artery, and also from the inferior vesical artery. The vesiculodeferential artery arises from the umbilical arteries, which branch directly from the internal iliac arteries. Blood is drained into the vesiculodeferential veins and the inferior vesical plexus, which drain into the internal iliac veins. Lymphatic drainage occurs along the venous routes, draining into the internal iliac nodes.The vesicles lie behind the bladder at the end of the vasa deferentia. They lie in the space between the bladder and the rectum; the bladder and prostate lie in front, the tip of the ureter as it enters the bladder above, and Denonvilliers fascia and the rectum behind.
Development
In the developing embryo, at the hind end lies a cloaca. This, over the fourth to the seventh week, divides into a urogenital sinus and the beginnings of the anal canal, with a wall forming between these two inpouchings called the urorectal septum. Two ducts form next to each other that connect to the urogenital sinus; the mesonephric duct and the paramesonephric duct, which go on to form the reproductive tracts of the male and female respectively.In the male, under the influence of testosterone, the mesonephric duct proliferates, forming the epididymis, ductus deferens and, via a small outpouching near the developing prostate, the seminal vesicles. Sertoli cells secrete anti-mullerian hormone, which causes the paramesonephric duct to regress.The development and maintenance of the seminal vesicles, as well as their secretion and size/weight, are highly dependent on androgens. The seminal vesicles contain 5α-reductase, which metabolizes testosterone into its much more potent metabolite, dihydrotestosterone (DHT). The seminal vesicles have also been found to contain luteinizing hormone receptors, and hence may also be regulated by the ligand of this receptor, luteinizing hormone.
Microanatomy
The inner lining of the seminal vesicles (the epithelium) is made of a lining of interspersed column-shaped and cube-shaped cells. There are varying descriptions of the lining as being pseudostratified and consisting of column-shaped cells only. When viewed under a microscope, the cells are seen to have large bubbles in their interior. This is because their interior, called cytoplasm, contains lipid droplets involved in secretion during ejaculation. The tissue of the seminal vesicles is full of glands, spaced irregularly. As well as glands, the seminal vesicles contain smooth muscle and connective tissue. This fibrous and muscular tissue surrounds the glands, helping to expel their contents. The outer surface of the glands is covered in peritoneum.
Function
The seminal vesicles secrete a significant proportion of the fluid that ultimately becomes semen. Fluid is secreted from the ejaculatory ducts of the vesicles into the vas deferens, where it becomes part of semen. This then passes through the urethra, where it is ejaculated during a male sexual response.About 70-85% of the seminal fluid in humans originates from the seminal vesicles. The fluid consists of nutrients including fructose and citric acid, prostaglandins, and fibrinogen. Nutrients help support sperm until fertilisation occurs; prostaglandins may also assist by softening mucous of the cervix, and by causing reverse contractions of parts of the female reproductive tract such as the fallopian tubes, to ensure that sperm are less likely to be expelled.
Clinical significance
Disease
Diseases of the Seminal vesicles as opposed to that of prostate gland are extremely rare and are infrequently reported in the medical literature.Congenital anomalies associated with the seminal vesicles include failure to develop, either completely (agenesis) or partially (hypoplasia), and cysts. Failure of the vesicles to form is often associated with absent vas deferens, or an abnormal connection between the vas deferens and the ureter. The seminal vesicles may also be affected by cysts, amyloidosis, and stones. Stones or cysts that become infected, or obstruct the vas deferens or seminal vesicles, may require surgical intervention.Seminal vesiculitis (also known as spermatocystitis) is an inflammation of the seminal vesicles, most often caused by bacterial infection. Symptoms can include vague back or lower abdominal pain; pain of the penis, scrotum or peritoneum; painful ejaculation; blood in the semen on ejaculation; irritative and obstructive voiding symptoms; and impotence. Infection may be due to sexually transmitted infections, as a complication of a procedure such as prostate biopsy. It is usually treated with antibiotics. If a person experiences ongoing discomfort, transurethral seminal vesiculoscopy may be considered. Intervention in the form of drainage through the skin or surgery may also be required if the infection becomes an abscess. The seminal vesicles may also be affected by tuberculosis, schistosomiasis and hydatid disease. These diseases are investigated, diagnosed and treated according to the underlying disease.Benign tumours of the seminal vesicles are rare. When they do occur, they are usually papillary adenomas and cystadenomas. They do not cause elevation of tumour markers, and are usually diagnosed based examination of tissue that has been removed after surgery. Primary adenocarcinoma of the seminal vesicles, although rare, constitutes the most common malignant cancer of the seminal vesicles; that said, the majority of malignant cancers affecting the vesicles are lesions that have extended into the vesicles from nearby parts of the body. When adenocarcinoma occurs, it can cause blood in the urine, blood in the semen, painful urination, urinary retention, or even urinary obstruction. Adenocarcinomata are usually diagnosed after they are excised, based on tissue diagnosis. Some produce the tumour marker Ca-125, which can be used to monitor for reoccurence afterwards. Even rarer neoplasms include sarcoma, squamous cell carcinoma, yolk sac tumor, neuroendocrine carcinoma, paraganglioma, epithelial stromal tumors and lymphoma.
Investigations
Symptoms due to diseases of the seminal vesicles may be vague and not able to be specifically attributable to the vesicles themselves; additionally, some conditions such as tumours or cysts may not cause any symptoms at all. When diseases is suspected, such as due to pain on ejaculation, blood in the urine, infertility, due to urinary tract obstruction, further investigations may be conducted.A digital rectal examination, which involves a finger inserted by a medical practitioner through the anus, may cause greater than usual tenderness of the prostate gland, or may reveal a large seminal vesicle. Palpation is dependent on the length of index finger as seminal vesicles are located above the prostate gland and retrovesical (behind the bladder).
A urine specimen may be collected, and is likely to demonstrate blood within the urine. Laboratory examination of seminal vesicle fluid requires a semen sample, e.g. for semen culture or semen analysis. Fructose levels provide a measure of seminal vesicle function and, if absent, bilateral agenesis or obstruction is suspected.Imaging of the vesicles is provided by medical imaging; either by transrectal ultrasound, CT or MRI scans. An examination using cystoscopy, where a flexible tube is inserted in the urethra, may show disease of the vesicles because of changes in the normal appearance of the nearby bladder trigone, or prostatic urethra.
Other animals
The evolution of seminal vesicles may have been influenced by sexual selection. They occur in many groups of mammals, but are absent in marsupials, monotremes, and carnivoras. The function is similar in all mammals they are present in, which is to secrete a fluid as part of semen that is ejaculated during the sexual response.
History
The action of the seminal vesicles has been described as early the second century AD by Galen, as "glandular bodies" that secrete substances alongside semen during reproduction. By the time of Herophilus the presence of the glands and associated ducts had been described. Around the time of the early 17th century the word used to describe the vesicles, parastatai, eventually and unambiguously was used to refer to the prostate gland, rather than the vesicles. The first time the prostate was portrayed in an individual drawing was by Reiner De Graaf in 1678.The first described use of laparoscopic surgery on the vesicles was described in 1993; this is now the preferred approach because of decreased pain, complications, and a shorter hospital stay.
Additional images
See also
Male accessory gland infection (MAGI)
Male accessory glands
References
External links
Histology image: 17501loa – Histology Learning System at Boston University - "Male Reproductive System: prostate, seminal vesicle"
Anatomy photo:44:04-0202 at the SUNY Downstate Medical Center - "The Male Pelvis: The Urinary Bladder"
Anatomy photo:44:08-0103 at the SUNY Downstate Medical Center - "The Male Pelvis: Structures Located Posterior to the Urinary Bladder" |
Biotinidase deficiency | Biotinidase deficiency is an autosomal recessive metabolic disorder in which biotin is not released from proteins in the diet during digestion or from normal protein turnover in the cell. This situation results in biotin deficiency.
Biotin is an important water-soluble nutrient that aids in the metabolism of fats, carbohydrates, and proteins. Biotin deficiency can result in behavioral disorders, lack of coordination, learning disabilities and seizures. Biotin supplementation can alleviate and sometimes totally stop such symptoms.
Signs and symptoms
Signs and symptoms of a biotinidase deficiency can appear several days after birth. These include seizures, hypotonia and muscle/limb weakness, ataxia, paresis, hearing loss, optic atrophy, skin rashes (including seborrheic dermatitis and psoriasis), and alopecia. If left untreated, the disorder can rapidly lead to coma and death.Biotinidase deficiency can also appear later in life. This is referred to as "late-onset" biotinidase deficiency. The symptoms are similar, but perhaps more mild, because if an individual survives the neonatal period they likely have some residual activity of biotin-related enzymes. Studies have noted individuals who were asymptomatic until adolescence or early adulthood. One study pointed out that untreated individuals may not show symptoms until age 21. Furthermore, in rare cases, even individuals with profound deficiencies of biotinidase can be asymptomatic.Symptom severity is predictably correlated with the severity of the enzyme defect. Profound biotinidase deficiency refers to situations where enzyme activity is 10% or less. Individuals with partial biotinidase deficiency may have enzyme activity of 10-30%.Functionally, there is no significant difference between dietary biotin deficiency and genetic loss of biotin-related enzyme activity. In both cases, supplementation with biotin can often restore normal metabolic function and proper catabolism of leucine and isoleucine.The symptoms of biotinidase deficiency (and dietary deficiency of biotin) can be quite severe. A 2004 case study from Metametrix detailed the effects of biotin deficiency, including aggression, cognitive delay, and reduced immune function.
Genetics
Mutations in the BTD gene cause biotinidase deficiency. Biotinidase is the enzyme that is made by the BTD gene. Many mutations that cause the enzyme to be nonfunctional or to be produced at extremely low levels have been identified. Biotin is a vitamin that is chemically bound to proteins. (Most vitamins are only loosely associated with proteins.) Without biotinidase activity, the vitamin biotin cannot be separated from foods and therefore cannot be used by the body. Another function of the biotinidase enzyme is to recycle biotin from enzymes that are important in metabolism (processing of substances in cells). When biotin is lacking, specific enzymes called carboxylases cannot process certain proteins, fats, or carbohydrates. Specifically, two essential branched-chain amino acids (leucine and isoleucine) are metabolized differently.Individuals lacking functional biotinidase enzymes can still have normal carboxylase activity if they ingest adequate amounts of biotin. The standard treatment regimen calls for 5–10 mg of biotin per day.Biotinidase deficiency is inherited in an autosomal recessive pattern, which means the defective gene is located on an autosome, and two copies of the defective gene - one from each parent - must be inherited for a person to be affected by the disorder. The parents of a child with an autosomal recessive disorder are usually not affected by the disorder, but are carriers of one copy of the defective gene. If both parents are carriers for the biotinidase deficiency, there is a 25% chance that their child will be born with it, a 50% chance the child will be a carrier, and a 25% chance the child will be unaffected.The chromosomal locus is at 3p25. The BTD gene has 4 exons of lengths 79 bp, 265 bp, 150 bp and 1502 bp, respectively. There are at least 21 different mutations that have been found to lead to biotinidase deficiency. The most common mutations in severe biotinidase deficiency (<10% normal enzyme activity) are: p. Cys33PhefsX36, p.Gln456His, p.Arg538Cys, p.Asp444His, and p.[Ala171Thr;Asp444His]. Almost all individuals with partial biotinidase deficiency (10-30% enzyme activity) have the mutation p.Asp444His in one allele of the BTD gene in combination with a second allele.
Pathophysiology
Symptoms of the deficiency are caused by the inability to reuse biotin molecules that are needed for cell growth, production of fatty acids and the metabolism of fats and amino acids. If left untreated, the symptoms can lead to later problems such as comas or death. Unless treatment is administered on a regular basis, symptoms can return at any point during the lifespan.
Diagnosis
Biotinidase deficiency can be found by genetic testing. This is often done at birth as part of newborn screening in several states throughout the United States. Results are found through testing a small amount of blood gathered through a heel prick of the infant. As not all states require that this test be done, it is often skipped in those where such testing is not required. Biotinidase deficiency can also be found by sequencing the BTD gene, particularly in those with a family history or known familial gene mutation.
Treatment
Treatment is possible but unless continued daily, problems may arise. Currently, this is done through supplementation of 5–10 mg of oral biotin a day. If symptoms have begun to show, standard treatments can take care of them, such as hearing aids for poor hearing.
Epidemiology
Based on the results of worldwide screening of biotinidase deficiency in 1991, the incidence of the disorder is:
5 in 137,401 for profound biotinidase deficiency
One in 109,921 for partial biotinidase deficiency
One in 61,067 for the combined incidence of profound and partial biotinidase deficiency
Carrier frequency in the general population is approximately one in 120.
See also
Biotin
Biotin deficiency
Multiple carboxylase deficiency
Holocarboxylase synthetase deficiency
3-Methylcrotonyl-CoA carboxylase deficiency
References
Further reading
Dobrowolski, Steven F.; Angeletti, Janine; Banas, Richard A.; Naylor, Edwin W. (2003). "Real time PCR assays to detect common mutations in the biotinidase gene and application of mutational analysis to newborn screening for biotinidase deficiency". Molecular Genetics and Metabolism. 78 (2): 100–7. doi:10.1016/S1096-7192(02)00231-7. PMID 12618081.
McMahon, Robert J. (2002). "Biotin in metabolism and molecular biology". Annual Review of Nutrition. 22: 221–39. doi:10.1146/annurev.nutr.22.121101.112819. PMID 12055344.
C. Neto, E.; Schulte, J.; Rubim, R.; Lewis, E.; Demari, J.; Castilhos, C.; Brites, A.; Giugliani, R.; et al. (2004). "Newborn screening for biotinidase deficiency in Brazil: biochemical and molecular characterizations". Brazilian Journal of Medical and Biological Research. 37 (3): 295–9. doi:10.1590/S0100-879X2004000300001. PMID 15060693.
Weber, Peter; Scholl, Sabine; Baumgartner, E Regula (2007). "Outcome in patients with profound biotinidase deficiency: relevance of newborn screening". Developmental Medicine & Child Neurology. 46 (7): 481–4. doi:10.1111/j.1469-8749.2004.tb00509.x. PMID 15230462.
Wolf, Barry (2003). "Biotinidase deficiency: New directions and practical concerns". Current Treatment Options in Neurology. 5 (4): 321–8. doi:10.1007/s11940-003-0038-4. PMID 12791199. S2CID 25158348.
External links
OMIM entries on Biotinidasa deficiency
This article incorporates public domain material from Genetics Home Reference. United States National Library of Medicine. |
Pulmonary consolidation | A pulmonary consolidation is a region of normally compressible lung tissue that has filled with liquid instead of air. The condition is marked by induration (swelling or hardening of normally soft tissue) of a normally aerated lung. It is considered a radiologic sign. Consolidation occurs through accumulation of inflammatory cellular exudate in the alveoli and adjoining ducts. The liquid can be pulmonary edema, inflammatory exudate, pus, inhaled water, or blood (from bronchial tree or hemorrhage from a pulmonary artery). Consolidation must be present to diagnose pneumonia: the signs of lobar pneumonia are characteristic and clinically referred to as consolidation.
Signs
Signs that consolidation may have occurred include:
Expansion of the thorax on inspiration is reduced on the affected side
Vocal fremitus is increased on the affected side
Percussion is dull in the affected area
Breath sounds are bronchial
Possible medium, late, or pan-inspiratory crackles
Vocal resonance is increased. Here, the patients voice (or whisper, as in whispered pectoriloquy) can be heard more clearly when there is consolidation, as opposed to the healthy lung where speech sounds muffled.
A pleural rub may be present.
A lower PAO2 than calculated in the alveolar gas equation
Diagnosis
Radiology
Typically, an area of white lung is seen on a standard X-ray. Consolidated tissue is more radio-opaque than normally aerated lung parenchyma, so that it is clearly demonstrable in radiography and on CT scans. Consolidation is often a middle-to-late stage feature/complication in pulmonary infections.
See also
Pulmonary infiltrate
References
== External links == |
Autoimmune encephalitis | Autoimmune encephalitis is a type of encephalitis that can result from a number of autoimmune diseases including:
Rasmussen encephalitis
Systemic lupus erythematosus
Behçets disease
Hashimotos encephalopathy
Autoimmune limbic encephalitis
Sydenhams chorea
== References == |
Acute radiation syndrome | Acute radiation syndrome (ARS), also known as radiation sickness or radiation poisoning, is a collection of health effects that are caused by being exposed to high amounts of ionizing radiation in a short period of time. Symptoms can start within an hour of exposure, and can last for several months. Early symptoms are usually nausea, vomiting and loss of appetite. In the following hours or weeks, initial symptoms may appear to improve, before the development of additional symptoms, after which either recovery or death follow.ARS involves a total dose of greater than 0.7 Gy (70 rad), that generally occurs from a source outside the body, delivered within a few minutes. Sources of such radiation can occur accidentally or intentionally. They may involve nuclear reactors, cyclotrons, certain devices used in cancer therapy, nuclear weapons, or radiological weapons. It is generally divided into three types: bone marrow, gastrointestinal, and neurovascular syndrome, with bone marrow syndrome occurring at 0.7 to 10 Gy, and neurovascular syndrome occurring at doses that exceed 50 Gy. The cells that are most affected are generally those that are rapidly dividing. At high doses, this causes DNA damage that may be irreparable. Diagnosis is based on a history of exposure and symptoms. Repeated complete blood counts (CBCs) can indicate the severity of exposure.Treatment of ARS is generally supportive care. This may include blood transfusions, antibiotics, colony-stimulating factors, or stem cell transplant. Radioactive material remaining on the skin or in the stomach should be removed. If radioiodine was inhaled or ingested, potassium iodide is recommended. Complications like leukemia and other cancers among those who survive are managed as usual. Short term outcomes depend on the dose exposure.ARS is generally rare. A single event can affect a large number of people, as happened in the atomic bombing of Hiroshima and Nagasaki and the Chernobyl nuclear power plant disaster. ARS differs from chronic radiation syndrome, which occurs following prolonged exposures to relatively low doses of radiation.
Signs and symptoms
Classically, ARS is divided into three main presentations: hematopoietic, gastrointestinal, and neuro vascular. These syndromes may be preceded by a prodrome. The speed of symptom onset is related to radiation exposure, with greater doses resulting in a shorter delay in symptom onset. These presentations presume whole-body exposure, and many of them are markers that are invalid if the entire body has not been exposed. Each syndrome requires that the tissue showing the syndrome itself be exposed (e.g., gastrointestinal syndrome is not seen if the stomach and intestines are not exposed to radiation). Some areas affected are:
Hematopoietic. This syndrome is marked by a drop in the number of blood cells, called aplastic anemia. This may result in infections, due to a low number of white blood cells, bleeding, due to a lack of platelets, and anemia, due to too few red blood cells in circulation. These changes can be detected by blood tests after receiving a whole-body acute dose as low as 0.25 grays (25 rad), though they might never be felt by the patient if the dose is below 1 gray (100 rad). Conventional trauma and burns resulting from a bomb blast are complicated by the poor wound healing caused by hematopoietic syndrome, increasing mortality.
Gastrointestinal. This syndrome often follows absorbed doses of 6–30 grays (600–3,000 rad). The signs and symptoms of this form of radiation injury include nausea, vomiting, loss of appetite, and abdominal pain. Vomiting in this time-frame is a marker for whole body exposures that are in the fatal range above 4 grays (400 rad). Without exotic treatment such as bone marrow transplant, death with this dose is common, due generally more to infection than gastrointestinal dysfunction.
Neurovascular. This syndrome typically occurs at absorbed doses greater than 30 grays (3,000 rad), though it may occur at doses as low as 10 grays (1,000 rad). It presents with neurological symptoms like dizziness, headache, or decreased level of consciousness, occurring within minutes to a few hours, with an absence of vomiting, and is almost always fatal, even with aggressive intensive care.Early symptoms of ARS typically include nausea, vomiting, headaches, fatigue, fever, and a short period of skin reddening. These symptoms may occur at radiation doses as low as 0.35 grays (35 rad). These symptoms are common to many illnesses, and may not, by themselves, indicate acute radiation sickness.
Dose effects
A similar table and description of symptoms (given in rems, where 100 rem = 1 Sv), derived from data from the effects on humans subjected to the atomic bombings of Hiroshima and Nagasaki, the indigenous peoples of the Marshall Islands subjected to the Castle Bravo thermonuclear bomb, animal studies and lab experiment accidents, have been compiled by the U.S. Department of Defense.A person who was less than 1 mile (1.6 km) from the atomic bomb Little Boys hypocenter at Hiroshima, Japan, was found to absorb about 9.46 grays (Gy) of ionizing radiation.The doses at the hypocenters of the Hiroshima and Nagasaki atomic bombings were 240 and 290 Gy, respectively.
Skin changes
Cutaneous radiation syndrome (CRS) refers to the skin symptoms of radiation exposure. Within a few hours after irradiation, a transient and inconsistent redness (associated with itching) can occur. Then, a latent phase may occur and last from a few days up to several weeks, when intense reddening, blistering, and ulceration of the irradiated site is visible. In most cases, healing occurs by regenerative means; however, very large skin doses can cause permanent hair loss, damaged sebaceous and sweat glands, atrophy, fibrosis (mostly keloids), decreased or increased skin pigmentation, and ulceration or necrosis of the exposed tissue. As seen at Chernobyl, when skin is irradiated with high energy beta particles, moist desquamation (peeling of skin) and similar early effects can heal, only to be followed by the collapse of the dermal vascular system after two months, resulting in the loss of the full thickness of the exposed skin. Another example of skin loss caused by high-level exposure of radiation is during the 1999 Tokaimura nuclear accident, where technician Hisashi Ouchi had lost a majority of his skin due to the high amounts of radiation he absorbed during the irradiation. This effect had been demonstrated previously with pig skin using high energy beta sources at the Churchill Hospital Research Institute, in Oxford.
Cause
ARS is caused by exposure to a large dose of ionizing radiation (> ~0.1 Gy) over a short period of time (> ~0.1 Gy/h). Alpha and beta radiation have low penetrating power and are unlikely to affect vital internal organs from outside the body. Any type of ionizing radiation can cause burns, but alpha and beta radiation can only do so if radioactive contamination or nuclear fallout is deposited on the individuals skin or clothing. Gamma and neutron radiation can travel much greater distances and penetrate the body easily, so whole-body irradiation generally causes ARS before skin effects are evident. Local gamma irradiation can cause skin effects without any sickness. In the early twentieth century, radiographers would commonly calibrate their machines by irradiating their own hands and measuring the time to onset of erythema.
Accidental
Accidental exposure may be the result of a criticality or radiotherapy accident. There have been numerous criticality accidents dating back to atomic testing during World War II, while computer-controlled radiation therapy machines such as Therac-25 played a major part in radiotherapy accidents. The latter of the two is caused by the failure of equipment software used to monitor the radiational dose given. Human error has played a large part in accidental exposure incidents, including some of the criticality accidents, and larger scale events such as the Chernobyl disaster. Other events have to do with orphan sources, in which radioactive material is unknowingly kept, sold, or stolen. The Goiânia accident is an example, where a forgotten radioactive source was taken from a hospital, resulting in the deaths of 4 people from ARS. Theft and attempted theft of radioactive material by clueless thieves has also led to lethal exposure in at least one incident.Exposure may also come from routine spaceflight and solar flares that result in radiation effects on earth in the form of solar storms. During spaceflight, astronauts are exposed to both galactic cosmic radiation (GCR) and solar particle event (SPE) radiation. The exposure particularly occurs during flights beyond low Earth orbit (LEO). Evidence indicates past SPE radiation levels that would have been lethal for unprotected astronauts. GCR levels that might lead to acute radiation poisoning are less well understood. The latter cause is rarer, with an event possibly occurring during the solar storm of 1859.
Intentional
Intentional exposure is controversial as it involves the use of nuclear weapons, human experiments, or is given to a victim in an act of murder. The intentional atomic bombings of Hiroshima and Nagasaki resulted in tens of thousands of casualties; the survivors of these bombings are known today as Hibakusha. Nuclear weapons emit large amounts of thermal radiation as visible, infrared, and ultraviolet light, to which the atmosphere is largely transparent. This event is also known as "Flash", where radiant heat and light are bombarded into any given victims exposed skin, causing radiation burns. Death is highly likely, and radiation poisoning is almost certain if one is caught in the open with no terrain or building masking-effects within a radius of 0–3 km from a 1 megaton airburst. The 50% chance of death from the blast extends out to ~8 km from a 1 megaton atmospheric explosion.Scientific testing on humans done without consent has been prohibited since 1997 in the United States. There is now a requirement for patients to give informed consent, and to be notified if experiments were classified. Across the world, the Soviet nuclear program involved human experiments on a large scale, which is still kept secret by the Russian government and the Rosatom agency. The human experiments that fall under intentional ARS exclude those that involved long term exposure. Criminal activity has involved murder and attempted murder carried out through abrupt victim contact with a radioactive substance such as polonium or plutonium.
Pathophysiology
The most commonly used predictor of ARS is the whole-body absorbed dose. Several related quantities, such as the equivalent dose, effective dose, and committed dose, are used to gauge long-term stochastic biological effects such as cancer incidence, but they are not designed to evaluate ARS. To help avoid confusion between these quantities, absorbed dose is measured in units of grays (in SI, unit symbol Gy) or rads (in CGS), while the others are measured in sieverts (in SI, unit symbol Sv) or rems (in CGS). 1 rad = 0.01 Gy and 1 rem = 0.01 Sv.In most of the acute exposure scenarios that lead to radiation sickness, the bulk of the radiation is external whole-body gamma, in which case the absorbed, equivalent, and effective doses are all equal. There are exceptions, such as the Therac-25 accidents and the 1958 Cecil Kelley criticality accident, where the absorbed doses in Gy or rad are the only useful quantities, because of the targeted nature of the exposure to the body.
Radiotherapy treatments are typically prescribed in terms of the local absorbed dose, which might be 60 Gy or higher. The dose is fractionated to about 2 Gy per day for "curative" treatment, which allows normal tissues to undergo repair, allowing them to tolerate a higher dose than would otherwise be expected. The dose to the targeted tissue mass must be averaged over the entire body mass, most of which receives negligible radiation, to arrive at a whole-body absorbed dose that can be compared to the table above.
DNA damage
Exposure to high doses of radiation cause DNA damage, later creating serious and even lethal chromosomal aberrations if left unrepaired. Ionizing radiation can produce reactive oxygen species, and does directly damage cells by causing localized ionization events. The former is very damaging to DNA, while the latter events create clusters of DNA damage. This damage includes loss of nucleobases and breakage of the sugar-phosphate backbone that binds to the nucleobases. The DNA organization at the level of histones, nucleosomes, and chromatin also affects its susceptibility to radiation damage. Clustered damage, defined as at least two lesions within a helical turn, is especially harmful. While DNA damage happens frequently and naturally in the cell from endogenous sources, clustered damage is a unique effect of radiation exposure. Clustered damage takes longer to repair than isolated breakages, and is less likely to be repaired at all. Larger radiation doses are more prone to cause tighter clustering of damage, and closely localized damage is increasingly less likely to be repaired.Somatic mutations cannot be passed down from parent to offspring, but these mutations can propagate in cell lines within an organism. Radiation damage can also cause chromosome and chromatid aberrations, and their effects depend on in which stage of the mitotic cycle the cell is when the irradiation occurs. If the cell is in interphase, while it is still a single strand of chromatin, the damage will be replicated during the S1 phase of cell cycle, and there will be a break on both chromosome arms; the damage then will be apparent in both daughter cells. If the irradiation occurs after replication, only one arm will bear the damage; this damage will be apparent in only one daughter cell. A damaged chromosome may cyclize, binding to another chromosome, or to itself.
Diagnosis
Diagnosis is typically made based on a history of significant radiation exposure and suitable clinical findings. An absolute lymphocyte count can give a rough estimate of radiation exposure. Time from exposure to vomiting can also give estimates of exposure levels if they are less than 10 Gray (1000 rad).
Prevention
A guiding principle of radiation safety is as low as reasonably achievable (ALARA). This means try to avoid exposure as much as possible and includes the three components of time, distance, and shielding.
Time
The longer that humans are subjected to radiation the larger the dose will be. The advice in the nuclear war manual entitled Nuclear War Survival Skills published by Cresson Kearny in the U.S. was that if one needed to leave the shelter then this should be done as rapidly as possible to minimize exposure.In chapter 12, he states that "[q]uickly putting or dumping wastes outside is not hazardous once fallout is no longer being deposited. For example, assume the shelter is in an area of heavy fallout and the dose rate outside is 400 roentgen (R) per hour, enough to give a potentially fatal dose in about an hour to a person exposed in the open. If a person needs to be exposed for only 10 seconds to dump a bucket, in this 1/360 of an hour he will receive a dose of only about 1 R. Under war conditions, an additional 1-R dose is of little concern." In peacetime, radiation workers are taught to work as quickly as possible when performing a task that exposes them to radiation. For instance, the recovery of a radioactive source should be done as quickly as possible.
Shielding
Matter attenuates radiation in most cases, so placing any mass (e.g., lead, dirt, sandbags, vehicles, water, even air) between humans and the source will reduce the radiation dose. This is not always the case, however; care should be taken when constructing shielding for a specific purpose. For example, although high atomic number materials are very effective in shielding photons, using them to shield beta particles may cause higher radiation exposure due to the production of bremsstrahlung x-rays, and hence low atomic number materials are recommended. Also, using material with a high neutron activation cross section to shield neutrons will result in the shielding material itself becoming radioactive and hence more dangerous than if it were not present.There are many types of shielding strategies that can be used to reduce the effects of radiation exposure. Internal contamination protective equipment such as respirators are used to prevent internal deposition as a result of inhalation and ingestion of radioactive material. Dermal protective equipment, which protects against external contamination, provides shielding to prevent radioactive material from being deposited on external structures. While these protective measures do provide a barrier from radioactive material deposition, they do not shield from externally penetrating gamma radiation. This leaves anyone exposed to penetrating gamma rays at high risk of ARS.
Naturally, shielding the entire body from high energy gamma radiation is optimal, but the required mass to provide adequate attenuation makes functional movement nearly impossible. In the event of a radiation catastrophe, medical and security personnel need mobile protection equipment in order to safely assist in containment, evacuation, and many other necessary public safety objectives.
Research has been done exploring the feasibility of partial body shielding, a radiation protection strategy that provides adequate attenuation to only the most radio-sensitive organs and tissues inside the body. Irreversible stem cell damage in the bone marrow is the first life-threatening effect of intense radiation exposure and therefore one of the most important bodily elements to protect. Due to the regenerative property of hematopoietic stem cells, it is only necessary to protect enough bone marrow to repopulate the exposed areas of the body with the shielded supply. This concept allows for the development of lightweight mobile radiation protection equipment, which provides adequate protection, deferring the onset of ARS to much higher exposure doses. One example of such equipment is the 360 gamma, a radiation protection belt that applies selective shielding to protect the bone marrow stored in the pelvic area as well as other radio sensitive organs in the abdominal region without hindering functional mobility.
More information on bone marrow shielding can be found in the "Health Physics Radiation Safety Journal". article Waterman, Gideon; Kase, Kenneth; Orion, Itzhak; Broisman, Andrey; Milstein, Oren (September 2017). "Selective Shielding of Bone Marrow: An Approach to Protecting Humans from External Gamma Radiation". Health Physics. 113 (3): 195–208. doi:10.1097/HP.0000000000000688. PMID 28749810. S2CID 3300412., or in the Organisation for Economic Co-operation and Development (OECD) and the Nuclear Energy Agency (NEA)s 2015 report: "Occupational Radiation Protection in Severe Accident Management" (PDF).
Reduction of incorporation
Where radioactive contamination is present, an elastomeric respirator, dust mask, or good hygiene practices may offer protection, depending on the nature of the contaminant. Potassium iodide (KI) tablets can reduce the risk of cancer in some situations due to slower uptake of ambient radioiodine. Although this does not protect any organ other than the thyroid gland, their effectiveness is still highly dependent on the time of ingestion, which would protect the gland for the duration of a twenty-four-hour period. They do not prevent ARS as they provide no shielding from other environmental radionuclides.
Fractionation of dose
If an intentional dose is broken up into a number of smaller doses, with time allowed for recovery between irradiations, the same total dose causes less cell death. Even without interruptions, a reduction in dose rate below 0.1 Gy/h also tends to reduce cell death. This technique is routinely used in radiotherapy.The human body contains many types of cells and a human can be killed by the loss of a single type of cells in a vital organ. For many short term radiation deaths (3–30 days), the loss of two important types of cells that are constantly being regenerated causes death. The loss of cells forming blood cells (bone marrow) and the cells in the digestive system (microvilli, which form part of the wall of the intestines) is fatal.
Management
Treatment usually involves supportive care with possible symptomatic measures employed. The former involves the possible use of antibiotics, blood products, colony stimulating factors, and stem cell transplant.
Antimicrobials
There is a direct relationship between the degree of the neutropenia that emerges after exposure to radiation and the increased risk of developing infection. Since there are no controlled studies of therapeutic intervention in humans, most of the current recommendations are based on animal research.The treatment of established or suspected infection following exposure to radiation (characterized by neutropenia and fever) is similar to the one used for other febrile neutropenic patients. However, important differences between the two conditions exist. Individuals that develop neutropenia after exposure to radiation are also susceptible to irradiation damage in other tissues, such as the gastrointestinal tract, lungs and central nervous system. These patients may require therapeutic interventions not needed in other types of neutropenic patients. The response of irradiated animals to antimicrobial therapy can be unpredictable, as was evident in experimental studies where metronidazole and pefloxacin therapies were detrimental.
Antimicrobials that reduce the number of the strict anaerobic component of the gut flora (i.e., metronidazole) generally should not be given because they may enhance systemic infection by aerobic or facultative bacteria, thus facilitating mortality after irradiation.An empirical regimen of antimicrobials should be chosen based on the pattern of bacterial susceptibility and nosocomial infections in the affected area and medical center and the degree of neutropenia. Broad-spectrum empirical therapy (see below for choices) with high doses of one or more antibiotics should be initiated at the onset of fever. These antimicrobials should be directed at the eradication of Gram-negative aerobic bacilli (i.e., Enterobacteriace, Pseudomonas) that account for more than three quarters of the isolates causing sepsis. Because aerobic and facultative Gram-positive bacteria (mostly alpha-hemolytic streptococci) cause sepsis in about a quarter of the victims, coverage for these organisms may also be needed.A standardized management plan for people with neutropenia and fever should be devised. Empirical regimens contain antibiotics broadly active against Gram-negative aerobic bacteria (quinolones: i.e., ciprofloxacin, levofloxacin, a third- or fourth-generation cephalosporin with pseudomonal coverage: e.g., cefepime, ceftazidime, or an aminoglycoside: i.e. gentamicin, amikacin).
Prognosis
The prognosis for ARS is dependent on the exposure dose, with anything above 8 Gy being almost always lethal, even with medical care. Radiation burns from lower-level exposures usually manifest after 2 months, while reactions from the burns occur months to years after radiation treatment. Complications from ARS include an increased risk of developing radiation-induced cancer later in life. According to the controversial but commonly applied linear no-threshold model, any exposure to ionizing radiation, even at doses too low to produce any symptoms of radiation sickness, can induce cancer due to cellular and genetic damage. The probability of developing cancer is a linear function with respect to the effective radiation dose. Radiation cancer may occur after ionizing radiation exposure following a latent period averaging 20 to 40 years.
History
Acute effects of ionizing radiation were first observed when Wilhelm Röntgen intentionally subjected his fingers to X-rays in 1895. He published his observations concerning the burns that developed that eventually healed, and misattributed them to ozone. Röntgen believed the free radical produced in air by X-rays from the ozone was the cause, but other free radicals produced within the body are now understood to be more important. David Walsh first established the symptoms of radiation sickness in 1897.Ingestion of radioactive materials caused many radiation-induced cancers in the 1930s, but no one was exposed to high enough doses at high enough rates to bring on ARS.
The atomic bombings of Hiroshima and Nagasaki resulted in high acute doses of radiation to a large number of Japanese people, allowing for greater insight into its symptoms and dangers. Red Cross Hospital Surgeon Terufumi Sasaki led intensive research into the syndrome in the weeks and months following the Hiroshima and Nagasaki bombings. Dr Sasaki and his team were able to monitor the effects of radiation in patients of varying proximities to the blast itself, leading to the establishment of three recorded stages of the syndrome. Within 25–30 days of the explosion, Sasaki noticed a sharp drop in white blood cell count and established this drop, along with symptoms of fever, as prognostic standards for ARS. Actress Midori Naka, who was present during the atomic bombing of Hiroshima, was the first incident of radiation poisoning to be extensively studied. Her death on 24 August 1945 was the first death ever to be officially certified as a result of ARS (or "Atomic bomb disease").
There are two major databases that track radiation accidents: The American ORISE REAC/TS and the European IRSN ACCIRAD. REAC/TS shows 417 accidents occurring between 1944 and 2000, causing about 3000 cases of ARS, of which 127 were fatal. ACCIRAD lists 580 accidents with 180 ARS fatalities for an almost identical period. The two deliberate bombings are not included in either database, nor are any possible radiation-induced cancers from low doses. The detailed accounting is difficult because of confounding factors. ARS may be accompanied by conventional injuries such as steam burns, or may occur in someone with a pre-existing condition undergoing radiotherapy. There may be multiple causes for death, and the contribution from radiation may be unclear. Some documents may incorrectly refer to radiation-induced cancers as radiation poisoning, or may count all overexposed individuals as survivors without mentioning if they had any symptoms of ARS.
Notable cases
The following table includes only those known for their attempted survival with ARS. These cases exclude chronic radiation syndrome such as Albert Stevens, in which radiation is exposed to a given subject over a long duration. The "result" column represents the time of exposure to the time of death attributed to the short and long term effects attributed to initial exposure. As ARS is measured by a whole-body absorbed dose, the "exposure" column only includes units of Gray (Gy).
Other animals
Thousands of scientific experiments have been performed to study ARS in animals. There is a simple guide for predicting survival and death in mammals, including humans, following the acute effects of inhaling radioactive particles.
See also
References
This article incorporates public domain material from websites or documents of the U.S. Armed Forces Radiobiology Research Institute and the U.S. Centers for Disease Control and Prevention
External links
"Emergency preparedness and subject matter expertise on the medical management of radiation incidents". U.S. Radiation Emergency Assistance Center Training Site REACts.{{cite web}}: CS1 maint: url-status (link)
"Fact sheet on Acute Radiation Syndrome". U.S. Centers for Disease Control and Prevention. Archived from the original on 16 July 2006. Retrieved 22 July 2006.
"The criticality accident in Sarov" (PDF). International Atomic Energy Agency. 2001. – A well documented account of the biological effects of a criticality accident.
"Armed Forces Radiobiology Research Institute". |
Photokeratitis | Photokeratitis or ultraviolet keratitis is a painful eye condition caused by exposure of insufficiently protected eyes to the ultraviolet (UV) rays from either natural (e.g. intense sunlight) or artificial (e.g. the electric arc during welding) sources. Photokeratitis is akin to a sunburn of the cornea and conjunctiva.
The injury may be prevented by wearing eye protection that blocks most of the ultraviolet radiation, such as welding goggles with the proper filters, a welders helmet, sunglasses rated for sufficient UV protection, or appropriate snow goggles. The condition is usually managed by removal from the source of ultraviolet radiation, covering the corneas, and administration of pain relief. Photokeratitis is known by a number of different terms including: snow blindness, arc eye, welders flash, bake eyes, corneal flash burns, flash burns, niphablepsia, or keratoconjunctivitis photoelectrica.
Signs and symptoms
Common symptoms include pain, intense tears, eyelid twitching, discomfort from bright light, and constricted pupils.
Cause
Any intense exposure to UV light can lead to photokeratitis. In 2010, the Department of Optometry at the Dublin Institute of Technology published that the threshold for photokeratitis is 0.12 J/m2. (Prior to this, in 1975, the Division of Biological Effects at the US Bureau of Radiological Health had published that the human threshold for photokeratitis is 50 J/m2.) Common causes include welding with failure to use adequate eye protection such as an appropriate welding helmet or welding goggles. This is termed arc eye, while photokeratitis caused by exposure to sunlight reflected from ice and snow, particularly at elevation, is commonly called snow blindness. It can also occur due to using tanning beds without proper eyewear. Natural sources include bright sunlight reflected from snow or ice or, less commonly, from sea or sand. Fresh snow reflects about 80% of the UV radiation compared to a dry, sandy beach (15%) or sea foam (25%). This is especially a problem in polar regions and at high altitudes, as with about every 300 m (1,000 ft) of elevation (above sea level), the intensity of UV rays increases by four percent.
Diagnosis
Fluorescein dye staining will reveal damage to the cornea under ultraviolet light.
Prevention
Photokeratitis can be prevented by using sunglasses or eye protection that transmits 5–10% of visible light and absorbs almost all UV rays. Additionally, these glasses should have large lenses and side shields to avoid incidental light exposure. Sunglasses should always be worn, even when the sky is overcast, as UV rays can pass through clouds.The Inuit, Yupik, and other Arctic peoples carved snow goggles from materials such as driftwood or caribou antlers to help prevent snow blindness. Curved to fit the users face with a large groove cut in the back to allow for the nose, the goggles allowed in a small amount of light through a long thin slit cut along their length. The goggles were held to the head by a cord made of caribou sinew.In the event of missing sunglass lenses, emergency lenses can be made by cutting slits in dark fabric or tape folded back onto itself. The SAS Survival Guide recommends blackening the skin underneath the eyes with charcoal (as the ancient Egyptians did) to avoid any further reflection.
Treatment
The pain may be temporarily alleviated with anaesthetic eye drops for the examination; however, they are not used for continued treatment, as anaesthesia of the eye interferes with corneal healing, and may lead to corneal ulceration and even loss of the eye. Cool, wet compresses over the eyes and artificial tears may help local symptoms when the feeling returns. Nonsteroidal anti-inflammatory drug (NSAID) eyedrops are widely used to lessen inflammation and eye pain, but have not been proven in rigorous trials. Systemic (oral) pain medication is given if discomfort is severe. Healing is usually rapid (24–72 hours) if the injury source is removed. Further injury should be avoided by isolation in a dark room, removing contact lenses, not rubbing the eyes, and wearing sunglasses until the symptoms improve.
See also
References
== External links == |
Ghost cell glaucoma | Ghost cell glaucoma (GCG) is a type of secondary glaucoma occurs due to long standing vitreous hemorrhage. The rigid and less pliable degenerated red blood cells (ghost cells) block the trabecular meshwork and increase the pressure inside eyes.
Pathophysiology
The ghost cells develop within the vitreous cavity, 1–3 weeks after vitreous hemorrhage. They obstruct the trabecular meshwork and eventually the pressure inside eye (intraocular pressure) increases and leads to glaucoma. A variety of ocular conditions may cause GCG. Main causes include ocular trauma, diabetes, sickle cell disease, uveitis, UGH syndrome, many eye surgeries etc.
Signs and symptoms
Myriad small cells may be seen in the aqueous humor during slit lamp examination. Intraocular pressure rises up to 30 to 70 mm Hg. The increased intraocular pressure may cause blurring of vision, headache, brow ache, nausea and/or vomiting. The angle of anterior chamber is seen open with gonioscopy.
Complications
If the increased intraocular pressure is uncontrolled, it may lead to optic nerve damage and irreversible visual impairment.
Treatment
The condition usually resolves once the vitreous hemorrhage has cleared. But, depending on the seriousness of the increased intraocular pressure, medical or surgical treatment may be advised. If IOP is not so high, medical therapy with aqueous suppressants is preferred. Surgery is advised if the intraocular pressure remains in 40- to 50-mm Hg range even after medical therapy. Anterior chamber can be cleaned by making a small paracentesis in the cornea and irrigating the anterior chamber with a saline solution. Repeat evacuation and aspiration are required if myriad cells accumulate again in anterior chamber.
History
Campbell et al. described Ghost cell glaucoma in 1976. Campbell and Grant described the condition and given the name ghost cell glaucoma. Fenton and Zimmerman called it hemolytic glaucoma.
== References == |
Supernumerary nipple | A supernumerary nipple is an additional instance of nipple occurring in mammals, including humans. They are often mistaken for moles. Studies variously report the prevalence of supernumerary nipples as approximately 1 in 18 and 1 in 40.The nipples appear along the two vertical "milk lines", which start in the armpit on each side, run down through the typical nipples and end at the groin. They are classified into eight levels of completeness from a simple patch of hair to a milk-bearing breast in miniature.
Types
Polythelia refers to the presence of an additional nipple alone while polymastia denotes the much rarer presence of additional mammary glands.
Although usually presenting on the milk line, pseudomamma can appear as far away as the foot.A possible relationship with mitral valve prolapse has been proposed.
Clinical significance
Clinical presentation
May remain undetected. Occasionally, the supernumerary nipple is noticed when hormonal changes during adolescence, menstruation, or pregnancy cause increased pigmentation, fluctuating swelling, tenderness, or even lactation.
Associations
It is said to be found in association with many syndromes and other conditions:
McKusick–Kaufman syndrome
Char syndrome
Simpson–Golabi–Behmel syndrome
Treatment and prognosis
Most often no treatment is required; however, a protruding embarrassing supernumerary nipple can be removed surgically, if desired. Removal using liquid nitrogen cryotherapy has also been described.
Society and culture
Television
The Triple Nipple Club is a documentary shown on Channel 4 which explored the biological mystery of the supernumerary nipple. First broadcast on 2 January 2008, it was directed and produced by Dan Louw and commissioned as part of Channel 4s First Cut series. The film focuses on Louws attempts to understand why he was born with extra nipples, a condition he shares with the likes of Mark Wahlberg, Lily Allen, and Tilda Swinton, as well as well known TV and film characters such as the Bond villain Scaramanga and Chandler Bing. Fascinated and confused by this seemingly pointless mutation, Louw sets off on a personal journey of discovery to try and unwrap "the riddle of the triple nipple". He starts out by consulting the man in the street and even a renowned teratologist, an expert in physical mutations. After testing the notion that extra nipples could be a sign of fertility, he discovers that they are actually an atavism, or evolutionary holdover – a sign of how humans evolved.
See also
Accessory breast
Grace Sherwood, sentenced to jail for witchcraft partly on the basis of having "two things like titts on her private parts of a black coller [color]"
Polydactyly
References
== External links == |
Subareolar abscess | Also called Zuskas disease (only nonpuerperal case), subareolar abscess is a subcutaneous abscess of the breast tissue beneath the areola of the nipple. It is a frequently aseptic inflammation and has been associated with squamous metaplasia of lactiferous ducts.
The term is usually understood to include breast abscesses located in the retroareolar region or the periareolar region but not those located in the periphery of the breast.
Subareolar abscess can develop both during lactation or extrapuerperal, the abscess is often flaring up and down with repeated fistulation.
Pathophysiology
90% of cases are smokers, however only a very small fraction of smokers appear to develop this lesion. It has been speculated that either the direct toxic effect or hormonal changes related to smoking could cause squamous metaplasia of lactiferous ducts. It is not well established whether the lesion regresses after smoking cessation.
Extrapuerperal cases are often associated with hyperprolactinemia or with thyroid problems. Also diabetes mellitus may be a contributing factor in nonpuerperal breast abscess.
Treatment
Treatment is problematic unless an underlying endocrine disorder can be successfully diagnosed and treated.
A study by Goepel and Panhke provided indications that the inflammation should be controlled by bromocriptine even in absence of hyperprolactinemia.Antibiotic treatment is given in case of acute inflammation. However, this alone is rarely effective, and the treatment of a subareaolar abscess is primarily surgical. In case of an acute abscess, incision and drainage are performed, followed by antibiotics treatment. However, in contrast to peripheral breast abscess which often resolves after antibiotics and incision and drainage, subareaolar breast abscess has a tendency to recur, often accompanied by the formation of fistulas leading from inflammation area to the skin surface. In many cases, in particular in patients with recurrent subareolar abscess, the excision of the affected lactiferous ducts is indicated, together with the excision of any chronic abscess or fistula. This can be performed using radial or circumareolar incision.There is no universal agreement on what should be the standard way of treating the condition. In a recent review article, antibiotics treatment, ultrasound evaluation and, if fluid is present, ultrasound-guided fine needle aspiration of the abscess with an 18 gauge needle, under saline lavage until clear, has been suggested as initial line of treatment for breast abscess in puerperal and non-puerperal cases including central (subareolar) abscess (see breast abscess for details). Elsewhere, it has been stated that treatment of subareolar abscess is unlikely to work if it does not address the ducts as such.Duct resection has been traditionally used to treat the condition; the original Hadfield procedure has been improved many times but long-term success rate remains poor even for radical surgery. Petersen even suggests that damage caused by previous surgery is a frequent cause of subareolar abscesses. Goepel and Pahnke and other authors recommend performing surgeries only with concomitant bromocriptine treatment.
Squamous metaplasia of lactiferous ducts
Squamous metaplasia of lactiferous ducts - abbreviated SMOLD is a change where the normal double layer cuboid epithelium of the lactiferous ducts is replaced by squamous keratinizing cell layers. The resulting epithelium is very similar to normal skin, hence some authors speak of epidermalization. SMOLD is rare in premenopausal women (possibly 0.1-3%) but more frequent (possibly up to 25%) in postmenopausal women where it does not cause any problems at all.
SMOLD appears to be a completely benign lesion and may exist without causing any symptoms. In principle it ought to be completely reversible as the classification as metaplasia would suggest. Because of difficulties in observing the actual changes and rare incidence of the lesion this does not appear to be documented.
The last section of the lactiferous ducts is always lined with squamous keratinizing epithelium which appears to have important physiological functions. For example, the keratin forms plugs sealing the duct entry and has bacteriostatic properties. In SMOLD the keratinizing lining which is supposed to form only the ends of the lactiferous ducts extends deep into the ducts.
SMOLD is distinct from squamous metaplasia that may occur in papilomatous hyperplasia. It is believed to be unrelated to squamous cell carcinoma of the breast which probably arises from different cell types.
The keratin plugs (debris) produced by SMOLD have been proposed as the cause for recurrent subareolar abscesses by causing secretory stasis. The epidermalized lining has also different permeability than the normal lining, hindering resorption of glandular secretions. The resorption is necessary to dispose of stalled secretions inside the duct - and at least equally important it affects osmotic balance which in turn is an important mechanism in the control of lactogenesis (this is relevant both in puerperal and nonpuerperal mastitis).
While in lactating women this would appear to be a very plausible pathogenesis, there is some uncertainty about the pathogenesis in non-lactating women where breast secretions should be apriori minimal. It appears pathologic stimulation of lactogenesis must be present as well to cause subareolar abscess and treatment success with bromocriptin appears to confirm this as compared to poor success rate of the usual antibiotic and surgical treatments documented by Hanavadi et al.Further uncertainty in the relation of SMOLD and the subareolar abscess is that squamous metaplasia is very often caused by inflammatory processes. SMOLD could be the cause of the inflammation – or the result of a previous or longstanding inflammation.
SMOLD usually affects multiple ducts and frequently (relative to extremely low absolute prevalence) both breasts hence it is very likely that systemic changes such as hormonal interactions are involved.
At least the following factors have been considered in the aetiology of SMOLD: reactive change to chronic inflammation, systemic hormonal changes, smoking, dysregulation in beta-catenin expression, changes in retinoic acid and vitamin D metabolism or expression.
Vitamin A deficiency may cause epidermilization of the ducts and squamous metaplasia and likely also contributes to infection. Vitamin A deficiency has been observed to cause squamous metaplasia in many types of epithelia. However supplementation with Vitamin A would be beneficial only in exceptional cases because normally the local catabolism of vitamin A will be the regulating factor.
Squamous metaplasia of breast epithelia is known to be more prevalent in postmenopausal women (where it does not cause any problems at all). Staurosporine, a nonspecific protein kinase C inhibitor can induce squamous metaplasia in breast tissue while other known PKC inhibitors did not show this effect. cAMP stimulation can also induce squamous metaplasia.
Research
Multiple imaging modalities may be necessary to evaluate abnormalities of the nipple-areolar complex.In two studies performed in Japan, high-resolution MRI with a microscopy coil yielding 0.137-mm in-plane resolution has been used to confirm the presence of abscesses, isolated fistulas and inflammation and to reveal their position in order to guide surgery.
References
Further reading
Kasales CJ, Han B, Smith JS, Chetlen AL, Kaneda HJ, Shereef S (February 2014). "Nonpuerperal mastitis and subareolar abscess of the breast". AJR. American Journal of Roentgenology (review). 202 (2): W133–9. doi:10.2214/AJR.13.10551. PMID 24450694. S2CID 27952386. |
Sexual sadism disorder | Sexual sadism disorder is the condition of experiencing sexual arousal in response to the extreme pain, suffering or humiliation of others. Several other terms have been used to describe the condition, and the condition may overlap with other conditions that involve inflicting pain. It is distinct from situations in which consenting individuals use mild or simulated pain or humiliation for sexual excitement. The words sadism and sadist are derived from the French writer and libertine Marquis de Sade, who wrote several novels depicting sexualized torture and violence.
Related terms and conditions
Current terminology
Sexual sadism disorder is the term employed by the current version of the Diagnostic and Statistical Manual (DSM-5) of the American Psychiatric Association. It refers to the "recurrent and intense sexual arousal from the physical or psychological suffering of another person, as manifested by fantasies, urges, or behaviors" (p. 696). It is classified as one of the paraphilias, called an "algolagnic disorder" (p. 685), which is one of the "anomalous activity preferences" (p. 685). The formal diagnosis of Sexual Sadism Disorder would apply if the individual has acted on these urges with a non-consenting person or if the urges cause significant distress to the individual.
Sadomasochism appears in the current version of the International Classification of Diseases (ICD-10) of the World Health Organization. It refers to the "preference for sexual activity that involves bondage or the infliction of pain or humiliation" (p. 172), and divides sadomasochism into sadism and masochism according to whether the individual prefers to be the provider or recipient of it. The ICD-10 specifies that mild forms of sadomasochism "are commonly used to enhance otherwise normal sexual activity" (p. 172), and that the diagnosis would apply only if the behavior is preferred or required for sexual gratification. The condition is classified as one of the disorders of sexual preference, which includes the paraphilias (p. 170).
Paraphilic coercive disorder refers to the preference for non-consenting over consenting sexual partners. It differs from sexual sadism disorder in that although the individual with this disorder may inflict pain or threats of pain in order to gain the compliance of the victim, the infliction of pain is not the individuals actual goal. The condition is typically described as a paraphilia and continues to undergo research, but does not appear in the current DSM or ICD. Alternate terms for the condition have included Biastophilia, Coercive Paraphilic Disorder, and Preferential Rape.BDSM or "bondage/discipline dominance/submission sadomasochism" is a colloquial term referring to the subculture of individuals who willingly engage in consenting forms of mild or simulated pain or humiliation. It is not currently a diagnosable condition in either the DSM or ICD system. Alternative terms have included Bondage and Discipline (B&D), Domination and Submission (D&S), and Sadism and Masochism (S&M). In scientific research, this sexual preference has also been called the hyperdominance pattern of sexual behavior. Unlike individuals with sexual sadism disorder or paraphilic coercive disorder, individuals with hyperdominance seek to provoke pleasure in their partner(s) with the pain/humiliation.
Previous terminology
Sexual sadism is the term previously employed by the DSM-III-R, DSM-IV, and DSM-IV-TR, where it was classified as a paraphilia. In these versions of the DSM, sexual sadism pertained only to the infliction of real (not simulated) suffering (p. 530). The condition was renamed sexual sadism disorder in DSM-5.
Sexual sadism was the term employed in the DSM-III, classifying the condition as a paraphilia. The DSM-III noted that "the imagery in a Paraphilia, such as simulated bondage, may be playful and harmless and acted out with a mutually consenting partner….In more extreme form, paraphilic imagery is acted out with a nonconsenting partner, and is noxious and injurious to the partner" (p. 267). In DSM-III, sexual sadism could be diagnosed if:
the person repeatedly and intentionally inflicted suffering on a nonconsenting person, to experience sexual excitement
repeatedly or exclusively preferred simulated or mild suffering with a consenting sexual partner
employs extensive, permanent, or potentially fatal suffering to achieve sexual excitement, regardless of the consent of the other person.Sadism was the term employed by the DSM-II. In that manual, the condition was classified as a sexual deviation, which was used to describe "individuals whose sexual interests are directed primarily toward…coitus performed under bizarre circumstances" (p. 44). The term "paraphilia" did not exist in the DSM-II, and diagnoses did not have specific criteria until DSM-III.
Sexual sadism was the phrase mentioned in DSM-I as one of the sexual deviations (p. 39), but neither it (nor any of the other sexual deviations) received a specific label or diagnostic criteria. The term paraphilia did not exist in the DSM-II, and diagnoses did not have specific criteria until DSM-III.
Sadistic personality disorder does not actually refer to any sexual interest, and instead refers to the pervasive disregard for the well-being of others. It is usually associated with a history of violence and criminality (which can include, but is not limited to sexual crimes).
Features
With paraphilic coercive disorder, the individual employs enough force to subdue a victim, but with sexual sadism disorder, the individual often continues to inflict harm regardless of the compliance of the victim, which sometimes escalates not only to the death of the victim, but also to the mutilation of the body. What is experienced by the sadist as sexual does not always appear obviously sexual to non-sadists: sadistic rapes do not necessarily include penile penetration of the victim. In a survey of offenses, 77% of cases included sexual bondage, 73% included anal rape, 60% included blunt force trauma, 57% included vaginal rape, and 40% included penetration of the victim by a foreign object. In 40% of cases, the offender kept a personal item of the victim as a souvenir.On personality testing, sadistic rapists apprehended by law enforcement have shown elevated traits of impulsivity, hypersexuality, callousness, and psychopathy.Although there appears to be a continuum of severity from mild (hyperdominance or BDSM) to moderate (paraphilic coercive disorder) to severe (sexual sadism disorder), it is not clear if they are genuinely related or only appear related superficially.Very little is known about how sexual sadism disorder develops. Most of the people diagnosed with sexual sadism disorder come to the attention of authorities by committing sexually motivated crimes. Surveys have also been conducted to include people who are interested in only mild and consensual forms of sexual pain/humiliation (BDSM).Most people with full-blown sexual sadism disorder are male, whereas the sex ratio of people interested in BDSM is closer to 2:1 male-to-female.People with sexual sadism disorder are at an elevated likelihood of having other paraphilic sexual interests.
Typology
Criminologist Lee Mellor created a six typology of sexually sadistic homicide offenders, based upon a combination of three binary factors: Destructive versus Preservative: Destructive sex sadists mutilate the bodies of their living victims, while Preservative sex sadists do not. Prolonged versus Brief: The Prolonged sex sadist tortures their victim for an hour or more, while the Brief sex sadist does so over less time. Elaborate versus Simple: Where Simple sex sadists tend to use one or two methods of torture, Elaborate sadists have three of the following four characteristics, (i) variation in torture methods, (ii) complex torture apparatus, (iii) psychological torture, (iv) record making (e.g., using notes/media to document the process). This renders eight possible categories, six of which Mellor was able to find multiple criminal offenders to exemplify:
This typology is compatible with the necrophilia typology, producing hybrid categories which help to understand the totality of the offenders paraphilic desires.
See also
Sexual masochism disorder
Biastophilia
Lust murder
Marquis de Sade, after whom sadism is named
Sadistic personality disorder
References
== External links == |
Congenital stenosis of vena cava | Congenital stenosis of vena cava is a congenital anomaly in which the superior vena cava or inferior vena cava has an aberrant interruption or coarctation.
In some cases, it can be asymptomatic, and in other cases it can lead to fluid accumulation and cardiopulmonary collapse.
Symptoms and signs
Congenital heart defects may not show signs or symptoms until later stages of the childs life and have a delayed diagnosis.
Congenital stenosis of the inferior vena cava is asymptomatic in many patients.
Adolescent males with the condition have shown to presents with symptoms such as spontaneous lower extremity DVT, leg swelling, leg pain, varices in the lower extremities, hepatic thrombosis and hematochezia.
Chylothorax has been observed rarely as a symptom of congenital stenosis of the superior vena cava in infant patients.
Chylothorax results as a rare complication in which chyle leaks into the thoracic space following direct incidental damage and can also lead to increased thoracic duct pressure.
Chylothorax leakage commonly occurs in patients with additional complex congenital heart lesions, increasing the risk of underlying vascular anomalies.
Other symptoms which may become present later than adolescence includes venous hypertension, post necrotic hepatic cirrhosis and portal hypertension from the manifestation of the condition.
Diagnosis
Congenital stenosis of the vena cava is a sub-classification of the overarching spectrum of congenital heart disease involving the vessels surrounding the heart resulting in disruption to normal cardiovascular blood flow.
Diagnosis commonly occurs in early adolescence, expressed as symptoms such as deep vein thrombosis (DVT) occurring spontaneously.
The mainstay diagnosis of the presenting DVT symptom is an ultrasound with venous Doppler.
Ultrasound with venous Doppler rarely identifies the inferior vena cava anomalies present from birth.
Difficulties in identifying the congenital stenosis of the vena cava makes diagnosis uncommon.
Diagnosis of congenital stenosis of the inferior vena cava can be rarely discovered through abdominal CT examinations, and may present with an array of clinical findings dependent on the drainage patterns of the individuals.
Further diagnostic tools such as a transthoracic echocardiogram can reveal the narrowing of the vena cava showing a low velocity of flow.
Congenital stenosis of the vena cava can also present as acute respiratory failure and effusion of the right lung on chest X-rays.
Treatments
Treatments may not be necessary for the congenital heart defect.
If required, treatments can include medication, catheter procedures, corrective surgery and heart transplants dependent on the severity of the defect, age of the patient and patients general health.
Symptomatic relief of venous hypertension, associated with the congenital heart defect, can be achieved through surgery as it reduces the likelihood of hepatic vein thrombosis.
Intravascular stents are a treatment method for Congenital Stenosis of the Vena Cava.
Expandable metallic stents have been used as part of a procedure to dilate and maintain stenotic vena cava.
Experiments carried out on mongrel dogs resulted in some failures for dilation and early migration, and occlusion complications in patients.
Immediate relief of persisting symptoms occurred in two patients.
Double balloon dilation is another technique used to treat stenosis of the vena cava.
Double balloon dilation involves catheters inserted in the left and right femoral vessels placed parallel to stenotic lesions and inflated simultaneously.
The two balloon technique creates a substantial decrease in pressure gradients by achieving greater dilation from the use of two smaller balloons as opposed to a single large balloon.
Balloons are inflated and deflated repeatedly to reduce the resistance of the vessels to inflation.
Once the balloons are removed an end-hole catheter is passed over the wires to ensure a moderate systemic pressure drop occurs and then a stent is placed.
Substantial pressure drops are common following single balloon dilation procedures.
Hydrophilic catheter treatments can also be used through placement of the catheter through the femoral veins to access the stenosis in the vena cava to measure haemodynamic and angiography.
Angiography allows for visualisation of the stenosis in the vena cava and measurements of the pressures and length of narrowing can be obtained from the technique, including the narrowest diameter of the stenosis.
Balloon angioplasties can also be performed in the narrowed vena cava using Sterling balloons.
Dilations are also performed with higher pressure Dorado balloons, using the same wire as the Sterling balloon.
Sustained results of increased flow and significant reduction in obstructions following stent implantation occurs from balloon angioplasty treatments.
Epidemiology
Congenital stenosis of the vena cava is a rare congenital heart disease affecting 0.7 - 8.7% of the population.
Vena cava anomalies are very rare and arise from incorrect development in the foetal heart.
The genetic occurrence leading to this condition is unknown but current studies identified the disease symptoms presents predominantly in adolescent males.
Prevalence of the condition is very low as stenotic anomalies in vena cavae development are uncommon.
Recognition of vena cava anomalies is difficult and can result in minor complications if left unrecognised.
Surgery is carried out for presenting symptoms associated with the condition.
Difficulties in diagnosis contribute to the low incident rates as many people live asymptomatically with this disease for many years, having no impact on the patients’ life.
References
== External links == |
Stiff-person syndrome | Stiff-person syndrome (SPS), also known as stiff-man syndrome (SMS), is a rare neurologic disorder of unclear cause characterized by progressive rigidity and stiffness. The stiffness primarily affects the truncal muscles and is superimposed by spasms, resulting in postural deformities. Chronic pain, impaired mobility, and lumbar hyperlordosis are common symptoms.
SPS occurs in about one in a million people and is most commonly found in middle-aged people. A small minority of patients have the paraneoplastic variety of the condition. Variants of the condition, such as stiff-limb syndrome which primarily affects a specific limb, are often seen.
SPS was first described in 1956. Diagnostic criteria were proposed in the 1960s and refined two decades later. In the 1990s and 2000s the roles of antibodies in the condition became more clear. SPS patients generally have GAD antibodies, which seldom occur in the general population. In addition to blood tests for GAD, electromyography tests can help confirm the conditions presence.
Benzodiazepine-class drugs are the most common treatment; they are used for symptom relief from stiffness. Other common treatments include baclofen, intravenous immunoglobin and rituximab. There is a limited but encouraging therapeutic experience of hematopoietic stem cell transplantation for SPS.
Signs and symptoms
Patients with stiff-person syndrome (SPS) experience progressive stiffness in their truncal muscles (torso muscles), which become rigid and stiff because the lumbar and abdominal muscles engage in constant contractions. Initially, stiffness occurs in the thoracolumbar paraspinal and
abdominal muscles. It later affects the proximal leg and abdominal wall muscles. The stiffness leads to a change in posture, and patients develop a rigid gait. Persistent lumbar hyperlordosis often occurs as it progresses. The muscle stiffness initially fluctuates, sometimes for days or weeks, but eventually begins to consistently impair mobility. As the disease progresses, patients sometimes become unable to walk or bend. Chronic pain is common and worsens over time but sometimes acute pain occurs as well. Stress, cold weather, and infections lead to an increase in symptoms, and sleep decreases them.SPS patients experience superimposed spasms and extreme sensitivity to touch and sound. These spasms primarily occur in the proximal limb and axial muscles. There are co-contractions of agonist and antagonist muscles. Spasms usually last for minutes and can recur over hours. Attacks of spasms are unpredictable and are often caused by fast movements, emotional distress, or sudden sounds or touches. In rare cases, facial muscles, hands, feet, and the chest can be affected and unusual eye movements and vertigo occur. There are brisk stretch reflexes and clonus occurs in patients. Late in the diseases progression, hypnagogic myoclonus can occur. Tachycardia and hypertension are sometimes also present.Because of the spasms, patients may become increasingly fearful, require assistance, and lose the ability to work, leading to depression, anxiety, and phobias, including agoraphobia and dromophobia. Most patients are psychologically normal and respond reasonably to their situations.Paraneoplastic SPS tends to affect the neck and arms more than other variations. It progresses very quickly, is more painful, and is more likely to include distal pain than classic SPS. Patients with paraneoplastic SPS generally lack other autoimmune issues but may have other paraneoplastic conditions.Stiff-limb syndrome is a variant of SPS. This syndrome develops into full SPS about 25% of the time. Stiffness and spasms are usually limited to the legs and hyperlordoisis generally does not occur. The stiffness begins in one limb and remains most prominent there. Sphincter and brainstem issues often occur with stiff-limb syndrome. Progressive encephalomyelitis with rigidity, another variant of the condition, includes symptoms of SPS with brainstem issues and autonomic disturbances. It involves polio-encephalomyelitis in the spine and brainstem. There is cerebellar and brainstem involvement. In some cases, the limbic system is affected, as well. Most patients have upper motoneuron issues and autonomic disturbances. Jerking SPS is another subtype of the condition. It begins like classical SPS and progresses for several years; up to 14 in some cases. It is then distinguished by the development of myoclonus as well as seizures and ataxia in some cases.
Causes
Patients with SPS generally have high amounts of high glutamic acid decarboxylase antibody titers. About 80 percent of SPS patients have GAD antibodies, compared with about one percent of the general population. The overwhelming majority of people who have GAD antibodies do not contract SPS, indicating that systematic synthesis of the antibody is not the sole cause of SPS. GAD, a presynaptic autoantigen, is generally thought to play a key role in the condition, but exact details of the way that autoantibodies affect SPS patients are not known. Most SPS patients with high-titer GAD antibodies also have antibodies that inhibit GABA-receptor-associated protein (GABARAP). Autoantibodies against amphiphysin and gephyrin are also sometimes found in SPS patients. The antibodies appear to interact with antigens in the brain neurons and the spinal cord synapses, causing a functional blockade with gamma-aminobutyric acid. This leads to GABA impairment, which probably causes the stiffness and spasms that characterizes SPS. There are low GABA levels in the motor cortexes of SPS patients.It is not known why GAD autoimmunity occurs in SPS patients, and whether SPS qualifies as a neuro-autoimmune disorder has been questioned. It is also unknown whether these antibodies are pathogenic. The amount of GAD antibody titers found in SPS patients does not correlate with disease severity, indicating that titre levels do not need to be monitored. It has not been proven that GAD antibodies are sole cause of SPS, and the possibility exists that they are a marker or an epiphenomenon of the conditions cause.In SPS patients, motor unit neurons fire involuntarily in a way that resembles a normal contraction. Motor unit potentials fire while the patient is at rest, particularly in the stiff muscles. The excessive firing of motor neurons may be caused by malfunctions in spinal and supra-segmental inhibitory networks that utilize GABA. Involuntary actions show up as voluntary on EMG scans; even when the patient tries to relax, there are agonist and antagonist contractions.In a minority of patients with SPS, breast, ovarian, or lung cancer manifests paraneoplasticly as proximal muscle stiffness. These cancers are associated with the synaptic proteins amphiphysin and gephyrin. Paraneoplastic SPS with amphiphysin antibodies and breast adenocarcinoma tend to occur together. These patients tend not to have GAD antibodies. Passive transfer of the disease by plasma injection has been shown in paraneoplastic SPS but not classical SPS.There is evidence of genetic risk of SPS. The HLA class II locus makes patients susceptible to the condition. Most SPS patients have the DQB1* 0201 allele. This allele is also associated with type 1 diabetes.
Diagnosis
SPS is diagnosed by evaluating clinical findings and excluding other conditions. There is no specific laboratory test that confirms its presence. Underdiagnosis and misdiagnosis are common.The presence of antibodies against GAD is the best indication of the condition that can be detected by blood and cerebrospinal fluid (CSF) testing. Anti-GAD65 is found in about 80 percent of SPS patients. Anti-thyroid, anti-intrinsic factor, anti-nuclear, anti-RNP, and anti-gliadin are also often present in blood tests. Electromyography (EMG) demonstrates involuntary motor unit firing in SPS patients. EMG can confirm the diagnosis by noting spasms in distant muscles as a result of subnoxious stimulation of cutaneous or mixed nerves. Responsiveness to diazepam helps confirm that the patient has SPS, as this decreases stiffness and motor unit potential firing.The same general criteria are used to diagnose paraneoplastic SPS as the normal form of the condition. Once SPS is diagnosed, poor response to conventional therapies and the presence of cancer indicate that it may be paraneoplastic. CT scans are indicated for SPS patients who respond poorly to therapy to determine if this is the case.A variety of conditions have similar symptoms to SPS, including myelopathies, dystonias, spinocerebellar degenerations, primary lateral sclerosis, neuromyotonia, and some psychogenic disorders. Tetanus, neuroleptic malignant syndrome, malignant hyperpyrexia, chronic spinal interneuronitis, serotonin syndrome, Multiple sclerosis, Parkinsons disease, and Isaacs syndrome should also be excluded.Patients fears and phobias often incorrectly lead doctors to think their symptoms are psychogenic, and they are sometimes suspected of malingering. It takes an average of six years after the onset of symptoms before the disease is diagnosed.
Treatment
There is no evidence-based criterion for treating SPS, and there have been no large controlled trials of treatments for the condition. The rarity of the disease complicates efforts to establish guidelines.GABAA agonists, usually diazepam but sometimes other benzodiazepines, are the primary treatment for SPS. Drugs that increase GABA activity alleviate muscle stiffness caused by a lack of GABAergic tone. They increase pathways that are dependent upon GABA and have muscle relaxant and anticonvulsant effects, often providing symptom relief. Because the condition worsens over time, patients generally require increased dosages, leading to more side effects. For this reason, gradual increase in dosage of benzodiazepines is indicated. Baclofen, a GABAB agonist, is generally used when individuals taking high doses of benzodiazepines have high side effects. In some cases it has shown improvements in electrophysiological and muscle stiffness when administered intravenously. Intrathecal baclofen administration may not have long-term benefits though, and there are potential serious side effects.Treatments that target the autoimmune response are also used. Intravenous immunoglobin is the best second-line treatment for SPS. It often decreases stiffness and improves quality of life and startle reflex. It is generally safe, but there are possible serious side effects and it is expensive. The European Federation of Neurological Societies suggests it be used when disabled patients do not respond well to diazepam and baclofen. Steroids, rituximab, and plasma exchange have been used to suppress the immune system in SPS patients, but the efficacy of these treatments is unclear. Botulinum toxin has been used to treat SPS, but it does not appear to have long-term benefits and has potential serious side effects. In paraneoplastic cases, tumors must be managed for the condition to be contained. Opiates are sometimes used to treat severe pain, but in some cases they exacerbate symptoms.Hematopoietic stem cell transplantation (HSCT) with high intensity conditioning protocol has been performed in a few cases with severe anti-GAD positive SPS, resulting in clinical remission. In carefully selected cases of severe, treatment refractory SPS, HSCT may be an effective therapeutic option.
Prognosis
The progression of SPS depends on whether it is a typical or abnormal form of the condition and the presence of comorbidities. Early recognition and neurological treatment can limit its progression. SPS is generally responsive to treatment, but the condition usually progresses and stabilizes periodically. Even with treatment, quality of life generally declines as stiffness precludes many activities. Some patients require mobility aids due to the risk of falls. About 65 percent of SPS patients are unable to function independently. About ten percent of SPS patients require intensive care at some point; sudden death occurs in about the same number of patients. These deaths are usually caused by metabolic acidosis or an autonomic crisis.
Epidemiology
SPS is estimated to have a prevalence of about one per million. Underdiagnosis and misdiagnosis hinder epidemiological information about the condition and may have led to its prevalence being underestimated. In the United Kingdom, 119 cases were identified between 2000 and 2005. It does not predominantly occur in any racial or ethnic group. The age of onset varies from about 30 to 60, and it most frequently occurs in people in their 40s. Five to ten percent of patients with SPS have the paraneoplastic variant of the condition. In one group of 127 patients, only 11 of them had paraneoplastic symptoms. About 35 percent of SPS patients have type I diabetes.
History
SPS was first described by Moersch and Woltman in 1956. Their description of the disease was based on 14 cases that they had observed over 32 years. Using electromyography, they noted that motor-unit firing suggested that voluntary muscle contractions were occurring in their patients. Previously, cases of SPS had been dismissed as psychogenic problems. Moersch and Woltman initially called the condition "stiff-man syndrome", but the first female patient was confirmed in 1958 and a young boy was confirmed to have it in 1960. Clinical diagnostic criteria were developed by Gordon et al. in 1967. They observed "persistent tonic contraction reflected in constant firing, even at rest" after providing patients with muscle relaxants and examining them with electromyography. In 1989, criteria for an SPS diagnosis were adopted that included episodic axial stiffness, progression of stiffness, lordosis, and triggered spasms. The name of the disease was shifted from "stiff-man syndrome" to the gender-neutral "stiff-person syndrome" in 1991.In 1988, Solimena et al. discovered that autoantibodies against GAD played a key role in SPS. Two years later, Solimena found the antibodies in 20 out of 33 patients examined. In the late 1980s, it was also demonstrated that the serum of SPS patients would bind to GABAergic neurons. In 2006, the role of GABARAP in SPS was discovered. The first case of paraneoplastic SPS was found in 1975. In 1993, antiamphiphysin was shown to play a role in paraneoplastic SPS, and seven years later antigephyrin was also found to be involved in the condition.In 1963, it was determined that diazepam helped alleviate symptoms of SPS. Corticosteroids were first used to treat the condition in 1988, and plasma exchange was first applied the following year. The first use of intravenous immunoglobulin to treat the condition came in 1994.
See also
Satoyoshi syndrome
Hyperekplexia
References
Bibliography
Alexopoulos, Harry; Dalakas, Marinos (2010). "A Critical Update on the Immunopathogenesis of Stiff Person Syndrome". European Journal of Clinical Investigation. 40 (11): 1018–25. doi:10.1111/j.1365-2362.2010.02340.x. PMID 20636380. S2CID 30688501.
Ali, Fatima; Rowley, Merrill; Jayakrishnan, Bindu; Teuber, Suzanne; Gershwin, Eric; Mackay, Ian (2011). "Stiff-Person Syndrome (SPS) and Anti-GAD-Related CNS Degenerations: Protean Additions to the Autoimmune Central Neuropathies". Journal of Autoimmunity. 37 (2): 79–87. doi:10.1016/j.jaut.2011.05.005. PMID 21680149.
Ciccotto, Giuseppe; Blaya, Maike; Kelley, Roger (2013). "Stiff Person Syndrome". Neurologic Clinics. 31 (1): 319–28. doi:10.1016/j.ncl.2012.09.005. PMID 23186907.
Darnell, Robert; Posner, Jerome (2011). Paraneoplastic Syndromes. Oxford University Press. ISBN 978-0-19-977273-5.
Duddy, Martin; Baker, Mark (2009). The Immunological Basis for Treatment of Stiff Person Syndrome. Stiff Person Syndrome. Frontiers of Neurology and Neuroscience. Vol. 26. pp. 147–66. doi:10.1159/000212375. ISBN 978-3-8055-9141-6. PMID 19349711.
Hadavi, Shahrzad; Noyce, Alastair; Leslie, David; Giovannoni, Gavin (2011). "Stiff Person Syndrome". Practical Neurology. 11 (5): 272–82. doi:10.1136/practneurol-2011-000071. PMID 21921002. S2CID 31265775.
Holmøy, Trygve; Geis, Christian (2011). "The Immunological Basis for Treatment of Stiff Person Syndrome". Journal of Neuroimmunology. 231 (1–2): 55–60. doi:10.1016/j.jneuroim.2010.09.014. PMID 20943276. S2CID 206274675.
Rakocevic, Goran; Floeter, Mary Kay (2012). "Autoimmune Stiff Person Syndrome and Related Myelopathies: Understanding of Electrophysiological and Immunological Processes". Muscle Nerve. 45 (5): 623–34. doi:10.1002/mus.23234. PMC 3335758. PMID 22499087.
External links
Stiff-Person Syndrome Information Page at NINDS |
Small plaque parapsoriasis | Small plaque parapsoriasis characteristically occurs with skin lesions that are round, oval, discrete patches or thin plaques, mainly on the trunk.: 452 : 207 Subtypes:
Xanthoerythrodermia perstans is a distinct variant with lesions that are yellow in color.: 452
Digitate dermatosis is a distinct variant with lesions in the shape of a finger and distributed symmetrically on the flanks.: 452
See also
Parapsoriasis
List of cutaneous conditions
References
== External links == |
Menotropin | Menotropin (also called human menopausal gonadotropin or hMG) is a hormonally active medication for the treatment of fertility disturbances. Frequently the plural is used as the medication is a mixture of gonadotropins. Menotropins are extracted from the urine of postmenopausal women.
Description and usage
Urine of postmenopausal women reflects the hypergonadotropic state of menopause -levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) are high - and contain a mixture of these gonadotropins. Other protein substances may be present, including small amounts of human chorionic gonadotropin (hCG). In 1949 Piero Donini found a relatively simple method to extract gonadotropins from urine of postmenopausal women. Menotropins were successfully introduced into clinical use by Bruno Lunenfeld in 1961. While earlier menotropin medications contained FSH and LH at a 1:1 ratio, the recognition that it is FSH that is critical for follicle stimulation has led to development of newer preparations that contain a much higher FSH/LH ratio, Fertinex being an example.Menotropin preparations are designed for use in selected women where they stimulate the ovaries to mature follicles, thus making them more fertile. They are administered by typically daily injection, intramuscularly or subcutaneously, for about ten days under close supervision to adjust dose and duration of therapy. They can also be used in hypogonadal men to stimulate sperm production.
Human urinary-derived menotropin preparations are exposed to the theoretical risk of infection from menopausal donors of urine. Nevertheless, the failure to irrefutably demonstrate infectivity following intracerebral inoculation with urine from transmissible spongiform encephalopathy (TSE)-infected hosts suggests that the risk associated with products derived from urine is merely theoretical.Recombinant gonadotropins have to a large degree replaced hMG in fertility treatments. The recombinant process allows for the production of pure FSH or LH not "contaminated" by other proteins that may be present after urinary extraction. While some head-on studies seem not to suggest that "pure FSH" gives better results than hMG, others claim that recombinant FSH is more efficient and reduces costs. A Cochrane Collaboration analysis did not reveal major differences in clinical outcomes when comparing urinary versus recombinant FSH.The Practice Committee of the American Society for Reproductive Medicine reported: “Compared with earlier crude animal extracts, modern highly purified urinary and recombinant gonadotropin products have clearly superior quality, specific activity, and performance. There are no confirmed differences in safety, purity, or clinical efficacy among the various available urinary or recombinant gonadotropin products.”
List of hMG preparations
A number of drug companies have and had marketed hMG preparations that include:
Gynogen HP (Sanzyme (P) Limited)Highly purified urinary FSH and LH in 1:1 ratioHumog (Bharat Serums And Vaccines Ltd)highly purified urinary FSH and LH in 1:1 ratioHumegon (Organon)
Menopur (Ferring Pharmaceuticals), 75 IU FSH and 75 IU LH activity
Merional, Meriofert (IBSA Institut)
Menogon
Metrodin (Serono)highly purified urinary FSHRepronex (Ferring Pharmaceuticals), 75 IU FSH and 75 IU LH
Pergonal (Serono),Pergonal was the major hMG prior to the arrival of recombinant gonadotropins containing 75 IU FSH and 75 IU LH.HMG Massone, 75 IU FSH and 75 IU LH
See also
Gonadotropin preparations
== References == |
Asfotase alfa | Asfotase alfa, sold under the brand name Strensiq, is a medication used in the treatment of people with perinatal/infantile- and juvenile-onset hypophosphatasia.The most common side effects include injection site reactions, hypersensitivity reactions (such as difficulty breathing, nausea, dizziness and fever), lipodystrophy (a loss of fat tissue resulting in an indentation in the skin or a thickening of fat tissue resulting in a lump under the skin) at the injection site, and ectopic calcifications of the eyes and kidney.The enzyme tissue non-specific alkaline phosphatase (ALP) plays a key role in creating and maintaining healthy bones, and managing calcium and phosphate in the body. People with hypophosphatasia cannot make enough working ALP, which leads to weak bones. Asfotase alfa is a version of the human ALP enzyme and serves as a replacement, thereby increasing levels of working ALP.
Medical uses
In the United States, asfotase alfa is indicated for the treatment of people with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP).In the European Union, asfotase alfa is indicated for long-term enzyme replacement therapy in people with paediatric-onset hypophosphatasia to treat the bone manifestations of the disease.
Adverse effects
The most common adverse effects in studies included injection site reactions (pain, itching, erythema, etc.), headache, limb pain, and haematoma. Possible rare side effects could not be assessed because of the low number of patients.
Interactions
Asfotase alfa interferes with alkaline phosphatase measurements. As asfotase alfa is a glycoprotein (as opposed to a small molecule), no relevant interactions via the cytochrome P450 liver enzymes are expected.
Pharmacology
Mechanism of action
Hypophosphatasia is caused by a genetic defect of tissue-nonspecific alkaline phosphatase (TNSALP), an enzyme that plays a role in bone mineralization. Asfotase alfa is a recombinant glycoprotein that contains the catalytic domain (the active site) of TNSALP. It is thus a form of enzyme replacement therapy.
Pharmacokinetics
After subcutaneous injection, asfotase alfa has a bioavailability of 46–98% and reaches highest blood plasma concentrations after 24 to 48 hours. Elimination half life is five days.
Chemistry
The peptide part of the glycoprotein asfotase alfa consists of two identical chains of 726 amino acids each, containing (1) the catalytic domain of TNSALP, (2) the Fc region of human immunoglobulin G1, and (3) a sequence of ten L-aspartate residues at the carboxy terminus. The two chains are linked by two disulfide bridges. Each chain also contains four internal disulfide bridges.The complete peptide sequence of one chain is
LVPEKEKDPK YWRDQAQETL KYALELQKLN TNVAKNVIMF LGDGMGVSTV TAARILKGQL
HHNPGEETRL EMDKFPFVAL SKTYNTNAQV PDSAGTATAY LCGVKANEGT VGVSAATERS
RCNTTQGNEV TSILRWAKDA GKSVGIVTTT RVNHATPSAA YAHSADRDWY SDNEMPPEAL
SQGCKDIAYQ LMHNIRDIDV IMGGGRKYMY PKNKTDVEYE SDEKARGTRL DGLDLVDTWK
SFKPRYKHSH FIWNRTELLT LDPHNVDYLL GLFEPGDMQY ELNRNNVTDP SLSEMVVVAI
QILRKNPKGF FLLVEGGRID HGHHEGKAKQ ALHEAVEMDR AIGQAGSLTS SEDTLTVVTA
DHSHVFTFGG YTPRGNSIFG LAPMLSDTDK KPFTAILYGN GPGYKVVGGE RENVSMVDYA
HNNYQAQSAV PLRHETHGGE DVAVFSKGPM AHLLHGVHEQ NYVPHVMAYA ACIGANLGHC
APASSLKDKT HTCPPCPAPE LLGGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV
KFNWYVDGVE VHNAKTKPRE EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE
KTISKAKGQP REPQVYTLPP SREEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT
TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPGKDIDDDD
DDDDDD
Asfotase alfa is produced in Chinese hamster ovary cells.
History
Asfotase alfa was granted orphan drug designation by the U.S. Food and Drug Administration (FDA) in September 2008.Asfotase alfa is manufactured by Alexion Pharmaceuticals and it was granted breakthrough therapy designation by the U.S. FDA in 2015 as it is the first and only treatment for perinatal, infantile and juvenile-onset HPP. It was approved in October 2015, in the U.S. and in August 2015, in the EU.The safety and efficacy of asfotase alfa were established in 99 participants with perinatal (disease occurs in utero and is evident at birth), infantile- or juvenile-onset HPP who received treatment for up to 6.5 years during four prospective, open-label studies. Study results showed that participants with perinatal- and infantile-onset HPP treated with asfotase alfa had improved overall survival and survival without the need for a ventilator (ventilator-free survival). Ninety-seven percent of treated participants were alive at one year of age compared to 42 percent of control participants selected from a natural history study group. Similarly, the ventilator-free survival rate at one year of age was 85 percent for treated participants compared to less than 50 percent for the natural history control participants.Participants with juvenile-onset HPP treated with asfotase alfa showed improvements in growth and bone health compared to control participants selected from a natural history database. All treated participants had improvement in low weight or short stature or maintained normal height and weight. In comparison, approximately 20 percent of control participants had growth delays over time, with shifts in height or weight from the normal range for children their age to heights and weights well below normal for age. Juvenile-onset participants also showed improvements in bone mineralization, as measured on a scale that evaluates the severity of rickets and other HPP-related skeletal abnormalities based on x-ray images. All treated participants demonstrated substantial healing of rickets on x-rays while some natural history control participants showed increasing signs of rickets over time.
References
External links
"Asfotase alfa". Drug Information Portal. U.S. National Library of Medicine. |
Metoprolol | Metoprolol, sold under the brand name Lopressor, among others, is a selective β1 receptor blocker medication. It is used to treat high blood pressure, chest pain due to poor blood flow to the heart, and a number of conditions involving an abnormally fast heart rate. By working on the beta-1 receptor of the cardiac muscle cells, it yields both a chronotropic and inotropic effect. It is also used to prevent further heart problems after myocardial infarction and to prevent headaches in those with migraines.Metoprolol is sold in formulations that can be taken by mouth or given intravenously. The medication is often taken twice a day. The extended-release formulation is taken once per day. Metoprolol may be combined with hydrochlorothiazide (a diuretic) in a single tablet.Common side effects include trouble sleeping, feeling tired, feeling faint, and abdominal discomfort. Large doses may cause serious toxicity. Risk in pregnancy has not been ruled out. It appears to be safe in breastfeeding. The metabolism of metoprolol can vary widely between patients, often as a result of hepatic impairment or CYP2D6 polymorphism. Care should be taken in patients with asthma; metoprolol should only be used in these patients when the benefits outweigh the risks, for example in heart failure. Stopping this drug should be done slowly to decrease the risk of further health problems.Metoprolol was first made in 1969, patented in 1970, and approved for medical use in 1982. It is on the World Health Organizations List of Essential Medicines. It is available as a generic drug. In 2020, it was the sixth most commonly prescribed medication in the United States, with more than 66 million prescriptions.
Medical uses
Metoprolol is used for a number of conditions, including hypertension, angina, acute myocardial infarction, supraventricular tachycardia, ventricular tachycardia, congestive heart failure, and prevention of migraine headaches. It is an adjunct in the treatment of hyperthyroidism.The different salt versions of metoprolol – metoprolol tartrate and metoprolol succinate – are approved for different conditions and are not interchangeable.Off-label uses include supraventricular tachycardia and thyroid storm.
Available forms
Metoprolol is sold in formulations that can be taken by mouth or given intravenously. The medication is often taken twice a day. The extended-release formulation is taken once a day. Metoprolol may be combined with hydrochlorothiazide (a diuretic) in a single tablet.
Adverse effects
Adverse effects, especially with higher doses, include dizziness, drowsiness, fatigue, diarrhea, unusual dreams, trouble sleeping, depression, and vision problems. β-blockers, including metoprolol, reduce salivary flow via inhibition of the direct sympathetic innervation of the salivary glands. Metoprolol may also cause the hands and feet to feel cold. Due to the high penetration across the blood-brain barrier, lipophilic beta blockers such as propranolol and metoprolol are more likely than other less lipophilic beta blockers to cause sleep disturbances such as insomnia, vivid dreams and nightmares.Serious side effects that are advised to be reported immediately include symptoms of bradycardia (resting heart rate slower than 60 beats per minute), persistent symptoms of dizziness, fainting and unusual fatigue, bluish discoloration of the fingers and toes and/or lips, numbness/tingling/swelling of the hands or feet, sexual dysfunction, erectile dysfunction, hair loss, mental/mood changes, depression, breathing difficulty, cough, dyslipidemia and increased thirst. Consuming alcohol while taking metoprolol may cause mild body rashes and is not advised.
Precautions
It’s well documented that metoprolol reduces long-term mortality and hospitalisation due to worsening heart failure. A meta-analysis further supports reduced incidence of heart failure worsening in patients treated with beta-blockers compared to placebo. However, in some circumstances, particularly when initiating metoprolol in patients with more symptomatic disease, an increased prevalence of hospitalisation and mortality has been reported within the first two months of starting. Patients should monitor for swelling of extremities, fatigue, and shortness of breath.This medicine may cause changes in blood sugar levels or cover up signs of low blood sugar, such as a rapid pulse rate. It also may cause some people to become less alert than they are normally, making it dangerous for them to drive or use machines.Greater care is required with use in those with liver problems or asthma. Stopping this drug should be done slowly to decrease the risk of further health problems.
Pregnancy and breastfeeding
Risk for the fetus has not been ruled out, per being rated pregnancy category C in the United States. Metoprolol is category C in Australia, meaning that it may be suspected of causing harmful effects on the human fetus (but no malformations). It appears to be safe in breastfeeding.
Overdose
Excessive doses of metoprolol can cause severe hypotension, bradycardia, metabolic acidosis, seizures, and cardiorespiratory arrest. Blood or plasma concentrations may be measured to confirm a diagnosis of overdose or poisoning in hospitalized patients or to assist in a medicolegal death investigation. Plasma levels are usually less than 200 μg/L during therapeutic administration, but can range from 1–20 mg/L in overdose victims.
Pharmacology
General pharmacological principles of metoprolol:
beta-1 selective
moderately lipophilic
without intrinsic sympathomimetic activity
with weak membrane stabilizing activity
decreases heart rate, contractility, and cardiac output, therefore decreasing blood pressure
Mechanism of action
Metoprolol blocks β1 adrenergic receptors in heart muscle cells, thereby decreasing the slope of phase 4 in the nodal action potential (reducing Na+ uptake) and prolonging repolarization of phase 3 (slowing down K+ release). It also suppresses the norepinephrine-induced increase in the sarcoplasmic reticulum (SR) Ca2+ leak and the spontaneous SR Ca2+ release, which are the major triggers for atrial fibrillation.
Pharmacokinetics
It undergoes α-hydroxylation and O-demethylation as a substrate of the cytochrome liver enzymes CYP2D6.
Chemistry
The active substance metoprolol is employed either as metoprolol succinate or as metoprolol tartrate (where 100 mg metoprolol tartrate corresponds to 95 mg metoprolol succinate). The tartrate is an immediate-release formulation and the succinate is an extended-release formulation.
Stereochemistry
Metoprolol contains a stereocenter and consists of two enantiomers. This is a racemate, i.e. a 1:1 mixture of (R)- and the (S)-form:
Legal status
Metoprolol was discovered in 1969 by Bengt Ablad and Enar Carlsson. Within the UK it is classified as a prescription-only drug in the beta blocker class and is regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). The MHRA is a government body set up in 2003 and is responsible for regulating medicines, medical devices, and equipment used in healthcare. The MHRA acknowledges that no product is completely risk free but takes into account research and evidence to ensure that any risks associated are minimal.The use of beta blockers such as metoprolol was approved in the U.S. by the Food and Drug Administration (FDA) in 1967. The FDA has approved beta blockers for the treatment of cardiac arrhythmias, hypertension, migraines, and others. Prescribers may choose to prescribe beta blockers for other treatments if there is just cause even though it is not approved by the FDA. Drug manufacturers, however, are unable to advertise beta blockers for other purposes that have not been approved by the FDA. Since the FDA does not regulate the practice of medicine after the drug has been approved, it is legal to prescribe beta blockers for other treatments such as performance anxiety.
Legislation
On 23 September 2011, the Medicines and Healthcare products Regulatory Agency (MHRA) granted the Intas Pharmaceuticals Limited marketing authorization (licences) for metoprolol tartrate (50 mg and 100 mg tablets) for medicinal prescription only; this was after it was established that there were no new or unexpected safety concerns and that the benefits of metoprolol tartrate were greater than the risks. Metoprolol tartrate is a generic version of Lopressor, which was licensed and authorized on 6 June 1997 to Novartis Pharmaceuticals.
In sport
Because beta blockers can be used to reduce heart rate and minimize tremors, which can enhance performance in sports such as archery, Metoprolol is banned by the world anti-doping agency in some sports. Some bans, as in all forms of billiards, darts, and golf, apply during competition only. In others, such as riflery competition, any form of beta blocker is banned by the National Collegiate Athletic Association.Urine tests are used to detect if beta blockers are present. Uncharged drugs and/or metabolites of beta blockers can be analysed by gas chromatography-mass spectrometry in selected ion monitoring (GC-MS-SIM). However, in modern times it is increasingly difficult to detect the presence of beta blockers used for sports doping purposes. A disadvantage to using GC-MS-SIM is that prior knowledge of the molecular structure of the target drugs/metabolites is required. Modern times have shown a variance in structures and hence novel beta blockers can go undetected.
Lawsuit
In the 2000s a lawsuit was brought against the manufacturers of Toprol XL (a time-release formula version of metoprolol) and its generic equivalent (metoprolol-succinate) claiming that to increase profits, lower cost generic versions of Toprol XL were intentionally kept off the market. It alleged such action by the pharmaceutical companies AstraZeneca AB, AstraZeneca LP, AstraZeneca Pharmaceuticals LP, and Aktiebolaget Hassle violated antitrust and consumer protection law. A settlement was reached in 2012, with the above manufacturers paying out $11 million in damages.
Environmental presence
In 2021, metoprolol was one of the 12 compounds identified in sludge samples taken from 12 wastewater treatment plants in California that were associated with estrogenic activity in in vitro.
References
Further reading
Dean L (2017). "Metoprolol Therapy and CYP2D6 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520381. Bookshelf ID: NBK425389.
External links
"Metoprolol". Drug Information Portal. U.S. National Library of Medicine. |
Sufentanil | Sufentanil, sold under the brand names Dsuvia and Sufenta, is a synthetic opioid analgesic drug approximately 5 to 10 times as potent as its parent drug, fentanyl, and 500 times as potent as morphine. Structurally, sufentanil differs from fentanyl through the addition of a methoxymethyl group on the piperidine ring (which increases potency but is believed to reduce duration of action), and the replacement of the phenyl ring by thiophene. Sufentanil first was synthesized at Janssen Pharmaceutica in 1974.Sufentanil is marketed for use by specialist centers under different trade names, such as Sufenta and Sufentil. Sufentanil with and without lidocaine or mepivacaine is available as a transdermal patch similar to Duragesic in Europe under trade names such as Chronogesic. It is available as a sublingual tablet under the trade name Dsuvia.
Medical uses
The main use of this medication is in operating suites and critical care where pain relief is required for a short period of time. It also offers properties of sedation and this makes it a good analgesic component of anesthetic regimen during an operation.Because of its extremely high potency, it is often used in surgery and post-operative pain management for patients that are heavily opioid dependent/opioid tolerant because of long term opiate use for chronic pain or illicit opiate use. Currently sufentanil is the most potent opioid painkiller available for use in humans. Although more potent narcotic pain medications do exist, all medications stronger than sufentanil are approved for veterinary use only. It is also used in surgery and post operative pain control in patients that are taking high dose buprenorphine for chronic pain because it is the only opioid that has a potency and binding affinity strong enough to displace buprenorphine from the opioid receptors in the central nervous system and provide analgesia.In 2018, the Food and Drug Administration (FDA) approved Dsuvia, a sublingual tablet form of the drug, that was developed in a collaboration between AcelRx Pharmaceuticals and the United States Department of Defense for use in battlefield settings where intravenous (IV) treatments may not be readily available. The decision to approve this new potent synthetic opioid came under criticism from politicians and from the chair of the FDA advisory committee, who fear that the tablets will be easily diverted to the illegal drug market.
Side effects
It is essential for the administering medical professional to be trained in airway management with readily available airway equipment because the drug causes significant respiratory depression and may cause respiratory arrest if given too rapidly or in too high a dose. Other opioid side effects such as heart rhythm irregularity, blood pressure changes and nausea/vomiting can also be present in patients given this drug and should be dealt with accordingly.
Sufentanil has been associated with extremely rare instances of life-threatening anaphylaxis.
Overdose
Management
Because sufentanil is very potent, practitioners must be prepared to reverse the effects of the drug should the patient exhibit symptoms of overdose such as respiratory depression or respiratory arrest. As for all other opioid-based medications, naloxone (trade name Narcan) is the definitive antidote for overdose. Depending on the amount administered, it can reverse the respiratory depression and, if enough is administered, completely reverse the effects of sufentanil.
See also
Betahydroxythiofentanyl
Carfentanil
R-30490
Thiafentanil
References
External links
"Sufentanil". Drug Information Portal. U.S. National Library of Medicine.
"Sufentanil citrate". Drug Information Portal. U.S. National Library of Medicine. |
Hydrocodone/ibuprofen | Hydrocodone/ibuprofen (INNs), sold under the brand name Vicoprofen, is a fixed-dose combination analgesic medication used in short-term therapy to relieve severe pain. Vicoprofen combines the analgesic and antitussive properties of hydrocodone with the analgesic, anti-inflammatory, and antipyretic properties of ibuprofen. In contrast to hydrocodone/acetaminophen combination analgesics such as Vicodin, this hydrocodone/ibuprofen avoids some of the liver toxicity which may occur from acetaminophen, but still presents significant dangers in hydrocodone overdose, namely respiratory depression. Vicoprofen is supplied in a fixed dose combination tablet which contains hydrocodone bitartrate, USP 7.5 mg with ibuprofen, USP 200 mg. Additional strengths of generic Vicoprofen are now available, in combinations of 5 mg/200 mg and 10 mg/200 mg respectively.
Medical uses
Hydrocodone/ibuprofen has a labeled indication for "short-term (generally <10 days) management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate".
Pregnancy
Opioids such as hydrocodone cross the placenta, and can therefore affect the fetus. Studies have shown a possible association between opioids and adverse outcomes such as birth defects, poor fetal growth, stillbirth, and preterm delivery. Prolonged use of opioids by a pregnant mother can also lead to neonatal withdrawal syndrome. NSAIDs such as ibuprofen should generally be avoided in pregnancy, as there are conflicting reports of birth defects after in utero exposure. However, it is accepted that NSAIDs prevent closure of the fetal ductus arteriosus, which happens during the later stages of pregnancy. Because of this, ibuprofen should be avoided after 30 weeks gestation.
Breastfeeding
Hydrocodone and ibuprofen are excreted in breast milk, so appropriate caution should be taken when prescribing to breastfeeding mothers.
Special populations
There is no evidence to support altered pharmacokinetic properties due to differences in gender or age. However, this drug combination has not been tested in children.
Adverse effects
The side effects for hydrocodone/ibuprofen are a combination of the side effects of the component drugs. Side effects experienced in more than 10% of the population taking the drug include: headache, drowsiness, dizziness, constipation, nausea, and dyspepsia.
Pharmacology
Pharmacokinetics
The two active components of the drug, ibuprofen and hydrocodone, do not affect each others absorption characteristics or other pharmacokinetic parameters. After an oral dose, the peak level of hydrocodone in the blood is reached 1.7 hours after administration. The blood levels of ibuprofen peak 1.8 hours after oral administration.
History
Discovery and development
The patent for Vicoprofen was filed in December 1984, and U.S. patent number 4,587,252 was granted in May 1986. Although ibuprofen and hydrocodone were already available on the market at this time, the fact that they had never been supplied together in a single formulation required approval from the FDA as if it were a new drug. Knoll filed an investigational new drug application on 30 December 1986. A new drug application was later filed by Knoll on 25 April 1996, and received final approval from the FDA on 23 September 1997. Vicoprofen tablets were initially formulated and packaged by Knoll, with ibuprofen supplied by Albemarle Corporation and hydrocodone supplied by Mallinckrodt Pharmaceuticals.The validity of Knolls patent on Vicoprofen has been challenged in federal court. In September 2002, the U.S. District Court for the Norther District of Illinois granted a motion of invalidity filed by Teva Pharmaceuticals against Knolls patent on Vicoprofen, ruling the patent was invalid as obvious. This ruling paved the way for Tevas abbreviated new drug application to be approved by the FDA which would allow them to manufacture and market their own generic. Knoll appealed the decision. In April 2003, Teva announced that its abbreviated new drug application had been approved by the FDA, and its generic would begin shipping immediately. In May 2004, the United States Court of Appeals for the Federal Circuit vacated the previous judgment by the U.S. District Court for the Northern District of Illinois, and the case was remanded back for further court proceedings. Teva continued to sell its generic during this time. The patent for Vicoprofen expired on 18 December 2004, officially opening the drug to generic manufacture. In July 2016, the FDA approved another generic equivalent, manufactured by Aurobindo Pharma Limited.
Ownership and promotion
Knoll pharmaceuticals, originally founded in Germany in 1886, became a subsidiary of BASF (a German chemical company) in 1975. It was under their control when Vicoprofen was originally developed and approved. In March 2000, Knoll Pharmaceuticals and Abbott Laboratories, an American health care company, announced a co-promotion agreement for Vicoprofen, in which Abbott would promote Vicoprofen to its network of buyers, including physicians, hospitals, and surgical centers. In June 2002, Abbott Laboratories, paid $6.9 billion to acquire the entire Knoll pharmaceutical unit from BASF, including Vicoprofen.
DEA classification
Vicoprofen was originally approved as a schedule III drug, but was later reclassified to a schedule II drug based on the DEA reclassification of hydrocodone containing products effective 6 October 2014.
Research
The new drug application for Vicoprofen was approved based on data from both single and multiple dose analgesia trials.
The single dose analgesia studies occurred in multiple surgical settings, including dental, back, and abdominal/gynecologic surgery in the U.S. and Puerto Rico. There were 1,537 patients enrolled over all trials, with 79% of the participants being female. There were 10 single dose analgesia trials included in the new drug application. All studies were similarly designed: after completion of a procedure in which pain was rated as moderate or severe, patients would be randomized into various treatment groups. The treatment groups included: ibuprofen only, hydrocodone only, Vicoprofen (hydrocodone/ibuprofen), and placebo. The participants pain would then be tracked over the next several hours by the self reporting of pain scores.There were four multiple dose trials included in the new drug application. These studies were all completed in the U.S., in settings including burn unit, post-operatively, and chronic pain settings. A total of 683 patients were enrolled in all of the multiple dose trials, with 57% of the participants being women. These studies also looked at self reported pain intensities over a 5-day period of multiple dosing. In these studies, patients were either given the trial drug Vicoprofen or one of two an active controls: codeine with acetaminophen (Tylenol #3) or oxycodone with acetaminophen (Percocet), depending on the trial. Patients were allowed to take a dose as needed but no more than every 4 to 6 hours for up to 5 days. These trials measured efficacy based on parameters including self reported pain scores, number of doses used, and duration of treatment.
Society and culture
Cost
The average wholesale price (AWP) of generic Vicoprofen varies based on the strength of the preparation. Pricing data gathered from Lexicomp in October 2017 indicates the AWP for a 100 count bottle of 7.5 mg/200 mg strength to be $114.62, a 100 count of 5 mg/200 mg strength to be $356.62 and a 100 count of 10 mg/200 mg strength to be $470.35. These prices are all for generic equivalents of Vicoprofen.
Utilization
In 2003, at the time of the approval announcement for the first generic equivalent, it was reported that annual sales of brand name Vicoprofen totaled $104 million. According to IMS, the hydrocodone/ibuprofen tablets 7.5 mg/200 mg, had an estimated market size of $15.7 million for the 12 months preceding May 2016.
See also
Fentanyl/fluanisone
Hydrocodone/aspirin
Hydrocodone/paracetamol
Morphine/naltrexone
Oxycodone/aspirin
Oxycodone/ibuprofen
Oxycodone/naloxone
Oxycodone/paracetamol
References
External links
"Hydrocodone tartrate mixture with ibuprofen". Drug Information Portal. U.S. National Library of Medicine. |
Captopril | Captopril, sold under the brand name Capoten among others, is an angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first oral ACE inhibitor found for the treatment of hypertension. It does not cause fatigue as associated with beta-blockers. Due to the adverse drug event of causing hyperkalemia, as seen with most ACE Inhibitors, the medication is usually paired with a diuretic.
Captopril was patented in 1976 and approved for medical use in 1980.
Structure–activity relationship
Captopril has an L-proline group which allows for it to be more bioavailable within oral formulations. The thiol moiety within the molecule has been associated with two significance adverse effects: the hapten or immune response. This immune response, also known as agranulocytosis, can explain the adverse drug events which may be seen in captopril with the allergic response, which would be: hives, severe stomach pain, difficulty breathing, swelling of the face, lips, tongue or throat.In terms of interaction with the enzyme, the molecules thiol moiety will attach to the binding site of the ACE enzyme. This will inhibit the port at which the angiotensin-1 molecule would normally bind, therefore inhibiting the downstream effects within the renin-angiotensin system.
Medical uses
Captoprils main uses are based on its vasodilation and inhibition of some renal function activities. These benefits are most clearly seen in:
Hypertension
Cardiac conditions such as congestive heart failure and after myocardial infarction
Preservation of kidney function in diabetic nephropathy.Additionally, it has shown mood-elevating properties in some patients. This is consistent with the observation that animal screening models indicate putative antidepressant activity for this compound, although one study has been negative. Formal clinical trials in depressed patients have not been reported.It has also been investigated for use in the treatment of cancer. Captopril stereoisomers were also reported to inhibit some metallo-β-lactamases.
Adverse effects
Adverse effects of captopril include cough due to increase in the plasma levels of bradykinin, angioedema, agranulocytosis, proteinuria, hyperkalemia, taste alteration, teratogenicity, postural hypotension, acute renal failure, and leukopenia.
Except for postural hypotension, which occurs due to the short and fast mode of action of captopril, most of the side effects mentioned are common for all ACE inhibitors. Among these, cough is the most common adverse effect. Hyperkalemia can occur, especially if used with other drugs which elevate potassium level in blood, such as potassium-sparing diuretics. Other side effects are:
Itching
Headache
Tachycardia
Chest pain
Palpitations
Dysgeusia
WeaknessThe adverse drug reaction (ADR) profile of captopril is similar to other ACE inhibitors, with cough being the most common ADR. However, captopril is also commonly associated with rash and taste disturbances (metallic or loss of taste), which are attributed to the unique thiol moiety.
Overdose
ACE inhibitor overdose can be treated with naloxone.
History
In the late 1960s, John Vane of the Royal College of Surgeons of England was working on mechanisms by which the body regulates blood pressure. He was joined by Sérgio Henrique Ferreira of Brazil, who had been studying the venom of a Brazilian pit viper, the jararaca (Bothrops jararaca), and brought a sample of the vipers venom. Vanes team found that one of the venoms peptides selectively inhibited the action of angiotensin-converting enzyme (ACE), which was thought to function in blood pressure regulation; the snake venom functions by severely depressing blood pressure. During the 1970s, ACE was found to elevate blood pressure by controlling the release of water and salts from the kidneys.
Captopril, an analog of the snake venoms ACE-inhibiting peptide, was first synthesized in 1975 by three researchers at the U.S. drug company E.R. Squibb & Sons Pharmaceuticals (now Bristol-Myers Squibb): Miguel Ondetti, Bernard Rubin, and David Cushman. Squibb filed for U.S. patent protection on the drug in February 1976, which was granted in September 1977, and captopril was approved for medical use in 1980. It was the first ACE inhibitor developed and was considered a breakthrough both because of its mechanism of action and also because of the development process. In the 1980s, Vane received the Nobel prize and was knighted for his work and Ferreira received the National Order of Scientific Merit from Brazil.
The development of captopril was among the earliest successes of the revolutionary concept of ligand-based drug design. The renin–angiotensin–aldosterone system had been extensively studied in the mid-20th century, and this system presented several opportune targets in the development of novel treatments for hypertension. The first two targets that were attempted were renin and ACE. Captopril was the culmination of efforts by Squibbs laboratories to develop an ACE inhibitor.
Ondetti, Cushman, and colleagues built on work that had been done in the 1960s by a team of researchers led by John Vane at the Royal College of Surgeons of England. The first breakthrough was made by Kevin K.F. Ng in 1967, when he found the conversion of angiotensin I to angiotensin II took place in the pulmonary circulation instead of in the plasma. In contrast, Sergio Ferreira found bradykinin disappeared in its passage through the pulmonary circulation. The conversion of angiotensin I to angiotensin II and the inactivation of bradykinin were thought to be mediated by the same enzyme.
In 1970, using bradykinin potentiating factor (BPF) provided by Sergio Ferreira, Ng and Vane found the conversion of angiotensin I to angiotensin II was inhibited during its passage through the pulmonary circulation. BPF was later found to be a peptide in the venom of a lancehead viper (Bothrops jararaca), which was a “collected-product inhibitor” of the converting enzyme. Captopril was developed from this peptide after it was found via QSAR-based modification that the terminal sulfhydryl moiety of the peptide provided a high potency of ACE inhibition.Captopril gained FDA approval on April 6, 1981. The drug became a generic medicine in the U.S. in February 1996, when the market exclusivity held by Bristol-Myers Squibb for captopril expired.
Chemical synthesis
A chemical synthesis of captopril by treatment of L-proline with (2S)-3-acetylthio-2-methylpropanoyl chloride under basic conditions (NaOH), followed by aminolysis of the protective acetyl group to unmask the drugs free thiol, is depicted in the figure at right.
Procedure 2 taken out of patent US4105776. See examples 28, 29a and 36.
Mechanism of action
Captopril blocks the conversion of angiotensin I to angiotensin II and prevents the degradation of vasodilatory prostaglandins, thereby inhibiting vasoconstriction and promoting systemic vasodilation.
Pharmacokinetics
Unlike the majority of ACE inhibitors, captopril is not administered as a prodrug (the only other being lisinopril). About 70% of orally administered captopril is absorbed. Bioavailability is reduced by presence of food in stomach. It is partly metabolised and partly excreted unchanged in urine. Captopril also has a relatively poor pharmacokinetic profile. The short half-life necessitates dosing two or three times per day, which may reduce patient compliance. Captopril has a short half-life of 2–3 hours and a duration of action of 12–24 hours.
See also
Captopril challenge test
Captopril suppression test
References
External links
"Captopril". Drug Information Portal. U.S. National Library of Medicine.
U.S. Patent 4,046,889 Archived 2019-05-18 at the Wayback Machine |
Ethinylestradiol/drospirenone | Ethinylestradiol/drospirenone (EE/DRSP), sold under the brand name Yasmin among others, is a combination of ethinylestradiol (EE), an estrogen, and drospirenone (DRSP), a progestin, antimineralocorticoid, and antiandrogen, which is used as a birth control pill to prevent pregnancy in women. It is also indicated for the treatment of moderate acne, premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and dysmenorrhea (painful menstruation) in women. The medication is taken by mouth and contains 30 μg EE and 3 mg DRSP per tablet (brand names Yasmin, others) or 20 μg EE and 3 mg DRSP per tablet (brand names Yaz, Yasminelle, Nikki, others). A formulation with levomefolic acid (vitamin B9) has also been marketed (brand names Beyaz, Safyral, others), with similar indications. EE/DRSP is marketed widely throughout the world.In 2019, it was the 148th most commonly prescribed medication in the United States, with more than 4 million prescriptions.
See also
Ethinylestradiol/drospirenone/levomefolic acid
Ethinylestradiol/drospirenone/prasterone
Estradiol/drospirenone
List of combined sex-hormonal preparations § Estrogens and progestogens
References
External links
"Drospirenone mixture with estradiol". Drug Information Portal. U.S. National Library of Medicine. |
Dexamethasone | Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena cava syndrome (a complication of some forms of cancer), and along with antibiotics in tuberculosis. In adrenocortical insufficiency, it may be used in combination with a mineralocorticoid medication such as fludrocortisone. In preterm labor, it may be used to improve outcomes in the baby. It may be given by mouth, as an injection into a muscle, as an injection into a vein, as a topical cream or ointment for the skin or as a topical ophthalmic solution to the eye. The effects of dexamethasone are frequently seen within a day and last for about three days.The long-term use of dexamethasone may result in thrush, bone loss, cataracts, easy bruising, or muscle weakness. It is in pregnancy category C in the United States, meaning that it should only be used when the benefits are predicted to be greater than the risks. In Australia, the oral use is category A, meaning it has been frequently used in pregnancy and not been found to cause problems to the baby. It should not be taken when breastfeeding. Dexamethasone has anti-inflammatory and immunosuppressant effects.Dexamethasone was first synthesized in 1957 by Philip Showalter Hench and was approved for medical use in 1958. It is on the World Health Organizations List of Essential Medicines. In 2019, it was the 359th most commonly prescribed medication in the United States, with fewer than 1 million prescriptions.
Medical uses
Anti-inflammatory
Dexamethasone is used to treat many inflammatory and autoimmune disorders, such as rheumatoid arthritis and bronchospasm. Idiopathic thrombocytopenic purpura, a decrease in numbers of platelets due to an immune problem, responds to 40 mg daily for four days; it may be administered in 14-day cycles. It is unclear whether dexamethasone in this condition is significantly better than other glucocorticoids.It is also given in small amounts before and/or after some forms of dental surgery, such as the extraction of the wisdom teeth, an operation which often causes puffy, swollen cheeks.Dexamethasone is commonly given as a treatment for croup in children, as a single dose can reduce the swelling of the airway to improve breathing and reduce discomfort.It is injected into the heel when treating plantar fasciitis, sometimes in conjunction with triamcinolone acetonide.It is useful to counteract allergic anaphylactic shock, if given in high doses.It is present in certain eye drops – particularly after eye surgery – and as a nasal spray, and certain ear drops (can be combined with an antibiotic and an antifungal). Dexamethasone intravitreal steroid implants have been approved by the US Food and Drug Administration (FDA) to treat ocular conditions such as diabetic macular edema, central retinal vein occlusion, and uveitis. Dexamethasone has also been used with antibiotics to treat acute endophthalmitis.Dexamethasone is used in transvenous screw-in cardiac pacing leads to minimize the inflammatory response of the myocardium. The steroid is released into the myocardium as soon as the screw is extended and can play a significant role in minimizing the acute pacing threshold due to the reduction of inflammatory response. The typical quantity present in a lead tip is less than 1.0 mg.Dexamethasone may be administered before antibiotics in cases of bacterial meningitis. It acts to reduce the inflammatory response of the body to the bacteria killed by the antibiotics (bacterial death releases proinflammatory mediators that can cause a response which is harmful), thus reducing hearing loss and neurological damage.
Cancer
People with cancer undergoing chemotherapy are often given dexamethasone to counteract certain side effects of their antitumor treatments. Dexamethasone can increase the antiemetic effect of 5-HT3 receptor antagonists, such as ondansetron. The exact mechanism of this interaction is not well-defined, but it has been theorized that this effect may be due to, among many other causes, inhibition of prostaglandin synthesis, anti-inflammatory effects, immunosuppressive effects, decreased release of endogenous opioids, or a combination of the aforementioned.In brain tumors (primary or metastatic), dexamethasone is used to counteract the development of edema, which could eventually compress other brain structures. It is also given in cord compression, where a tumor is compressing the spinal cord. Evidence on the safety and efficacy of using dexamethasone to treat malignant brain tumors is not clear.Dexamethasone is also used as a direct chemotherapeutic agent in certain hematological malignancies, especially in the treatment of multiple myeloma, in which dexamethasone is given alone or in combination with other chemotherapeutic drugs, including most commonly with thalidomide (Thal-dex), lenalidomide, bortezomib (Velcade, Vel-dex), or a combination of doxorubicin (Adriamycin) and vincristine or bortezomib/lenalidomide/dexamethasone.
COVID-19
Dexamethasone is recommended by the National Health Service in the UK and the National Institutes of Health (NIH) in the US for people with COVID-19 who need either mechanical ventilation or supplemental oxygen (without ventilation).The Infectious Diseases Society of America (IDSA) guideline panel suggests the use of glucocorticoids for people with severe COVID-19, defined as people with SpO2 ≤94% on room air, and those who require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). The IDSA recommends against the use of glucocorticoids for those with COVID-19 without hypoxemia requiring supplemental oxygen.The World Health Organization (WHO) recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of people with COVID-19 (strong recommendation, based on moderate certainty evidence). The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID-19 (conditional recommendation, based on low certainty evidence).The Oxford University RECOVERY Trial issued a press release announcing preliminary results that the drug could reduce deaths by about a third in participants on ventilators and by about a fifth in participants on oxygen; it did not benefit people who did not require respiratory support. A meta-analysis of seven clinical trials of critically ill COVID-19 participants, each treated with one of three different corticosteroids found a statistically significant reduction in death. The largest reduction was obtained with dexamethasone (36% compared to placebo).In September 2020, the European Medicines Agency (EMA) endorsed the use of dexamethasone in adults and adolescents, from twelve years of age and weighing at least 40 kilograms (88 lb), who require supplemental oxygen therapy. Dexamethasone can be taken by mouth or given as an injection or infusion (drip) into a vein.In November 2020, the Public Health Agency of Canadas Clinical Pharmacology Task Group recommended dexamethasone for hospitalized patients requiring mechanical ventilation. Although dexamethasone, and other glucocorticoids, reduce mortality in COVID-19 they have also been associated with an increased risk of secondary infections, secondary infections being a significant issue in critically ill COVID-19 patients.The mechanism of action of dexamethasone involves suppression of late-stage interferon type I programs in severe COVID-19 patients.
Endocrine
Dexamethasone is the treatment for the very rare disorder of glucocorticoid resistance.In adrenal insufficiency and Addisons disease, dexamethasone is prescribed when the patient does not respond well to prednisone or methylprednisolone.It can be used in congenital adrenal hyperplasia in older adolescents and adults to suppress Adrenocorticotropic hormone (ACTH) production. It is typically given at night.
Pregnancy
Dexamethasone may be given to women at risk of delivering prematurely to promote maturation of the fetus lungs. This administration, given from one day to one week before delivery, has been associated with low birth weight, although not with increased rates of neonatal death.Dexamethasone has also been used during pregnancy as an off-label prenatal treatment for the symptoms of congenital adrenal hyperplasia (CAH) in female babies. CAH causes a variety of physical abnormalities, notably ambiguous genitalia. Early prenatal CAH treatment has been shown to reduce some CAH symptoms, but it does not treat the underlying congenital disorder. This use is controversial: it is inadequately studied, only around one in ten of the fetuses of women treated are at risk of the condition, and serious adverse events have been documented. Experimental use of dexamethasone in pregnancy for fetal CAH treatment was discontinued in Sweden when one in five cases had adverse events.A small clinical trial found long-term effects on verbal working memory among the small group of children treated prenatally, but the small number of test subjects means the study cannot be considered definitive.
High-altitude illnesses
Dexamethasone is used in the treatment of high-altitude cerebral edema (HACE), as well as high-altitude pulmonary edema (HAPE). It is commonly carried on mountain-climbing expeditions to help climbers deal with complications of altitude sickness.
Nausea and vomiting
Intravenous dexamethasone is effective for prevention of nausea and vomiting in people who had surgery and whose post-operative pain was treated with long-acting spinal or epidural spinal opioids.The combination of dexamethasone and a 5-HT3 receptor antagonist such as ondansetron is more effective than a 5-HT3 receptor antagonist alone in preventing postoperative nausea and vomiting.
Sore throat
A single dose of dexamethasone or another steroid speeds improvement of a sore throat.
Contraindications
Contraindications of dexamethasone include, but are not limited to:
Uncontrolled infections
Known hypersensitivity to dexamethasone
Cerebral malaria
Systemic fungal infection
Concurrent treatment with live virus vaccines (including smallpox vaccine)
Adverse effects
The exact incidence of the adverse effects of dexamethasone are not available, hence estimates have been made as to the incidence of the adverse effects below based on the adverse effects of related corticosteroids and on available documentation on dexamethasone.
Common
Unknown frequency
Withdrawal
Sudden withdrawal after long-term treatment with corticosteroids can lead to:
Interactions
Known drug interactions include:
Inducers of hepatic microsomal enzymes such as barbiturates, phenytoin, and rifampicin can reduce the half-life of dexamethasone.
Cotreatment with oral contraceptives can increase its volume of distribution.
Pharmacology
Pharmacodynamics
As a glucocorticoid, dexamethasone is an agonist of the glucocorticoid receptor (GR). It is highly selective for the GR over the mineralocorticoid receptor (MR), and in relation to this, has minimal mineralocorticoid activity. This is in contrast to endogenous corticosteroids like cortisol, which bind to and activate both the GR and the MR. Dexamethasone is 25 times more potent than hydrocortisone (cortisol) as a glucocorticoid. Its affinity (Ki) for the GR was about 1.2 nM in one study.The activation of the GR by dexamethasone results in dose-dependent suppression of the hypothalamic–pituitary–adrenal axis (HPA axis) and of production of endogenous corticosteroids by the adrenal glands, thereby reducing circulating endogenous concentrations of corticosteroids like cortisol and corticosterone.Dexamethasone poorly penetrates the blood–brain barrier into the central nervous system due to binding to P-glycoprotein. However, higher doses of dexamethasone override the export capacity of P-glycoprotein and enter the brain to produce central activation of GRs. In conjunction with the suppression of endogenous corticosteroids by dexamethasone, this results in skewed ratios of activation of peripheral versus central GRs as well as skewed ratios of activation of GRs versus MRs when compared to non-synthetic corticosteroids. These differences can have significant clinical relevance.
Chemistry
Dexamethasone is a synthetic pregnane corticosteroid and derivative of cortisol (hydrocortisone) and is also known as 1-dehydro-9α-fluoro-16α-methylhydrocortisone or as 9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione. The molecular and crystal structure of dexamethasone has been determined by X-ray crystallography. It is a stereoisomer of betamethasone, the two compounds differing only in the spatial configuration of the methyl group at position 16 (see steroid nomenclature).
Synthesis
To synthesize dexamethasone, 16β-methylprednisolone acetate is dehydrated to the 9,11-dehydro derivative. This is then reacted with a source of hypobromite, such as basic N-bromosuccinimide, to form the 9α-bromo-11β-hydrin derivative, which is then ring-closed to an epoxide. A ring-opening reaction with hydrogen fluoride in tetrahydrofuran gives dexamethasone.
History
Dexamethasone was first synthesized by Philip Showalter Hench in 1957. It was introduced for medical use in 1958.On 16 June 2020, the RECOVERY Trial announced preliminary results stating that dexamethasone improves survival rates of hospitalized patients with COVID-19 receiving oxygen or on a ventilator. Benefits were only observed in patients requiring respiratory support; those who did not require breathing support saw a worse survival rate than the control group, although the difference may have been due to chance.
A preprint containing the full dataset was published on 22 June 2020, and demand for dexamethasone surged after publication of the preprint. The preliminary report was published in The New England Journal of Medicine on 18 July 2020. The final report was published in February 2021.The World Health Organization (WHO) states that dexamethasone should be reserved for seriously ill and critical patients receiving COVID-19 treatment in a hospital setting, and the WHO Director-General stated that "WHO emphasizes that dexamethasone should only be used for patients with severe or critical disease, under close clinical supervision. There is no evidence this drug works for patients with mild disease or as a preventative measure, and it could cause harm." In July 2020, the WHO stated they are in the process of updating treatment guidelines to include dexamethasone or other steroids. In September 2020, the WHO released updated guidance on using corticosteroids for COVID-19.In July 2020, the European Medicines Agency (EMA) started reviewing results from the RECOVERY study arm that involved the use of dexamethasone in the treatment of patients with COVID-19 admitted to the hospital to provide an opinion on the results and in particular the potential use of dexamethasone for the treatment of adults with COVID-19. In September 2020, the EMA received an application for marketing authorization of dexamethasone for COVID-19.
Society and culture
Price
Dexamethasone is inexpensive. In the United States a month of medication is typically priced less than US$25. In India, a course of treatment for preterm labor is about US$0.50. The drug is available in most areas of the world.
Nonmedical use
Dexamethasone is given in legal Bangladesh brothels to prostitutes not yet of legal age, causing weight gain aimed at making them appear older and healthier to customers and police.Dexamethasone and most glucocorticoids are banned by sporting bodies including the World Anti-Doping Agency.
Veterinary use
Combined with marbofloxacin CAS number 115550-35-1and clotrimazole, dexamethasone is available under the name Aurizon, CAS number 50-02-2, and used to treat difficult ear infections, especially in dogs. It can also be combined with trichlormethiazide to treat horses with swelling of distal limbs and general bruising.
See also
Dexamethasone suppression test
References
External links
"Dexamethasone". Drug Information Portal. U.S. National Library of Medicine.
"Dexamethasone Ophthalmic". MedlinePlus.
"Dexamethasone Injection". MedlinePlus. |
Miglustat | Miglustat, sold under the brand name Zavesca, is a medication used to treat type I Gaucher disease (GD1). It is also known as N-butyldeoxynojirimycin, and is a derivative of the anti-diabetic 1-deoxynojirimycin. It was developed by Oxford GlycoSciences and is marketed by Actelion.
Miglustat has been approved in the EU, Japan, and Canada for treating progressive neurological complications in people with Niemann–Pick disease, type C (NPC).
It was approved for medical use in the European Union in November 2002, and for medical use in the United States in July 2003.
Medical uses
Miglustat is indicated to treat adults with mild to moderate type I Gaucher disease for whom enzyme replacement therapy is unsuitable.
Contraindications
Miglustat is contraindicated for people with neurological conditions, kidney problems, women who are pregnant, and men and women planning to conceive a child.
Adverse effects
Serious side effects include pain, burning, numbness or tingling in the hands, arms, legs, or feet; shaking hands that cannot be controlled; changes in vision; and easy bruising or bleeding. Common side effects include gastrointestinal effects (including diarrhea, stomach pain or bloating, gas, loss of appetite, weight loss, upset stomach, vomiting, constipation), dry mouth, muscular effects (including weakness, muscle cramps, especially in the legs, feeling of heaviness in the arms or legs, unsteadiness when walking), back pain, dizziness, nervousness, headache, memory problems, and difficult or irregular menstruation (period).
Mechanism of action
Type I Gauchers disease is an autosomal recessive disorder; parents are generally healthy carriers with one functional and one mutated (nonfunctioning) copy of the Gaucher disease gene, GBA. People with type I Gaucher have a defect in the enzyme called glucocerebrosidase (also known as acid β-glucosidase). Glucocerebrosidase is an enzyme, and its function is to convert glucocerebroside (also known as glucosylceramide) into ceramide and glucose. When this enzyme doesnt work, glucocerebroside accumulates, which in turn causes liver and spleen enlargement, changes in the bone marrow and blood, and bone disease. It functions as a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions which results in the synthesis of most glycosphingolipids.Earlier treatments on the market (imiglucerase (approved in 1995), velaglucerase (approved in 2010), taliglucerase alfa (Elelyso) (approved in 2012)) are enzyme replacement therapy - they are functioning versions of the enzyme that doesnt work. Miglustat works differently - it prevents the formation of the substance that builds up when the enzyme doesnt work; this is called substrate reduction therapy.
Chemistry
Miglustat is an iminosugar, a synthetic analogue of D-glucose and a white to off-white crystalline solid that has a bitter taste.
Society and culture
Legal status
Miglustat has been approved in the EU, Canada, and Japan for treating progressive neurological complications in people with Niemann–Pick disease, type C (NPC). Miglustat has not received approval for this indication outside of these countries and use for this disease, including the US, is off-label.
Research
In July 2004, Actelion started a clinical trial of miglustat to treat Tay–Sachs disease, particularly late-onset Tay–Sachs with an estimated enrollment of 10 subjects; the trial ended August 2007.In November 2007, Actelion initiated a clinical trial with miglustat in people with cystic fibrosis (CF) who have the ΔF508 in both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene; the study ended in March 2008. The cystic fibrosis trial showed no effect.
See also
Migalastat, a drug for the treatment of Fabry disease, with a similar structure
Miglitol, an oral antidiabetic drug with a similar structure
References
External links
"Miglustat". Drug Information Portal. U.S. National Library of Medicine. |
Poractant alfa | Poractant alfa is a pulmonary surfactant sold under the brand name Curosurf by Chiesi Farmaceutici. Poractant alfa is an extract of natural porcine lung surfactant. As with other surfactants, marked improvement on oxygenation may occur within minutes of the administration of poractant alfa.
The new generic form of surfactant is Varasurf (Sheep Lung Surfactant) developed in PersisGen Co. and commercialized by ArnaGen Pharmad. It has fully comparable quality profile with Curosurf.
Pharmacology
Each milliliter of poractant alfa contains 80 mg of surfactant (extract) that includes 76 mg of phospholipids and 1 mg of protein of which 0.2 mg is surfactant protein B (SP-B). Depending on local country registration, CUROSURF is available in 1.5 mL vials, 3.0 mL vials, and/or twin packs containing two 1.5 mL vials.The amount of phospholipids is calculated from the content of phosphorus and contains 55 mg of phosphatidylcholine of which 30 mg is dipalmitoylphosphatidylcholine.
Other adverse effects
Transient episodes of bradycardia, decreased oxygen saturation, hypotension, or endotracheal tube blockage may occur.
Mechanism of action
Endogenous pulmonary surfactant reduces surface tension at the air-liquid interface of the alveoli during mechanical ventilation and stabilizes the alveoli against collapse at resting transpulmonary pressures.A deficiency of pulmonary surfactant in preterm infants results in respiratory distress syndrome. Poractant alfa compensates for the surfactant deficiency and restores surface activity to the lung tissue.
History
Surfactant deficiency was identified as the cause of respiratory distress syndrome (RDS) as long ago as 1959. Trials of surfactant replacement in the 1960s were unsuccessful because the preparations used contained only phospholipids and they were administered inefficiently by nebulization. In the 1970s Bengt Robertson and Göran Enhörning showed that natural surfactant, containing both phospholipids and proteins, could ameliorate the signs of RDS in immature rabbits. In the 1980s Bengt Robertson and Tore Curstedt developed a porcine surfactant, Curosurf (named after their surnames), which was effective in immature animals and was used in a pilot clinical trial beginning in 1983. Subsequent randomized clinical trials were planned a year later by Bengt Robertson, Tore Curstedt and Henry Halliday, and the first trial was begun in 1985. This showed that Curosurf reduced pulmonary air leaks and neonatal mortality in preterm infants with severe RDS. A second trial, coordinated by Christian P. Speer, demonstrated that multiple doses of Curosurf were more effective than a single dose. Subsequent trials conducted by the Collaborative European Multicenter Study Group, which included among others Guilio Bevilacqua, Janna Koppe, Ola Saugstad, Nils Svenningsen and Jean-Pierre Relier, showed that early treatment was more effective than later administration and that infants treated at birth had similar neurodevelopmental status to untreated controls at a corrected age of 2 years. Members of the Collaborative European Multicenter Study Group in Denmark and Sweden performed studies to demonstrate the benefits of a combination of surfactant treatment and early continuous positive airway pressure.As with other surfactants, marked improvements in oxygenation may occur within minutes of the administration of Curosurf.
== References == |
Ziconotide | Ziconotide (SNX–111; Prialt), also called intrathecal ziconotide (ITZ) because of its administration route, is an atypical analgesic agent for the amelioration of severe and chronic pain. Derived from Conus magus, a cone snail, it is the synthetic form of an ω-conotoxin peptide. It is 1,000 times as powerful as morphine.In December 2004 the Food and Drug Administration approved ziconotide when delivered as an infusion into the cerebrospinal fluid using an intrathecal pump system.
Discovery
Ziconotide is derived from the toxin of the cone snail species Conus magus. Scientists have been intrigued by the effects of the thousands of chemicals in marine snail toxins since the initial investigations in the late 1960s by Baldomero Olivera. Olivera, now a professor of biology in the University of Utah, was inspired by accounts of the deadly effects of these toxins from his childhood in the Philippines. Ziconotide was discovered in the early 1980s by University of Utah research scientist Michael McIntosh, when he was barely out of high school and working with Baldomero Olivera.Ziconotide was developed into an artificially manufactured drug by Elan Corporation. It was approved for sale under the name Prialt by the U.S. Food and Drug Administration on December 28, 2004, and by the European Commission on February 22, 2005. Azur Pharma acquired worldwide rights (except Europe) to Prialt in 2010.
Mechanism of action
Ziconotide is a hydrophilic molecule that is freely soluble in water and is practically insoluble in methyl t-butyl ether. Ziconotide acts as a selective N-type voltage-gated calcium channel blocker. This action inhibits the release of pro-nociceptive neurochemicals like glutamate, calcitonin gene-related peptide (CGRP), and substance P in the brain and spinal cord, resulting in pain relief.
Therapeutic use
Due to the profound side effects or lack of efficacy when delivered through more common routes, such as orally or intravenously, ziconotide must be administered intrathecally (i.e. directly into the spinal fluid). As this is the most expensive and invasive method of drug delivery and involves additional risks of its own, ziconotide therapy is generally considered appropriate (as evidenced by the range of use approved by the FDA in the US) only for “management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies or IT morphine”. Research is ongoing to determine whether ziconotide can be formulated in a way that would allow it to be administered by less invasive means.However, this must be weighed against the high level of pain management, both in terms of degree and length, and the apparent lack of tolerance and other signs of dependence even after extended treatment along with the need for alternatives to other therapies that have not worked for the patient. Ziconotide is also contraindicated for patients with certain preexisting mental disorders (e.g. psychosis) due to evidence that they are more susceptible to certain severe side effects.
Adverse reactions
The most common side effects are dizziness, nausea, confusion, nystagmus, and headache. Others may include weakness, hypertonia, ataxia, abnormal vision, anorexia, somnolence, unsteadiness on feet, vertigo, urinary retention, pruritus, increased sweating, diarrhea, nausea, vomiting, asthenia, fever, rigors, sinusitis, muscle spasms, myalgia, insomnia, anxiety, amnesia, tremor, memory impairment, and induced psychiatric disorders. Other side effects which are less frequent but still clinically significant include auditory and visual hallucinations, thoughts of suicide, acute kidney failure, atrial fibrillation, cardiovascular accident, sepsis, new or worsening depression, paranoia, disorientation, meningitis, and seizures. Therefore, it is contraindicated in people with a history of psychosis, schizophrenia, clinical depression, and bipolar disorder. Recent incidents suggesting a link between intrathecal ziconotide treatment and increased risk of suicide have led to calls for strict and ongoing psychiatric monitoring of patients to avoid suicide occurring in vulnerable individuals. There is no known antidote.
Structure
Ziconotide is a peptide with the amino acid sequence
H-Cys-Lys-Gly-Lys-Gly-Ala-Lys-Cys-Ser-Arg-Leu-Met-Tyr-Asp-Cys-Cys-Thr-Gly-Ser-Cys-Arg-Ser-Gly-Lys-Cys-NH2 (CKGKGAKCSRLMYDCCTGSCRSGKC-NH2) and contains 3 disulfide bonds (Cys1-Cys16, Cys8-Cys20, and Cys15-Cys25).
Patents
The drug was patented by Neurex Corp., a U.S. company purchased in 1998 by Élan Corporation, plc of Ireland. U.S. patents assigned to Elan include 5,859,186, 5,795,864 5,770,690, 5,587,454, and 5,587,454.
References
External links
"Ziconotide". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT00076544 for "Ziconotide Effectiveness and Safety Trial in Patients with Chronic Severe Pain" at ClinicalTrials.gov |
Orlistat | Orlistat, sold under the brand name Xenical among others, is a medication used to treat obesity. Its primary function is preventing the absorption of fats from the human diet by acting as a lipase inhibitor, thereby reducing caloric intake. It is intended for use in conjunction with a healthcare provider-supervised reduced-calorie diet.Orlistat is the saturated derivative of lipstatin, a potent natural inhibitor of pancreatic lipases isolated from the bacterium Streptomyces toxytricini. However, due to its relative simplicity and stability, orlistat was chosen over lipstatin for development as an anti-obesity drug.The effectiveness of orlistat in promoting weight loss is definite but modest. Pooled data from clinical trials suggest that people given orlistat in addition to lifestyle modifications, such as diet and exercise, lose about 2–3 kilograms (4–7 lb) more than those not taking the drug over the course of a year. Orlistat also modestly reduces blood pressure and appears to prevent the onset of type 2 diabetes, whether from the weight loss itself or other effects. It reduces the incidence of diabetes type II in people who are obese around the same amount that lifestyle changes do.Benefits aside, however, orlistat is noted for its gastrointestinal side effects (sometimes referred to as treatment effects), which can include steatorrhea (oily, loose stools). They decrease with time, however, and are the most frequently reported adverse effects of the drug. In Australia, the United States and the European Union, orlistat is available for sale without a prescription. Over-the-counter approval was controversial in the United States, with consumer advocacy group Public Citizen repeatedly opposing it on safety and efficacy grounds. Generic formulations of orlistat are available in some countries. In Australia it has been listed as an S3 medication, available from a pharmacist without a prescription, since 2000.
Medical uses
Orlistat is used for the treatment of obesity. The amount of weight loss achieved with orlistat varies. In one-year clinical trials, between 35.5% and 54.8% of subjects achieved a 5% or greater decrease in body mass, although not all of this mass was necessarily fat. Between 16.4% and 24.8% achieved at least a 10% decrease in body fat. After orlistat was stopped, a significant number of subjects regained weight—up to 35% of the weight they had lost. It reduces the incidence of diabetes type II in people who are obese around the same amount that lifestyle changes do. Long-term use of orlistat also leads to a very modest reduction in blood pressure (mean reductions of 2.5 and 1.9 mmHg in systolic and diastolic blood pressure respectively).
Contraindications
Orlistat is contraindicated in:
Malabsorption
Hypersensitivity to orlistat
Reduced gallbladder function (e.g. after cholecystectomy)
Pregnancy and breastfeeding
Anorexia and Bulimia
Use caution with: obstructed bile duct, impaired liver function, and pancreatic disease
Side effects
The primary side effects of the drug are gastrointestinal-related, and include steatorrhea (oily, loose stools with excessive flatus due to unabsorbed fats reaching the large intestine), fecal incontinence and frequent or urgent bowel movements. To minimize these effects, foods with high fat content should be avoided; the manufacturer advises consumers to follow a low-fat, reduced-calorie diet. Oily stools and flatulence can be controlled by reducing the dietary fat content to somewhere in the region of 15 grams per meal. The manual for Alli makes it clear that orlistat treatment involves aversion therapy, encouraging the user to associate eating fat with unpleasant treatment effects.Side effects are most severe when beginning therapy and may decrease in frequency with time; It has also been suggested that the decrease in side effects over time may be associated with long-term compliance with a low-fat diet.On 26 May 2010, the U.S. Food and Drug Administration (FDA) approved a revised label for Xenical to include new safety information about cases of severe liver injury that have been reported rarely with the use of this medication.An analysis of over 900 orlistat users in Ontario showed that their rate of acute kidney injury was more than triple that of non-users.A study from 2013 looked at 94,695 participants receiving orlistat in the UK between 1999 and 2011. The study showed no evidence of an increased risk of liver injury during treatment. They concluded:
The incidence of acute liver injury was higher in the periods both immediately before and immediately after the start of orlistat treatment. This suggests that the observed increased risks of liver injury linked to the start of treatment may reflect changes in health status associated with the decision to begin treatment rather than any causal effect of the drug.
Long-term
Despite a higher incidence of breast cancer amongst those taking orlistat in early, pooled clinical trial data—the analysis of which delayed FDA review of orlistat—a two-year study published in 1999 found similar rates between orlistat and placebo (0.54% versus 0.51%), and evidence that tumors predated treatment in 3 of the 4 participants who had them. There is evidence from an in vitro study to suggest that the introduction of specific varied preparations containing orlistat, namely the concurrent administration of orlistat and the monoclonal antibody trastuzumab, can induce cell death in breast cancer cells and block their growth.Fecal fat excretion promotes colon carcinogenesis. In 2006 the results of 30-day study were published indicating that orlistat at a dosage of 200 mg/kg chow administered to rats consuming a high-fat chow and receiving two 25 mg/kg doses of the potent carcinogen 1,2-dimethylhydrazine produced significantly higher numbers of aberrant crypt foci (ACF) colon lesions than did the carcinogen plus high-fat chow without orlistat. ACF lesions are believed to be one of the earliest precursors of colon cancer.
Precautions
Absorption of fat-soluble vitamins and other fat-soluble nutrients is inhibited by the use of orlistat.
Interactions
Orlistat may reduce plasma levels of ciclosporin (also known as "cyclosporin" or "cyclosporine", trade names Sandimmune, Gengraf, Neoral, etc.), an immunosuppressive drug frequently used to prevent transplant rejection; the two drugs should therefore not be administered concomitantly. Orlistat can also impair absorption of the antiarrhythmic amiodarone. The Medicines and Healthcare products Regulatory Agency (MHRA) has suggested the possibility that orlistat could reduce the absorption of antiretroviral HIV medications.
Mechanism of action
Orlistat works by inhibiting gastric and pancreatic lipases, the enzymes that break down triglycerides in the intestine. When lipase activity is blocked, triglycerides from the diet are not hydrolyzed into absorbable free fatty acids, and instead are excreted unchanged. Only trace amounts of orlistat are absorbed systemically; the primary effect is local lipase inhibition within the GI tract after an oral dose. The primary route of elimination is through the feces.
Orlistat was also found to inhibit the thioesterase domain of fatty acid synthase (FAS), an enzyme involved in the proliferation of cancer cells but not normal cells. However, potential side effects of orlistat, such as inhibition of other cellular off-targets or poor bioavailability, might hamper its application as an effective antitumor agent. One profiling study undertook a chemical proteomics approach to look for new cellular targets of orlistat, including its off-targets. Orlistat also shows potential activity against the Trypanosoma brucei parasite.Orlistat prevents approximately 30% of dietary fat from being absorbed.
Legal status
Orlistat is available both with and without a prescription.
Australia and New Zealand
In Australia and New Zealand, orlistat is available as a "Pharmacist Only Medicine. In 2007, the Committee decided to keep orlistat as a Schedule 3 drug, but withdrew its authorization of direct-to-consumer Xenical advertising, stating this "increased pressure on pharmacists to provide orlistat to consumers...this in turn had the potential to result in inappropriate patterns of use".
United States
On 23 January 2006, a U.S. Food and Drug Administration advisory panel voted 11 to 3 to recommend the approval of an OTC formulation of orlistat, to be sold under the brand name Alli by GlaxoSmithKline. Approval was granted on 7 February 2007, and Alli became the first weight loss drug officially sanctioned by the U.S. government for over-the-counter use.
Consumer advocacy organization Public Citizen opposed over-the-counter approval for orlistat.Alli became available in the U.S. in June 2007. It is sold as 60 mg capsules—half the dosage of prescription orlistat.
European Union and Switzerland
On 21 January 2009, the European Medicines Agency granted approval for the sale of orlistat without a prescription.At least since September 2017, tablets with 60 mg orlistat can be freely sold in Swiss drugstores. Formulations with 120 mg per tablet require a prescription, but can be sold without one in pharmacies under an exemption rule, which is based on a list of easily diagnosable diseases.
Generic formulations
U.S. patent protection for Xenical, originally to end on 18 June 2004, was extended by five years (until 2009) by the U.S. Patent and Trademark Office. The extension was granted on 20 July 2002, and expired on 18 June 2009.Generic orlistat is available in Iran under the brand Venustat manufactured by Aburaihan Pharmaceutical co., in India, under the brands Orlean (Eris), Vyfat, Olistat, Obelit, Orlica and Reeshape. In Russia, orlistat is available under the brand names Xenical (Hoffmann–La Roche), Orsoten/Orsoten Slim (KRKA d. d.) and Xenalten (OBL-Pharm). In Austria, orlistat is available under the brand name Slimox. In Malaysia, orlistat is available under the brand name Cuvarlix and is marketed by Pharmaniaga. In the Philippines orlistat is available under the brand name RedoXfat Plus manufactured by ATC Healthcare
Society and culture
Cost
At times, such as in spring 2012, orlistat has come into short supply, with consequent price increases because of nonavailability of one of the drugs components.
Counterfeit products
In January 2010, the U.S. Food and Drug Administration issued an alert stating that some counterfeit versions of Alli sold over the Internet contain no orlistat, and instead contain the weight-loss drug sibutramine. The concentration of sibutramine in these counterfeit products is at least twice the amount recommended for weight loss.
References
Further reading
Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, et al. (February 1994). "Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties". Journal of Medicinal Chemistry. 37 (3): 408–14. doi:10.1021/jm00029a013. PMID 8308867.
Hanessian S, Tehim A, Chen P (1993). "Total synthesis of (−)-tetrahydrolipstatin". The Journal of Organic Chemistry. 58 (27): 7768. doi:10.1021/jo00079a022.
Peng-Yu Y, Kai L, Mun Hong N, JLear M, RWenk M, SQin Y (2010). "Activity-based proteome profiling of potential cellular targets of Orlistat−an FDA-approved drug with anti-tumor activities". Journal of the American Chemical Society. 132 (2): 656–66. doi:10.1021/ja907716f. PMID 20028024.
Peng-Yu Y, Min W, Kai L, Mun Hong N, Omar S, JLear M, Siu Kwan S, Cynthia Y H, SQin Y (2012). "Parasite-based screening and proteome profiling reveal orlistat, an FDA-approved drug, as a potential anti Trypanosoma brucei agent". Chemistry: A European Journal. 18 (27): 8403–13. doi:10.1002/chem.201200482. PMID 22674877.
External links
"Orlistat". Drug Information Portal. U.S. National Library of Medicine. |
Phenelzine | Phenelzine, sold under the brand name Nardil, among others, is a nonselective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class which is used as an antidepressant and anxiolytic. Along with tranylcypromine and isocarboxazid, phenelzine is one of the few nonselective and irreversible MAOIs still in widespread clinical use. It is available in Australia, the United Kingdom, the United States, and Canada. It is taken by mouth.
Indications
Phenelzine is used primarily in the treatment of major depressive disorder (MDD). Patients with depressive symptomology characterized as "atypical", "nonendogenous", and/or "neurotic" respond particularly well to phenelzine. The medication is also useful in patients who do not respond favorably to first and second-line treatments for depression, or are "treatment-resistant". In addition to being a recognized treatment for major depressive disorder, phenelzine is effective in treating dysthymia, bipolar depression (BD), panic disorder (PD), social anxiety disorder, bulimia, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD).
Pharmacology
Pharmacodynamics
Phenelzine is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It inhibits both of the respective isoforms of MAO, MAO-A and MAO-B, and does so almost equally, with slight preference for the former. By inhibiting MAO, phenelzine prevents the breakdown of the monoamine neurotransmitters serotonin, melatonin, norepinephrine, epinephrine, and dopamine, as well as the trace amine neuromodulators such as phenethylamine, tyramine, octopamine, and tryptamine. This leads to an increase in the extracellular concentrations of these neurochemicals and therefore an alteration in neurochemistry and neurotransmission. This action is thought to be the primary mediator in phenelzines therapeutic benefits.
Phenelzine and its metabolites also inhibit at least two other enzymes to a lesser extent, of which are alanine transaminase (ALA-T), and γ-aminobutyric acid transaminase (GABA-T), the latter of which is not caused by phenelzine itself, but by a phenelzine metabolite phenylethylidenehydrazine (PEH). By inhibiting ALA-T and GABA-T, phenelzine causes an increase in the alanine and GABA levels in the brain and body. GABA is the major inhibitory neurotransmitter in the mammalian central nervous system, and is very important for the normal suppression of anxiety, stress, and depression. Phenelzines action in increasing GABA concentrations may significantly contribute to its antidepressant, and especially, anxiolytic/antipanic properties, the latter of which have been considered superior to those of other antidepressants. As for ALA-T inhibition, though the consequences of disabling this enzyme are currently not well understood, there is some evidence to suggest that it is this action of the hydrazines (including phenelzine) which may be responsible for the occasional incidence of hepatitis and liver failure.
Phenelzine has also been shown to metabolize to phenethylamine (PEA). PEA acts as a releasing agent of norepinephrine and dopamine, and this occurs in the same manner as amphetamine (very similar in structure) by being taken up into vesicles, and displacing, and causing the release of those monoamines (though with markedly different pharmacokinetics such as a far shorter duration of action). Although this is indeed the same mechanism to which some (but not all) of amphetamines effects are attributable to, this is not all that uncommon a property among phenethylamines in general, many of which do not have psychoactive properties comparable to amphetamine. Amphetamine is different in that it binds with high affinity to the reuptake pumps of dopamine, norepinephrine, and serotonin, which phenethylamine and related molecules may as well to some extent, but with far less potency, such that it is basically insignificant in comparison. And, often being metabolized too quickly or not having the solubility to enable it to have a psychostimulant effect in humans. Claims that phenethylamine has comparable or roughly similar effects to psychostimulants such as amphetamine when administered are misconstrued. Phenethylamine does not have any obvious, easily discernible, reliably induced effects when administered to humans. Phenelzines enhancement of PEA levels may contribute further to its overall antidepressant effects to some degree. In addition, phenethylamine is a substrate for MAO-B, and treatment with MAOIs that inhibit MAO-B such as phenelzine have been shown to consistently and significantly elevate its concentrations.
Phenelzine usually requires six to eight weeks of treatment, and a minimum dose of 60 mg/day, to achieve therapeutic effects. The reason for the delay in therapeutic effect is not fully understood, but it is believed to be due to many factors, including achieving steady-state levels of MAO inhibition and the resulting adaptations in mean neurotransmitter levels, the possibility of necessary desensitization of autoreceptors which normally inhibit the release of neurotransmitters like serotonin and dopamine, and also the upregulation of enzymes such as serotonin N-acetyltransferase. Typically, a therapeutic response to MAOIs is associated with an inhibition of at least 80-85% of monoamine oxidase activity.
Pharmacokinetics
Phenelzine is administered orally in the form of phenelzine sulfate and is rapidly absorbed from the gastrointestinal tract. Time to peak plasma concentration is 43 minutes and half-life is 11.6 hours. Unlike most other drugs, phenelzine irreversibly disables MAO, and as a result, it does not necessarily need to be present in the blood at all times for its effects to be sustained. Because of this, upon phenelzine treatment being ceased, its effects typically do not actually wear off until the body replenishes its enzyme stores, a process which can take as long as 2–3 weeks.
Phenelzine is metabolized primarily in the liver and its metabolites are excreted in the urine. Oxidation is the primary routine of metabolism, and the major metabolites are phenylacetic acid and parahydroxyphenylacetic acid, recovered as about 73% of the excreted dose of phenelzine in the urine over the course of 96 hours after single doses. Acetylation to N2-acetylphenelzine is a minor pathway. Phenelzine may also interact with cytochrome P450 enzymes, inactivating these enzymes through formation of a heme adduct. Two other minor metabolites of phenelzine, as mentioned above, include phenylethylidenehydrazine and phenethylamine.
Adverse effects
Common side effects of phenelzine may include dizziness, blurry vision, dry mouth, headache, lethargy, sedation, somnolence, insomnia, anorexia, weight gain or loss, nausea and vomiting, diarrhea, constipation, urinary retention, mydriasis, muscle tremors, hyperthermia, sweating, hypertension or hypotension, orthostatic hypotension, paresthesia, hepatitis, and sexual dysfunction (consisting of loss of libido and anorgasmia). Rare side effects usually only seen in susceptible individuals may include hypomania or mania, psychosis and acute liver failure, the last of which is usually only seen in people with pre-existing liver damage, old age, long-term effects of alcohol consumption, or viral infection.
Interactions
The MAOIs have certain dietary restrictions and drug interactions. The amount of such restrictions and interactions is far less than previously thought, and MAOIs are generally safe medications when administered correctly. Hypertensive crisis is generally a rare occurrence while taking MAOIs, yet may result from the overconsumption of tyramine-containing foods. As a result, patients on phenelzine and other MAOIs must avoid excess quantities of certain foods that contain tyramine such as aged cheeses and cured meats, among others. Serotonin syndrome may result from an interaction with certain drugs which increase serotonin activity such as selective serotonin reuptake inhibitors, serotonin releasing agents, and serotonin agonists.
As is the case with other MAOIs, there is a concern regarding phenelzine and the use of both local and general anesthetics. Anyone taking phenelzine should inform their dentist before proceeding with dental surgery, and surgeon in any other contexts.
Phenelzine has also been linked to vitamin B6 deficiency. Transaminases such as GABA-transaminase have been shown to be dependent upon vitamin B6 and may be involved in a potentially related process, since the phenelzine metabolite phenylethylidenehydrazine (PEH) is a GABA transaminase inhibitor. Both phenelzine and vitamin B6 are rendered inactive upon these reactions occurring. For this reason, it may be recommended to supplement with vitamin B6 while taking phenelzine. The pyridoxine form of B6 is recommended for supplementation, since this form has been shown to reduce hydrazine toxicity from phenelzine and, in contrast, the pyridoxal form has been shown to increase the toxicity of hydrazines.
Research
Phenelzine showed promise in a phase II clinical trial from March 2020 in treating prostate cancer.
Phenelzine has also been shown to have neuroprotective effects in animal models.
History
Synthesis of phenelzine was first described by Emil Votoček and Otakar Leminger in 1932.
See also
Phenylethylidenehydrazine
Hydrazine (antidepressant)
Isocarboxazid
Libby Zion Law (a case involving phenelzine and pethidine)
Monoamine oxidase inhibitor
Tranylcypromine
References
External links
"Phenelzine". Drug Information Portal. U.S. National Library of Medicine. |
Progesterone (medication) | Progesterone (P4) is a medication and naturally occurring steroid hormone. It is a progestogen and is used in combination with estrogens mainly in hormone therapy for menopausal symptoms and low sex hormone levels in women. It is also used in women to support pregnancy and fertility and to treat gynecological disorders. Progesterone can be taken by mouth, in through the vagina, and by injection into muscle or fat, among other routes. A progesterone vaginal ring and progesterone intrauterine device used for birth control also exist in some areas of the world.Progesterone is well tolerated and often produces few or no side effects. However, a number of side effects are possible, for instance mood changes. If progesterone is taken by mouth or at high doses, certain central side effects including sedation, sleepiness, and cognitive impairment can also occur. The medication is a naturally occurring progestogen and hence is an agonist of the progesterone receptor (PR), the biological target of progestogens like endogenous progesterone. It opposes the effects of estrogens in various parts of the body like the uterus and also blocks the effects of the hormone aldosterone. In addition, progesterone has neurosteroid effects in the brain.Progesterone was first isolated in pure form in 1934. It first became available as a medication later that year. Oral micronized progesterone (OMP), which allowed progesterone to be taken by mouth, was introduced in 1980. A large number of synthetic progestogens, or progestins, have been derived from progesterone and are used as medications as well. Examples include medroxyprogesterone acetate and norethisterone. In 2019, it was the 188th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Medical uses
Hormone therapy
Menopause
Progesterone is used in combination with an estrogen as a component of menopausal hormone therapy for the treatment of menopausal symptoms in peri- and postmenopausal women. It is used specifically to provide endometrial protection against unopposed estrogen-induced endometrial hyperplasia and cancer in women with intact uteruses. A 2016 systematic review of endometrial protection with progesterone recommended 100 mg/day continuous oral progesterone, 200 mg/day cyclic oral progesterone, 45 to 100 mg/day cyclic vaginal progesterone, and 100 mg alternate-day vaginal progesterone. Twice-weekly 100 mg vaginal progesterone was also recommended, but more research is needed on this dose and endometrial monitoring may be advised. Transdermal progesterone was not recommended for endometrial protection.The REPLENISH trial was the first adequately powered study to show that continuous 100 mg/day oral progesterone with food provides adequate endometrial protection. Cyclic 200 mg/day oral progesterone has also been found to be effective in the prevention of endometrial hyperplasia, for instance in the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. However, the PEPI trial was not adequately powered to fully quantify endometrial hyperplasia or cancer risk. No adequately powered studies have assessed endometrial protection with vaginal progesterone. In any case, the Early versus Late Intervention Trial with Estradiol (ELITE) found that cyclic 45 mg/day vaginal progesterone gel showed no significant difference from placebo in endometrial cancer rates. Due to the vaginal first-pass effect, low doses of vaginal progesterone may allow for adequate endometrial protection. Although not sufficiently powered, various other smaller studies have also found endometrial protection with oral or vaginal progesterone. There is inadequate evidence for endometrial protection with transdermal progesterone cream.Oral progesterone has been found to significantly reduce hot flashes relative to placebo. The combination of an estrogen and oral progesterone likewise reduces hot flashes. Estrogen plus oral progesterone has been found to significantly improve quality of life. The combination of an estrogen and 100 to 300 mg/day oral progesterone has been found to improve sleep outcomes. Moreover, sleep was improved to a significantly better extent than estrogen plus medroxyprogesterone acetate. This may be attributable to the sedative neurosteroid effects of progesterone. Reduction of hot flashes may also help to improve sleep outcomes. Based on animal research, progesterone may be involved in sexual function in women. However, very limited clinical research suggests that progesterone does not improve sexual desire or function in women.The combination of an estrogen and oral progesterone has been found to improve bone mineral density (BMD) to a similar extent as an estrogen plus medroxyprogesterone acetate. Progestogens, including progesterone, may have beneficial effects on bone independent of those of estrogens, although more research is required to confirm this notion. The combination of an estrogen and oral or vaginal progesterone has been found to improve cardiovascular health in women in early menopause but not in women in late menopause. Estrogen therapy has a favorable influence on the blood lipid profile, which may translate to improved cardiovascular health. The addition of oral or vaginal progesterone has neutral or beneficial effects on these changes. This is in contrast to various progestins, which are known to antagonize the beneficial effects of estrogens on blood lipids. Progesterone, both alone and in combination with an estrogen, has been found to have beneficial effects on skin and to slow the rate of skin aging in postmenopausal women.In the French E3N-EPIC observational study, the risk of diabetes was significantly lower in women on menopausal hormone therapy, including with the combination of an oral or transdermal estrogen and oral progesterone or a progestin.
Transgender women
Progesterone is used as a component of feminizing hormone therapy for transgender women in combination with estrogens and antiandrogens. However, the addition of progestogens to HRT for transgender women is controversial and their role is unclear. Some patients and clinicians believe anecdotally that progesterone may enhance breast development, improve mood, and increase sex drive. However, there is a lack of evidence from well-designed studies to support these notions at present. In addition, progestogens can produce undesirable side effects, although bioidentical progesterone may be safer and better tolerated than synthetic progestogens like medroxyprogesterone acetate.Because some believe that progestogens are necessary for full breast development, progesterone is sometimes used in transgender women with the intention of enhancing breast development. However, a 2014 review concluded the following on the topic of progesterone for enhancing breast development in transgender women:
Our knowledge concerning the natural history and effects of different cross-sex hormone therapies on breast development in [transgender] women is extremely sparse and based on low quality of evidence. Current evidence does not provide evidence that progestogens enhance breast development in [transgender] women. Neither do they prove the absence of such an effect. This prevents us from drawing any firm conclusion at this moment and demonstrates the need for further research to clarify these important clinical questions.
Data on menstruating women shows there is no correlation between water retention, and levels of progesterone or estrogen. Despite this, some theorise progesterone might cause temporary breast enlargement due to local fluid retention, and may thus give a misleading appearance of breast growth. Aside from a hypothetical involvement in breast development, progestogens are not otherwise known to be involved in physical feminization.In some cases, transgender women use progesterone to alleviate symptoms of estrogen withdrawal. Estrogen must be withdrawn from transgender womens hormonal regime before they undergo sex reassignment surgery.
Pregnancy support
Vaginally dosed progesterone is being investigated as potentially beneficial in preventing preterm birth in women at risk for preterm birth. The initial study by Fonseca suggested that vaginal progesterone could prevent preterm birth in women with a history of preterm birth. According to a recent study, women with a short cervix that received hormonal treatment with a progesterone gel had their risk of prematurely giving birth reduced. The hormone treatment was administered vaginally every day during the second half of a pregnancy. A subsequent and larger study showed that vaginal progesterone was no better than placebo in preventing recurrent preterm birth in women with a history of a previous preterm birth, but a planned secondary analysis of the data in this trial showed that women with a short cervix at baseline in the trial had benefit in two ways: a reduction in births less than 32 weeks and a reduction in both the frequency and the time their babies were in intensive care.In another trial, vaginal progesterone was shown to be better than placebo in reducing preterm birth prior to 34 weeks in women with an extremely short cervix at baseline. An editorial by Roberto Romero discusses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment. A meta-analysis published in 2011 found that vaginal progesterone cut the risk of premature births by 42 percent in women with short cervixes. The meta-analysis, which pooled published results of five large clinical trials, also found that the treatment cut the rate of breathing problems and reduced the need for placing a baby on a ventilator.
Fertility support
Progesterone is used for luteal support in assisted reproductive technology (ART) cycles such as in vitro fertilization (IVF). It is also used to correct luteal phase deficiency to prepare the endometrium for implantation in infertility therapy and is used to support early pregnancy.
Birth control
A progesterone vaginal ring is available for birth control when breastfeeding in a number of areas of the world. An intrauterine device containing progesterone has also been marketed under the brand name Progestasert for birth control, including previously in the United States.
Gynecological disorders
Progesterone is used to control persistent anovulatory bleeding. It is used in non-pregnant women with a delayed menstruation of one or more weeks, in order to allow the thickened endometrial lining to slough off. This process is termed a progesterone withdrawal bleed. Progesterone is taken orally for a short time (usually one week), after which it is discontinued and bleeding should occur.
Other uses
Progesterone is of unclear benefit for the reversal of mifepristone-induced abortion. Evidence is insufficient to support use in traumatic brain injury.Progesterone has been used as a topical medication applied to the scalp to treat female and male pattern hair loss. Variable effectiveness has been reported, but overall its effectiveness for this indication in both sexes has been poor.
Breast pain
Progesterone is approved under the brand name Progestogel as a 1% topical gel for local application to the breasts to treat breast pain in certain countries. It is not approved for systemic therapy. It has been found in clinical studies to inhibit estrogen-induced proliferation of breast epithelial cells and to abolish breast pain and tenderness in women with the condition. However, in one small study in women with cyclic breast pain it was ineffective. Vaginal progesterone has also been found to be effective in the treatment of breast pain and tenderness.
Premenstrual syndrome
Historically, progesterone has been widely used in the treatment of premenstrual syndrome. A 2012 Cochrane review found insufficient evidence for or against the effectiveness of progesterone for this indication. Another review of 10 studies found that progesterone was not effective for this condition, although it stated that insufficient evidence is available currently to make a definitive statement on progesterone in premenstrual syndrome.
Catamenial epilepsy
Progesterone can be used to treat catamenial epilepsy by supplementation during certain periods of the menstrual cycle.
Available forms
Progesterone is available in a variety of different forms, including oral capsules; sublingual tablets; vaginal capsules, tablets, gels, suppositories, and rings; rectal suppositories; oil solutions for intramuscular injection; and aqueous solutions for subcutaneous injection. A 1% topical progesterone gel is approved for local application to the breasts to treat breast pain, but is not indicated for systemic therapy. Progesterone was previously available as an intrauterine device for use in hormonal contraception, but this formulation was discontinued. Progesterone is also limitedly available in combination with estrogens such as estradiol and estradiol benzoate for use by intramuscular injection.In addition to approved pharmaceutical products, progesterone is available in unregulated custom compounded and over-the-counter formulations like systemic transdermal creams and other preparations. The systemic efficacy of transdermal progesterone is controversial and has not been demonstrated.
Contraindications
Contraindications of progesterone include hypersensitivity to progesterone or progestogens, prevention of cardiovascular disease (a Black Box warning), thrombophlebitis, thromboembolic disorder, cerebral hemorrhage, impaired liver function or disease, breast cancer, reproductive organ cancers, undiagnosed vaginal bleeding, missed menstruations, miscarriage, or a history of these conditions. Progesterone should be used with caution in people with conditions that may be adversely affected by fluid retention such as epilepsy, migraine headaches, asthma, cardiac dysfunction, and renal dysfunction. It should also be used with caution in patients with anemia, diabetes mellitus, a history of depression, previous ectopic pregnancy, and unresolved abnormal Pap smear. Use of progesterone is not recommended during pregnancy and breastfeeding. However, the medication has been deemed usually safe in breastfeeding by the American Academy of Pediatrics, but should not be used during the first four months of pregnancy. Some progesterone formulations contain benzyl alcohol, and this may cause a potentially fatal "gasping syndrome" if given to premature infants.
Side effects
Progesterone is well tolerated, and many clinical studies have reported no side effects. Side effects of progesterone may include abdominal cramps, back pain, breast tenderness, constipation, nausea, dizziness, edema, vaginal bleeding, hypotension, fatigue, dysphoria, depression, and irritability, among others. Central nervous system depression, such as sedation and cognitive/memory impairment, can also occur.Vaginal progesterone may be associated with vaginal irritation, itchiness, and discharge, decreased libido, painful sexual intercourse, vaginal bleeding or spotting in association with cramps, and local warmth or a "feeling of coolness" without discharge. Intramuscular injection may cause mild-to-moderate pain at the site of injection. High intramuscular doses of progesterone have been associated with increased body temperature, which may be alleviated with paracetamol treatment.Progesterone lacks undesirable off-target hormonal activity, in contrast to various progestins. As a result, it is not associated with androgenic, antiandrogenic, estrogenic, or glucocorticoid effects. Conversely, progesterone can still produce side effects related to its antimineralocorticoid and neurosteroid activity. Compared to the progestin medroxyprogesterone acetate, there are fewer reports of breast tenderness with progesterone. In addition, the magnitude and duration of vaginal bleeding with progesterone are reported to be lower than with medroxyprogesterone acetate.
Central depression
Progesterone can produce central nervous system depression as an adverse effect, particularly with oral administration or with high doses of progesterone. These side effects may include drowsiness, sedation, sleepiness, fatigue, sluggishness, reduced vigor, dizziness, lightheadedness, confusion, and cognitive, memory, and/or motor impairment. Limited available evidence has shown minimal or no adverse influence on cognition with oral progesterone (100–600 mg), vaginal progesterone (45 mg gel), or progesterone by intramuscular injection (25–200 mg). However, high doses of oral progesterone (300–1200 mg), vaginal progesterone (100–200 mg), and intramuscular progesterone (100–200 mg) have been found to result in dose-dependent fatigue, drowsiness, and decreased vigor. Moreover, high single doses of oral progesterone (1200 mg) produced significant cognitive and memory impairment. Intravenous infusion of high doses of progesterone (e.g., 500 mg) has been found to induce deep sleep in humans. Some individuals are more sensitive and can experience considerable sedative and hypnotic effects at lower doses of oral progesterone (e.g., 400 mg).Sedation and cognitive and memory impairment with progesterone are attributable to its inhibitory neurosteroid metabolites. These metabolites occur to a greater extent with oral progesterone, and may be minimized by switching to a parenteral route. Progesterone can also be taken before bed to avoid these side effects and to help with sleep. The neurosteroid effects of progesterone are unique to progesterone and are not shared with progestins.
Breast cancer
Breast cell proliferation has been found to be significantly increased by the combination of an oral estrogen plus cyclic medroxyprogesterone acetate in postmenopausal women but not by the combination of transdermal estradiol plus oral progesterone. Studies of topical estradiol and progesterone applied to the breasts for 2 weeks have been found to result in highly pharmacological local levels of estradiol and progesterone. These studies have assessed breast proliferation markers and have found increased proliferation with estradiol alone, decreased proliferation with progesterone, and no change in proliferation with estradiol and progesterone combined. In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, the combination of estrogen and cyclic oral progesterone resulted in a higher mammographic breast density than estrogen alone (3.1% vs. 0.9%) but a non-significantly lower breast density than the combination of estrogen and cyclic or continuous medroxyprogesterone acetate (3.1% vs. 4.4–4.6%). Higher breast density is a strong known risk factor for breast cancer. Other studies have had mixed findings however. A 2018 systematic review reported that breast density with an estrogen plus oral progesterone was significantly increased in three studies and unchanged in two studies. Changes in breast density with progesterone appear to be less than with the compared progestins.In large short-term observational studies, estrogen alone and the combination of estrogen and oral progesterone have generally not been associated with an increased risk of breast cancer. Conversely, the combination of estrogen and almost any progestin, such as medroxyprogesterone acetate or norethisterone acetate, has been associated with an increased risk of breast cancer. The only exception among progestins is dydrogesterone, which has shown similar risk to that of oral progesterone. Breast cancer risk with estrogen and progestin therapy is duration-dependent, with the risk being significantly greater with more than 5 years of exposure relative to less than 5 years. In contrast to shorter-term studies, the longer-term observations (>5 years) of the French E3N study showed significant associations of both estrogen plus oral progesterone and estrogen plus dydrogesterone with higher breast cancer risk, similarly to estrogen plus other progestogens. Oral progesterone has very low bioavailability and has relatively weak progestogenic effects. The delayed onset of breast cancer risk with estrogen plus oral progesterone is potentially consistent with a weak proliferative effect of oral progesterone on the breasts. As such, a longer duration of exposure may be necessary for a detectable increase in breast cancer risk to occur. In any case, the risk remains lower than that with most progestins. A 2018 systematic review of progesterone and breast cancer concluded that short-term use (<5 years) of an estrogen plus progesterone is not associated with a significant increase in risk of breast cancer but that long-term use (>5 years) is associated with greater risk. The conclusions for progesterone were the same in a 2019 meta-analysis of the worldwide epidemiological evidence by the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC).Most data on breast density changes and breast cancer risk are with oral progesterone. Data on breast safety with vaginal progesterone are scarce. The Early versus Late Intervention Trial with Estradiol (ELITE) was a randomized controlled trial of about 650 postmenopausal women who used estradiol and 45 mg/day cyclic vaginal progesterone. Incidence of breast cancer was reported as an adverse effect. The absolute incidences were 10 cases in the estradiol plus vaginal progesterone group and 8 cases in the control group. However, the study was not adequately powered for quantifying breast cancer risk.
Blood clots
Whereas the combination of estrogen and a progestin is associated with increased risk of venous thromboembolism (VTE) relative to estrogen alone, there is no difference in risk of VTE with the combination of estrogen and oral progesterone relative to estrogen alone. Hence, in contrast to progestins, oral progesterone added to estrogen does not appear to increase coagulation or VTE risk. The reason for the differences between progesterone and progestins in terms of VTE risk are unclear. However, they may be due to very low progesterone levels and relatively weak progestogenic effects produced by oral progesterone. In contrast to oral progesterone, non-oral progesterone—which can achieve much higher progesterone levels—has not been assessed in terms of VTE risk.
Overdose
Progesterone is likely to be relatively safe in overdose. Levels of progesterone during pregnancy are up to 100-fold higher than during normal menstrual cycling, although levels increase gradually over the course of pregnancy. Oral dosages of progesterone of as high as 3,600 mg/day have been assessed in clinical trials, with the main side effect being sedation. There is a case report of progesterone misuse with an oral dosage of 6,400 mg per day. Administration of as much as 500 mg progesterone by intravenous infusion in humans was uneventful in terms of toxicity, but did induce deep sleep, though the individuals were still able to be awakened with sufficient stimulation.
Interactions
There are several notable drug interactions with progesterone. Certain selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, and sertraline may increase the GABAA receptor-related central depressant effects of progesterone by enhancing its conversion into 5α-dihydroprogesterone and allopregnanolone via activation of 3α-HSD. Progesterone potentiates the sedative effects of benzodiazepines and alcohol. Notably, there is a case report of progesterone abuse alone with very high doses. 5α-Reductase inhibitors such as finasteride and dutasteride inhibit the conversion of progesterone into the inhibitory neurosteroid allopregnanolone, and for this reason, may have the potential to reduce the sedative and related effects of progesterone.Progesterone is a weak but significant agonist of the pregnane X receptor (PXR), and has been found to induce several hepatic cytochrome P450 enzymes, such as CYP3A4, especially when concentrations are high, such as with pregnancy range levels. As such, progesterone may have the potential to accelerate the metabolism of various medications.
Pharmacology
Pharmacodynamics
Progesterone is a progestogen, or an agonist of the nuclear progesterone receptors (PRs), the PR-A, PR-B, and PR-C. In addition, progesterone is an agonist of the membrane progesterone receptors (mPRs), including the mPRα, mPRβ, mPRγ, mPRδ, and mPRϵ. Aside from the PRs and mPRs, progesterone is a potent antimineralocorticoid, or antagonist of the mineralocorticoid receptor, the biological target of the mineralocorticoid aldosterone. In addition to its activity as a steroid hormone, progesterone is a neurosteroid. Among other neurosteroid activities, and via its active metabolites allopregnanolone and pregnanolone, progesterone is a potent positive allosteric modulator of the GABAA receptor, the major signaling receptor of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).The PRs are expressed widely throughout the body, including in the uterus, cervix, vagina, fallopian tubes, breasts, fat, skin, pituitary gland, hypothalamus, and in other areas of the brain. In accordance, progesterone has numerous effects throughout the body. Among other effects, progesterone produces changes in the female reproductive system, the breasts, and the brain. Progesterone has functional antiestrogenic effects due to its progestogenic activity, including in the uterus, cervix, and vagina. The effects of progesterone may influence health in both positive and negative ways. In addition to the aforementioned effects, progesterone has antigonadotropic effects due to its progestogenic activity, and can inhibit ovulation and suppress gonadal sex hormone production.The activities of progesterone besides those mediated by the PRs and mPRs are also of significance. Progesterone lowers blood pressure and reduces water and salt retention among other effects via its antimineralocorticoid activity. In addition, progesterone can produce sedative, hypnotic, anxiolytic, euphoric, cognitive-, memory-, and motor-impairing, anticonvulsant, and even anesthetic effects via formation of sufficiently high concentrations of its neurosteroid metabolites and consequent GABAA receptor potentiation in the brain.There are differences between progesterone and progestins, such as medroxyprogesterone acetate and norethisterone, with implications for pharmacodynamics and pharmacokinetics, as well as for efficacy, tolerability, and safety.
Pharmacokinetics
The pharmacokinetics of progesterone are dependent on its route of administration. The medications is approved in the form of oil-filled capsules containing micronized progesterone for oral administration, termed oral micronized progesterone or OMP. It is also available in the form of vaginal or rectal suppositories or pessaries, topical creams and gels, oil solutions for intramuscular injection, and aqueous solutions for subcutaneous injection.Routes of administration that progesterone has been used by include oral, intranasal, transdermal/topical, vaginal, rectal, intramuscular, subcutaneous, and intravenous injection. Vaginal progesterone is available in the form of progesterone capsules, tablets or inserts, gels, suppositories or pessaries, and rings.
Chemistry
Progesterone is a naturally occurring pregnane steroid and is also known as pregn-4-ene-3,20-dione. It has a double bond (4-ene) between the C4 and C5 positions and two ketone groups (3,20-dione), one at the C3 position and the other at the C20 position. Due to its pregnane core and C4(5) double bond, progesterone is often abbreviated as P4. It is contrasted with pregnenolone, which has a C5(6) double bond and is often abbreviated as P5.
Derivatives
A large number of progestins, or synthetic progestogens, have been derived from progesterone. They can be categorized into several structural groups, including derivatives of retroprogesterone, 17α-hydroxyprogesterone, 17α-methylprogesterone, and 19-norprogesterone, with a respective example from each group including dydrogesterone, medroxyprogesterone acetate, medrogestone, and promegestone. The progesterone ethers quingestrone (progesterone 3-cyclopentyl enol ether) and progesterone 3-acetyl enol ether are among the only examples that do not belong to any of these groups. Another major group of progestins, the 19-nortestosterone derivatives, exemplified by norethisterone (norethindrone) and lev |
Progesterone (medication) | onorgestrel, are not derived from progesterone but rather from testosterone.A variety of synthetic inhibitory neurosteroids have been derived from progesterone and its neurosteroid metabolites, allopregnanolone and pregnanolone. Examples include alfadolone, alfaxolone, ganaxolone, hydroxydione, minaxolone, and renanolone. In addition, C3 and C20 conjugates of progesterone, such as progesterone carboxymethyloxime (progesterone 3-(O-carboxymethyl)oxime; P4-3-CMO), P1-185 (progesterone 3-O-(L-valine)-E-oxime), EIDD-1723 (progesterone 20E-[O-[(phosphonooxy)methyl]oxime] sodium salt), EIDD-036 (progesterone 20-oxime; P4-20-O), and VOLT-02 (chemical structure unreleased), have been developed as water-soluble prodrugs of progesterone and its neurosteroid metabolites.
Synthesis
Chemical syntheses of progesterone have been published.
History
Discovery and synthesis
The hormonal action of progesterone was discovered in 1929. Pure crystalline progesterone was isolated in 1934 and its chemical structure was determined. Later that year, chemical synthesis of progesterone was accomplished. Shortly following its chemical synthesis, progesterone began being tested clinically in women.
Injections and implants
In 1933 or 1934, Schering introduced progesterone in oil solution as a medication by intramuscular injection under the brand name Proluton. This was the first pharmaceutical formulation of progesterone to be marketed for medical use. It was initially a corpus luteum extract, becoming pure synthesized progesterone only subsequently. A clinical study of the formulation was published in 1933. Multiple formulations of progesterone in oil solution for intramuscular injection, under the brand names Proluton, Progestin, and Gestone, were available by 1936. A parenteral route was used because oral progesterone had very low activity and was thought to be inactive. Progesterone was initially very expensive due to the large doses required. However, with the start of steroid manufacturing from diosgenin in the 1940s, costs greatly decreased.Subcutaneous pellet implants of progesterone were first studied in women in the late 1930s. They were the first long-acting progestogen formulation. Pellets were reported to be extruded out of the skin within a few weeks at high rates, even when implanted beneath the deep fascia, and also produced frequent inflammatory reactions at the site of implantation. In addition, they were absorbed too slowly and achieved unsatisfactorily low progesterone levels. Consequently, they were soon abandoned, in favor of other preparations such as aqueous suspensions. However, subcutaneous pellet implants of progesterone were later studied as a form of birth control in women in the 1980s and early 1990s, though no preparations were ultimately marketed.Aqueous suspensions of progesterone crystals for intramuscular injection were first described in 1944. These preparations were on the market in the 1950s under a variety of brand names including Flavolutan, Luteosan, Lutocyclin M, and Lutren, among others. Aqueous suspensions of steroids were developed because they showed much longer durations than intramuscular injection of steroids in oil solution. However, local injection site reactions, which do not occur with oil solutions, have limited the clinical use of aqueous suspensions of progesterone and other steroids. Today, a preparation with the brand name Agolutin Depot remains on the market in the Czech Republic and Slovakia. A combined preparation of progesterone, estradiol benzoate, and lidocaine remains available with the brand name Clinomin Forte in Paraguay as well. In addition to aqueous suspensions, water-in-oil emulsions of steroids were studied by 1949, and long-acting emulsions of progesterone were introduced for use by intramuscular injection under the brand names Progestin and Di-Pro-Emulsion (with estradiol benzoate) by the 1950s. Due to lack of standardization of crystal sizes, crystalline suspensions of steroids had marked variations in effect. Emulsions were said to be even more unreliable.Macrocrystalline aqueous suspensions of progesterone as well as microspheres of progesterone were investigated as potential progestogen-only injectable contraceptives and combined injectable contraceptives (with estradiol) by the late 1980s and early 1990s but were never marketed.Aqueous solutions of water-insoluble steroids were first developed via association with colloid solubility enhancers in the 1940s. An aqueous solution of progesterone for use by intravenous injection was marketed by Schering AG under the brand name Primolut Intravenous by 1962. One of its intended uses was the treatment of threatened abortion, in which rapid-acting effect was desirable. An aqueous solution of progesterone complexed with cyclodextrin to increase its water solubility was introduced for use by once-daily subcutaneous injection in Europe under the brand name Prolutex in the mid-2010s.In the 1950s, long-acting parenteral progestins such as hydroxyprogesterone caproate, medroxyprogesterone acetate, and norethisterone enanthate were developed and introduced for use by intramuscular injection. They lacked the need for frequent injections and the injection site reactions associated with progesterone by intramuscular injection and soon supplanted progesterone for parenteral therapy in most cases.
Oral and sublingual
The first study of oral progesterone in humans was published in 1949. It found that oral progesterone produced significant progestational effects in the endometrium in women. Prior to this study, animal research had suggested that oral progesterone was inactive, and for this reason, oral progesterone had never been evaluated in humans. A variety of other early studies of oral progesterone in humans were also published in the 1950s and 1960s. These studies generally reported oral progesterone to be only very weakly active. Oral non-micronized progesterone was introduced as a pharmaceutical medication around 1953, for instance as Cyclogesterin (1 mg estrogenic substances and 30 mg progesterone tablets) for menstrual disturbances by Upjohn, though it saw limited use. Another preparation, which contained progesterone alone, was Synderone (trademark registered by Chemical Specialties in 1952).Sublingual progesterone in women was first studied in 1944 by Robert Greenblatt. Buccal progesterone tablets were marketed by Schering under the brand name Proluton Buccal Tablets by 1949. Sublingual progesterone tablets were marketed under the brand names Progesterone Lingusorbs and Progesterone Membrettes by 1951. A sublingual tablet formulation of progesterone has been approved under the brand name Luteina in Poland and Ukraine and remains marketed today.Progesterone was the first progestogen that was found to inhibit ovulation, both in animals and in women. Injections of progesterone were first shown to inhibit ovulation in animals between 1937 and 1939. Inhibition of fertilization by administration of progesterone during the luteal phase was also demonstrated in animals between 1947 and 1949. Ovulation inhibition by progesterone in animals was subsequently re-confirmed and expanded on by Gregory Pincus and colleagues in 1953 and 1954. Findings on inhibition of ovulation by progesterone in women were first presented at the Fifth International Conference on Planned Parenthood in Tokyo, Japan in October 1955. Three different research groups presented their findings on this topic at the conference. They included Pincus (in conjunction with John Rock, who did not attend the conference); a nine-member Japanese group led by Masaomi Ishikawa; and the two-member team of Abraham Stone and Herbert Kupperman. The conference marked the beginning of a new era in the history of birth control. The results were subsequently published in scientific journals in 1956 in the case of Pincus and in 1957 in the case of Ishikawa and colleagues. Rock and Pincus also subsequently described findings from 1952 that "pseudopregnancy" therapy with a combination of high doses of diethylstilbestrol and oral progesterone prevented ovulation and pregnancy in women.Unfortunately, the use of oral progesterone as a hormonal contraceptive was plagued by problems. These included the large and by extension expensive doses required, incomplete inhibition of ovulation even at high doses, and a frequent incidence of breakthrough bleeding. At the 1955 Tokyo conference, Pincus had also presented the first findings of ovulation inhibition by oral progestins in animals, specifically 19-nortestosterone derivatives like noretynodrel and norethisterone. These progestins were far more potent than progesterone, requiring much smaller doses orally. By December 1955, inhibition of ovulation by oral noretynodrel and norethisterone had been demonstrated in women. These findings as well as results in animals were published in 1956. Noretynodrel and norethisterone did not show the problems associated with oral progesterone—in the studies, they fully inhibited ovulation and did not produce menstruation-related side effects. Consequently, oral progesterone was abandoned as a hormonal contraceptive in women. The first birth control pills to be introduced were a noretynodrel-containing product in 1957 and a norethisterone-containing product in 1963, followed by numerous others containing a diversity of progestins. Progesterone itself has never been introduced for use in birth control pills.More modern clinical studies of oral progesterone demonstrating elevated levels of progesterone and end-organ responses in women, specifically progestational endometrial changes, were published between 1980 and 1983. Up to this point, many clinicians and researchers apparently still thought that oral progesterone was inactive. It was not until almost half a century after the introduction of progesterone in medicine that a reasonably effective oral formulation of progesterone was marketed. Micronization of progesterone and suspension in oil-filled capsules, which allowed progesterone to be absorbed several-fold more efficiently by the oral route, was first studied in the late 1970s and described in the literature in 1982. This formulation, known as oral micronized progesterone (OMP), was then introduced for medical use under the brand name Utrogestan in France in 1982. Subsequently, oral micronized progesterone was introduced under the brand name Prometrium in the United States in 1998. By 1999, oral micronized progesterone had been marketed in more than 35 countries. In 2019, the first combination of oral estradiol and progesterone was introduced under the brand name Bijuva in the United States.A sustained-release (SR) formulation of oral micronized progesterone, also known as "oral natural micronized progesterone sustained release" or "oral NMP SR", was marketed in India in 2012 under the brand name Gestofit SR. Many additional brand names followed. The preparation was originally developed in 1986 by a compounding pharmacy called Madison Pharmacy Associates in Madison, Wisconsin in the United States.
Vaginal, rectal, and uterine
Vaginal progesterone suppositories were first studied in women by Robert Greenblatt in 1954. Shortly thereafter, vaginal progesterone suppositories were introduced for medical use under the brand name Colprosterone in 1955. Rectal progesterone suppositories were first studied in men and women by Christian Hamburger in 1965. Vaginal and rectal progesterone suppositories were introduced for use under the brand name Cyclogest by 1976. Vaginal micronized progesterone gels and capsules were introduced for medical use under brand names such as Utrogestan and Crinone in the early 1990s. Progesterone was approved in the United States as a vaginal gel in 1997 and as a vaginal insert in 2007. A progesterone contraceptive vaginal ring known as Progering was first studied in women in 1985 and continued to be researched through the 1990s. It was approved for use as a contraceptive in lactating mothers in Latin America by 2004. A second progesterone vaginal ring known as Fertiring was developed as a progesterone supplement for use during assisted reproduction and was approved in Latin America by 2007.Development of a progesterone-containing intrauterine device (IUD) for contraception began in the 1960s. Incorporation of progesterone into IUDs was initially studied to help reduce the risk of IUD expulsion. However, while addition of progesterone to IUDs showed no benefit on expulsion rates, it was unexpectedly found to induce endometrial atrophy. This led in 1976 to the development and introduction of Progestasert, a progesterone-containing product and the first progestogen-containing IUD. Unfortunately, the product had various problems that limited its use. These included a short duration of efficacy of only one year, a high cost, a relatively high 2.9% failure rate, a lack of protection against ectopic pregnancy, and difficult and sometimes painful insertions that could necessitate use of a local anesthetic or analgesic. As a result of these issues, Progestasert never became widely used, and was discontinued in 2001. It was used mostly in the United States and France while it was marketed.
Transdermal and topical
A topical gel formulation of progesterone, for direct application to the breasts as a local therapy for breast disorders such as breast pain, was introduced under the brand name Progestogel in Europe by 1972. No transdermal formulations of progesterone for systemic use have been successfully marketed, in spite of efforts of pharmaceutical companies towards this goal. The low potency of transdermal progesterone has thus far precluded it as a possibility. Although no formulations of transdermal progesterone are approved for systemic use, transdermal progesterone is available in the form of creams and gels from custom compounding pharmacies in some countries, and is also available over-the-counter without a prescription in the United States. However, these preparations are unregulated and have not been adequately characterized, with low and unsubstantiated effectiveness.
Society and culture
Generic names
Progesterone is the generic name of the drug in English and its INN, USAN, USP, BAN, DCIT, and JAN, while progestérone is its name in French and its DCF. It is also referred to as progesteronum in Latin, progesterona in Spanish and Portuguese, and progesteron in German.
Brand names
Progesterone is marketed under a large number of brand names throughout the world. Examples of major brand names under which progesterone has been marketed include Crinone, Crinone 8%, Cyclogest, Endogest, Endometrin, Estima, Geslutin, Gesterol, Gestone, Luteina, Luteinol, Lutigest, Lutinus, Microgest, Progeffik, Progelan, Progendo, Progering, Progest, Progestaject, Progestan, Progesterone, Progestin, Progestogel, Prolutex, Proluton, Prometrium, Prontogest, Strone, Susten, Utrogest, and Utrogestan.
Availability
Progesterone is widely available in countries throughout the world in a variety of formulations. Progesterone in the form of oral capsules; vaginal capsules, tablets/inserts, and gels; and intramuscular oil have widespread availability. The following formulations/routes of progesterone have selective or more limited availability:
A tablet of micronized progesterone which is marketed under the brand name Luteina is indicated for sublingual administration in addition to vaginal administration and is available in Poland and Ukraine.
A progesterone suppository which is marketed under the brand name Cyclogest is indicated for rectal administration in addition to vaginal administration and is available in Cyprus, Hong Kong, India, Malaysia, Malta, Oman, Singapore, South Africa, Thailand, Tunisia, Turkey, the United Kingdom, and Vietnam.
An aqueous solution of progesterone complexed with β-cyclodextrin for subcutaneous injection is marketed under the brand name Prolutex in the Czech Republic, Hungary, Italy, Poland, Portugal, Slovakia, Spain, and Switzerland.
A non-systemic topical gel formulation of progesterone for local application to the breasts to treat breast pain is marketed under the brand name Progestogel and is available in Belgium, Bulgaria, Colombia, Ecuador, France, Georgia, Germany, Hong Kong, Lebanon, Peru, Romania, Russia, Serbia, Switzerland, Tunisia, Venezuela, and Vietnam. It was also formerly available in Italy, Portugal, and Spain, but was discontinued in these countries.
A progesterone intrauterine device was previously marketed under the brand name Progestasert and was available in Canada, France, the United States, and possibly other countries, but was discontinued.
Progesterone vaginal rings are marketed under the brand names Fertiring and Progering and are available in Chile, Ecuador, and Peru.
A sustained-release tablet formulation of oral micronized progesterone (also known as "oral natural micronized progesterone sustained release" or "oral NMP SR") is marketed in India under the brand names Dubagest SR, Gestofit SR, and Susten SR, among many others.In addition to single-drug formulations, the following progesterone combination formulations are or have been marketed, albeit with limited availability:
A combination pack of progesterone capsules for oral use and estradiol gel for transdermal use is marketed under the brand name Estrogel Propak in Canada.
A combination pack of progesterone capsules and estradiol tablets for oral use is marketed in an under the brand name Duogestan in Belgium.
Progesterone and estradiol in an aqueous suspension for use by intramuscular injection is marketed under the brand name Cristerona FP in Argentina.
Progesterone and estradiol in microspheres in an oil solution for use by intramuscular injection is marketed under the brand name Juvenum in Mexico.
Progesterone and estradiol benzoate in an oil solution for use by intramuscular injection is marketed under the brand names Duogynon, Duoton Fort T P, Emmenovis, Gestrygen, Lutofolone, Menovis, Mestrolar, Metrigen Fuerte, Nomestrol, Phenokinon-F, Prodiol, Pro-Estramon-S, Proger F, Progestediol, and Vermagest and is available in Belize, Egypt, El Salvador, Ethiopia, Guatemala, Honduras, Italy, Lebanon, Malaysia, Mexico, Nicaragua, Taiwan, Thailand, and Turkey.
Progesterone and estradiol hemisuccinate in an oil solution for use by intramuscular injection is marketed under the brand name Hosterona in Argentina.
Progesterone and estrone for use by intramuscular injection is marketed under the brand name Synergon in Monaco.
United States
As of November 2016, progesterone is available in the United States in the following formulations:
Oral: Capsules: Prometrium (100 mg, 200 mg, 300 mg)
Vaginal: Tablets: Endometrin (100 mg); Gels: Crinone (4%, 8%)
Intramuscular injection: Oil: Progesterone (50 mg/mL)A 25 mg/mL concentration of progesterone oil for intramuscular injection and a 38 mg/device progesterone intrauterine device (Progestasert) have been discontinued.An oral combination formulation of micronized progesterone and estradiol in oil-filled capsules (brand name Bijuva) is marketed in the United States for the treatment of menopausal symptoms and endometrial hyperplasia.Progesterone is also available in unregulated custom preparations from compounding pharmacies in the United States. In addition, transdermal progesterone is available over-the-counter in the United States, although the clinical efficacy of transdermal progesterone is controversial.
Research
Progesterone was studied as a progestogen-only injectable contraceptive, but was never marketed. Combinations of estradiol and progesterone as a macrocrystalline aqueous suspension and as an aqueous suspension of microspheres have been studied as once-a-month combined injectable contraceptives, but were likewise never marketed.Progesterone has been assessed for the suppression of sex drive and spermatogenesis in men. In one study, 100 mg rectal suppositories of progesterone given five times per day for 9 days resulted in progesterone levels of 5.5 to 29 ng/mL and suppressed circulating testosterone and growth hormone levels by about 50% in men, but did not affect libido or erectile potency in this short treatment period. In other studies, 50 mg/day progesterone by intramuscular injection for 10 weeks in men produced azoospermia, decreased testicular size, markedly suppressed libido and erectile potency, and resulted in minimal semen volume upon ejaculation.An oil and water nanoemulsion of progesterone (particles of <1 mm in diameter) using micellar nanoparticle technology for transdermal administration known as Progestsorb NE was under development by Novavax for use in menopausal hormone therapy in the 2000s. However, development was discontinued in 2007 and the formulation was never marketed.
See also
Estradiol/progesterone
Estradiol benzoate/progesterone
Estradiol hemisuccinate/progesterone
References
== Further reading == |
Didanosine | Didanosine (ddI, DDI), sold under the brand name Videx, is a medication used to treat HIV/AIDS. It is used in combination with other medications as part of highly active antiretroviral therapy (HAART). It is of the reverse-transcriptase inhibitor class.
Didanosine was first described in 1975 and approved for use in the United States in 1991.
Adverse effects
The most common adverse events with didanosine are diarrhea, nausea, vomiting, abdominal pain, fever, headache, and rash. Peripheral neuropathy occurred in 21-26% of participants in key didanosine trials.Pancreatitis is rarely observed but has caused occasional fatalities, and has black box warning status. Other reported serious adverse events are retinal changes, optic neuritis and alterations of liver functions. The risk of some of these serious adverse events is increased by drinking alcohol.
In February 2010, the United States Food and Drug Administration issued a statement that patients using didanosine (Videx) are at risk for a rare but potentially fatal liver disorder, non-cirrhotic portal hypertension.
Drug interactions
A significant interaction has also been recorded with allopurinol, and administration of these drugs together should be avoided.
Reduction in indinavir and delavirdine plasma levels have been shown to occur when administered simultaneously with didanosine; these drugs should be administered at different times.
Ketoconazole, itraconazole, ciprofloxacin should be administered at a different time from didanosine due to interactions with the buffering agent.
Administration with drugs with overlapping toxicity, such as zalcitabine and stavudine, is not recommended.
Alcohol can exacerbate didanosines toxicity, and avoiding drinking alcohol while taking didanosine is recommended.
Resistance
Drug resistance to didanosine does develop, though slower than to zidovudine (ZDV). The most common mutation observed in vivo is L74V in the viral pol gene, which confers cross-resistance to zalcitabine; other mutations observed include K65R and M184V .
Mechanism of action
Didanosine (ddI) is a nucleoside analogue of adenosine. It differs from other nucleoside analogues, because it does not have any of the regular bases, instead it has hypoxanthine attached to the sugar ring. Within the cell, ddI is phosphorylated to the active metabolite of dideoxyadenosine triphosphate, ddATP, by cellular enzymes. Like other anti-HIV nucleoside analogs, it acts as a chain terminator by incorporation and inhibits viral reverse transcriptase by competing with natural dATP.
Pharmacokinetics
Oral absorption of didanosine is fairly low (42%) but rapid. Food substantially reduces didanosine bioavailability, and the drug should be administered on an empty stomach. The half-life in plasma is only 1.5 hours, but in the intracellular environment more than 12 hours. An enteric-coated formulation is now marketed as well. Elimination is predominantly renal; the kidneys actively secrete didanosine, the amount being 20% of the oral dose.
History
The related pro-drug of didanosine, 2′,3′-dideoxyadenosine (ddA), was initially synthesized by Morris J. Robins (professor of Organic Chemistry at Brigham Young University) and R.K. Robins in 1964. Subsequently, Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan in the National Cancer Institute (NCI) found that ddA and ddI could inhibit HIV replication in the test tube and conducted initial clinical trials showing that didanosine had activity in patients infected with HIV. On behalf of the NCI, they were awarded patents on these activities. Since the NCI does not market products directly, the National Institutes of Health (NIH) awarded a ten-year exclusive license to Bristol-Myers Squibb Co. (BMS) to market and sell ddI as Videx tablets.
Didanosine became the second drug approved for the treatment of HIV infection in many other countries, including in the United States by the Food and Drug Administration (FDA) on October 9, 1991. Its FDA approval helped bring down the price of zidovudine (ZDV), the initial anti-HIV drug. [Source needed on pricing effect.]
Didanosine has weak acid stability and is easily damaged by stomach acid. Therefore, the original formula approved by the FDA used chewable tablets that included an antacid buffering compound to neutralize stomach acid. The chewable tablets were not only large and fragile, they also were foul-tasting and the buffering compound would cause diarrhea. Although the FDA had not approved the original formulation for once-a-day dosing it was possible for some people to take it that way.
At the end of its ten-year license, BMS re-formulated Videx as Videx EC and patented that, which reformulation the FDA approved in 2000. The new formulation is a smaller capsule containing coated microspheres instead of using a buffering compound. It is approved by the FDA for once-a-day dosing. Also at the end of that ten-year period, the NIH licensed didanosine to Barr Laboratories under a non-exclusive license, and didanosine became the first generic anti-HIV drug marketed in the United States.
One of the patents for ddI expired in the United States on August 29, 2006, but other patents extend beyond that time.
Sources
Further reading
External links
"Didanosine". Drug Information Portal. U.S. National Library of Medicine. |
Vorinostat | Vorinostat (rINN) also known as Suberoylanilide hydroxamic acid (suberoyl+anilide+hydroxamic acid abbreviated as SAHA) is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities.
Vorinostat is marketed under the name Zolinza ( zoh-LIN-zə) by Merck for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) when the disease persists, gets worse, or comes back during or after two systemic therapies. The compound was developed by Columbia University chemist Ronald Breslow and Memorial Sloan-Kettering researcher Paul Marks
Medical uses
Vorinostat was the first histone deacetylase inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of CTCL on October 6, 2006. It also failed to demonstrate efficacy in treating acute myeloid leukemia in a phase II study.
Mechanism of action
Vorinostat has been shown to bind to the active site of histone deacetylases and act as a chelator for zinc ions also found in the active site of histone deacetylases.
Vorinostats inhibition of histone deacetylases results in the accumulation of acetylated histones and acetylated proteins, including transcription factors crucial for the expression of genes needed to induce cell differentiation. It acts on class I, II and IV of histone deacetylase.
Clinical trials
Vorinostat has also been used to treat Sézary syndrome, another type of lymphoma closely related to CTCL.A recent study suggested that vorinostat also possesses some activity against recurrent glioblastoma multiforme, resulting in a median overall survival of 5.7 months (compared to 4–4.4 months in earlier studies). Further brain tumor trials are planned in which vorinostat will be combined with other drugs.
Including vorinostat in treatment of advanced non-small-cell lung carcinoma (NSCLC) showed improved response rates and increased median progression free survival and overall survival.It has given encouraging results in a phase II trial for myelodysplastic syndromes in combination with idarubicin and cytarabine.
Preclinical investigations
Vorinostat is being investigated as a potential HIV latency reversing agent (LRA) as part of an investigational therapeutic strategy known as "shock and kill." Vorinostat was shown to reactivate HIV in latently HIV-infected T cells, both in vitro and in vivo.Vorinostat also has shown some activity against the pathophysiological changes in α1-antitrypsin deficiency and cystic fibrosis.
Recent evidence also suggests vorinostat can be a therapeutic tool for Niemann-Pick type C1 (NPC1), a rare lysosomal lipid storage disease.Preclinical experiments by University of Alabama at Birmingham researchers suggest the cancer drugs vorinostat, belinostat and panobinostat might be repurposed to treat infections caused by human papillomavirus, or HPV.
See also
Trichostatin A
References
External links
Vorinostat bound to proteins in the PDB |
Sayyid | Sayyid (UK:, US: ; Arabic: سيد [ˈsæjjɪd]; Persian: [sejˈjed]; meaning sir, Lord, Master; Arabic plural: سادة sādah; feminine: سيدة sayyidah; Persian: [sejˈjede]) is an honorific title denoting people accepted as descendants of the Islamic prophet Muhammad through his grandsons, Hasan ibn Ali and Husayn ibn Ali,: 31 sons of Muhammads daughter Fatima and his cousin and son-in-law Ali (Ali ibn Abi Talib).: 149 While in the early islamic period the title Al-Sayyid was applied on all the members of the of banu hashim, the tribe of the Islamic Prophet Muhammad. But later on the title was made specific to those of Hasani and Hussaini descent, Primarily by the Fatimid Caliphs.
Female sayyids are given the titles sayyida, syeda, alawiyah or sharifa. In some regions of the Islamic world, such as in India, the descendants of Muhammad are given the title amīr or mīr, meaning "aristocrats", "commander", or "ruler". In Shia Islam the son of a non Sayyid father and a Sayyida mother claim the title Mirza, whereas in Sunni Islam a son of a non Sayyid father and a Sayyida mother can claim the title Sayyid or Sharif fulfilling special requirements.A few Arabic language experts state that it has its roots in the word al-asad الأسد, meaning "lion", probably because of the qualities of valour and leadership.: 158 : 265 The word is derived from the verb sāda, meaning to rule. The title seyyid/sayyid (pl. sâda as in sādat Quraysh or the chiefs of Quraysh tribe) does not mean descendant of the prophet, for it existed before Islam.Hans Wehr Dictionary of Modern Written Arabic defines seyyid as master, chief, sovereign, or lord. It also denotes someone respected and of a status. Sayyid is also a common first name. Prominent figures are: Sayed Darwish, Sayyid Qutb, Sayed Mekawy.
Although reliable statistics are unavailable, conservative estimates put the number of Sayyids in the tens of millions.In the Arab world, sayyid is the equivalent of the English word "liege lord" or "master" when referring to a descendant of Muhammad, as in Sayyid Ali Sultan. The word sidi (from the contracted form sayyidī, "my liege") is often used in Arabic.Another term with a very similar meaning is Sharīf.
History
The Sayyids are by definition a branch of Banu Hashim, which traces its lineage to Adnan, and therefore directly descends from Ishmael (Ismaeyl), and collaterally descends from his paternal half-brother Isaac (Ishaaq), the sons of Abraham (Ibrahim).
Banū Hāshim (Arabic: بنو هاشم) is the clan of Muhammad, whose great-grandfather was Hashim ibn Abd Manaf, for whom the clan is named. Members of this clan are referred to as Hashemites. Descendants of Muhammad usually carry the titles Sayyid, Syed, Hashmi, Sayed or Sharif, or the Ashraf clan (synonymous to Ahl al-Bayt). Today, two sovereign monarchs – Abdullah II of Jordan and Muhammad VI of Morocco – and the former royal family of Libya are also considered to be a part of Banu Hashim.
The Hashemites (Arabic: الهاشميون, Al-Hāshimīyūn; also House of Hashim) are the ruling royal family of Jordan. The House was also the royal family of Syria (1920), Hejaz (1916–1925) and Iraq (1921–1958). The family belongs to the Dhawu Awn, one of the branches of the Hasanid Sharifs of Mecca – also known as Hashemites – who ruled Mecca continuously from the 10th century until its conquest by the House of Saud in 1924. Their eponymous ancestor is Hashim ibn Abd Manaf, great-grandfather of Muhammad.
Traditionally, Islam has had a rich history of the veneration of relics, especially of those attributed to Muhammad. The most genuine prophetic relics are believed to be those housed in the Hirkai Serif Odasi (Chamber of the Holy Mantle) in Istanbuls Topkapı Palace.
Indication of descent
In the early period, other than general usage, the Arabs also allowed the terms Sayyid and Sharif to descendants from both Hasan ibn Ali and Husayn ibn Ali. However, in the modern era, the term Sharif (Sharifah for females) has been used to denote descendants from Hasan, and the term Sayyid (Sayyidah, Syeda for females) has been used to denote descendants from Husayn.Shia Sayyid scholars wear black turbans, while non-Sayyid Shia scholars wear other colors (most commonly white). Sunni Sayyids often use the last name Shah or Hashmi. The descendants of Ali and his other wives are called Alevi sayyid; they are titled Shah, Sain, Miya Fakir or Dewan. Those Sayyids who are Shia often include the following titles in their names to indicate the figure from whom they trace their descent:
Note: (For non-Arabic speakers) When transliterating Arabic words into English there are two approaches.
1. The user may transliterate the word letter for letter (e.g., "الزيدي" becomes "a-l-z-ai-d-i").
2. The user may transcribe the pronunciation of the word (e.g., "الزيدي" becomes "a-zz-ai-d-i"); in Arabic grammar, some consonants (n, r, s, sh, t and z) cancel the l (ل) from the word "the" al (ال) (see sun and moon letters). When the user sees the prefixes an, ar, as, ash, at, az, etc... this means the word is the transcription of the pronunciation.
An i, wi (Arabic), or i, vi (Persian) ending could perhaps be translated by the English suffixes -ite or -ian. The suffix transforms a personal name or place name into the name of a group of people connected by lineage or place of birth. Hence Ahmad al-Hassani could be translated as Ahmad, the descendant of Hassan, and Ahmad al-Manami as Ahmad from the city of Manama. For further explanation, see Arabic names.1Also, El-Husseini, Al-Husseini, Husseini, and Hussaini.
2Those who use the term Sayyid for all descendants of Ali ibn Abi Talib regard Allawis or Alavis as Sayyids. However, Allawis are not descendants of Muhammad, as they are descended from the children of Ali and the women he married after the death of Fatima, such as Umm ul-Banin (Fatima bint Hizam). Those who limit the term Sayyid to descendants of Muhammad through Fatima, Allawis/Alavis are the same how Sayyids.
Some Sayyids are Najeeb Al Tarfayn, meaning "Noble on both sides", which indicates that both of their parents are Sayyid.
Existence of descendants of Hasan al-Askari
The existence of any descendant of Hasan al Askari is disputed by many people. Some genealogies of Middle Eastern and Central Asian families (mostly from Persia), East Africa (mostly in Somalia and Ethiopia), Khorasan, Samarqand, and Bukhara show that Hasan al-Askari had a second son called Sayyid Ali Akbar, which indicates that al-Askari had children and substantiates the existence of Muhammad al Mahdi. Whether in fact al-Askari did have children is still disputed, perhaps because of the political conflicts between the followers of the Imamah and the leadership of the Abbasids and Ghulat Shiites who do not believe in Hasan al-Askaris Imamah. Another group of historians studying the pedigrees of some Central Asian saints shejere (genealogy trees) believe that the Twelfth Imam was not the only son of Hasan al-Askari, and that the Eleventh Imam had two sons: Sayyid Muhammad (i.e., the Shia Mahdi) and Sayyid Ali Akbar. According to the earliest reports as from official family tree documents and records, Imam Hasan al-Askari fathered seven children and was survived by six. The names of his biological children were: Imam Muhammad al-Mahdi, Musa, Ja’far, Ibrahim, Fatima, Ayesha, and ‘Ali, sometimes referred to as Akbar, Asghar or Abdullah.Sayyid ‘Ali Akbar bin Imam Hasan al-Askari is Sultan Saadat (Sodot) who died in Termez. His burial place is located in the main mausoleum Sultan Saodat memorial complex in Termez. According to other old genealogical sources Sayyid Ali was the second son of Sayyid Imam Muhammad al Askari who is considered the elder brother of imam Hasan al-AskariThese Central Asian notable sayyid families have historical genealogical manuscripts that are confirmed with seals by many Naqibs, Muftis, Imams, Kadi Kuzzats, A’lams, Khans, and Emirs of those times. One descendant of Sayyid Ali Akbar was Saint Ishan (Eshon) Imlo of Bukhara. Ishan Imlo is called "saint of the last time" in Bukhara, as it is believed that after him there were no more saints – Asian Muslims generally revere him as the last of the saints. According to the source, Ishan Imlo died in 1162 AH (1748–1749); his mausoleum (mazar) is in a cemetery in Bukhara. Notable descendants of Sayyid Ali Akbar are Sufi saints like Bahauddin Naqshband, descendant after eleven generations; Khwaja Khawand Mahmud known as Hazrat Ishaan, descendant after eighteen generations; the two brothers Sayyid ul Sadaat Sayyid Mir Jan and Sayyid ul Sadaat Mir Sayyid Mahmud Agha, maternal descendants of Hasan al Askari; qadi Qozi Sayyid Bahodirxon; and Sufi saints Tajuddin Muhammad Badruddin and Pir Baba.
In her book Pain and Grace: A Study of Two Mystical Writers of Eighteenth-Century Muslim India, Dr. Annemarie Schimmel writes:
Khwaja Mir Dards family, like many nobles, from Bukhara; led their pedigree back to Bahauddin Naqshband, after whom the Naqshbandi order is named, and who was a descendant, in the 11th generation of the 11th Shia imam al-Hasan al-Askari.
Although Shiite historians generally reject the claim that Hasan al-Askari fathered children other than Muhammad al-Mahdi, Bab Mawlid Abi Muhammad al-Hasan writes, in the Shiite hadith book Usul al-Kafi:
When the caliph got news of Hasan Askaris illness, he instructed his agents to keep a constant watch over the house of the Imam...he sent some of these midwives to examine the slave girls of the Imam to determine if they were pregnant. If a woman was found pregnant she was detained and imprisoned....
Africa
Most of the Muslim historians claimed that three of the descendants of Ali ibn Abu Talib migrated into Somalia and Ethiopia. The two Ashrafs migrated to Ethiopia and the remaining sayyid settled in Somalia.
Ethiopia
Most of the Muslim historians and geologists claimed that one of the Ashrafs called Hajji Ali migrated into southern part of Ethiopia. After he migrated there, he got a baby and named him Gen-Silte. His children then called by their fathers name "Silte". according to the Silte tribesmen, the father of Hajji Aliyye(Hajji Ali) was Hajji Omar bin Osman, who was an Arab. He used to live in Hijaz, now part of Saudi Arabia. He migrated to Harar first, then settled in the southern part of Omnan which is now a part of Silte.
Middle East
Men belonging to the Sayyid families or tribes in the Arab world used to wear white or ivory coloured daggers like jambiyas, khanjars or shibriyas to demarcate their nobility amongst other Arab men, although this custom has been restricted due to the local laws of the variously divided Arab countries.
Iraq
The Sayyid families in Iraq are so numerous that there are books written especially to list the families and connect their trees. Some of these families are: the Alyassiri, Al Aqeeqi, Al-Nasrullah, Al-Wahab, Al-Hashimi,Al-Barznji, Al-Quraishi, Al-Marashi, Al-Witry, Al-Obaidi, Al-Samarai, Al-Zaidi, Al-Aaraji, Al-Baka, Al-Hasani, Al-Hussaini, Al-Shahristani, Al-Qazwini Al-Qadri, Tabatabaei, Al- Alawi, Al-Ghawalib (Al-Ghalibi), Al-Musawi, Al-Awadi (not to be confused with the Al-Awadhi Huwala family), Al-Gharawi, Al-Sabzewari, Al-Shubber, Al-Hayali, Al-Kamaludeen and many others.
Iran
Sayyids (in Persian: سید Seyyed) are found in vast numbers in Iran. The Chief of "National Organization for Civil Registration" of Iran declared that more than 6 million of Iranians are Sayyid. The majority of Sayyids migrated to Iran from Arab lands predominantly in the 15th to 17th centuries during the Safavid era. The Safavids transformed the religious landscape of Iran by imposing Twelver Shiism on the populace. Since most of the population embraced Sunni Islam, and an educated version of Shiism was scarce in Iran at the time, Ismail imported a new group of Shia Ulama who predominantly were Sayyids from traditional Shiite centers of the Arabic-speaking lands, such as Jabal Amel (of southern Lebanon), Syria, Bahrain, and southern Iraq in order to create a state clergy. The Safavids offered them land and money in return for loyalty. These scholars taught Twelver Shiism, made it accessible to the population, and energetically encouraged conversion to Shiism.During the reign of Shah Abbas the Great, the Safavids also imported to Iran more Arab Shias, predominantly Sayyids, built religious institutions for them, including many Madrasas (religious schools), and successfully persuaded them to participate in the government, which they had shunned in the past (following the Hidden imam doctrine).Common Sayyid family surnames in Iran are Husseini, Mousavi, Kazemi, Razavi, Eshtehardian, Tabatabaei, Hashemi, Hassani, Jafari, Emami, Ahmadi, Zaidi, Imamzadeh, Sherazi, Kermani (kirmani), Shahidi, and Mahdavi.
Bahrain
In Bahrain Sayyids are used to refer to great grand childrens of the Prophet Muhammed.Sayyids are funded every where and in vast populations although number are contradicted.Sayyids started living in Bahrain since the beging of the 8th century.The Bahrainis spurted, Imam Ali in his wars in the Camel, Siffin and Nahrawan, and several Bahraini men emerged from the leaders of the Commander of the Faithful including the companion Zayd ibn Suhan al-Abdi who was killed in the Battle of the Camel when he was fighting alongside the Commander of Imam Ali. And the companion Sasaa bin SohanAl Abdi who was the ambassador of the Commander of the Faithful to Mu`awiyah, and he and Mu`awiyah have many stories that historians have transmitted to us. Historians have called them this title because they agreed on a Thursday that they would die for the sake of the Commander of the Faithful. The tomb of Zayd ibn Suhan is still visited in Bahrain and is called by Bahrainis as Prince Zaid, as well as the tomb of the great companion Sasaa bin Sohan Al Abdi who is buried in Bahrain.
Oman
In Oman, Sayyid is used by members of the Al Said ruling royal family. The absolute ruler of the country retains the title Sultan with members of the royal family eligible for succession to the throne given the title Sheikh, these may also use the title Sayyid should they wish to, although as Sheikh supersedes this, it is not a widely used practice. Members of the extended family or members by marriage carry the title Sayyid or Sayyida for a female. Such titles in Oman are hereditary through paternal lineage or in some exceptional circumstances, such as an honorary title given by royal decree. Members of the Al Said family use the term Sayyid solely as a title and not as a means of indicating descent, as the Al Said royal family does not descend from Banu Hashim or from Imam Ali and instead descends from the Qahtanite Zahran tribe.
Yemen
In Yemen the Sayyids are more generally known as sadah; they are also referred to as Hashemites. In terms of religious practice they are Shia, Sunni, and Sufi. Sayyid families in Yemen include the Rassids, the Qasimids, the Mutawakkilites, the Hamideddins, some Al-Zaidi of Marib, Sanaa, and Sadah, the Ba Alawi sada families in Hadhramaut, Mufadhal of Sanaa, Al-Shammam of Sadah, the Sufyan of Juban, and the Al-Jaylani of Juban.
Libya
The Sayyids in Libya are Sunni, including the former royal family, which is originally Zaidi-Moroccan (also known as the Senussi family). The El-Barassa Family are Ashraf as claimed by the sons of Abdulsalam ben Meshish, a descendant of Hassan bin Ali bin Abi Talib.
South Asia
Although people in South Asia claim Hashemite descent, genealogy family trees are studied to authenticate claims. In 1901 the total number of Sayyids in British India was counted as 1,339,734.
History of South Asian Sayyids
Sayyids migrated many centuries ago from different parts of the Middle East and Central Asia (Turkestan) during the invasion of the Mongols, Ghaznavid dynasty, Delhi Sultanate, and Mughal Empire, encompassing a timespan of roughly until the late 19th century. Sayyids migrated to Sindh, Uch, Bihar Sharif, Sheikhpura, and Attock Khurd (Punjab) and settled there very early. Other early migrant Sayyids moved deep into the south to the Deccan sultanates located in the Deccan Plateau region in the time of the Bahmani Sultanate, and later Golkonda, Nizam Shahi of Ahmednagar, Bijapur, Bidar, and Berar. Several visited India as merchants or escaped from the Abbasid, Umayyad and Safavid. Their names appear in Indian history at the dissolution of the Mughal Empire, when the Sayyid brothers created and dethroned emperors at their will (1714–1720). The first Muslims appointed to the Council of India and the first appointed to the privy council were both Sayyids.
Afghanistan
In Afghanistan, Sayyids (Sadat) are recognized as an ethnic group.
On 13 March 2019, addressing the Sadat gathering at the presidential palace (Arg), President Ashraf Ghani said that he will issue a decree on the inclusion of Sadat ethnic group in new electronic national identity card (e-NIC).President Ashraf Ghani decreed mentioning Sadat tribe in the electronic national identity on 15 March 2019.Sayyids of the north are generally located in Balkh and Kunduz; while in the east they can be found in Nangarhar. While most are Sunni Muslims, some in the Bamiyan province are to Shia.
India
The total Sayyid population in India is 7,017,000, with the largest populations in Uttar Pradesh (1,493,000), Maharashtra (1,108,000), Karnataka (766,000), Andhra Pradesh (727,000), Rajasthan (497,000), Bihar (419,000), West Bengal (372,000), Madhya Pradesh (307,000), Gujarat (245,000), Tamil Nadu (206,000), and 25,000 in Jammu and Kashmir. Sayyids are also found in the north-eastern state of Assam, where they are locally also referred to as Dawans.In India, Sayyids of Hadramawt (who originated mainly from the Arabian Peninsula and the Persian Gulf) gained widespread fame. There is a big community of Sayyids settled in and around the Nanganallur region in Chennai that trace their ancestry directly to the Sayyids of Iraq.Traditional Sayyid families rarely marry outside their community, and emphasise marrying into Najeeb Altarfain (of Sayyid descent from both the mothers and fathers side) families. This insistence on endogamy has begun to decline among the more urbanized families, with an increase in exogamy with other groups such as the Shaikh and Mughals.Historically, the Sayyids of Uttar Pradesh were substantial landowners, often absentees, and this was especially the case with the Awadh taluqdars. In the urban townships, Sayyid families served as priests, teachers, and administrators with the British colonial authorities given the community a preference in recruitment. Though they account for less than 3% of Muslim population, they control a majority of economic resources. The community also has a very high literacy rate. The independence and partition of India in 1947 was traumatic for the community, with many families becoming divided and some moving to Pakistan. This was followed by the abolition of the zamindari system, where land was redistributed to those who till the land. Many Sayyids who remained on the land are now medium and small scale farmers, while in urban areas, there has been a shift towards modern occupations.The Sayyids of Punjab belong to the Hasani (descendants of Hasan), Husaini (descendants of Husayn), Zaidi (descendants of Zayd ibn Ali, grandson of Husayn), Rizvi, (descendants of Ali al-Ridha), and Naqvi and their sub-caste Bukhari (descendants of Ali al-Hadi).
North India
The earliest migration of Sayyids from Afghanistan to North India took place in 1032 when Gazi Saiyyed Salar Sahu (general and brother-in-law of Sultan Mahmud of Ghazni) and his son Ghazi Saiyyad Salar Masud established their military headquarters at Satrikh (16 km (9.9 mi) from Zaidpur) in the Barabanki district of Uttar Pradesh. They are considered to be the first Muslim settlers in North India. In 1033 Ghazi Saiyyad Salar Masud was killed at the battle of Bahraich, the location of his mazr. Ghazi Saiyyad Salar Masud had no children. His parental uncle Syed Maroofuddin Ghazi and his family lived in Tijara until 1857 before they migrated to Bhopal. Syed Ahmed Rizvi Kashmiri and Khan Bahadur Aga Syed Hussain were both Rizvi Sayyids through Aaqa Meer Sayyid Hussain Qomi Rizvi, whose sacred shrine is in the Zainageer Village of Sopore, Kashmir. Iraqi Sayyids or Iraqi biradri in Eastern Uttar Pradesh are descendants of Sayyid Masud Al Hussaini who was the direct descendant of Muhammads grandson Hussain ibn Ali and came to India from Iraq during the reign of Sultan Muhammad bin Tughlaq in 1330 A.D. He settled with his seven sons and forty champions in Ghazipur (U.P.) as some of them (i.e., Syed Abu Bakr in Nonahra, Ghazipur) converted to Sunni Islam in the reign of Sultan Ibrahim Lodhi around 1517. His Shia descendants are now known as Sayyids of Ghazipur.Sayyids of Syed nagli, or Said Nagli, or the Baquari Syeds had migrated from Termez (Present day Uzbekistan) during the Sultanate era. Sikandar Lodi was the ruler of Delhi when Mir Syed Mohammad al Hussain al Hussaini al Termezi Haji al Haramain came to India and settled at Syed Nagli. He was a Baquari Syed who drew his lineage from Muhammad al Baqir.
Perhaps the most important figure in the history of the Sayyid in Uttar Pradesh was Sayyid Basrullah Shustari, who moved from Mashad in Iran in 1549 and joined the court of the Mughal Emperor Akbar. Akbar appointed Shustari as his chief justice, who used his position to strengthen the status of the various Sayyid families. They were preferred in administrative posts and formed a privileged elite. When the Mughal Empire disintegrated, the Sayyid played an important role in the turbulent politics of the time. The new British colonial authorities that replaced the Mughals after the Battle of Buxar made a pragmatic decision to work with the various Sayyid jagirdars. Several Sayyid taluqdars in Awadh were substantial landowners under the British colonial regime, and many other Sayyid contributed to state administration. After the abolition of the zamindari system, many Sayyid zamindars (e.g. that of Ghazipur) had to leave their homes.
Uttar Pradesh
The ancestor of the Bārha Sayyids, Sayyid Abul Farah Al Hussaini Al Wasti, left his original home in Wasit, Iraq, with his twelve sons at the end of the 13th century and migrated to India, where he obtained four villages in Sirhind-Fategarh. By the 16th century Abul Farahs descendants had taken over Bārha villages in Muzaffarnagar.The Sayyeds of Abdullapur Meerut are descendants of great saint Jalaluddin Surkh-Posh Bukhari. They had a large Jagirdara consisting of 52 villages.Abdullapur named after Syed Mir Abdulla Naqvi Al Bukhari, he built Kot Fort of this place in the 16th century, it was his main residence. Bukhari of Abdullapur are fractionate into Kannauji Bukhari and Jalal Bukhari. Kannaujis are descendants of Jalaludin Haider through Syed Mehboob Alam Naqvi-ul Bukhari Al-Maroof Shah Jewna or Shah Jewna son of warrior and chief advisor of Sikandar Lodi. Famous writer Syed Qudrat Naqvi Al Bukhari was born here later migrated to Pakistan after partition, his famous books are Ghalib kaun hai, Asaas-i-Urdu, Ghalib-i-sad rang, Seerat-un-Nabi, Hindi-Urdu lughat, Mutala-i-Abdul Haq, Lisani maqalaat.The Sayyids of Bilgram are Hussaini Sayyids, who first migrated from Wasit, Iraq, in the 13th century. Their ancestor, Syed Mohammad Sughra |
Sayyid | , a Zaidi Sayyid of Iraq, arrived in India during the rule of Sultan Iltutmish. In 1217–18 the family conquered and settled in Bilgram.A notable Sufi that belonged to a Sayyid family was Syed Salar Masud, from whom many of the Sayyid families of Awadh claim their lineage. Sayyids of Salon (Raebareli), Jarwal (Bahraich), Kintoor (Barabanki), and Zaidpur (Barabanki) were well-known Taluqadars (feudal lords) of Awadh province.
Sadaat also found in Kannauj trace their lineage from Husayn through Ali al-Hadi, a branch of Naqvi Bukhari. Famous Pir Syed Mehboob Alam Naqvi-ul Bukhari Al-Maroof Shah Jewna son of great warrior Syed Sadaruddin Shah Kabeer Naqvi (saint and also chief advisor) of Sikandar Lodi was also born in Kannauj and spent 66yrs of his life in kannauj later moved to Shah Jeewna. Makhdoom Jahaniya Mosque is still present in Shikana,Kannauj. Nawab Siddiq Hasan Khan was also from Kannauj, he is a Bukhari Naqvi Sayyed converted from Shia Islam to Sunni Islam in the early 1800s.
Bihar
There are different families of syeds in Bihar who belong to direct descendent of Imam Hasan and Imam Hussain. Mostly there are Hussaini (Rizvi, Zaidi, Baqri) along with Hasani (Malik, Quadri or Geelani). Sadaat are settle in different part of bihar including shia and sunni sects. They are mostly migrated to bihar from Iraq and Iran.
Sufi Saint Sharafuddin Maneri belongs to Banu hashim family of Imam Taj Faqih Rh. In Bihar, Sayyids were landlords, judges, barristers, intellectuals, civil servant, clerics, teachers, businessmen and farmers. Sufi Saint and a worrior Malik Ibrahim Bayu who conquered Bihar during the time of tughlaq is one the most famous personality in bihar. Bihars first prime minister Mohammad Yunus Nobel prize nominee and Padma shri winner Syed Hassan (educationist), Political Scientist Abu Bakr Ahmad Haleem was the Pro-Vice Chancellor of Aligarh University and Karachi University, The great Abdul Bari (professor),Zaid Hamid Syed Zaid Zaman Hamid is a Pakistani far-right, Islamist political commentator and was included in 500 most influential muslims in world and Brigadier Malik Mokhtar Karim are few names from Malik Sadaat of bihar.
Zaidi Sadaat of Bihar are the descendants of Sufi saint Syed Ahmad Jajneri and Syed Mohammed Jajneri. Syed Ahmad Jajneri migrated to India from Baghdad during the reign of Muhammad of Ghor and later migrated to Bihar. He was the direct descendant of Zayd ibn Ali who was the grandson of Husayn ibn Ali and therefore his descendants are called Husseini(Zaidi)Sadaat. His descendants are mostly settled in Bihar Sharif, Munger, Sheikhpura and Jamui region of Bihar.
Most prominent personalities of Sadaat of Bihar were from Desna, Bihar. For Example Syed Mohammed Saeed Raza, Abdul Qavi Desnavi and Sulaiman Nadvi. Desnas library, established in 1892, had thousands of old Persian and Urdu manuscripts. After the partition of India, during uncertain times of mass emigration to Pakistan, the books were donated to Khuda Bakhsh Khan Library in Patna, where a Desna section was established to house these treasures. Other famous personalities of Bihari Syed were Syed Sultan Ahmed, Syed Hasan Imam and Sir Imam Ali.
Gujarat
In Gujarat, most of the Sayyid families are descended from individuals invited by the Muslim rulers of Gujarat to serve as advisers and administrators, and were granted jagirs. During the period of Sultan Mahmud Begada (1458–1511), the sultan provided land to three Sayyid brothers and a grant to settle there after the victory of Pavagadh Fort. In 1484 the sultan conquered the fort on 21 November 1484 and transferred his capital to Champaner, which he completely rebuilt at the foothills of the Pavagadh Fort and named it Muhammadabad. During Mughal rule in Gujarat (1570–1750), the Sayyid held the majority of the civil and ecclesiastical posts. For example, the Sayyids of Thasra, Kheda district, were invited to serve as administrators and judges by the Mughal Emperor, Aurangzeb, and were provided land grants to settle there. They also comprised a significant portion of the Mughal army, and many are still found in old Muslim garrison towns like Ahmedabad. Many of the early Sufi saints that came to Gujarat belonged to Sayyid families, most of which came from Central Asia, Iran, Yemen, Oman, Basra, and Bahrain.
South India
Kerala
Thangals, a social group in among the Muslims of Kerala (most whom follow the Shafii madhab), are roughly equivalent to the Sayyids. The thangal families are numerous in Kerala. Most members of the community practices endogamy and some are considered as saints. Thangal families have many gradations of status on social and economic scale. Influential of the thangals generally come from prominent business families. They usually exercise their influence through commerce and politics.
Tamil Nadu
There are a notable number of Sayyids in Tamil Nadu that mostly concentrate in the cities like Erwadi, Nagore, Madurai, and Kayalpattinam. Badusha Sulthan Syed Ibrahim Shaheed of Ervadi, a Hussaini descendant of Mohammed and a ruler of Madinah, travelled to South India in the middle of the 12th century. His descendants who live in Ervadi with the clan name Levvai are from a single forefather and are Sayyids. The heirs of Shahul Hamid Abdul Qadir badusha of Nagore who live there and are called with clan name of Sahib or Saab or Saabu are Sayyids. Kazi Syed Tajuddin the son of Mufti Jamaluddin al Maabari who founded the Kazimar Big Mosque in the 13th century the first mosque in Madurai is a Hussaini descendant of Mohammed and hence belong to Syed family. Until recently, his descendants (Syeds-Qazis-Huqdars) lived in the same Kazimar Street locality in the center of Madurai city for over seven centuries and managed the Kazimar Big Mosque constructed by their forefather. Syed Tajuddins younger son Kazi Alauddin lived in Kayalpattinam and his shrine is found there.
Genetic studies of Sayyids of the Indian sub-continent
The authors of the study, the Y chromosomes of self-identified Syeds from the Indian sub-continent are no less diverse than those non-Syeds from the same regions, suggested that Syed status, rather than being strictly patrilineal, may have been passed through other routes.The paper, "Y chromosomes of self-identified Syeds from the Indian subcontinent", by Elise M. S. Belle, Saima Shah, Tudor Parfitt, and Mark G. Thomas showed that "self-identified Syeds had no less genetic diversity than those non-Syeds from the same regions, suggesting that there is no biological basis to the belief that self-identified Syeds in this part of the world share a recent common ancestry. However, self-identified men belonging to the ‘Islamic honorific lineages’ (Syeds, Hashemites, Quraysh and Ansari) show a greater genetic affinity to Arab populations—despite the geographic distance – than do their neighbouring populations from South Asia.In Northern India, 29 per cent of the Shia Muslim belong to haplogroup J. There are 18 per cent belonging mainly to haplogroup J2 and another 11 per cent belong to haplogroup J1, which both represent Middle Eastern lineages. J1 is exclusively Near Eastern.
Southeast Asia
Most of the Alawi Sayyids who moved to Southeast Asia were descendants of Ali ibn Husayn Zayn al-Abidin, especially of Ba Alawi sada, many of which were descendants of migrants from Hadhramaut. Even though they are alleged descendants of Husayn, it is uncommon for the female Sayyids to be called Sayyidah; they are more commonly called Sharifah. Most of them live in Brunei, Indonesia, Malaysia, Singapore, Moro Province in Philippines, Pattani and Cambodia. Many of the royal families of this region such as the previous royal families of the Philippines (Sultanate of Sulu, Sultanate of Maguindanao, Confederation of Sultanates of Ranao), Singapore (Sultanate of Singapore), Malaysia (Sultanates of Johor and Perlis), Indonesia (Sultanates of Siak, Pontianak, Gowa, some Javanese Sultanates), and the existing royal family of Brunei (House of Bolkiah) are also Sayyids, especially of BaAlawi.Some common surnames of these Sayyids are al-Saqqaf, Shihab (or Shahab), al-Aidaroos, al-Habsyi (or al-Habshi), al-Kaff, al-Aththos, al-Haddad, al-Jufri (or al-Jifri), al-Muhdhar, al-Shaikh Abubakar, al-Qadri, al-Munawwar.
Genetic Y-DNA research
According to Islamic prophetic tradition, Muhammad was descended from Abraham through Ismail. Some researchers have suggested using Y chromosome genetic data from Sayyid groups and from Jewish and Samaritan sources to reconstruct genetic information about the historical Abraham.
Tesayyud
In the Ottoman Empire, tax breaks for "the People of the House" encouraged many people to buy certificates of descent or forge genealogies; the phenomenon of teseyyüd – falsely claiming noble ancestry – spread across ethnic, class, and religious boundaries. In the 17th century, an Ottoman bureaucrat estimated that there were 300,000 impostors. In 18th-century Anatolia, nearly all upper-class urban people claimed descent from Muhammad.
Prince Sayyid
Descendants of Hazrat Ishaan, who are known as Imams of Naqshbandi Sunni Islam and supreme leaders of the Naqshbandi Sufi Order are widely known to bear the title "Sardar Sayyid" or "Amir Sayyid", which means "Prince Sayyid" in English. The royal or princely attribute comes in on the occasion of their relationship to the Mughal Imperial (Amir) and Afghan Royal family (Sardar). The Imam of Naqshbandi Sunni Islam, who is known for bearing this title is customarily addressed as "His Serene Highness Prince Sayyid" Raphael Dakik, who is a member of the Afghan Royal Family and paternal and maternal descendant of Hazrat Ishaan from the family of Sayyid Mir Jan in the 12th generation.
Maternal descendance
According to Irans religious leader and the Deobandi creed—a creed especially followed by patriarchal Pashtun tribes—the status of being a Sayyid can only be attributed through patrilineal lineage. According to Shia opinions, children of a Sayyida mother and a non-Sayyid father are referred to as Mirza. The Persian notation "Mirza", which is a derivation of the word "Mirzada" (i.e., Son of a "Mir") has various meanings: one is a Sayyid leader of a Sayyid branch or community, simultaneously being a religious Islamic scholar. Thus, a Sayyid of patrilineal lineage, being the son of a Mir, can also be called "Mirza". This example substantiates the fact that there are different opinions concerning the transmission of the title Sayyid. Another historical opinion of Ottoman Naqib al Ashrafs expresses that children of maternal prophetical descent are called Sharif.: 131 However, in 1632 when an Ottoman court challenged a man wearing a Sayyids green turban, he established that he was a Sayyid on his mothers side, which was accepted by the court.: 130 In patriarchal societies, women usually have to assimilate themselves into their husbands status. However, this does not affect female descendants of Muhammad as it is seen as a sacred blood relation. Thus, the heraldic title can be given to an individual through his or hers mothers line in accordance to Ottoman Naqib al-Ashrafs. Even the Zaynabids, the descendants of Lady Zainab, the daughter of Ali ibn Abi Talib can also be titled Sayyid or Sharif, according to the Egyptian Al-Suyuti. In Tajikistan matrilineal descendants are honoured.It is to be added that the supervision over the family of Bahauddin Naqshband and his descendants has been passed on through the maternal line. Hazrat Ishaan was a maternal descendant of Bahauddin Naqshband and his successor Sayyid Mir Jan was in turn again a descendant of Hazrat Ishaan from his mothers side.This indicates the possibility of even being a Mir or Naqib ul Ashraf from the mothers side.The requisites of it are the following:
Being able to trace his lineage back to Prophet Muhammad as ancestor
Being a Pious Muslim
Receiving the blessings of previous Naqib ul Ashraf, Mir or Sayyid ul Sadaat
Total affiliation as an Alid, meaning a son of Ali Ibn Abi Talib, hence neglecting any other affiliations
Being learned in Quran and Sunnah
Being a knowledgeable practicing Sufi
Noble and well-mannered character
For a Mir especially, being qualified as a leaderThe above remuneration is in accordance with a Hadith of Prophet Muhammad in which he declares that a hypocrite is not to be addressed as a "Sayyid". Hence it is even problematic in a judicial point of view to call a patrilineal descendant of Ali Ibn Abi Talib a Sayyid, when he does not meet the above-mentioned criteria.
See also
Family tree of Muhammad
Kohen, a similar status in Judaism
Sharīf, another term with a very similar meaning
Notes
References
Sources
This article incorporates text from a publication now in the public domain: Chisholm, Hugh, ed. (1911). "Sayad". Encyclopædia Britannica (11th ed.). Cambridge University Press.
Van Arendonk, C.; Graham, W.A. (1960–2007). "Sharīf". In Bearman, P. J.; Bianquis, Th.; Bosworth, C. E.; van Donzel, E.; Heinrichs, W. P. (eds.). Encyclopaedia of Islam, Second Edition. |
Amikacin | Amikacin is an antibiotic medication used for a number of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections. It is also used for the treatment of multidrug-resistant tuberculosis. It is used by injection into a vein using an IV or into a muscle.Amikacin, like other aminoglycoside antibiotics, can cause hearing loss, balance problems, and kidney problems. Other side effects include paralysis, resulting in the inability to breathe. If used during pregnancy it may cause permanent deafness in the baby. Amikacin works by blocking the function of the bacterias 30S ribosomal subunit, making it unable to produce proteins.Amikacin was patented in 1971, and came into commercial use in 1976. It is on the World Health Organizations List of Essential Medicines. It is derived from kanamycin.
Medical uses
Amikacin is most often used for treating severe infections with multidrug-resistant, aerobic Gram-negative bacteria, especially Pseudomonas, Acinetobacter, Enterobacter, E. coli, Proteus, Klebsiella, and Serratia. The only Gram-positive bacteria that amikacin strongly affects are Staphylococcus and Nocardia. Amikacin can also be used to treat non-tubercular mycobacterial infections and tuberculosis (if caused by sensitive strains) when first-line drugs fail to control the infection. It is rarely used alone.It is often used in the following situations:
Bronchiectasis
Bone and joint infections
Granulocytopenia, when combined with ticarcillin, in people with cancer
Intra-abdominal infections (such as peritonitis) as an adjunct to other medicines, like clindamycin, metronidazole, piperacillin/tazobactam, or ampicillin/sulbactam
Meningitis:
for meningitis by E. coli, as an adjunct to imipenem
for meningitis caused by Pseudomonas, as an adjunct to meropenem
for meningitis caused by Acetobacter, as an adjunct to imipenem or colistin
for neonatal meningitis caused by Streptococcus agalactiae or Listeria monocytogenes, as an adjunct to ampicillin
for neonatal meningitis caused by Gram negative bacteria such as E. coli, as adjunct to a 3rd-generation cephalosporin
Mycobacterial infections, including as a second-line agent for active tuberculosis. It is also used for infections by Mycobacterium avium, M. abcessus, M. chelonae, and M. fortuitum.
Rhodococcus equi, which causes an infection resembling tuberculosis
Respiratory tract infections, including as an adjunct to beta-lactams or carbapenem for hospital-acquired pneumonia
Sepsis, including that in neonates, as an adjunct to beta-lactams or carbapenem
Skin and suture-site infections
Urinary tract infections that are caused by bacteria resistant to less toxic drugs (often by Enterobacteriaceae or P. aeruginosa)Amikacin may be combined with a beta-lactam antibiotic for empiric therapy for people with neutropenia and fever.
Available forms
Amikacin may be administered once or twice a day and is usually given by the intravenous or intramuscular route, though it can be given via nebulization. There is no oral form available, as amikacin is not absorbed orally. In people with kidney failure, dosage must be adjusted according to the creatinine clearance, usually by reducing the dosing frequency. In people with a CNS infection such as meningitis, amikacin can be given intrathecally (by direct injection into the spine) or intraventricularly (by injection into the ventricles of brain).An liposome inhalation suspension is also available and approved to treat Mycobacterium avium complex (MAC) in the United States. The application for Arikayce was withdrawn in the European Union because the Committee for Medicinal Products for Human Use (CHMP) was of the opinion that the benefits of Arikayce did not outweigh its risks.
Special populations
Amikacin should be used in smaller doses in the elderly, who often have age-related decreases in kidney function, and children, whose kidneys are not fully developed yet. It is considered pregnancy category D in both the United States and Australia, meaning they have a probability of harming the fetus. Around 16% of amikacin crosses the placenta; while the half-life of amikacin in the mother is 2 hours, it is 3.7 hours in the fetus. A pregnant woman taking amikacin with another aminoglycoside has a possibility of causing congenital deafness in her child. While it is known to cross the placenta, amikacin is only partially secreted in breast milk.In general, amikacin should be avoided in infants. Infants also tend to have a larger volume of distribution due to their higher concentration of extracellular fluid, where aminoglycosides reside.The elderly tend to have amikacin stay longer in their system; while the average clearance of amikacin in a 20-year-old is 6 L/hr, it is 3 L/hr in an 80-year-old.Clearance is even higher in people with cystic fibrosis.In people with muscular disorders such as myasthenia gravis or Parkinsons disease, amikacins paralytic effect on neuromuscular junctions can worsen muscle weakness.
Adverse effects
Side-effects of amikacin are similar to those of other aminoglycosides. Kidney damage and ototoxicity (which can lead to hearing loss) are the most important effects, occurring in 1–10% of users. The nephro- and ototoxicity are thought to be due to aminoglycosides tendency to accumulate in the kidneys and inner ear.
Amikacin can cause neurotoxicity if used at a higher dose or for longer than recommended. The resulting effects of neurotoxicity include vertigo, numbness, tingling of the skin (paresthesia), muscle twitching, and seizures. Its toxic effect on the 8th cranial nerve causes ototoxicity, resulting in loss of balance and, more commonly, hearing loss. Damage to the cochlea, caused by the forced apoptosis of the hair cells, leads to the loss of high-frequency hearing and happens before any clinical hearing loss can be detected. Damage to the ear vestibules, most likely by creating excessive oxidative free radicals. It does so in a time-dependent rather than dose-dependent manner, meaning that risk can be minimized by reducing the duration of use.Amikacin causes nephrotoxicity (damage to the kidneys), by acting on the proximal renal tubules. It easily ionizes to a cation and binds to the anionic sites of the epithelial cells of the proximal tubule as part of receptor-mediated pinocytosis. The concentration of amikacin in the renal cortex becomes ten times that of amikacin in the plasma; it then most likely interferes with the metabolism of phospholipids in the lysosomes, which causes lytic enzymes to leak into the cytoplasm. Nephrotoxicity results in increased serum creatinine, blood urea nitrogen, red blood cells, and white blood cells, as well as albuminuria (increased output of albumin in the urine), glycosuria (excretion of glucose into the urine), decreased urine specific gravity, and oliguria (decrease in overall urine output). It can also cause urinary casts to appear. The changes in renal tubular function also change the electrolyte levels and acid-base balance in the body, which can lead to hypokalemia and acidosis or alkalosis. Nephrotoxicity is more common in those with pre-existing hypokalemia, hypocalcemia, hypomagnesemia, acidosis, low glomerular filtration rate, diabetes mellitus, dehydration, fever, and sepsis, as well as those taking antiprostaglandins. The toxicity usually reverts once the antibiotic course has been completed, and can be avoided altogether by less frequent dosing (such as once every 24 hours rather than once every 8 hours).Amikacin can cause neuromuscular blockade (including acute muscular paralysis) and respiratory paralysis (including apnea).Rare side effects (occurring in fewer than 1% of users) include allergic reactions, skin rash, fever, headaches, tremor, nausea and vomiting, eosinophilia, arthralgia, anemia, hypotension, and hypomagnesemia. In intravitreous injections (where amikacin is injected into the eye), macular infarction can cause permanent vision loss.The amikacin liposome inhalation suspension prescribing information includes a boxed warning regarding the increased risk of respiratory conditions including hypersensitivity pneumonitis (inflamed lungs), bronchospasm (tightening of the airway), exacerbation of underlying lung disease and hemoptysis (spitting up blood) that have led to hospitalizations in some cases. Other common side effects in patients taking amikacin liposome inhalation suspension are dysphonia (difficulty speaking), cough, ototoxicity (damaged hearing), upper airway irritation, musculoskeletal pain, fatigue, diarrhea and nausea.
Contraindications
Amikacin should be avoided in those who are sensitive to any aminoglycoside, as they are cross-allergenic (that is, an allergy to one aminoglycoside also confers hypersensitivity to other aminoglycosides). It should also be avoided in those sensitive to sulfite (seen more among people with asthma), since most amikacin usually comes with sodium metabisulfite, which can cause an allergic reaction.In general, amikacin should not be used with or just before/after another drug that can cause neurotoxicity, ototoxicity, or nephrotoxicity. Such drugs include other aminoglycosides; the antiviral acyclovir; the antifungal amphotericin B; the antibiotics bacitracin, capreomycin, colistin, polymyxin B, and vancomycin; and cisplatin, which is used in chemotherapy.Amikacin should not be used with neuromuscular blocking agents, as they can increase muscle weakness and paralysis.
Interactions
Amikacin can be inactivated by other beta-lactams, though not to the extent as other aminoglycosides, and is still often used with penicillins (a type of beta-lactam) to create an additive effect against certain bacteria, and carbapenems, which can have a synergistic against some Gram-positive bacteria. Another group of beta-lactams, the cephalosporins, can increase the nephrotoxicity of aminoglycoside as well as randomly elevating creatinine levels. The antibiotics chloramphenicol, clindamycin, and tetracycline have been known to inactivate aminoglycosides in general by pharmacological antagonism.The effect of amikacin is increased when used with drugs derived from the botulinum toxin, anesthetics, neuromuscular blocking agents, or large doses of blood that contains citrate as an anticoagulant.Potent diuretics not only cause ototoxicity themselves, but they can also increase the concentration of amikacin in the serum and tissue, making the ototoxicity even more likely. Quinidine also increases levels of amikacin in the body. The NSAID indomethacin can increase serum aminoglycoside levels in premature infants. Contrast mediums such as ioversol increases the nephrotoxicity and otoxicity caused by amikacin.Amikacin can decrease the effect certain vaccines, such as the live BCG vaccine (used for tuberculosis), the cholera vaccine, and the live typhoid vaccine by acting as a pharmacological antagonist.
Pharmacology
Mechanism of action
Amikacin irreversibly binds to 16S rRNA and the RNA-binding S12 protein of the 30S subunit of prokaryotic ribosome and inhibits protein synthesis by changing the ribosomes shape so that it cannot read the mRNA codons correctly. It also interferes with the region that interacts with the wobble base of the tRNA anticodon. It works in a concentration-dependent manner, and has better action in an alkaline environment.At normal doses, amikacin-sensitive bacteria respond within 24–48 hours.
Resistance
Amikacin evades attacks by all antibiotic-inactivating enzymes that are responsible for antibiotic resistance in bacteria, except for aminoacetyltransferase and nucleotidyltransferase. This is accomplished by the L-hydroxyaminobuteroyl amide (L-HABA) moiety attached to N-1 (compare to kanamycin, which simply has a hydrogen), which blocks the access and decreases the affinity of aminoglycoside-inactivating enzymes. Amikacin ends up with only one site where these enzymes can attack, while gentamicin and tobramycin have six.Bacteria that are resistant to streptomycin and capreomycin are still susceptible to amikacin; bacteria that are resistant to kanamycin have varying susceptibility to amikacin. Resistance to amikacin also confers resistance to kanamycin and capreomycin.Resistance to amikacin and kanamycin in Mycobacterium, the causative agent of tuberculosis, is due to a mutation in the rrs gene, which codes for the 16S rRNA. Mutations such as these reduce the binding affinity of amikacin to the bacterias ribosome. Variations of aminoglycoside acetyltransferase (AAC) and aminoglycoside adenylyltransferase (AAD) also confer resistance: resistance in Pseudomonas aeruginosa is caused by AAC(6)-IV, which also confers resistance to kanamycin, gentamicin, and tobramycin, and resistance in Staphylococcus aureus and S. epidermidis is caused by AAD(4,4), which also confers resistance to kanamycin, tobramycin, and apramycin. Some strains of S. aureus can also inactivate amikacin by phosphorylating it.
Pharmacokinetics
Amikacin is not absorbed orally and thus must be administered parenterally. It reaches peak serum concentrations in 0.5–2 hours when administered intramuscularly. Less than 11% of the amikacin actually binds to plasma proteins. It is distributed into the heart, gallbladder, lungs, and bones, as well as in bile, sputum, interstitial fluid, pleural fluid, and synovial fluids. It is usually found at low concentrations in the cerebrospinal fluid, except when administered intraventricularly. In infants, amikacin is normally found at 10–20% of plasma levels in the spinal fluid, but the amount reaches 50% in cases of meningitis. It does not easily cross the blood-brain barrier or enter ocular tissue.While the half-life of amikacin is normally two hours, it is 50 hours in those with end-stage renal disease.The vast majority (95%) of amikacin from an IM or IV dose is secreted unchanged via glomerular filtration and into the urine within 24 hours. Factors that cause amikacin to be excreted via urine include its relatively low molecular weight, high water solubility, and unmetabolized state.
Chemistry
Amikacin is derived from kanamycin A:
Veterinary use
While amikacin is only FDA-approved for use in dogs and for intrauterine infection in horses, it is one of the most common aminoglycosides used in veterinary medicine, and has been used in dogs, cats, guinea pigs, chinchillas, hamsters, rats, mice, prairie dogs, cattle, birds, snakes, turtles and tortoises, crocodilians, bullfrogs, and fish. It is often used for respiratory infections in snakes, bacterial shell disease in turtles, and sinusitis in macaws. It is generally contraindicated in rabbits and hares (though it has still been used) because it harms the balance of intestinal microflora.In dogs and cats, amikacin is commonly used as a topical antibiotic for ear infections and for corneal ulcers, especially those that are caused by Pseudomonas aeruginosa. The ears are often cleaned before administering the medication, since pus and cellular debris lessen the activity of amikacin. Amikacin is administered to the eye when prepared as an ophthalmic ointment or solution, or when injected subconjunctivally. Amikacin in the eye can be accompanied by cephazolin. Despite its use there amikacin (and all aminoglycosides) are toxic to intraocular structures.In horses, amikacin is FDA-approved for uterine infections (such as endometriosis and pyometra) when caused by susceptible bacteria. It is also used in topical medication for the eyes and arthroscopic lavage; when combined with a cephalosporin, is used to treat subcutaneous infections that are caused by Staphylococcus. For infections in the limbs or joints, it is often administered with a cephalosporin via limb perfusion directly into the limb or injected into the joint. Amikacin is also injected into the joints with the anti-arthritic medication Adequan in order to prevent infection.Side effects in animals include nephrotoxicity, ototoxicity, and allergic reactions at IM injection sites. Cats tend to be more sensitive to the vestibular damage caused by ototoxicity. Less frequent side effects include neuromuscular blockade, facial edema, and peripheral neuropathy.The half-life in most animals is one to two hours.Treating overdoses of amikacin requires kidney dialysis or peritoneal dialysis, which reduce serum concentrations of amikacin, and/or penicillins, some of which can form complexes with amikacin that deactivate it.
Liposome inhalation suspension
Amikacin liposome inhalation suspension was the first drug approved under the US limited population pathway for antibacterial and antifungal drugs (LPAD pathway). It also was approved under the accelerated approval pathway. The U.S. Food and Drug Administration (FDA) granted the application for amikacin liposome inhalation suspension fast track, breakthrough therapy, priority review, and qualified infectious disease product (QIDP) designations. The FDA granted approval of Arikayce to Insmed, Inc.The safety and efficacy of amikacin liposome inhalation suspension, an inhaled treatment taken through a nebulizer, was demonstrated in a randomized, controlled clinical trial where patients were assigned to one of two treatment groups. One group of patients received amikacin liposome inhalation suspension plus a background multi-drug antibacterial regimen, while the other treatment group received a background multi-drug antibacterial regimen alone. By the sixth month of treatment, 29 percent of patients treated with amikacin liposome inhalation suspension had no growth of mycobacteria in their sputum cultures for three consecutive months compared to 9 percent of patients who were not treated with amikacin liposome inhalation suspension.
References
External links
"Amikacin". Drug Information Portal. U.S. National Library of Medicine.
"Amikacin sulfate". Drug Information Portal. U.S. National Library of Medicine. |
Ondansetron | Ondansetron, sold under the brand name Zofran among others, is a medication used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, or surgery. It is also effective for treating gastroenteritis. It can be given by mouth or by injection into a muscle or into a vein.Common side effects include diarrhea, constipation, headache, sleepiness, and itchiness. Serious side effects include QT prolongation and severe allergic reaction. It appears to be safe during pregnancy but has not been well studied in this group. It is a serotonin 5-HT3 receptor antagonist. It does not have any effect on dopamine receptors or muscarinic receptors.Ondansetron was patented in 1984 and approved for medical use in 1990. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 60th most commonly prescribed medication in the United States, with more than 11 million prescriptions.
Medical uses
Although an effective antiemetic agent, the high cost of brand-name ondansetron initially limited its use to controlling postoperative nausea and vomiting and chemotherapy-induced nausea and vomiting.
Cancer treatment
The 5-HT3 receptor antagonists are the primary medications used to treat and prevent chemotherapy-induced nausea and vomiting and radiotherapy-induced nausea and vomiting.
Postoperative
A number of medications including ondansetron appear to be effective in controlling postoperative nausea and vomiting. It is more effective than metoclopramide, and less sedating than cyclizine or droperidol.
Pregnancy
Ondansetron is used off-label to treat morning sickness and hyperemesis gravidarum of pregnancy. It is typically used after other antinausea drugs have failed.There appears to be a low risk of harm to the baby with use during pregnancy, though there may be an increase in heart problems among the babies.Ondansetron is in pregnancy category B in the US. It is not known if ondansetron is excreted in breast milk.
Cyclic vomiting syndrome
Ondansetron is one of several antiemetic drugs used during the vomiting phase of cyclic vomiting syndrome.
Gastroenteritis
Trials in emergency department settings support the use of ondansetron to reduce vomiting associated with gastroenteritis and dehydration. A retrospective review found it was used commonly for this purpose, being administered in over 58% of cases. Its use reduced hospital admissions, but was also associated with higher rates of return visits to the emergency department. Furthermore, people who had initially received ondansetron were more likely to be admitted on the return visit than people who had not received the drug. However, this effect may simply be due to the agent being used more frequently in people who present with more severe illness. Its use was not found to mask serious diagnoses.
Special populations
Children
Ondansetron has rarely been studied in people under 4 years of age. As such, little data is available to guide dosage recommendations.
Elderly
It is not necessary to adjust the dosage for people under 75 years of age. The use of ondansetron has not been studied in people older than 75 years of age, and it is not known if dosage should be adjusted for this group.
Poor liver function
The maximum recommended dose for people with severe liver function impairment is 8 mg/day. In these people, ondansetron is cleared from the body at half to one-third the rate as in healthy people. The concentration of ondansetron in body tissues as opposed to plasma is also higher than in healthy people.
Adverse effects
Headache is the most common adverse effect. A review of use for post-operative nausea and vomiting found that for every 36 people treated, one would experience headache, which could be severe.Constipation, diarrhea, and dizziness are other commonly reported side effects. It is broken down by the hepatic cytochrome P450 system and it has little effect on the metabolism of other drugs broken down by this system. Anecdotally, ototoxicity has also been reported if injected too quickly.
QT prolongation
Use of ondansetron has been associated with prolongation of the QT interval, which can lead to a potentially fatal heart rhythm known as torsades de pointes. Although this may happen in any person with any formulation, the risk is most salient with the injectable (intravenous) form of the drug and increases with dose. The risk is also higher in people taking other medicines that prolong the QT interval, as well as in people with congenital long QT syndrome, congestive heart failure, and/or bradyarrhythmias. As such, single doses of injectable ondansetron should not exceed 16 mg at one time. (Oral dosing recommendations remain intact, including the recommendation of a single 24-mg oral dose when indicated.) Electrolyte imbalances should be corrected before the use of injectable ondansetron. People are cautioned to seek immediate medical care if symptoms such as irregular heartbeat/palpitations, shortness of breath, dizziness, or fainting occur while taking ondansetron.
Overdose
No specific treatment is available for ondansetron overdose; people are managed with supportive measures. An antidote to ondansetron is not known.
Pharmacology
Pharmacodynamics
Ondansetron is a highly selective serotonin 5-HT3 receptor antagonist, with low affinity for dopamine receptors. The 5-HT3 receptors are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema in the medulla. Serotonin is released by the enterochromaffin cells of the small intestine in response to chemotherapeutic agents and may stimulate vagal afferents (via 5-HT3 receptors) to initiate the vomiting reflex. It is thought that ondansetrons antiemetic action is mediated mostly via antagonism of vagal afferents with a minor contribution from antagonism of central receptors.
Pharmacokinetics
Ondansetron may have a degree of peripheral selectivity due to binding to P-glycoprotein and efflux out of the brain at the blood–brain barrier.
History
Ondansetron (marketed under the brand name Zofran) was developed in the mid-1980s by GlaxoSmithKline in London. It was granted US patent protection in September 1987, received a use patent June 1988, and was approved by the US FDA in January 1991. It was granted another divisional patent in November 1996. Finally, owing to GlaxoSmithKlines research on pediatric use, ondansetrons patent protection was extended until December 2006. By this final year of its patent (2006), Zofran had become the 20th highest-selling brand-name drug in the United States, with sales of US$1.3 billion in the first 9 months of 2006 (80% from the US). The first generic versions were approved by the US FDA in December 2006, with marketing approval granted to Teva Pharmaceuticals USA and SICOR Pharmaceuticals. In 2018, University of São Paulo and Biolab were granted a patent for an orodispersible form of the drug.
Society and culture
Publication bias
In 1997, ondansetron was the subject of a meta-analysis case study published in the British Medical Journal. Researchers examined 84 trials, with 11,980 people receiving ondansetron, published between 1991 and September 1996. Intravenous ondansetron 4 mg versus placebo was investigated in 16 reports and three further reports which had been duplicated a total of six times. The number needed to treat (NNT) to prevent vomiting within 24 hours was 9.5, with 95% confidence interval 6.9 to 15, in the 16 nonduplicated reports. In the three duplicated reports, the NNT was significantly lower at 3.9 (3.3 to 4.8). When all 25 reports were combined, the apparent NNT improved to 4.9 (4.4 to 5.6). Inclusion of duplicate reports led to a 23% overestimation of ondansetrons antiemetic efficacy.In addition, the authors found the covert duplication of reports on ondansetron was not easy to detect, because of lack of cross-referencing between papers, and reports containing duplicate findings were cited in eight reviews of the drug. Their analysis was a subject of an editorial in the Journal of the American Medical Association in 1999.
Availability
Ondansetron is a generic drug and is available in many countries under many brand names.
Routes of administration
It can be given by mouth, as a tablet or orally disintegrating tablet, or by injection into a muscle or into a vein.
Research
Psychiatric disorders
A 2006 double-blind, randomized controlled trial indicated ondansetron may have value in the treatment of schizophrenia, as an adjunct to haloperidol. The study found the combination to significantly improve negative schizophrenia symptoms, and people taking both drugs experienced fewer of the adverse effects commonly associated with haloperidol. An earlier, smaller, open-label trial had found ondansetron to be useful in treating antipsychotic-induced tardive dyskinesia in people with schizophrenia, and the study patients also showed significant improvement in the diseases symptoms.Early studies have also examined ondansetron as a possible treatment for psychosis resulting from advanced Parkinsons disease. Its apparent benefits despite a lack of any significant antagonistic properties at dopamine receptors or the 5-HT2A receptor raises interesting questions about the etiology of psychosis.
Substance use
There is tentative evidence that it may be useful in decreasing the desired effects of alcohol. There is also some tentative evidence in those who are addicted to stimulants.
Postanesthetic shivering
Two small, placebo-controlled trials have been conducted to assess the efficacy of ondansetron for postanesthetic shivering, a common occurrence after surgery. Ondansetron was found to be as effective as pethidine (meperidine, Demerol) when given as a single intravenous dose before anesthesia.
References
External links
"Ondansetron". Drug Information Portal. U.S. National Library of Medicine. |
Ethinylestradiol/levonorgestrel | Ethinylestradiol/levonorgestrel (EE/LNG) is a combined birth control pill made up of ethinylestradiol, an estrogen and levonorgestrel a progestin. It is used for birth control, symptoms of menstruation, endometriosis, and as emergency contraception. It is taken by mouth. Some preparations of EE/LNG additionally contain an iron supplement in the form of ferrous bisglycinate or ferrous fumarate.Side effects can include nausea, headache, blood clots, breast pain, depression, and liver problems. Use is not recommended during pregnancy, the initial three weeks after childbirth, and in those at high risk of blood clots. However, it may be started immediately after a miscarriage or abortion. Smoking while using combined birth control pills is not recommended. It works by stopping ovulation, making the mucus at the opening to the cervix thick, and making the uterus not suitable for implantation.Ethinylestradiol/levonorgestrel has been approved for medical use in the United States at least since 1982. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. It is marketed under a large number of brand names. In 2019, it was the 124th most commonly prescribed medication in the United States, with more than 5 million prescriptions.
See also
Birth control pill formulations
List of combined sex-hormonal preparations
== References == |
Rimantadine | Rimantadine (INN, sold under the trade name Flumadine) is an orally administered antiviral drug used to treat, and in rare cases prevent, influenzavirus A infection. When taken within one to two days of developing symptoms, rimantadine can shorten the duration and moderate the severity of influenza. Rimantadine can mitigate symptoms, including fever. Both rimantadine and the similar drug amantadine are derivates of adamantane. Rimantadine is found to be more effective than amantadine because when used the patient displays fewer symptoms. Rimantadine was approved by the Food and Drug Administration (FDA) in 1994.
Rimantadine was approved for medical use in 1993. Seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to rimantadine, and it is no longer recommended to prescribe for treatment of the flu.
Medical use
Influenza A
Rimantadine inhibits influenza activity by binding to amino acids in the M2 transmembrane channel and blocking proton transport across the M2 channel. Rimantadine is believed to inhibit influenzas viral replication, possibly by preventing the uncoating of the viruss protective shells, which are the envelope and capsid. The M2 channel is known to be responsible for viral replication in the influenza virus. Genetic studies suggest that the virus M2 protein, an ion channel specified by virion M2 gene, plays an important role in the susceptibility of influenza A virus to inhibition by rimantadine.Rimantadine is bound inside the pore to amantadine specific amino acid binding sites with hydrogen binding and van der Waals interactions. The ammonium group (with neighboring water molecules) is positioned towards the C terminus with the amantadane group is positioned towards the N-terminus when bound inside the M2 pore.
Influenza resistance
Resistance to rimantadine can occur as a result of amino acid substitutions at certain locations in the transmembrane region of M2. This prevents binding of the antiviral to the channel.The mutation S31N binding site with rimantadine is shown in the image to the left. It shows rimantadine binding into lumenal (top) or peripheral (bottom) binding sites with influenza M2 channel Serine 31 (gold) or Asparagine 31 (blue).
Rimantadine enantiomers interactions with M2
Rimantadine, when sold as flumadine, is present as a racemic mixture; the R and S states are both present in the drug. Solid state NMR studies have shown that the R enantiomer has a stronger binding affinity to the M2 channel pore than the S-enantiomer of rimantadine. Antiviral assay and electrophysiology studies show that there is no significant difference between the R and S enantiomers in binding affinity to amino acids in the M2 channel. Since the enantiomers have similar binding affinity, they also have similar ability to block the channel pore and work as an effective antiviral.
Rimantadine enantiomers R and S are pictured interacting with the M2 pore below to the right. This image shows that there is not a significant modeled difference between the R and S enantiomers.
Parkinsons disease
Rimantadine, like its antiviral cousin amantadine, possesses some NMDA antagonistic properties and is used as an antiparkinsonic drug (i.e., in the treatment of Parkinsons disease). However, in general, neither rimantadine nor amantadine is a preferred agent for this therapy and would be reserved for cases of the disease that are less responsive to front-line treatments.
Other
Rimantadine is shown to be effective against other RNA-containing viruses. It can treat arboviruses like Saint Louis encephalitis and Sindbis. Other viruses that can be treated with Rimantadine include respiratory synctial and parainfluenza viruses. Rimantadine has also been shown to treat chronic hepatitis C.
Drug interactions
Taking paracetamol (acetaminophen, Tylenol) or acetylsalicylic acid (aspirin) while taking rimantadine is known to reduce the bodys uptake of rimantadine by approximately 12%.
Cimetidine also affects the bodys uptake of rimantadine.
Taking anticholigenic drugs with amantadine may increase underlying seizure disorders and aggravate congestive heart failure.
Side effects
Rimantadine can produce gastrointestinal and central nervous system adverse effects. Approximately 6% of patients (compared to 4% of patients taking a placebo) reported side-effects at a dosage of 200 mg/d. Common side effects include:
nausea
upset stomach
nervousness
tiredness
lightheadedness
trouble sleeping (insomnia)
difficulty concentrating
confusion
anxiety
Rimantadine shows fewer CNS symptoms than its sister drug Amantadine.
Synthesis
1-carboxyadamatanones are reduced with sodium borohydride to create racemic hydroxy acid. Excess methyllithium is then added to create methyl ketones which when reduced with lithium aluminum hydride gives the amine group.The synthesis pictured to the left is a synthesis of rimantadine as synthesized in Europe
History
Rimantadine was discovered in 1963 and patented in 1965 in the US by William W. Prichard in Du Pont & Co., Wilmington, Delaware (patent on new chemical compound U.S. Patent 3,352,912, 1965 and on the first method of synthesis U.S. Patent 3,592,934, 1967). Prichards methods of synthesis of rimantadine from the corresponding ketone oxime were based on its reduction with lithium aluminum hydride.
See also
Adapromine
Bromantane
Memantine
Tromantadine
Synonyms
1-(1-Adamantyl)ethanamine, 1-(Adamantan-1-yl)ethanamine, 1-(adamantan-1-yl)ethan-1-aminem, alpha-Methyl-1-adamantanemethylamine, alpha-Methyladamantanemethylamine, Rimantadine [INN:BAN], Rimantadinum [INN-Latin], 1-(1-Adamantyl)ethylamin, Remantadine, Rimantadina [INN-Spanish], 1-Adamantan-1-yl-ethylamine, RIMANTADIN, HSDB 7438, CHEMBL959, BRN 2715740, 1-Adamantanemethylamine, .alpha.-methyl-, .alpha.-Methyladamantanemethylamine, 1-(1-adamantyl)-ethylamine, 1-(tricyclo[3.3.1.1~3,7~]dec-1-yl)ethanamine, Riamantadine, Rimantadina, Rimantadinum, Tricyclo(3.3.1.13,7)decane-1-methanamine, alpha-methyl-, [1-(1-adamantyl)ethyl]amine hydrochloride, Tricyclo(3.3.1.1(sup 3,7))decane-1-methanamine, alpha-methyl-, 1-ADAMANTANEMETHYLAMINE, alpha-METHYL-, 1-Rimantadine, 887336-05-2, Tricyclo[3.3.1.13,7]decane-1-methanamine, a-methyl-, Rimant, 1-(1-adamantyl)ethylamine, Rimantadine (INN), Enamine_005755, NCGC00159491-02, Rimant & .alpha. IFN, Rimantadine (Flumadine), Rimantidine & .alpha.IFN, 1-Adamantan-1-ylethylamine, rimantidin, Rimantadin A, (R)-1-(Adamantan-1-yl)ethan-1-amine, 1-adamantanylethylamine, Maybridge1_002066, SCHEMBL2981, 1-tricyclo[3.3.1.1~3,7~]dec-1-ylethanamine, Oprea1_602732, SCHEMBL2619249, CHEMBL1201272, DTXSID2023561, SCHEMBL20409367, CHEBI:94440, CTK6A4437, HMS1410F13, HMS2090L19, HMS3604N13, HMS3655J05, 1-Adamantanemethylamine, ?-methyl-, ALBB-013870, BCP12269, HY-B0338, ZX-AN012619, ANW-72018, BBL013215, BDBM50216627, MFCD00869344, s1964, STK177253, (alpha-methyl-1-adamantyl)methylamine, AKOS000264537, AKOS006238592, AKOS016038537, .alpha.-Methyl-1-adamantanemethylamine, AM84461, API0024288, BBV-156986, CCG-236078, CS-2380, DB00478, FCH3207896, MCULE-9027470290, IDI1_007990, NCGC00159491-03, NCGC00159491-05, AK-58175, AS-68744, CC-34261, LS-15019, OR315791, SBI-0206810.P001, AB0012750, AX8049536, DB-042207, FT-0630403, H6325, ST45025920, SW220023-1, EN300-33990, C07236, D08483, Q421711-[(3R,5S,7s)-adamantan-1-yl]ethan-1-amine, AB00638368-09, AB00959689-03, AB01506092_02, AB01506092_03, 392R284, C-06592, BRD-A84282119-003-01-2, Z56757137, 1-(Tricyclo[3.3.1.1>3,7>]dec-1-yl)ethanamine (HCl), Tricyclo(3.3.1.1^3,7)decane-1-methanamine, .alpha.-methyl-, 1-(1-Adamantyl)ethylamine Hydrochloride;Rimantadine hydrochloride, Tricyclo(3.3.1.1(sup 3,7))decane-1-methanamine, .alpha.-methyl-, Tricyclo[3,3,1,1(3,7)]decane-1-methanamine, .alpha.-methyl-, Tricyclo(3.3.1.1^3,7)decane-1-methanamine, .alpha.-methyl- & IFN.alpha
References
External links
U.S. FDA press release announcing rimantadines approval
U.S. Center for Drug Evaluation and Research rimantadine description
U.S. NIH rimantadine description
U.S. CDC flu anti-viral treatment information |
Ramipril | Ramipril, sold under the brand name Altace among others, is an ACE inhibitor type medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It can also be used as a preventative medication in patients over 55 years old to reduce the risk of having a heart attack, stroke or cardiovascular death in patients shown to be at high risk, such as some diabetics and patients with vascular disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth.Common side effects include headaches, dizziness, feeling tired, and cough. Serious side effects may include liver problems, angioedema, kidney problems, and high blood potassium. Use in pregnancy and breastfeeding is not recommended. It is an ACE inhibitor and works by decreasing renin-angiotensin-aldosterone system activity.Ramipril was patented in 1981 and approved for medical use in 1989. It is available as a generic medication. In 2019, it was the 178th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Structure and Activity Relationship
Ramipril is a pro-drug. The molecule must be hydrolyzed by the esterase at the OCH2CH3 and form a carboxylate. This carboxylate then interacts with the positive Zn+2 to inhibit the ACE enzyme. The COOH helps orient it with the enzyme. Ramipril is similar in structure to the Trandolapril ACE Inhibitor but it has a cyclopentane instead of cyclohexane.
Medical uses
Medical uses include:
High blood pressure
Congestive heart failure
Following heart attack in people with evidence of heart failure
People over 55 years at high risk: prevention of heart attack, stroke, cardiovascular death, or need of revascularization procedures
To prevent the onset and progression of kidney damage due to diabetes with or without protein in the urine. Randomized trial evidence suggests that a maximum tolerable dose prevents cardiovascular events and death in patients with diabetic kidney disease.
Contraindications
Contraindications to its use include volume-depleted patients, a history of angioedema while on an ACE inhibitor, pregnancy and hypotension.People should not take ramipril (or any ACE inhibitors) if they have hyperkalemia. It is also recommended to avoid using salt-substitutes as this can further increase potassium levels in the blood.Ramipril can be considered safe and well-tolerated for most people with renovascular disease (narrowing of the artery to one or both kidneys) only if close blood test monitoring is available at the start of therapy. Treatment with Ramipril in some patients with significant narrowing in both kidneys can increase serum creatinine concentration (measured in the blood test), which returns to baseline upon therapy cessation.
Adverse effects
Shakiness
Dry cough
Dizziness and light-headedness due to low blood pressure
Fatigue, especially in the early stages
Mouth dryness in the early stages
Nausea
Fainting
Signs of infection (e.g., fever, chills, persistent sore throat)
Chest pain
Neutropenia (low white blood cells)
Impotence (erectile dysfunction)
HyperkalemiaSerious allergic reactions to this drug are unlikely, but immediate medical attention must be sought if they occur. Symptoms of a serious allergic reaction include, but are not limited to a rash or swelling of the face, mouth, tongue, or throat. In extreme cases, ramipril may lead to potentially fatal liver problems.
Mechanism of action
ACE inhibitors inhibit the actions of angiotensin converting enzyme (ACE), thereby lowering the production of angiotensin II and decreasing the breakdown of bradykinin. The decrease in angiotensin II results in relaxation of arteriole smooth muscle leading to a decrease in total peripheral resistance, reducing blood pressure as the blood is pumped through widened vessels. Its effect on bradykinin is responsible for the dry cough side effect.
Ramipril, a prodrug or precursor drug, is converted to the active metabolite ramiprilat by carboxylesterase 1. Ramiprilat is mostly excreted by the kidneys. Its half-life is variable (3–16 hours), and is prolonged by heart and liver failure, as well as kidney failure.
Society and culture
US patent
The compound was protected by a patent which was assigned to the German pharmaceutical company Hoechst AG (since merged into Aventis) on 29 October 1991. The patent was scheduled to expire on 29 October 2008. On 11 September 2007, in an appeal by the Indian company Lupin Ltd., the United States Court of Appeals for the Federal Circuit reversed a district court trial verdict and found that Aventiss patent on ramipril was invalid for "obviousness", opening this drug to generic manufacturers.
Brand names
It is marketed as Prilace by Arrow Pharmaceuticals in Australia, Ramipro by Westfield Pharma in the Philippines, Triatec by Sanofi-Aventis in Italy and United States and Altace by King Pharmaceuticals in the United States, Novapril by Pharmanova in Ghana, Ramitens by PharmaSwiss, Ampril by Krka in Slovenia, Corpril by Cemelog-BRS in Hungary, Piramil and Prilinda by Hemofarm in Serbia, by Lek in Poland and by Novartis and Opsonin Pharma Limited as Ramace in Bangladesh, and in Canada as Altace (Sonfi) and Ramipril (Pharmascience).
Ramipril is marketed in India under the brand names Cardace, Zigpril, Ramistar, Odipril and Zorem . Ramipril is marketed in Myanmar under brand name Endpril .
Research
The Heart Outcomes and Prevention Evaluation trial seemed to show ramipril possessed cardioprotective qualities which extended beyond its qualities as an antihypertensive. However, the trial and the interpretation of its results have been criticised.The Acute Infarction Ramipril Efficacy (AIRE) trial showed a 27% reduction in mortality for patients receiving ramipril for chronic heart failure following a myocardial infarction.
Ramipril was found to have similar results as telmisartan, an angiotensin II receptor blocker.
References
External links
"Ramipril". Drug Information Portal. U.S. National Library of Medicine. |
Fentanyl | Fentanyl, also spelled fentanil, is a potent synthetic opioid used as a pain medication. Together with other drugs, fentanyl is used for anesthesia. It is also used illicitly as a recreational drug, sometimes mixed with heroin, cocaine, benzodiazepines or methamphetamine. Its potentially deadly overdose effects can be neutralized by naloxone. Fentanyl is commonly used to create counterfeit pills disguised as OxyContin, Xanax, Adderall, among others. It has a rapid onset and its effects generally last under two hours. Medically, it is used by injection, nasal spray, or skin patch, or absorbed through the cheek as a lozenge or tablet.Common adverse effects of fentanyl include nausea, vomiting, constipation, itching, sedation, confusion, and injuries related to poor coordination. Serious adverse effects may include respiratory depression, hallucinations, serotonin syndrome, low blood pressure, or development of an opioid use disorder. Fentanyl works by activating μ-opioid receptors. It is around 100 times stronger than morphine and about 50 times stronger than heroin.
Fentanyl was first made by Paul Janssen in 1960 and approved for medical use in the United States in 1968. In 2015, 1,600 kilograms (3,500 pounds) were used in healthcare globally. As of 2017, fentanyl was the most widely used synthetic opioid in medicine; in 2019, it was the 278th most commonly prescribed medication in the United States, with more than one million prescriptions. It is on the World Health Organizations List of Essential Medicines.In 2021, fentanyl and fentanyl analogues accounted for most drug overdose deaths in the United States with 71,238 deaths. Compared with heroin, it is more potent, has higher profit margins, and, because it is compact, has simpler logistics. It can be cut into, or even replace entirely, the supply of heroin and other opiates. The flow of fentanyl mainly originates in Chinese factories which produce fentanyl or fentanyl precursors; it is then trafficked to other countries for illicit production and sale. In the United States, finished fentanyl arrives primarily from Mexico smuggled by cartels.
Medical uses
Anesthesia
Intravenous fentanyl is often used for anesthesia and to treat pain. To induce anesthesia, it is given with a sedative-hypnotic, like propofol or thiopental, and a muscle relaxant. To maintain anesthesia, inhaled anesthetics and additional fentanyl may be used. These are often given in 15–30 minute intervals throughout procedures such as endoscopy and surgeries and in emergency rooms.For pain relief after surgery, use can decrease the amount of inhalational anesthetic needed for emergence from anesthesia. Balancing this medication and titrating the drug based on expected stimuli and the persons responses can result in stable blood pressure and heart rate throughout a procedure and a faster emergence from anesthesia with minimal pain.
Regional anesthesia
Fentanyl is the most commonly used intrathecal opioid because its lipophilic profile allows a quick onset of action (5–10 min.) and intermediate duration of action (60–120 min.). Spinal administration of hyperbaric bupivacaine with fentanyl may be the optimal combination. The almost immediate onset of fentanyl reduces visceral discomfort and even nausea during the procedure.
Obstetrics
Fentanyl is sometimes given intrathecally as part of spinal anesthesia or epidurally for epidural anaesthesia and analgesia. Because of fentanyls high lipid solubility, its effects are more localized than morphine, and some clinicians prefer to use morphine to get a wider spread of analgesia. It is widely used in obstetrical anesthesia because of its short time to action peak (about 5 min.), the rapid termination of its effect after a single dose, and the occurrence of relative cardiovascular stability. In obstetrics, the dose must be closely regulated in order to prevent large amounts of transfer from mother to fetus. At high doses, the drug may act on the fetus to cause postnatal respiratory distress. For this reason, shorter acting agents such as alfentanyl or remifentanil may be more suitable in the context of inducing general anaesthesia.
Pain management
The bioavailability of intranasal fentanyl is about 70–90%, but with some imprecision due to clotted nostrils, pharyngeal swallow, and incorrect administration. For both emergency and palliative use, intranasal fentanyl is available in doses of 50, 100, and 200 µg. In emergency medicine, safe administration of intranasal fentanyl with a low rate of side effects and a promising pain-reducing effect was demonstrated in a prospective observational study in about 900 out-of-hospital patients.In children, intranasal fentanyl is useful for the treatment of moderate and severe pain and is well tolerated.
Chronic pain
It is also used in the management of chronic pain including cancer pain. Often, transdermal patches are used. The patches work by slowly releasing fentanyl through the skin into the bloodstream over 48 to 72 hours, allowing for long-lasting pain management. Dosage is based on the size of the patch, since, in general, the transdermal absorption rate is constant at a constant skin temperature. Each patch should be changed every 72 hours. Rate of absorption is dependent on a number of factors. Body temperature, skin type, amount of body fat, and placement of the patch can have major effects. The different delivery systems used by different makers will also affect individual rates of absorption. Under normal circumstances, the patch will reach its full effect within 12 to 24 hours; thus, fentanyl patches are often prescribed with a fast-acting opioid (such as morphine or oxycodone) to handle breakthrough pain. It is unclear if fentanyl gives long-term pain relief to people with neuropathic pain.
Breakthrough pain
Sublingual fentanyl dissolves quickly and is absorbed through the sublingual mucosa to provide rapid analgesia. Fentanyl is a highly lipophilic compound, which is well absorbed sublingually and generally well tolerated. Such forms are particularly useful for breakthrough cancer pain episodes, which are often rapid in onset, short in duration, and severe in intensity.
Palliative care
In palliative care, transdermal fentanyl patches have a definitive, but limited role for:
people already stabilized on other opioids who have persistent swallowing problems and cannot tolerate other parenteral routes such as subcutaneous administration.
people with moderate to severe kidney failure.
troublesome side effects of oral morphine, hydromorphone, or oxycodone.When using the transdermal patch, patients must be careful to minimize or avoid external heat sources (direct sunlight, heating pads, etc.), which can trigger the release of too much medication and cause potentially deadly complications.
Combat medicine
USAF Pararescue combat medics in Afghanistan used fentanyl lozenges in the form of lollipops on combat casualties from IED blasts and other trauma. The stick is taped to a finger and the lozenge put in the cheek of the person. When enough fentanyl has been absorbed, the (sedated) person generally lets the lollipop fall from the mouth, indicating sufficient analgesia and somewhat reducing the likelihood of overdose and associated risks.
Dyspnea
Fentanyl can also be used for patients in whom morphine is not tolerated, or whose breathlessness is refractory to morphine. Fentanyl is especially useful for concomitant treatment in palliative care settings where pain and shortness of breath are severe and need to be treated with high strength opioids.
Other
Some routes of administration such as nasal sprays and inhalers generally result in a faster onset of high blood levels, which can provide more immediate analgesia but also more severe side effects, especially in overdose. The much higher cost of some of these appliances may not be justified by marginal benefit compared with buccal or oral options. Intranasal fentanyl appears to be equally effective as IV morphine and superior to intramuscular morphine for the management of acute hospital pain.A fentanyl patient-controlled transdermal system (PCTS) is under development, which aims to allow patients to control administration of fentanyl through the skin to treat postoperative pain.
Adverse effects
Fentanyls most common side effects, which affect more than 10% of people, include nausea, vomiting, constipation, dry mouth, somnolence, confusion, and asthenia (weakness). Less frequently, in 3–10% of people, fentanyl can cause abdominal pain, headache, fatigue, anorexia and weight loss, dizziness, nervousness, anxiety, depression, flu-like symptoms, dyspepsia (indigestion), shortness of breath, hypoventilation, apnoea, and urinary retention. Fentanyl use has also been associated with aphasia. Despite being a more potent analgesic, fentanyl tends to induce less nausea, as well as less histamine-mediated itching, than morphine.The duration of action of fentanyl has sometimes been underestimated, leading to harm in a medical context. In 2006, the U.S. Food and Drug Administration (FDA) began investigating several respiratory deaths, but doctors in the United Kingdom were not warned of the risks with fentanyl until September 2008. The FDA reported in April 2012 that twelve young children had died and twelve more made seriously ill from separate accidental exposures to fentanyl skin patches.
Respiratory depression
The most dangerous adverse effect of fentanyl is respiratory depression, that is, decreased sensitivity to carbon dioxide leading to reduced rate of breathing, which can cause anoxic brain injury or death. This risk is decreased when the airway is secured with an endotracheal tube (as during anesthesia). This risk is higher in specific groups, like those with obstructive sleep apnea.Other factors that increase the risk of respiratory depression are:
High fentanyl doses
Sleep
Older age
Simultaneous use of CNS depressants like benzodiazepines, barbiturates, alcohol, and inhaled anesthetics
Hyperventilation
Decreased CO2 levels in the serum
Respiratory acidosis
Decreased fentanyl clearance from the body
Decreased blood flow to the liver
Renal insufficiencySustained release fentanyl preparations, such as patches, may also produce unexpected delayed respiratory depression. The precise reason for sudden respiratory depression is unclear, but there are several hypotheses:
Saturation of the body fat compartment in people with rapid and profound body fat loss (people with cancer, cardiac or infection-induced cachexia can lose 80% of their body fat).
Early carbon dioxide retention causing cutaneous vasodilation (releasing more fentanyl), together with acidosis, which reduces protein binding of fentanyl, releasing yet more fentanyl.
Reduced sedation, losing a useful early warning sign of opioid toxicity and resulting in levels closer to respiratory-depressant levels.Another related complication of fentanyl overdoses includes the so-called wooden chest syndrome, which quickly induces complete respiratory failure by paralyzing the thoracic muscles, explained in more detail in the Muscle rigidity section below.
Heart and blood vessels
Bradycardia: Fentanyl decreases the heart rate by increasing vagal nerve tone in the brainstem, which increases the parasympathetic drive.
Vasodilation: It also vasodilates arterial and venous blood vessels through a central mechanism, by primarily slowing down vasomotor centers in the brainstem. To a lesser extent, it does this by directly affecting blood vessels. This is much more profound in patients who have an already increased sympathetic drive, like patients who have high blood pressure or congestive heart failure. It does not affect the contractility of the heart when regular doses are administered.
Muscle rigidity
If high boluses of fentanyl are administered quickly, muscle rigidity of the vocal cords can make bag-mask ventilation very difficult. The exact mechanism of this effect is unknown, but it can be prevented and treated using neuromuscular blockers.
Wooden chest syndrome
A prominent idiosyncratic adverse effect of fentanyl also includes a sudden onset of rigidity of the abdominal muscles and the diaphragm, which induces respiratory failure; this is seen with high doses and is known as wooden chest syndrome. The syndrome is believed to be the main cause of death as a result of fentanyl overdoses.Wooden chest syndrome is reversed by naloxone and is believed to be caused by a release of noradrenaline, which activates α-adrenergic receptors and also possibly via an activation of cholinergic receptors.Wooden chest syndrome is unique to the most powerful opioids—which today comprise fentanyl and its analogs—while other less-powerful opioids like heroin produce mild rigidity of the respiratory muscles to a much lesser degree.
Overdose
Fentanyl poses an exceptionally high overdose risk in humans, due to having an extremely unpredictable fatal dosage when mixed with other drugs. In its pure form, overdoses are only moderately unpredictable, with most overdose deaths occurring at serum concentrations of between 150 and 250 ng/mL. In contexts of poly-substance use, blood fentanyl concentrations of approximately 7 ng/ml or greater have been associated with fatalities. Over 85% of overdoses involved at least one other drug, and there was no clear correlation showing at which level the mixtures were fatal. The dosages of fatal mixtures varied by over three magnitudes in some cases. This extremely unpredictable volatility with other drugs makes it especially difficult to avoid fatalities.Naloxone can completely or partially reverse an opioid overdose. In July 2014, the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK issued a warning about the potential for life-threatening harm from accidental exposure to transdermal fentanyl patches, particularly in children, and advised that they should be folded, with the adhesive side in, before being discarded. The patches should be kept away from children, who are most at risk from fentanyl overdose. In the US, fentanyl and fentanyl analogs caused over 29,000 deaths in 2017, a large increase over the previous four years.
Most of the recent increases in fentanyl deaths do not involve prescription fentanyl but are related to illicitly made fentanyl that is being mixed with or sold as heroin. Death from fentanyl overdose continues to be a public health issue of national concern in Canada since September 2015. In 2016, deaths from fentanyl overdoses in the province of British Columbia averaged two persons per day. In 2017 the death rate rose over 100% with 368 overdose-related deaths in British Columbia between January and April 2017.Fentanyl has started to make its way into heroin as well as illicitly manufactured opioids and benzodiazepines. Fentanyl contamination in cocaine, methamphetamine, ketamine, MDMA, and other drugs is common. A kilogram of heroin laced with fentanyl may sell for more than US$100,000, but the fentanyl itself may be produced far more cheaply, for about US$6,000 per kilogram. Fentanyl was often produced in China and exported illegally to the U.S. The UK illicit drug market is no longer reliant on China, as domestic fentanyl production is replacing imports.As of 2018, fentanyl was the most commonly listed opioid in overdose drug deaths, surpassing heroin. From 2013 until 2016, overdose deaths involving fentanyl were increasing by 113% per year. In 2021, the Public Health Agency of Canada noted that 87% of accidental apparent opioid toxicity deaths involved fentanyl.The intravenous dose causing 50% of opioid-naive experimental subjects to die (LD50) is "3 mg/kg in rats, 1 mg/kg in cats, 14 mg/kg in dogs, and 0.03 mg/kg in monkeys." The LD50 in mice has been given as 6.9 mg/kg by intravenous administration, 17.5 mg/kg intraperitoneally, 27.8 mg/kg by oral administration. The LD50 in humans is unknown, but its estimated that the lethal dose may be as low as 2 mg in some people depending on body size, tolerance, and past usage.
Myths and moral panic
In the late 2010s, some media outlets began to report stories of police officers being hospitalised after touching powdered fentanyl, or after brushing it from their clothing. Topical (or transdermal; via the skin) and inhalative exposure to fentanyl is extremely unlikely to cause intoxication or overdose (except in cases of prolonged exposure with very large quantities of fentanyl), and first responders such as paramedics and police officers are at minimal risk of fentanyl poisoning through accidental contact with intact skin. A 2020 article from the Journal of Medical Toxicology stated that "the consensus of the scientific community remains that illness from unintentional exposures is extremely unlikely, because opioids are not efficiently absorbed through the skin and are unlikely to be carried in the air." The effects being reported in these cases, including rapid heartbeat, hyperventilation and chills, were not symptoms of a fentanyl overdose, and were more commonly associated with a panic attack.A 2021 paper expressed concern that these physical fears over fentanyl may inhibit effective emergency response to overdoses by causing responding officers to spend additional time on unnecessary precautions. The media coverage could also perpetuate a wider social stigma that people who use drugs are dangerous to be around.
Prevention
Many public health initiatives have been started to prevent the misuse and overdose of fentanyl. One of the initiatives that have been started to prevent fentanyl overdose is from the CDC [1]. The effort has been categorized as a Health Alert Network Advisory signaled to a multitude of professionals within the health field. The advisory explains four key action points. Those points include the (a) local need to expand the distribution and use of naloxone and overdose prevention education, (b) expand awareness, access, and availability of treatment for substance use disorders, (c) intervene early with individuals at highest risk for overdose, and (d) improve detection of overdose outbreaks to facilitate more effective response.Another initiative is a social media campaign from the United States Drug Enforcement Administration (DEA) called "One Pill Can Kill". This social media campaigns goal was to spread awareness of the prevalence of counterfeit pills that are being sold in America that is leading to the large overdose epidemic in America. This campaign also shows the difference between counterfeit pills and real pills. This campaign also offers resources for help with drug addiction and rehabilitation.In New Jersey another initiative was started called "The Partnership for a Drug-Free New Jersey" (PDFNJ) was created to inform the people of New Jersey the harm of taking drugs and where to dispose of expired or unneeded prescription medications. Some of this programs campaigns also focus on children and teaching children how to deal with the influence and peer pressures of these drugs.
Pharmacology
Classification
Fentanyl is a synthetic opioid in the phenylpiperidine family, which includes sufentanil, alfentanil, remifentanil, and carfentanil. Some fentanyl analogues such as carfentanil are up to 10,000 times stronger than morphine.
Structure-activity
The structures of opioids share many similarities. Whereas opioids like codeine, hydrocodone, oxycodone, and hydromorphone are synthesized by simple modifications of morphine, fentanyl and its relatives are synthesized by modifications of meperidine. Meperidine is a fully synthetic opioid, and other members of the phenylpiperidine family like alfentanil and sufentanil are complex versions of this structure.
Like other opioids, fentanyl is a weak base that is highly lipid-soluble, protein-bound, and protonated at physiological pH. All of these factors allow it to rapidly cross cellular membranes, contributing to its quick effect in the body and the central nervous system.
Mechanism of action
Fentanyl, like other opioids, acts on opioid receptors. These receptors are G-protein-coupled receptors, which contain seven transmembrane portions, intracellular loops, extracellular loops, intracellular C-terminus, and extracellular N-terminus. The extracellular N-terminus is important in differentiating different types of binding substrates. When fentanyl binds, downstream signaling leads to the inhibitory effects, such as decreased cAMP production, decreased calcium ion influx, and increased potassium efflux. This inhibits the ascending pathways in the central nervous system to increase pain threshold by changing the perception of pain; this is mediated by decreasing propagation of nociceptive signals, resulting in analgesic effects.As a μ-receptor agonist, fentanyl binds 50 to 100 times more potently than morphine. It can also bind to the delta and kappa opioid receptors but with a lower affinity. It has high lipid solubility, allowing it to more easily penetrate the central nervous system. It attenuates "second pain" with primary effects on slow-conducting, unmyelintated C-fibers and is less effective on neuropathic pain and "first pain" signals through small, myelinated A-fibers.Fentanyl can produce the following clinical effects strongly, through μ-receptor agonism.
Supraspinal analgesia (μ1)
Respiratory depression (μ2)
Physical dependence
Muscle rigidityIt produces sedation and spinal analgesia through Κ-receptor agonism.
Therapeutic effects
Pain relief: Primarily, fentanyl provides the relief of pain by acting on the brain and spinal μ-receptors.
Sedation: Fentanyl produces sleep and drowsiness, as the dosage is increased, and can produce the δ-waves often seen in natural sleep on electroencephalogram.
Suppression of the cough reflex: Fentanyl can decrease the struggle against an endotracheal tube and excessive coughing by decreasing the cough reflex, becoming useful when intubating people who are awake and have compromised airways. After receiving a bolus dose of fentanyl, people can also experience paradoxical coughing, which is a phenomenon that is not well understood.
Detection in biological fluids
Fentanyl may be measured in blood or urine to monitor for abuse, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Commercially available immunoassays are often used as initial screening tests, but chromatographic techniques are generally used for confirmation and quantitation. The Marquis Color test may also be used to detect the presence of fentanyl. Using formaldehyde and sulfuric acid, the solution will turn purple when introduced to opium drugs. Blood or plasma fentanyl concentrations are expected to be in a range of 0.3–3.0 μg/L in persons using the medication therapeutically, 1–10 μg/L in intoxicated people, and 3–300 μg/L in victims of acute overdosage. Paper spray-mass spectrometry (PS-MS) may be useful for initial testing of samples.
History
Fentanyl was first synthesized in Belgium by Paul Janssen under the label of his relatively newly formed Janssen Pharmaceutica in 1959. It was developed by screening chemicals similar to pethidine (meperidine) for opioid activity. The widespread use of fentanyl triggered the production of fentanyl citrate (the salt formed by combining fentanyl and citric acid in a 1:1 stoichiometric ratio). Fentanyl citrate entered medical use as a general anaesthetic in 1968, manufactured by McNeil Laboratories under the trade name Sublimaze.In the mid-1990s, Janssen Pharmaceutica developed and introduced into clinical trials the Duragesic patch, which is a formulation of an inert alcohol gel infused with select fentanyl doses, which are worn to provide constant administration of the opioid over a period of 48 to 72 hours. After a set of successful clinical trials, Duragesic fentanyl patches were introduced into medical practice.
Following the patch, a flavored lollipop of fentanyl citrate mixed with inert fillers was introduced in 1998 under the brand name of Actiq, becoming the first quick-acting formation of fentanyl for use with chronic breakthrough pain.In 2009, the US Food and Drug Administration approved Onsolis (fentanyl buccal soluble film), a fentanyl drug in a new dosage form for cancer pain management in opioid-tolerant subjects. It uses a medication delivery technology called BEMA (BioErodible MucoAdhesive), a small dissolvable polymer film containing various fentanyl doses applied to the inner lining of the cheek.Fentanyl has a US DEA ACSCN of 9801 and a 2013 annual aggregate manufacturing quota of 2,108.75 kg, unchanged from the prior year.
Society and culture
Legal status
In the UK, fentanyl is classified as a controlled Class A drug under the Misuse of Drugs Act 1971.In the Netherlands, fentanyl is a List I substance of the Opium Law.
In the U.S., fentanyl is a Schedule II controlled substance per the Controlled Substance Act. Distributors of Abstral are required to implement an FDA-approved risk evaluation and mitigation strategy (REMS) program. In order to curb misuse, many health insurers have begun to require precertification and/or quantity limits for Actiq prescriptions.In Canada, fentanyl is considered a schedule I drug as listed in Canadas Controlled Drugs and Substances Act.Estonia is known to have been home to the worlds longest documented fentanyl epidemic, especially following the Taliban ban on opium poppy cultivation in Afghanistan.A 2018 report by The Guardian indicated that many major drug suppliers on the dark web have voluntarily banned the trafficking of fentanyl.
Recreational use
Illicit use of pharmaceutical fentanyl and its analogues first appeared in the mid-1970s in the medical community and continues in the present. More than 12 different analogues of fentanyl, all unapproved and clandestinely produced, have been identified in the U.S. drug traffic. In February 2018, the U.S. Drug Enforcement Administration indicated that illicit fentanyl analogs have no medically valid use, and thus applied a "Schedule I" classification to them.Fentanyl analogues may be hundreds of times more potent than heroin. Fentanyl is used orally, smoked, snorted, or injected. Fentanyl is sometimes sold as heroin or oxycodone, sometimes leading to overdoses. Many fentanyl overdoses are initially classified as heroin overdoses. Recreational use is not particularly widespread in the EU except for Tallinn, Estonia, where it has largely replaced heroin. Estonia has the highest rate of 3-methylfentanyl overdose deaths in the EU, due to its high rate of recreational use.Fentanyl is sometimes sold on the black market in the form of transdermal fentanyl patches such as Duragesic, diverted from legitimate medical supplies. The gel from inside the patches is sometimes ingested or injected.Another form of fentanyl that has appeared on the streets is the Actiq lollipop formulation. The pharmacy retail price ranges from US$15 to US$50 per unit based on the strength of the lozenge, with the black market cost ranging from US$5 to US$25, depending on the dose. The attorneys general of Connecticut and Pennsylvania have launched investigations into its diversion from the legitimate pharmaceutical market, including Cephalons "sales and promotional practices for Provigil, Actiq and Gabitril."Non-medical use of fentanyl by individuals without opioid tolerance can be very dangerous and has resulted in numerous deaths. Even those with opiate tolerances are at high risk for overdoses. Like all opioids, the effects of fentanyl can be reversed with naloxone, or other opiate antagonists. Naloxone is increasingly available to the public. Long acting or sustained release opioids may require repeat dosage. Illicitly synthesized fentanyl powder has also appeared on the United States market. Because of the extremely high strength of pure fentanyl powder, it is very difficult to dilute appropriately, and often the resulting mixture may be far too strong and, therefore, very dangerous.Some heroin dealers mix fentanyl powder with heroin to increase potency or compensate for low-quality heroin. In 2006, illegally manufactured, non-pharmaceutical fentanyl often mixed with cocaine or heroin caused an outbreak of overdose deaths in the United States and Canada, heavily concentrated in the cities of Dayton, Ohio; Chicago; Detroit; and Philadelphia.
Enforcement
Several large quantities of illicitly produced fentanyl have been seized by U.S. law enforcement agencies. In November 2016, the DEA uncovered an operation making counterfeit oxycodone and Xanax from a home in Cottonwood Heights, Utah. They found about 70,000 pills in the appearance of oxycodone and more than |
Fentanyl | 25,000 in the appearance of Xanax. The DEA reported that millions of pills could have been distributed from this location over the course of time. The accused owned a tablet press and ordered fentanyl in powder form from China. A seizure of a record amount of fentanyl occurred on 2 February 2019, by U.S. Customs and Border Protection in Nogales, Arizona. The 254 pounds (115 kg) of fentanyl, which was estimated to be worth US$3.5M, was concealed in a compartment under a false floor of a truck transporting cucumbers. The "China White" form of fentanyl refers to any of a number of clandestinely produced analogues, especially α-methylfentanyl (AMF). One US Department of Justice publication lists "China White" as a synonym for a number of fentanyl analogues, including 3-methylfentanyl and α-methylfentanyl, which today are classified as Schedule I drugs in the United States. Part of the motivation for AMF is that, despite the extra difficulty from a synthetic standpoint, the resultant drug is more resistant to metabolic degradation. This results in a drug with an increased duration.In June 2013, the United States Centers for Disease Control and Prevention (CDC) issued a health advisory to emergency departments alerting to 14 overdose deaths among intravenous drug users in Rhode Island associated with acetylfentanyl, a synthetic opioid analog of fentanyl that has never been licensed for medical use. In a separate study conducted by the CDC, 82% of fentanyl overdose deaths involved illegally manufactured fentanyl, while only 4% were suspected to originate from a prescription.Beginning in 2015, Canada has seen a number of fentanyl overdoses. Authorities suspected that the drug was being imported from Asia to the western coast by organized crime groups in powder form and being pressed into pseudo-OxyContin tablets. Traces of the drug have also been found in other recreational drugs including cocaine, MDMA, and heroin. The drug has been implicated in multiple deaths from the homeless to young professionals, including teens and young parents. Because of the rising deaths across the country, especially in British Columbia where 1,716 deaths were reported in 2020 and 1,782 from January to October 2021, Health Canada is putting a rush on a review of the prescription-only status of naloxone in an effort to combat overdoses of the drug. In 2018, Global News reported allegations that diplomatic tensions between Canada and China hindered cooperation to seize imports, with Beijing being accused of inaction.Fentanyl has been discovered for sale in illicit markets in Australia in 2017 and in New Zealand in 2018. In response, New Zealand experts called for wider availability of naloxone.In May 2019, China regulated the entire class of fentanyl-type drugs and two fentanyl precursors. Nevertheless it remains the principal origin of fentanyl in the United States: Mexican cartels source fentanyl precursors from China which are finished in Mexico and smuggled to the United States. Following the 2022 visit by Nancy Pelosi to Taiwan, China halted cooperation with the United States on combatting drug trafficking.India has also emerged as a source of fentanyl and fentanyl precursors, where Mexican cartels have already developed networks for the import of synthetic drugs. It is possible fentanyl and precursor production may disperse to other countries such as Nigeria, South Africa, Indonesia, Myanmar, and the Netherlands.In 2020, the Myanmar military and police confiscated 990 gallons of methyl fentanyl, as well as precursors for the illicit synthesis of the drug. According to the United Nations Office on Drugs and Crime, the Shan State of Myanmar has been identified as a major source for fentanyl derivatives. In 2021, the agency reported a further drop in opium poppy cultivation in Burma, as the region’s synthetic drug market continues to expand and diversify.
Recalls
In February 2004, a leading fentanyl supplier, Janssen Pharmaceutica Products recalled one lot, and later, additional lots of fentanyl (brand name: Duragesic) patches because of seal breaches that might have allowed the medication to leak from the patch. A series of class II recalls was initiated in March 2004, and in February 2008 ALZA Corporation recalled their 25 µg/h Duragesic patches due to a concern that small cuts in the gel reservoir could result in accidental exposure of patients or health care providers to the fentanyl gel.
Brand names
Brand names include Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Haldid, Onsolis, Instanyl, Abstral, Lazanda and others.
Cost
In the United States, the 800 mcg tablet was 6.75 times more expensive as of 2020 than the lozenge.
Storage and disposal
The fentanyl patch is one of a few medications that may be especially harmful, and in some cases fatal, with just one dose, if misused by a child. Experts have advised that any unused fentanyl patches be kept in a secure location out of childrens sight and reach, such as a locked cabinet.
In British Columbia, Canada, where there are environmental concerns about toilet flushing or garbage disposal, pharmacists recommend that unused patches be sealed in a child-proof container that is then returned to a pharmacy. In the United States where patches cannot always be returned through a medication take-back program, flushing is recommended for fentanyl patches because it is the fastest and surest way to remove them from the home to prevent them from ingestion by children, pets or others not intended to use them.
Notable deaths
Wilco guitarist Jay Bennett died on 24 May 2009 from an accidental overdose of fentanyl, shortly after he publicly revealed that he needed hip replacement surgery which he could not afford due to his health insurance considering the situation a "pre-existing condition."
Slipknot bassist Paul Gray died on 24 May 2010 from an overdose of morphine and fentanyl.
Medical examiners concluded that musician Prince died on 21 April 2016, from an accidental fentanyl overdose. Fentanyl was among many substances identified in counterfeit pills recovered from his home, especially some that were mislabeled as Watson 385, a combination of hydrocodone and paracetamol.
Author & journalist Michelle McNamara died on 21 April 2016, from an accidental overdose; medical examiners determined fentanyl was a contributing factor.
Canadian video game composer Saki Kaskas died of a fentanyl overdose on 11 November 2016; he had been battling heroin addiction for over a decade.
American rapper Lil Peep died of an accidental fentanyl overdose on 15 November 2017.
On 19 January 2018, the medical examiner-coroner for the county of Los Angeles said musician Tom Petty died from an accidental drug overdose as a result of mixing medications that included fentanyl, acetyl fentanyl, and despropionyl fentanyl (among others). He was reportedly treating "many serious ailments" that included a broken hip.
In 2018, American rapper Mac Miller died from an accidental overdose of fentanyl, cocaine and alcohol.
On 16 December 2018, American tech entrepreneur Colin Kroll, founder of social media video-sharing app Vine and quiz app HQ Trivia, died from an overdose of fentanyl, heroin, and cocaine.
On 1 July 2019, American baseball player Tyler Skaggs died from pulmonary aspiration while under the influence of fentanyl, oxycodone, and alcohol.
On 1 January 2020, American rapper, singer, and songwriter Lexii Alijai died from accidental toxicity resulting from the combination of alcohol and fentanyl.
On 20 August 2020, American singer, songwriter and musician Justin Townes Earle died from an accidental overdose caused by cocaine laced with fentanyl.
On 24 August 2020, Riley Gale, frontman for the Texas metal band Power Trip, died as a result of the toxic effects of fentanyl in a manner that was ruled accidental.
On 22 April 2021, Digital Underground frontman, rapper, and musician Shock G died from an accidental overdose of fentanyl, meth, and alcohol.
On 6 September 2021, actor Michael K. Williams, who rose to fame through his critically acclaimed role as Omar Little on the HBO drama series The Wire, died from an overdose of fentanyl, parafluorofentanyl, heroin, and cocaine.
State use
In August 2018, Nebraska became the first American state to use fentanyl to execute a prisoner. Carey Dean Moore, at the time one of the longest-serving death row inmates in the United States, was executed at the Nebraska State Penitentiary. Moore received a lethal injection, administered as an intravenous series of four drugs that included fentanyl citrate, to inhibit breathing and render the subject unconscious. The other drugs included diazepam as a tranquilizer, cisatracurium besylate as a muscle relaxant, and potassium chloride to stop the heart. The use of fentanyl in execution caused concern among death penalty experts because it was part of a previously untested drug cocktail. The execution was also protested by anti-death penalty advocates at the prison during the execution and later at the Nebraska capitol building.Russian Spetsnaz security forces are suspected to have used a fentanyl analogue, or derivative, to incapacitate people rapidly in the Moscow theater hostage crisis in 2002. The siege was ended, but some hostages may have died from the gas after their health was severely taxed during the days long siege. The Russian Health Minister later stated that the gas was based on fentanyl, but the exact chemical agent has not been identified.
Veterinary use
Fentanyl in injectable formulation is commonly used for analgesia and as a component of balanced sedation and general anesthesia in small animal patients. Its potency and short duration of action make it particularly useful in critically ill patients. In addition, it tends to cause less vomiting and regurgitation than other pure-opiate (codeine, morphine) and synthetic pure-opioid agonists (oxycodone, hydromorphone) when given as a continuous post-operative infusion. As with other pure-opioid agonists, fentanyl can be associated with dysphoria in both dogs and cats.Transdermal fentanyl has also been used for many years in dogs and cats for post-operative analgesia. This is usually done with off-label fentanyl patches manufactured for humans with chronic pain. In 2012, a highly concentrated (50 mg/mL) transdermal solution, trade name Recuvyra, has become commercially available for dogs only. It is FDA approved to provide four days of analgesia after a single application before surgery. It is not approved for multiple doses or other species. The drug is also approved in Europe.
See also
List of fentanyl analogues
Purdue Pharma
References
Further reading
External links
Fentanyl. U.S. National Library of Medicine (Report). Drug Information Portal. National Institutes of Health.
Fentanyl. US DEA information (Report). Archived from the original on 19 October 2002.
Fentanyl. National Institute for Occupational Safety and Health (Report). Emergency Response Database. Center for Disease Control. 8 July 2021.
"Fentanyl landscape | PiHKAL · info". isomerdesign.com. |
Desogestrel | Desogestrel is a progestin medication which is used in birth control pills for women. It is also used in the treatment of menopausal symptoms in women. The medication is available and used alone or in combination with an estrogen. It is taken by mouth.Side effects of desogestrel include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and others. Desogestrel is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has very weak androgenic and glucocorticoid activity and no other important hormonal activity. The medication is a prodrug of etonogestrel (3-ketodesogestrel) in the body.Desogestrel was discovered in 1972 and was introduced for medical use in Europe in 1981. It became available in the United States in 1992. Desogestrel is sometimes referred to as a "third-generation" progestin. Along with norethisterone, it is one of the only progestins that is widely available as a progestogen-only "mini pill" for birth control. Desogestrel is marketed widely throughout the world. It is available as a generic medication. In 2019, the version with ethinylestradiol was the 128th most commonly prescribed medication in the United States, with more than 5 million prescriptions.
Medical uses
Desogestrel is used in hormonal contraception in women, specifically in birth control pills. It is used alone in progestogen-only pills ("mini pills") and in combination with the estrogen ethinylestradiol in combined oral contraceptive pills. Desogestrel and norethisterone are the only progestins that are widely used as a progestogen-only "mini pill". It is also the only newer-generation progestin with reduced androgenic activity that is used in such formulations. In addition to hormonal contraception, desogestrel has been used in combination with estrogens such as estradiol as a component of menopausal hormone therapy. The medication has also been used in the treatment of endometriosis.
Available forms
Desogestrel is available alone in the form of 75 μg oral tablets and at a dose of 150 μg in combination with 20 or 30 μg ethinylestradiol in oral tablets. These formulations are all indicated specifically for contraceptive purposes.
Contraindications
Contraindications of desogestrel include:
Allergy to desogestrel or any other ingredients
Active thrombosis (deep vein thrombosis or pulmonary embolism)
Jaundice or severe liver disease
Hormone-sensitive cancers (e.g., breast cancer)
Unexplained vaginal bleedingDesogestrel is not indicated for use in pregnancy. It is not contraindicated during lactation and breastfeeding.
Side effects
Common side effects of desogestrel may include menstrual irregularities, amenorrhea, headaches, nausea, breast tenderness, and mood changes (e.g., depression), as well as weight gain, acne, and hirsutism. However, it has also been reported to not adversely affect weight. In addition, acne and hirsutism are negligible when combined with ethinylestradiol, and this combination can actually be used to treat such symptoms. Desogestrel can also cause changes in total, LDL, and HDL cholesterol. Uncommon side effects of desogestrel may include vaginal infection, contact lens intolerance, vomiting, hair loss, dysmenorrhea, ovarian cysts, and fatigue, while rare side effects include rash, urticaria, and erythema nodosum. Breast discharge, ectopic pregnancies, and aggravation of angioedema may also occur with desogestrel. Serious side effects of combined oral contraceptives containing desogestrel may include venous thromboembolism, arterial thromboembolism, hormone-dependent tumors (e.g., liver tumors, breast cancer), and melasma.
Overdose
No serious harmful effects have been reported with overdose of desogestrel. Symptoms may include nausea, vomiting, and, in young girls, slight vaginal bleeding. In safety studies, dosages of up to 750 μg/day desogestrel in women showed no adverse effects on laboratory and various other parameters and produced no reported subjective side effects. There is no antidote to desogestrel overdose and treatment should be based on symptoms.
Interactions
Inducers of liver enzymes can increase the metabolism of desogestrel and etonogestrel and reduce their circulating levels. This may result in contraceptive failure. Examples of liver enzyme inducers include barbiturates (e.g., phenobarbital), bosentan, carbamazepine, efavirenz, phenytoin, primidone, rifampicin, and possibly also felbamate, griseofulvin, oxcarbazepine, rifabutin, St. Johns Wort, and topiramate. Many antivirals for HIV/AIDS and HCV, such as boceprevir, nelfinavir, nevirapine, ritonavir, and telaprevir, may increase or decrease levels of desogestrel and etonogestrel. CYP3A4 inhibitors including strong inhibitors like clarithromycin, itraconazole, and ketoconazole and moderate inhibitors like diltiazem, erythromycin, and fluconazole may increase levels of desogestrel and etonogestrel. Hormonal contraceptives may interfere with the metabolism of other drugs, resulting in increased levels (e.g., ciclosporine) or decreased levels (e.g., lamotrigine).
Pharmacology
Pharmacodynamics
Desogestrel is a prodrug of etonogestrel (3-ketodesogestrel), and, via this active metabolite, it has progestogenic activity, antigonadotropic effects, very weak androgenic activity, very weak glucocorticoid activity, and no other hormonal activity.
Progestogenic activity
Desogestrel is a progestogen, or an agonist of the progesterone receptor (PR). It is an inactive prodrug of etonogestrel with essentially no affinity for the PR itself (about 1% of that of promegestone). Hence, etonogestrel is exclusively responsible for the effects of desogestrel. Etonogestrel has about 150% of the affinity of promegestone and 300% of the affinity of progesterone for the PR. Desogestrel (via etonogestrel) is a very potent progestogen and inhibits ovulation at very low doses, in the low microgram range. The effective minimum dosage for inhibition of ovulation is 60 μg/day desogestrel (alone, not in combination with an estrogen). However, some studies in combination with oral estradiol have suggested that higher doses may be necessary. Desogestrel and etonogestrel are among the most potent progestogens available, along with gestodene and levonorgestrel (which have effective ovulation-inhibiting dosages 40 μg/day and 60 μg/day, respectively). Oral desogestrel is clinically on the order of 5,000 times more potent than oral micronized progesterone (which has an effective ovulation-inhibiting dosage of more than 300 mg/day) in humans.Due to its progestogenic activity, desogestrel has potent functional antiestrogenic effects in certain tissues. It dose-dependently antagonizes the effects of ethinylestradiol on the vaginal epithelium, cervical mucus, and endometrium, with marked progestogenic effects occurring at a dosage of 60 μg/day. There is a rise in body temperature in some women at 30 μg/day and in all women at 60 μg/day. Desogestrel also has antigonadotropic effects, which are similarly due to its progestogenic activity. The contraceptive effects of desogestrel in women are mediated not only by prevention of ovulation via its antigonadotropic effects but also by its marked progestogenic and antiestrogenic effects on cervical mucus and the endometrium.Aside from its progestogenic activity, desogestrel also has some off-target hormonal activity at other steroid hormone receptors (see below). However, these activities are relatively weak, and desogestrel is said to be one of the most selective and pure progestogens used in oral contraceptives.
Antigonadotropic effects
Desogestrel has antigonadotropic effects via its progestogenic activity, similarly to other progestogens. It has been found to reduce testosterone levels by 15% in women at a dosage of 125 μg/day. In addition, desogestrel has been extensively investigated as an antigonadotropin at dosages of 150 to 300 μg/day in combination with testosterone in male contraceptive regimens. One study found that 150 μg/day and 300 μg/day desogestrel alone in healthy young men suppressed luteinizing hormone (LH) levels by about 35% and 42%, respectively; follicle-stimulating hormone (FSH) levels by about 47% and 55%, respectively; and testosterone levels by about 59% and 68%, respectively. LH levels were suppressed maximally by desogestrel within 3 days, whereas 14 days were necessary for maximal suppression of FSH and testosterone levels. A previous study by the same authors found that increasing the dosage of desogestrel from 300 μg/day to 450 μg/day resulted in no further suppression of gonadotropin concentrations. The addition of a low dose of 50 or 100 mg/week intramuscular testosterone enanthate after 3 weeks increased testosterone levels and further suppressed LH and FSH levels, to the limits of assay detection (i.e., to undetectable or near-undetectable levels), in both the 150 μg/day and 300 μg/day desogestrel groups. Upon cessation of treatment, levels of LH, FSH, and testosterone all recovered to baseline values within 4 weeks.
Androgenic activity
Etonogestrel has about 20% of the affinity of metribolone and 50% of the affinity of levonorgestrel for the androgen receptor (AR) while desogestrel has no affinity for this receptor. The 5α-reduced metabolite of etonogestrel, 5α-dihydroetonogestrel (3-keto-5α-dihydrodesogestrel), also has some affinity for the AR (about 17% of that of metribolone). Desogestrel (via etonogestrel) has very low androgenic potency, about 1.9 to 7.4% of that of methyltestosterone in animal assays, and hence is considered to be a very weak androgen. Although etonogestrel has about the same affinity for the AR as norethisterone, due to the relatively increased progestogenic potency and decreased androgenic activity of etonogestrel, the drug has markedly higher selectivity for the PR over the AR than older 19-nortestosterone progestins like norethisterone and levonorgestrel. Conversely, its selectivity for the PR over the AR is similar to other newer 19-nortestosterone progestins like gestodene and norgestimate. It has been estimated that 150 μg/day desogestrel has less than one-sixth of the androgenic effect of 1 mg/day norethisterone (these being common dosages of the drugs used in combined oral contraceptives). Clinical studies with norethisterone even at very high dosages (e.g., 10 to 60 mg/day) have observed only mild androgenic effects in a minority of women including acne, increased sebum production, hirsutism, and slight virilization of female fetuses.In accordance with its very weak androgenic activity, desogestrel has minimal effects on lipid metabolism and the blood lipid profile, although there may still be some significant changes. Desogestrel also reduces sex hormone-binding globulin (SHBG) levels by 50% when given to women alone, but when combined with 30 μg/day ethinylestradiol, which in contrast strongly activates SHBG production, there is a 200% increase in SHBG concentrations. Desogestrel may slightly reduce ethinylestradiol-induced increases in SHBG levels. However, at the dosages used in oral contraceptives and in combination with ethinylestradiol, which has potent functional antiandrogenic effects mainly due to increased SHBG levels, the androgenic activity of desogestrel is said to be essentially without any clinical relevance. Indeed, combined oral contraceptives containing ethinylestradiol and desogestrel have been found to significantly decrease free concentrations of testosterone and to possess overall antiandrogenic effects, significantly reducing symptoms of acne and hirsutism in women with hyperandrogenism.
Glucocorticoid activity
Desogestrel has no affinity for the glucocorticoid receptor, but etonogestrel has about 14% of the affinity of dexamethasone for this receptor. Hence, desogestrel and etonogestrel have weak glucocorticoid activity. At typical clinical dosages, the glucocorticoid activity of desogestrel is said to be negligible or very weak and hence not clinically relevant. However, it may nonetheless possibly influence vascular function, with some upregulation of the thrombin receptor observed with etonogestrel in vascular smooth muscle cells in vitro. This could, in theory, increase coagulation and contribute to an increased risk of venous thromboembolism and atherosclerosis. The affinity of etonogestrel for the glucocorticoid receptor is a product of its C11 methylene substitution, as substitutions at the C11 position are a common feature of corticosteroids and as levonorgestrel, which is etonogestrel without the C11 methylene group (17α-ethynyl-18-methyl-19-nortestosterone), has only 1% of the affinity of dexamethasone for the receptor and hence is considered to have negligible glucocorticoid activity.
Other activities
Desogestrel and etonogestrel have no affinity for the estrogen receptor, and hence have no estrogenic activity. However, the metabolite 3β-hydroxydesogestrel has weak affinity for the estrogen receptor (about 2% of that of estradiol), although the significance of this is uncertain.Desogestrel and etonogestrel have no affinity for the mineralocorticoid receptor, and hence have no mineralocorticoid or antimineralocorticoid activity.Desogestrel and etonogestrel show some albeit weak inhibition of 5α-reductase (5.7% inhibition at 0.1 μM, 34.9% inhibition at 1 μM) and cytochrome P450 enzymes (e.g., CYP3A4) (IC50 = 5 μM) in vitro.Desogestrel stimulates the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1). Certain other progestins act similarly in this assay, whereas progesterone acts neutrally. It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies.
Pharmacokinetics
The bioavailability of desogestrel has been found to range from 40 to 100%, with an average of 76%. This significant interindividual variability is comparable to that with norethisterone and levonorgestrel. Peak concentrations of etonogestrel occur about 1.5 hours after a dose while concentrations of desogestrel are very low and have disappeared by 3 hours after a dose. Steady-state levels of etonogestrel are achieved after about 8 to 10 days of daily administration. Accumulation of etonogestrel is thought to be related to progressive inhibition of 5α-reductase and cytochrome P450 monooxygenases (e.g., CYP3A4). The plasma protein binding of desogestrel is 99% and it is bound exclusively to albumin. Etonogestrel is bound 95 to 98% to plasma proteins. It is bound about 65 to 66% to albumin and 30 to 32% to SHBG, with 2 to 5% free in the circulation. While desogestrel is not bound to SHBG, etonogestrel has relatively high affinity for this plasma protein of 3 to 15% of that of dihydrotestosterone, although this is considerably less than that of the related progestins levonorgestrel and gestodene. Neither desogestrel nor etonogestrel are bound by corticosteroid-binding globulin.Desogestrel is a prodrug of etonogestrel (3-ketodesogestrel) and upon ingestion is rapidly and completely transformed into this metabolite in the intestines and liver. Hydroxylation of the C3 position of desogestrel catalyzed by cytochrome P450-dependent enzymes, with 3α-hydroxydesogestrel and 3β-hydroxydesogetrel as intermediates, followed by oxidation of the C3 hydroxyl group, is responsible for the transformation. A small percentage of desogestrel is metabolized into levonorgestrel, which involves the removal of the C11 methylene group. Following further metabolism of etonogestrel, which occurs mainly by reduction of the Δ4-3-keto group (by 5α- and 5β-reductases) and hydroxylation (by monooxygenases), the major metabolite of desogestrel is 3α,5α-tetrahydroetonogestrel. Desogestrel has a very short terminal half-life of about 1.5 hours while etonogestrel has a relatively long elimination half-life of about 21 to 38 hours, reflecting the nature of desogestrel as a prodrug. Desogestrel and etonogestrel are eliminated exclusively as metabolites 50% in urine and 35% in feces.
Chemistry
Desogestrel, also known as 3-deketo-11-methylene-17α-ethynyl-18-methyl-19-nortestosterone or as 11-methylene-17α-ethynyl-18-methylestr-4-en-17β-ol, is a synthetic estrane steroid and a derivative of testosterone. It is more specifically a derivative of norethisterone (17α-ethynyl-19-nortestosterone) and is a member of the gonane (13β-ethylgonane or 18-methylestrane) subgroup of the 19-nortestosterone family of progestins. Desogestrel is the C3 deketo analogue of etonogestrel and the C3 deketo and C11 methylene analogue of levonorgestrel.
Synthesis
A chemical synthesis of desogestrel has been published.
History
Desogestrel was synthesized in 1972 by Organon International in the Netherlands and was first described in the literature in 1975. It was developed following the discovery that C11 substitutions enhance the biological activity of norethisterone. Desogestrel was introduced for medical use in 1981 under the brand names Marvelon and Desogen in the Netherlands. Along with gestodene and norgestimate, it is sometimes referred to as a "third-generation" progestin based on the time of its introduction to the market. It was the first of the three "third-generation" progestins to be introduced. Although desogestrel was introduced in 1981 and was widely used in Europe from this time, it was not introduced in the United States until 1992.
Society and culture
Generic names
Desogestrel is the generic name of the drug and its INN, USAN, BAN, DCF, DCIT, and JAN. While under development, it was known as ORG-2969.
Brand names
Desogestrel is marketed under a variety of brand names throughout the world including Alenvona, Apri, Azalia, Azurette, Bekyree, Caziant, Cerazette, Cerelle, Cesia, Cyclessa, Cyred, Denise, Desogen, Desirett, Diamilla, Emoquette, Enskyce, Feanolla, Gedarel, Gracial, Hana, Isibloom, Juleber, Kalliga, Kariva, Laurina, Linessa, Lovima, Marvelon, Mercilon, Mircette, Mirvala, Novynette, Ortho-Cept, Pimtrea, Reclipsen, Regulon, Simliya, Solia, Velivet, Viorele, and Volnea among others.
Availability
Desogestrel is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, many other European countries, Australia, New Zealand, South Africa, Latin America, Asia, and elsewhere. In the United States, it is available only in combination with ethinylestradiol as a combined oral contraceptive; it is not available alone and is not approved for any other indications.In the UK, in July 2021, some Desogestrel pills were made available to purchase over the counter, without requiring a prescription from a doctor beforehand. Pharmacists use a suitability questionnaire to determine if the medication is going to be suitable for the person, and if it is then they can purchase it from a pharmacy or online (all online purchases require the suitability questionnaire completed before the medication is sent to the customer).
Controversy
In February 2007, the consumer advocacy group Public Citizen released a petition requesting that the Food and Drug Administration ban oral contraceptives containing desogestrel in the United States, citing studies going as far back as 1995 that suggest the risk of dangerous blood clots is doubled for women on such pills in comparison to other oral contraceptives. In 2009, Public Citizen released a list of recommendations that included numerous alternative, second-generation birth control pills that women could take in place of oral contraceptives containing desogestrel. Most of those second-generation medications have been on the market longer and have been shown to be as effective in preventing unwanted pregnancy, but with a lower risk of blood clots. Medications cited specifically in the petition include Apri-28, Cyclessa, Desogen, Kariva, Mircette, Ortho-Cept, Reclipsen, Velivet, and some generic pills, all of which contain desogestrel in combination with ethinylestradiol. Medications containing desogestrel as the only active ingredient (as opposed to being used in conjunction with ethinylestradiol, like in combined oral contraceptives) do not show an increased thrombosis risk and are therefore safer than second-generation birth-control pills in regards to thrombosis.
Research
Desogestrel has been studied extensively as an antigonadotropin for use in combination with testosterone as a hormonal contraceptive in men. Such combinations have been found to be effective in producing reversible azoospermia in most men and reversible azoospermia or severe oligozoospermia in almost all men.
References
Further reading
Chez RA (1989). "Clinical aspects of three new progestogens: desogestrel, gestodene, and norgestimate". Am. J. Obstet. Gynecol. 160 (5 Pt 2): 1296–300. doi:10.1016/S0002-9378(89)80016-X. PMID 2524163.
op ten Berg M (1991). "Desogestrel: using a selective progestogen in a combined oral contraceptive". Adv Contracept. 7 (2–3): 241–50. doi:10.1007/BF01849414. PMID 1835255. S2CID 74471093.
Stone S (1993). "Clinical review of a monophasic oral contraceptive containing desogestrel and ethinyl estradiol". Int J Fertil Menopausal Stud. 38 Suppl 3: 117–21. PMID 8260969.
Collins D (1993). "Selectivity information on desogestrel". Am. J. Obstet. Gynecol. 168 (3 Pt 2): 1010–6. doi:10.1016/0002-9378(93)90330-L. PMID 8447353.
McClamrock HD, Adashi EY (1993). "Pharmacokinetics of desogestrel". Am. J. Obstet. Gynecol. 168 (3 Pt 2): 1021–8. doi:10.1016/0002-9378(93)90332-D. PMID 8447355.
Kaunitz AM (1993). "Combined oral contraception with desogestrel/ethinyl estradiol: tolerability profile". Am. J. Obstet. Gynecol. 168 (3 Pt 2): 1028–33. doi:10.1016/0002-9378(93)90333-E. PMID 8447356.
Archer DF (1994). "Clinical and metabolic features of desogestrel: a new oral contraceptive preparation". Am. J. Obstet. Gynecol. 170 (5 Pt 2): 1550–5. doi:10.1016/S0002-9378(94)05018-0. PMID 8178905.
Sobel NB (1994). "Progestins in preventive hormone therapy. Including pharmacology of the new progestins, desogestrel, norgestimate, and gestodene: are there advantages?". Obstet. Gynecol. Clin. North Am. 21 (2): 299–319. doi:10.1016/S0889-8545(21)00630-6. PMID 7936546.
Fotherby K (1995). "Twelve years of clinical experience with an oral contraceptive containing 30 micrograms ethinyloestradiol and 150 micrograms desogestrel". Contraception. 51 (1): 3–12. doi:10.1016/0010-7824(94)00010-T. PMID 7750281.
Kaplan B (1995). "Desogestrel, norgestimate, and gestodene: the newer progestins". Ann Pharmacother. 29 (7–8): 736–42. doi:10.1177/106002809502907-817. PMID 8520092. S2CID 45885232.
Stone SC (1995). "Desogestrel". Clin Obstet Gynecol. 38 (4): 821–8. doi:10.1097/00003081-199538040-00017. PMID 8616978.
Stanczyk FZ (1997). "Pharmacokinetics of the new progestogens and influence of gestodene and desogestrel on ethinylestradiol metabolism". Contraception. 55 (5): 273–82. doi:10.1016/S0010-7824(97)00030-9. PMID 9220223.
Lammers P, Blumenthal PD, Huggins GR (1998). "Developments in contraception: a comprehensive review of Desogen |
Desogestrel | (desogestrel and ethinyl estradiol)". Contraception. 57 (5 Suppl): 1S–27S. doi:10.1016/S0010-7824(98)00030-4. PMID 9673846.
Benagiano G, Primiero FM (2003). "Seventy-five microgram desogestrel minipill, a new perspective in estrogen-free contraception". Ann. N. Y. Acad. Sci. 997 (1): 163–73. Bibcode:2003NYASA.997..163B. doi:10.1196/annals.1290.019. PMID 14644823. S2CID 25421859.
Scala C, Leone Roberti Maggiore U, Remorgida V, Venturini PL, Ferrero S (2013). "Drug safety evaluation of desogestrel". Expert Opin Drug Saf. 12 (3): 433–44. doi:10.1517/14740338.2013.788147. hdl:11567/576120. PMID 23560561. S2CID 25923595.
Grandi G, Cagnacci A, Volpe A (2014). "Pharmacokinetic evaluation of desogestrel as a female contraceptive". Expert Opin Drug Metab Toxicol. 10 (1): 1–10. doi:10.1517/17425255.2013.844229. PMID 24102478. S2CID 275170.
External links
"Desogestrel". Drug Information Portal. U.S. National Library of Medicine. |
Netupitant/palonosetron | Netupitant/palonosetron, sold under the brand name Akynzeo, is a fixed-dose combination medication used for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. It is marketed and distributed by Helsinn Therapeutics. Netupitant is an NK1 receptor antagonist and palonosetron is a 5-HT3 receptor antagonist.The capsules contain netupitant and palonosetron hydrochloride. The intravenous version is a combination of fosnetupitant chloride hydrochloride and palonosetron hydrochloride.
Contraindications
Netupitant/palonosetron may be contraindicated during pregnancy.
Adverse effects
The most common side effects include headache, weakness, fatigue, upset stomach, constipation, and skin redness. The overall profile of adverse effects is comparable to that of palonosetron (see Palonosetron#Adverse effects); no common adverse effects can be attributed to netupitant.
Interactions
Pharmacology
History
Netupitant/palonosetron was approved for use in the United States in October 2014. It was approved for use in the European Union in May 2015. The intravenous version, which contains the prodrug fosnetupitant in place of netupitant, was approved in the United States in April 2018.
References
External links
"Netupitant mixture with palonosetron". Drug Information Portal. U.S. National Library of Medicine.
"Fosnetupitant". Drug Information Portal. U.S. National Library of Medicine.
"Fosnetupitant and Palonosetron (Professional Patient Advice)". Drugs.com. |
Tiotixene | Tiotixene, or thiothixene, sold under the brand name Navane among others, is a typical antipsychotic of the thioxanthene class which is related to chlorprothixene and is used in the treatment of psychoses like schizophrenia and bipolar mania. It was introduced in the United States in 1967 by Pfizer.Tiotixene is also related to thioproperazine and pipotiazine, members of the phenothiazine class.
Pharmacology
Pharmacodynamics
Tiotixene acts primarily as a highly potent antagonist of the dopamine D2 and D3 receptors (subnanomolar affinity). It is also an antagonist of the histamine H1, α1-adrenergic, and serotonin 5-HT7 receptors (low nanomolar affinity), as well as of various other receptors to a much lesser extent (lower affinity). It does not have any anticholinergic activity. Antagonism of the D2 receptor is thought to be responsible for the antipsychotic effects of tiotixene.
History
Tiotixene was introduced in 1967.
Chemistry
Tiotixene is a member of the thioxanthene class of antipsychotics. Analogues include chlorprothixene, clopenthixol, flupentixol, and zuclopenthixol.
== References == |
Tirofiban | Tirofiban, sold under the brand name Aggrastat, is an antiplatelet medication. It belongs to a class of antiplatelets named glycoprotein IIb/IIIa inhibitors. Tirofiban is a small molecule inhibitor of the protein-protein interaction between fibrinogen and the platelet integrin receptor GP IIb/IIIa and is the first drug candidate whose origins can be traced to a pharmacophore-based virtual screening lead.Tirofiban has been available as a generic medication in the United States since April 2021.
Medical uses
Tirofiban is indicated to reduce the rate of thrombotic cardiovascular events (combined endpoint of death, myocardial infarction, or refractory ischemia/repeat cardiac procedure) in people with non-ST elevation acute coronary syndrome.
Contraindications and precautions
Tirofiban is contraindicated in patients with:
Known hypersensitivity to any component of tirofiban.
History of thrombocytopenia with prior exposure to tirofiban.
Active internal bleeding, or history of bleeding diathesis, major surgical procedure or severe physical trauma within the previous month.
Adverse reactions
Bleeding is the most commonly reported adverse reaction.
Use in pregnancy
Tirofiban has been demonstrated to cross the placenta in pregnant rats and rabbits. Although the doses employed in these studies were a multiple of those used in human beings. no adverse effects on the offspring in both animals have been seen. However, there are no adequate and well controlled studies in pregnant women. Therefore, tirofiban should be used during pregnancy only if clearly indicated.
Nursing mothers: It is not known whether tirofiban is excreted in human milk. However, significant levels of tirofiban are excreted in rat milk. Therefore, nursing should be discontinued during the period of drug administration and the milk discarded. Nursing may resume 24 hours after cessation of treatment with tirofiban.
Pediatric use
Safety and effectiveness in children have not been established.
Other precautions and laboratory exams
The activated partial thromboplastin time is the most reliable coagulation parameter and should be obtained regularly during treatment, particular if a bleeding episode occurs that may be associated with tirofiban therapy. Other important hematological parameters are platelet count, clotting time, hematocrit and hemoglobin. Proper technique regarding artery site access for sheath placement and removal of sheath should be followed. Arterial sheaths should be removed when the patients activated clotting time is < 180 seconds or 2 to 6 hours following withdrawal of heparin.
Side effects
The following side effects were noted under treatment with tirofiban and heparin (and aspirin, if tolerated). Other drugs were used as necessary.
The major adverse effect is bleeding on local sites of clinical intervention and systemically (regarding parts of the body or the whole body system). Major bleeding has occurred in 1.4% of patients and minor bleeding in 10.5%. Transfusions were required to terminate bleeding and to improve bleeding-related anemia in 4.0% of all patients. Geriatric patients have experienced more bleeding episodes than younger, women more than men.
Thrombocytopenia was more often seen in the tirofiban + heparin group (1.5%) than in the heparin control group (0.8%). This adverse effect was usually readily reversible within days.
Positive fecal and urine hemoglobin tests have also been reported.
Post-marketing events have been the occurrence of intracranial bleeding, retroperitoneal bleeding, pulmonary hemorrhage and spinal-epidural hematoma. Fatal bleeding have been reported rarely.
Sometimes, thrombocytopenia was associated with chills, low-grade fever or bleeding complications (see above).
Cases of hypersensitivity including anaphylaxis have occurred.
Interactions
The concomitant application of warfarin or other oral anticoagulants may increase the risk of serious bleeding events. The decision whether maintenance therapy with these drugs should be discontinued during tirofiban treatment has to be made by the responsible clinician.
Pharmacology
Tirofiban has a rapid onset and short duration of action after proper IV administration. Coagulation parameters turn to normal 4 to 8 hours after the drug is withdrawn.
Chemistry
Tirofiban is a synthetic, non-peptide inhibitor of the interaction of fibrinogen with the integrin glycoprotein IIb/IIIa on human platelets. The Merck chemistry team of George Hartman, Melissa Egbertson and Wasyl Halczenko developed tirofiban from a lead compound discovered in focused screening of small molecule replacements of the key arginine-glycine-aspartic acid (Arg-Gly-Asp) subunit of fibrinogen. Computation of the distance between the charged Arg and Asp sites in fibrinogen provided guidance leading to directed screening success. Tirofiban constitutes an antithrombotic, specifically an inhibitor of platelet aggregation.
Tirofiban is a modified version of a molecule found in the venom of the saw-scaled viper Echis carinatus.
History
The drug is marketed under the brand name Aggrastat in the US by Medicure Pharma, in China by Eddingpharm, and in the rest of the world by Correvio International Sàrl.
According to the US Orange Book, it was first approved in the US on 20 April 2000. Patent numbers 5733919; 5965581 and 5972967 all expired in October 2016. Patent 5978698 expired in October 2017. Patent 6136794 expired in January 2019. Patent 6770660 expires in June 2023.
References
Further reading
Hartman GD, Egbertson MS, Halczenko W, Laswell WL, Duggan ME, Smith RL, Naylor AM, Manno PD, Lynch RJ, Zhang G (November 1992). "Non-peptide fibrinogen receptor antagonists. 1. Discovery and design of exosite inhibitors". Journal of Medicinal Chemistry. 35 (24): 4640–2. doi:10.1021/jm00102a020. PMID 1469694.
External links
"Tirofiban". Drug Information Portal. U.S. National Library of Medicine. |
Paromomycin | Paromomycin is an antimicrobial used to treat a number of parasitic infections including amebiasis, giardiasis, leishmaniasis, and tapeworm infection. It is a first-line treatment for amebiasis or giardiasis during pregnancy. Otherwise it is generally a second line treatment option. It is taken by mouth, applied to the skin, or by injection into a muscle.Common side effects when taken by mouth include loss of appetite, vomiting, abdominal pain, and diarrhea. When applied to the skin side effects include itchiness, redness, and blisters. When given by injection there may be fever, liver problems, or hearing loss. Use during breastfeeding appears to be safe. Paromomycin is in the aminoglycoside family of medications and causes microbe death by stopping the creation of bacterial proteins.Paromomycin was discovered in the 1950s from a type of streptomyces and came into medical use in 1960. It is on the World Health Organizations List of Essential Medicines. Paromomycin is available as a generic medication.
Medical uses
It is an antimicrobial used to treat intestinal parasitic infections such as cryptosporidiosis and amoebiasis, and other diseases such as leishmaniasis.
Paromomycin was demonstrated to be effective against cutaneous leishmaniasis in clinical studies in the USSR in the 1960s, and in trials with visceral leishmaniasis in the early 1990s.The route of administration is intramuscular injection and capsule.
Paromomycin topical cream with or without gentamicin is an effective treatment for ulcerative cutaneous leishmaniasis, according to the results of a phase-3, randomized, double-blind, parallel group–controlled trial.
Pregnancy and breastfeeding
The medication is poorly absorbed. The effect it may have on the baby is still unknown.There is limited data regarding the safety of taking paromomycin while breastfeeding but because the drug is poorly absorbed minimal amounts of drug will be secreted in breastmilk.
HIV/AIDS
There is limited evidence that paromomycin can be used in persons coinfected with HIV and Cryptosporidium. A few small trials have showed a reduction in oocyst shedding after treatment with paromomycin.
Adverse effects
The most common adverse effects associated with paromomycin sulfate are abdominal cramps, diarrhea, heartburn, nausea, and vomiting. Long-term use of paromomycin increases the risk for bacterial or fungal infection. Signs of overgrowth include white patches in the oral cavities. Other less common adverse events include myasthenia gravis, kidney damage, enterocolitis, malabsorption syndrome, eosinophilia, headache, hearing loss, ringing in the ear, itching, severe dizziness, and pancreatitis.
Interactions
Paromomycin belongs to the aminoglycoside drug class and therefore are toxic to the kidneys and to ears. These toxicities are additive and are more likely to occur when used with other drugs that cause ear and kidney toxicity. Concurrent use of foscarnet increases the risk of kidney toxicity. Concurrent use of colistimethate and paromomycin can cause a dangerous slowing of breathing known as respiratory depression, and should be done with extreme caution if necessary. When used with systemic antibiotics such as paromomycin, the cholera vaccine can cause an immune response. Use with strong diuretics, which can also harm hearing, should be avoided. Paromomycin may have dangerous reactions when used with the paralytic succinylcholine by increasing its neuromuscular effects.There are no known food or drink interactions with paromomycin.
Mechanism
Paromomycin is a protein synthesis inhibitor in nonresistant cells by binding to 16S ribosomal RNA. This broad-spectrum antibiotic soluble in water, is very similar in action to neomycin. Antimicrobial activity of paromomycin against Escherichia coli and Staphylococcus aureus has been shown. Paromomycin works as an antibiotic by increasing the error rate in ribosomal translation. Paromomycin binds to a RNA loop, where residues A1492 and A1493 are usually stacked, and expels these two residues. These two residues are involved in detection of correct Watson-Crick pairing between the codon and anti codon. When correct interactions are achieved, the binding provides energy to expel the two residues. Paromomycin binding provides enough energy for residue expulsion and thus results in the ribosome incorporating the incorrect amino acid into the nascent peptide chain.
Pharmacokinetics
Absorption
GI absorption is poor. Any obstructions or factors which impair GI motility may increase the absorption of the drug from the digestive tract. In addition, any structural damage, such as lesions or ulcerations, will tend to increase drug absorption.For intramuscular (IM) injection, the absorption is rapid. Paromomycin will reach peak plasma concentration within one hour following IM injection. The in-vitro and in-vivo activities parallel those of neomycin.
Elimination
Almost 100% of the oral dose is eliminated unchanged via feces. Any absorbed drug will be excreted in urine.
History
Paromomycin was discovered in the 1950s amongst the secondary metabolites of a variety of Streptomyces then known as Streptomyces krestomuceticus, now known as Streptomyces rimosus. It came into medical use in 1960.
References
External links
"Paromomycin". Drug Information Portal. U.S. National Library of Medicine. |
Artemether/lumefantrine | Artemether/lumefantrine, sold under the trade name Coartem among others, is a combination of the two medications artemether and lumefantrine. It is used to treat malaria caused by Plasmodium falciparum that is not treatable with chloroquine. It is not typically used to prevent malaria. It is taken by mouth.Common side effects include muscle and joint pains, fever, loss of appetite, and headache. Serious side effects include prolongation of the QT interval. While not well studied, it appears to be safe for use in pregnancy. The dose does not need changing in those with mild or moderate kidney or liver problems.The combination came into medical use in 1992. They were both developed in China. It is on the World Health Organizations List of Essential Medicines. It is not available as a generic medication.
Medical uses
The combination is an effective and well-tolerated malaria treatment, providing high cure rates even in areas of multi-drug resistance.
Side effects
Coartem can cause anaphylactic reactions. The drug frequently causes headache, dizziness and anorexia, although mild forms in most cases. Other fairly common side effects (more than 3% of patients) include sleep disorder, tinnitus, tremor, palpitation, as well as unspecific reactions like vertigo, gastrointestinal disorders, itch and nasopharyngitis.
Interactions
Food, in particular fat, enhances the absorption of both artemether and lumefantrine, and patients are advised to take the tablets with food as soon as a meal can be tolerated. Coartem has a potential to prolong the QT interval, so combinations with other drugs having that property can cause irregular heartbeat, potentially leading to lethal ventricular fibrillation. The combination with halofantrine, another antimalarial, can cause a life-threatening QT prolongation. Drugs and other substances influencing the activity of the liver enzyme CYP3A4, including grapefruit juice, can either increase or lower blood levels of artemether/lumefantrine, depending on the sort of substance. This can either lead to more severe side effects or to reduced efficiency.
History
In 2001, the first fixed dose artemisinin-based combination therapy to meet the World Health Organizations (WHO) pre-qualification criteria for efficacy, safety and quality was created. It is approved in over 80 countries worldwide, including various countries in Africa, as well as Swissmedic, the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA).
Society and culture
Access to treatment
Coartem is provided without profit to developing countries using grants from the Global Fund to Fight AIDS, Tuberculosis and Malaria, US Presidents Malaria Initiative along with other donors. Novartis has lowered the price of Coartem by 50% since 2001, increasing access to patients around the world. The first significant price reduction occurred in 2006, when the price of Coartem decreased from an average of US$1.57 to US$1.00. In 2006, due to an improved supply situation for the natural ingredient artemisinin, Novartis was able to undertake the pharmaceutical industrys most aggressive manufacturing scale-up of its kind from 4 million treatments in 2004 to 62 million treatments in 2006. Novartis and its partners invested heavily in expanding production capacity at their facilities in China, and Suffern, New York. This increase in production capacity ensured that supplies of Coartem met demand which enabled Novartis to further decrease the price of Coartem. In April 2008, Novartis further reduced the public sector price of Coartem by approximately 20%, to an average of US$0.80 (or US$0.37 for a childs treatment pack). This price reduction was made possible through production efficiency gains.
Prior to this program, Novartis was criticised for a court case they launched against India, seeking to prohibit the marketing of cheap generic drugs. An Indian court ruled against Novartis, saying that the case was a "threat to people suffering from cancer [...] and other diseases who are too poor to pay for them".
Approval in the United States
On April 8, 2009, the U.S. Food and Drug Administration (FDA) announced that Coartem was approved for the treatment of acute, uncomplicated malaria infections in adults and children weighing at least five kilograms (approximately 11 pounds) becoming the first artemisinin-based combination therapy approved in the United States.
Dispersible
In January 2009, Novartis and Medicines for Malaria Venture (MMV) launched Coartem Dispersible, an artemisinin-based combination therapy developed specifically for children with malaria. Coartem Dispersible contains the same ratio of artemether and lumefantrine as Coartem. It works as well as other formulations. The sweet-tasting Coartem Dispersible tablets disperse quickly in small amounts of water, easing administration and ensuring effective dosing.
== References == |
Cabergoline | Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinsons disease, and for other indications. It is taken by mouth.
Cabergoline is an ergot derivative and a potent dopamine D2 receptor agonist.Cabergoline was patented in 1980 and approved for medical use in 1993.
Medical uses
Lactation suppression
Hyperprolactinemia
Adjunctive therapy of prolactin-producing pituitary gland tumors (prolactinomas);
Monotherapy of Parkinsons disease in the early phase;
Combination therapy, together with levodopa and a decarboxylase inhibitor such as carbidopa, in progressive-phase Parkinsons disease;
In some countries also: ablactation and dysfunctions associated with hyperprolactinemia (amenorrhea, oligomenorrhea, anovulation, nonpuerperal mastitis and galactorrhea);
Treatment of uterine fibroids.
Adjunctive therapy of acromegaly, cabergoline has low efficacy in suppressing growth hormone levels and is highly efficient in suppressing hyperprolactinemia that is present in 20-30% of acromegaly cases; growth hormone and prolactin are similar structurally and have similar effects in many target tissues, therefore targeting prolactin may help symptoms when growth hormone secretion can not be sufficiently controlled by other methods;Cabergoline is frequently used as a first-line agent in the management of prolactinomas due to its higher affinity for D2 receptor sites, less severe side effects, and more convenient dosing schedule than the older bromocriptine, though in pregnancy bromocriptine is often still chosen since there is less data on safety in pregnancy for cabergoline.
Off-label
It has at times been used as an adjunct to SSRI antidepressants as there is some evidence that it counteracts certain side effects of those drugs, such as reduced libido and anorgasmia. It also has been suggested that it has a possible recreational use in reducing or eliminating the male refractory period, thereby allowing men to experience multiple ejaculatory orgasms in rapid succession, and at least two scientific studies support those speculations.: e28–e33 Additionally, a systematic review and meta-analysis concluded that prophylactic treatment with cabergoline reduces the incidence, but not the severity, of ovarian hyperstimulation syndrome (OHSS), without compromising pregnancy outcomes, in females undergoing stimulated cycles of in vitro fertilization (IVF). Also, a study on rats found that cabergoline reduces voluntary alcohol consumption, possibly by increasing GDNF expression in the ventral tegmental area. It may be used in the treatment of restless legs syndrome.
Pregnancy and lactation
Relatively little is known about the effects of this medication during pregnancy and lactation. In some cases the related bromocriptine may be an alternative when pregnancy is expected.
Pregnancy: available preliminary data indicates a somewhat increased rate of congenital abnormalities in patients who became pregnant while treated with cabergoline.. However, one study concluded that "foetal exposure to cabergoline through early pregnancy does not induce any increase in the risk of miscarriage or foetal malformation."
Lactation: In rats cabergoline was found in the maternal milk. Since it is not known if this effect also occurs in humans, breastfeeding is usually not recommended if/when treatment with cabergoline is necessary.
Lactation suppression: In some countries cabergoline (Dostinex) is sometimes used as a lactation suppressant. It is also used in veterinary medicine to treat false pregnancy in dogs.
Contraindications
Hypersensitivity to ergot derivatives
Pediatric patients (no clinical experience)
Severely impaired liver function or cholestasis
Concomitant use with drugs metabolized mainly by CYP450 enzymes such as erythromycin and ketoconazole, because increased plasma levels of cabergoline may result (although cabergoline undergoes minimal CYP450 metabolism).
Cautions: severe cardiovascular disease, Raynauds disease, gastroduodenal ulcers, active gastrointestinal bleeding, hypotension.
Side effects
Side effects are mostly dose dependent. Much more severe side effects are reported for treatment of Parkinsons disease and (off-label treatment) for restless leg syndrome which both typically require very high doses. The side effects are considered mild when used for treatment of hyperprolactinemia and other endocrine disorders or gynecologic indications where the typical dose is one hundredth to one tenth that for Parkinsons disease.Cabergoline requires slow dose titration (2–4 weeks for hyperprolactinemia, often much longer for other conditions) to minimise side effects. The extremely long bioavailability of the medication may complicate dosing regimens during titration and require particular precautions.
Cabergoline is considered the best tolerable option for hyperprolactinemia treatment although the newer and less tested quinagolide may offer similarly favourable side effect profile with quicker titration times.
Approximately 200 patients with newly diagnosed Parkinsons disease participated in a clinical study of cabergoline monotherapy. Seventy-six (76) percent reported at least one side effect. These side effects were chiefly mild or moderate:
GI tract: Side effects were extremely frequent. Fifty-three percent of patients reported side effects. Very frequent: Nausea (30%), constipation (22%), and dry mouth (10%). Frequent: Gastric irritation (7%), vomiting (5%), and dyspepsia (2%).
Psychiatric disturbances and central nervous system (CNS): Altogether 51 percent of patients were affected. Very frequent: Sleep disturbances (somnolence 18%, insomnia 11%), vertigo (27%), and depression (13%). Frequent: dyskinesia (4%) and hallucinations (4%).
Cardiovascular: Approximately 30 percent of patients experienced side effects. Most frequent were hypotension (10%), peripheral edema (14%) and non-specific edema (2%). Arrhythmias were encountered in 4.8%, palpitations in 4.3%, and angina pectoris in 1.4%.In a combination study with 2,000 patients also treated with levodopa, the incidence and severity of side effects was comparable to monotherapy. Encountered side effects required a termination of cabergoline treatment in 15% of patients. Additional side effects were infrequent cases of hematological side effects, and an occasional increase in liver enzymes or serum creatinine without signs or symptoms.
As with other ergot derivatives, pleuritis, exudative pleura disease, pleura fibrosis, lung fibrosis, and pericarditis are seen. These side effects are noted in less than 2% of patients. They require immediate termination of treatment. Clinical improvement and normalization of X-ray findings are normally seen soon after cabergoline withdrawal. It appears that the dose typically used for treatment of hyperprolactinemia is too low to cause this type of side effects.
Valvular heart disease
In two studies published in the New England Journal of Medicine on January 4, 2007, cabergoline was implicated along with pergolide in causing valvular heart disease. As a result of this, the FDA removed pergolide from the U.S. market on March 29, 2007. Since cabergoline is not approved in the U.S. for Parkinsons Disease, but for hyperprolactinemia, the drug remains on the market. The lower doses required for treatment of hyperprolactinemia have been found to be not associated with clinically significant valvular heart disease or cardiac valve regurgitation.
Interactions
No interactions were noted with levodopa or selegiline. The drug should not be combined with other ergot derivatives. Dopamine antagonists such as antipsychotics and metoclopramide counteract some effects of cabergoline. The use of antihypertensive drugs should be intensively monitored because excessive hypotension may result from the combination.
Pharmacology
Pharmacodynamics
Cabergoline is a long-acting dopamine D2 receptor agonist. In-vitro rat studies show a direct inhibitory effect of cabergoline on the prolactin secretion in the lactotroph cells of the pituitary gland and cabergoline decreases serum prolactin levels in reserpinized rats. Although cabergoline is commonly described principally as a D2 receptor agonist, it also possesses significant affinity for the dopamine D3, and D4, serotonin 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C, and α2-adrenergic receptors, as well as moderate/low affinity for the dopamine D1, serotonin 5-HT7, and α1-adrenergic receptors. Cabergoline functions as an partial or full agonist at all of these receptors except for the 5-HT7, α1-adrenergic, and α2-adrenergic receptors, where it acts as an antagonist. Cabergoline has been associated with cardiac valvulopathy due to activation of 5-HT2B receptors.
Pharmacokinetics
Following a single oral dose, resorption of cabergoline from the gastrointestinal (GI) tract is highly variable, typically occurring within 0.5 to 4 hours. Ingestion with food does not alter its absorption rate. Human bioavailability has not been determined since the drug is intended for oral use only. In mice and rats the absolute bioavailability has been determined to be 30 and 63 percent, respectively. Cabergoline is rapidly and extensively metabolized in the liver and excreted in bile and to a lesser extent in urine. All metabolites are less active than the parental drug or inactive altogether. The human elimination half-life is estimated to be 63 to 68 hours in patients with Parkinsons disease and 79 to 115 hours in patients with pituitary tumors. Average elimination half-life is 80 hours.
The therapeutic effect in treatment of hyperprolactinemia will typically persist for at least 4 weeks after cessation of treatment.
History
Cabergoline was first synthesized by scientists working for the Italian drug company Farmitalia-Carlo Erba in Milan who were experimenting with semisynthetic derivatives of the ergot alkaloids, and a patent application was filed in 1980. The first publication was a scientific abstract at the Society for Neuroscience meeting in 1991.Farmitalia-Carlo Erba was acquired by Pharmacia in 1993, which in turn was acquired by Pfizer in 2003.Cabergoline was first marketed in The Netherlands as Dostinex in 1992. The drug was approved by the FDA on December 23, 1996. It went generic in late 2005 following US patent expiration.
Society and culture
Brand names
Brand names of cabergoline include Cabaser, Dostinex, Galastop (veterinary), and Kelactin (veterinary), among others.
Research
Cabergoline was studied in one person with Cushings disease, to lower adrenocorticotropic hormone (ACTH) levels and cause regression of ACTH-producing pituitary adenomas.
References
External links
Cabergoline, Mayo Clinic |
Urofollitropin | Urofollitropin is a purified form of follicle-stimulating hormone (FSH) that is manufactured by extraction from human urine and then purified to remove various proteins and other substances. FSH is important in the development of follicles (eggs) produced by the ovaries. Given by subcutaneous injection, it is used in combination with human chorionic gonadotropin (hCG) to assist in ovulation and fertility. It is also used with in vitro fertilization methods. The dosage is adjusted to each individuals response.The most common side effects are abdominal or pelvic pain, bloating, as well as redness, pain or swelling at the injection site. Follitropin is possibly associated with increased risk of endometrial carcinoma. It is not for use during pregnancy, as there is evidence for birth defects under follitropin treatment.Bravelle sold in the United States from March 2014 through October 2015 is subject to a recall and refund by its maker, Ferring Pharmaceuticals, because certain batches of the medicine had a lower strength than stated.
References
External links
Bravelle, by Ferring Pharmaceuticals, Switzerland
Fostimon by Institut Biochemique SA, Switzerland |
Verapamil | Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina (chest pain from not enough blood flow to the heart), and supraventricular tachycardia. It may also be used for the prevention of migraines and cluster headaches. It is given by mouth or by injection into a vein.Common side effects include headache, low blood pressure, nausea, and constipation. Other side effects include allergic reactions and muscle pains. It is not recommended in people with a slow heart rate or heart failure. It is believed to cause problems for the fetus if used during pregnancy. It is in the non–dihydropyridine calcium channel blocker family of medications.Verapamil was approved for medical use in the United States in 1981. It is on the World Health Organizations List of Essential Medicines. Verapamil is available as a generic medication. Long acting formulations exist. In 2019, it was the 141st most commonly prescribed medication in the United States, with more than 4 million prescriptions.
Medical uses
Verapamil is used for controlling ventricular rate in supraventricular tachycardia and migraine headache prevention. It is a class-IV antiarrhythmic and more effective than digoxin in controlling ventricular rate. Verapamil is not listed as a first line agent by the guidelines provided by JAMA in JNC-8. However, it may be used to treat hypertension if patient has co-morbid atrial fibrillation or other types of arrhythmia.Verapamil is also used intra-arterially to treat cerebral vasospasm. Verapamil is used to treat the condition cluster headache. Tentative evidence supports the use of verapamil topically to treat plantar fibromatosis.
Contraindications
Use of verapamil is generally avoided in people with severe left ventricular dysfunction, hypotension (systolic blood pressure less than 90 mm Hg), cardiogenic shock, and hypersensitivity to verapamil. It is also contraindicated in people with atrial flutter or fibrillation and an existing accessory tract such as in Wolff-Parkinson-White syndrome.
Side effects
The most common side effect of verapamil is constipation (7.3%). While the definite mechanism by which Verapamil causes constipation has not been studied, studies have been conducted to rule out mechanisms of actions that might yield this adverse effect. In a study conducted by The National Library of Medicine titled, "Effect of Verapamil on the Human Intestinal Transit", the study found that verapamil does not have an effect on upper GI transit but rather in the colon.Other side effects include dizziness (3.3%), nausea (2.7%), low blood pressure (2.5%), and headache 2.2%. Other side effects seen in less than 2% of the population include: edema, congestive heart failure, pulmonary edema, fatigue, elevated liver enzymes, shortness of breath, low heart rate, atrioventricular block, rash and flushing. Along with other calcium channel blockers, verapamil is known to induce gingival enlargement.
Overdose
Acute overdose is often manifested by nausea, weakness, slow heart rate, dizziness, low blood pressure, and abnormal heart rhythms. Plasma, serum, or blood concentrations of verapamil and norverapamil, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities. Blood or plasma verapamil concentrations are usually in a range of 50–500 μg/L in persons on therapy with the drug, but may rise to 1–4 mg/L in acute overdose patients and are often at levels of 5–10 mg/L in fatal poisonings.
Mechanism of action
Verapamils mechanism in all cases is to block voltage-dependent calcium channels. In cardiac pharmacology, calcium channel blockers are considered class-IV antiarrhythmic agents. Since calcium channels are especially concentrated in the sinoatrial and atrioventricular nodes, these agents can be used to decrease impulse conduction through the AV node, thus protecting the ventricles from atrial tachyarrhythmias. Verapamil is also a Kv voltage gated potassium channel blocker.Calcium channels are also present in the smooth muscle lining blood vessels. By relaxing the tone of this smooth muscle, calcium channel blockers dilate the blood vessels. This has led to their use in treating high blood pressure and angina pectoris. The pain of angina is caused by a deficit in oxygen supply to the heart.
Calcium channel blockers like verapamil dilate the coronary blood vessels, which increases the supply of blood and oxygen to the heart. They also cause dilatation of systemic peripheral vessels as well, causing a reduction in the workload of the heart. Thereby reducing myocardial oxygen consumption.
Cluster headaches
Preventive therapy with verapamil is believed to work because it has an effect on the circadian rhythm and on CGRPs. As CGRP-release is controlled by voltage-gated calcium channels.
Pharmacokinetic details
More than 90% of verapamil is absorbed when given orally, but due to high first-pass metabolism, bioavailability is much lower (10–35%). It is 90% bound to plasma proteins and has a volume of distribution of 3–5 L/kg. It takes 1 to 2 hours to reach peak plasma concentration after oral administration. It is metabolized in the liver to at least 12 inactive metabolites (though one metabolite, norverapamil, retains 20% of the vasodilatory activity of the parent drug). As its metabolites, 70% is excreted in the urine and 16% in feces; 3–4% is excreted unchanged in urine. This is a nonlinear dependence between plasma concentration and dosage. Onset of action is 1–2 hours after oral dosage. Half-life is 5–12 hours (with chronic dosages). It is not cleared by hemodialysis. It is excreted in human milk. Because of the potential for adverse reaction in nursing infants, nursing should be discontinued while verapamil is administered.Verapamil has been reported to be effective in both short-term and long-term treatment of mania and hypomania. Addition of magnesium oxide to the verapamil treatment protocol enhances the antimanic effect.
Veterinary use
Intra-abdominal adhesions are common in rabbits following surgery. Verapamil can be given postoperatively in rabbits which have suffered trauma to abdominal organs to prevent formation of these adhesions. Such effect was not documented in another study with ponies.
Uses in cell biology
Verapamil inhibits the ATP-binding cassette (ABC) transporter family of proteins found in stem cells and has been used to study cancer stem cells (CSC) within head and neck squamous cell carcinomas.Verapamil is also used in cell biology as an inhibitor of drug efflux pump proteins such as P-glycoprotein and other ABC transporter proteins. This is useful, as many tumor cell lines overexpress drug efflux pumps, limiting the effectiveness of cytotoxic drugs or fluorescent tags. It is also used in fluorescent cell sorting for DNA content, as it blocks efflux of a variety of DNA-binding fluorophores such as Hoechst 33342. Radioactively labelled verapamil and positron emission tomography can be used with to measure P-glycoprotein function.
See also
Gallopamil
Tiapamil
References
External links
"Verapamil". Drug Information Portal. U.S. National Library of Medicine.
"Verapamil hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Oxcarbazepine | Oxcarbazepine, sold under the brand name Trileptal among others, is a medication used to treat epilepsy. For epilepsy it is used for both focal seizures and generalized seizures. It has been used both alone and as add-on therapy in people with bipolar disorder who have had no success with other treatments. It is taken by mouth.Common side effects include nausea, vomiting, dizziness, drowsiness, double vision and trouble with walking. Serious side effects may include anaphylaxis, liver problems, pancreatitis, suicide ideation, and an abnormal heart beat. While use during pregnancy may harm the baby, use may be less risky than having a seizure. Use is not recommended during breastfeeding. In those with an allergy to carbamazepine there is a 25% risk of problems with oxcarbazepine. How it works is not entirely clear.Oxcarbazepine was patented in 1969 and came into medical use in 1990. It is available as a generic medication. In 2019, it was the 162nd most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Medical uses
Oxcarbazepine is an anticonvulsant used to reduce the occurrence of epileptic episodes, and is not intended to cure epilepsy. Oxcarbazepine is used alone or in combination with other medications for the treatment of focal (partial) seizures in adults. In pediatric populations, it can be used by itself for the treatment of partial seizures for children 4 years and older, or in combination with other medications for children 2 years and older. There is some evidence to support its effectiveness in reducing seizure frequency when used as an add-on therapy for drug-resistant focal epilepsy but there are concerns over tolerability.
Pregnancy
There is limited data analyzing the impact of oxcarbazepine on a human fetus. Animal studies have shown increased fetal abnormalities in pregnant rats and rabbits exposed to oxcarbazepine during pregnancy. In addition, oxcarbazepine is structurally similar to carbamazepine, which is considered to be teratogenic in humans (pregnancy category D). Oxcarbazepine should only be used during pregnancy if the benefits justify the risks.Pregnant women on oxcarbazepine should be closely monitored, as plasma levels of the active metabolite licarbazepine have been shown to potentially decrease during pregnancy.
Breastfeeding
Oxcarbazepine and its metabolite licarbazepine are both present in human breast milk and thus, some of the active drug can be transferred to a nursing infant. When considering whether to continue this medication in nursing mothers, the impact of the drugs side effect profile on the infant, should be weighed against its anti-epileptic benefit for the mother.
Side effects
Side effects are dose-dependent. The most common include dizziness, blurred or double vision, nystagmus, ataxia, fatigue, headaches, nausea, vomiting, sleepiness, difficulty in concentration and mental sluggishness.Other rare side effects of oxcarbazepine include severe low blood sodium (hyponatremia), anaphylaxis / angioedema, hypersensitivity (especially if experienced with carbamazepine), toxic epidermal necrolysis, Stevens–Johnson syndrome, and thoughts of suicide.Measurement of serum sodium levels should be considered in maintenance treatment or if symptoms of hyponatremia develop. Low blood sodium is seen in 20-30% of people taking oxcarbazepine and 8-12% of those experience severe hyponatremia. Some side effects, such as headaches, are more pronounced shortly after a dose is taken and tend to fade with time (60 to 90 minutes). Other side effects include stomach pain, tremor, rash, diarrhea, constipation, decreased appetite and dry mouth. Photosensitivity is a potential side-effect and people could experience severe sunburns as a result of sun exposure.Oxcarbazepine may lead to hypothyroxinemia. The well-known reduction in free and total thyroxine concentration may be due to both peripheral and central mechanisms.
Interactions
Oxcarbazepine, licarbazepine and many other common drugs influence each other through interaction with the Cytochrome P450 family of enzymes. This leads to a cluster of dozens of common drugs interacting with one another to varying degrees, some of which are especially noteworthy:
Oxcarbazepine and licarbazepine are potent inhibitors of CYP2C19 and thus have the potential to increase plasma concentration of drugs, which are metabolized through this pathway. Other antiepileptics, which are CYP2C19 substrates and thus may be metabolised at a reduced rate when combined with oxcarbazepine include diazepam, hexobarbital, mephenytoin, methylphenobarbital, nordazepam, phenobarbital, phenytoin, primidone. However, many classes of drugs are ligands to CYP2C19.
In addition, oxcarbazepine and licarbazepine are CYP3A4 and CYP3A5 inducers and thus have the potential to decrease the plasma concentration of CYP3A4 and CYP3A5 substrates. Drugs which are CYP3A4 or CYP3A5 substrates and therefore may have reduced efficacy include calcium channel antagonists against high blood pressure and oral contraceptives. However, whether the extent of CYP3A4/5 induction at therapeutic doses reaches clinical significance is unclear.
Furthermore, for example phenytoin and phenobarbital are known to reduce plasma levels of licarbazepine through induction of Cytochrome P450 enzymes.
Pharmacology
Oxcarbazepine is a prodrug, which is largely metabolized to its pharmacologically active 10-monohydroxy derivative licarbazepine (sometimes abbreviated MHD). Oxcarbazepine and MHD exert their action by blocking voltage-sensitive sodium channels, thus leading to the stabilization of hyper-excited neural membranes, suppression of repetitive neuronal firing and diminishment propagation of synaptic impulses. Furthermore, anticonvulsant effects of these compounds could be attributed to enhanced potassium conductance and modulation of high-voltage activated calcium channels.
Pharmacokinetics
Oxcarbazepine has high bioavailability upon oral administration. In a study in humans, only 2% of oxcarbazepine remained unchanged, 70% were reduced to licarbazepine; the rest were minor metabolites. The half-life of oxcarbazepine is considered to be about 2 hours, whereas licarbazepine has a half-life of nine hours. Through its chemical difference to carbamazepine metabolic epoxidation is avoided, reducing hepatic risks. Licarbazepine is metabolised by conjugation with Glucuronic acid. Approximately 4% are oxidised to the inactive 10,11-dihydroxy derivative. Elimination is almost completely renal, with faeces accounting to less than 4%. 80% of the excreted substances are to be attributed to licarbazepine or its glucuronides.
Pharmacodynamics
Both oxcarbazepine and licarbazepine were found to show anticonvulsant properties in seizure models done on animals. These compounds had protective functions whenever tonic extension seizures were induced electrically, but such protection was less apparent whenever seizures were induced chemically. There was no observable tolerance during a four weeks course of treatment with daily administration of oxcarbazepine or licarbazepine in electroshock test on mice and rats. Most of the antiepileptic activity can be attributed to licarbazepine. Aside from its reduction in side effects, it is presumed to have the same main mechanism as carbamazepine, sodium channel inhibition, and is generally used to treat the same conditions.
Pharmacogenetics
The human leukocyte antigen (HLA) allele B*1502 has been associated with an increased incidence of Stevens–Johnson syndrome and toxic epidermal necrolysis in people treated with carbamazepine, and thus those treated with oxcarbazepine might have similar risks. People of Asian descent are more likely to carry this genetic variant, especially some Malaysian populations, Koreans (2%), Han Chinese (2–12%), Indians (6%), Thai (8%), and Philippines (15%). Therefore, it has been suggested to consider genetic testing in these people prior to initiation of treatment.
Structure
Oxcarbazepine is a structural derivative of carbamazepine, with a ketone in place of the carbon–carbon double bond on the dibenzazepine ring at the 10 position (10-keto). This difference helps reduce the impact on the liver of metabolizing the drug, and also prevents the serious forms of anemia or agranulocytosis occasionally associated with carbamazepine. Aside from this reduction in side effects, it is thought to have the same mechanism as carbamazepine — sodium channel inhibition (presumed to be the main mechanism of action) – and is generally used to treat the same conditions.
Oxcarbazepine is a prodrug which is activated to licarbazepine in the liver.
History
First made in 1966, it was patent-protected by Geigy in 1969 through DE 2011087 . It was approved for use as an anticonvulsant in Denmark in 1990, Spain in 1993, Portugal in 1997, and eventually for all other EU countries in 1999. It was approved in the US in 2000. In September 2010, Novartis, of which Geigy are part of its corporate roots, pleaded guilty to marketing Trileptal for the unapproved uses of neuropathic pain and bipolar disorder.
Research
Research has investigated the use of oxcarbazepine as a mood stabilizer in bipolar disorder, with further evidence needed to fully assess its suitability. It may be beneficial in trigeminal neuralgia.
References
External links
"Oxcarbazepine". Drug Information Portal. U.S. National Library of Medicine. |
Dostarlimab | Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody used as a medication for the treatment of endometrial cancer. Dostarlimab is a programmed death receptor-1 (PD-1)–blocking monoclonal antibody.The most common side effects reported in the US include fatigue/asthenia, nausea, diarrhea, anemia, and constipation. Additional side effects reported in the European Union include vomiting, joint pain, itching, rash, fever, and hypothyroidism (low levels of thyroid hormones).Dostarlimab was approved for the treatment of endometrial cancer in both the United States and the European Union in April 2021.Based on the GARNET trial, Dostarlimab (Jemperli) gained accelerated approval from the Food and Drug Administration (FDA) in April 2022. Jemperlis mechanism of action allows it to act directly on cancerous cells. Follow-up appointments accompanying long-term treatments or long-term post-operative therapies are not necessary with dostarlimab.
Medical uses
In the United States, dostarlimab is indicated for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen. Platinum-based agents such as cisplatin, carboplatin and oxaliplatin are mainstays of treatment when it comes to cancer chemotherapy treatment. It is also indicated for the treatment of solid tumors.In the European Union, dostarlimab is indicated as monotherapy for the treatment of adults with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI H) recurrent or advanced endometrial cancer (EC) that has progressed on or following prior treatment with a platinum-containing regimen.In August 2021, the US Food and Drug Administration (FDA) granted accelerated approval to dostarlimab for adults with mismatch repair deficient (dMMR) recurrent or advanced solid tumors, as determined by an FDA-approved test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.
Endometrial cancer
Endometrial cancer (EC) is a disease where cancerous cells reside in the lining of the uterus (endometrium). There are four stages in EC, ranging from staying settled in the endometrium to the cancer spreading to other organs in the body. This disease can be treated if discovered at the beginning of development. In those with chemoresistant MSI-high tumors, studies conducted on dostarlimab and pembrolizumab display promising results of the tumors reacting well to the therapies.
Solid tumors
Solid tumors are tumors that do not contain any liquid or cysts, which can occur in many places including bones, muscles and organs. The most common types of solid tumors are sarcomas and carcinomas. Dostarlimab can used to treat recurrent or advance tumors for patients who have tried alternative treatment options.
Side effects
Serious adverse reactions in >2% of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and fever (pyrexia).Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrine disease (endocrinopathies), and nephritis.The most common side effects reported while taking this medication during a trial were dyspnea, asthenia, fatigue, and nausea.Symptoms of overdose are similar to the side effect profile of the medication, so it could involve significant immune-mediated reactions.
Immune-mediated adverse reactions
Dostarlimab is a monoclonal antibody that binds to PD-1 to block it from binding PD-1 ligands to remove inhibition of immune response. With this, it causes risk for immune-mediated adverse reactions. These reactions can be severe or fatal and occur in any part of the body: organs or tissues.Examples of immune-mediated adverse reactions include immune-mediated pneumonitis, colitis, hepatitis, adrenal insufficiency, hypophysitis, thyroid disorders, nephritis with renal dysfunction, and dermatologic reactions.
Pregnancy and lactation
Dostarlimab can cause harm to a fetus. The death of the fetus can occur from the immune systems reaction to the fetus through the examination of its mechanism in animal studies. Dostarlimab is a human immunoglobulin G (IgG4), which could permeate through the placental barrier. This may risk harm to the developing fetus as the drug may be passed on from the mother.Data is not available regarding the presence of dostarlimab in breastmilk.
Hepatotoxicity
Dostarlimab causes mild to moderate elevations to serum aminotransferase and alkaline phosphatase in 15-25% of recipients. Serum ALT elevation above five times the normal range occurs in 2-3% of recipients. Some people treated with dostarlimab can develop immune related liver injury.Some symptoms of liver injury or acute liver failure can include jaundice, pain in the upper right abdomen, ascites, nausea/vomiting, and disorientation or confusion.
Pharmacology
Dostarlimab is a humanized IgG4 monoclonal antibody that was derived from a mouse antibody which was humanized via Complementarity Determining Region (CDR) grafting. Its serum half-life is 25.4 days.Other PD-1 antibodies included nivolumab (Opdivo) and pembrolizumab (Keytruda), both of which have uses in many different types of cancers which include classical Hodgkin lymphoma, renal cell carcinoma, and breast cancer. Another PD-1 antibody is cemiplimab (Libtayo) which was approved for treatment of squamous cell carcinoma, basal cell carcinoma and non-small cell lung cancer.
Mechanism of action
Dostarlimab binds to the PD-1 receptor, with high affinity, to block its activity with PD-1 ligands (PD-L1) and PD-L2). PD-1 is a co-inhibitory receptor that is an important checkpoint protein for regulating T-cell tolerance. When PD-1 is constantly stimulated by PD-1 ligands, which are highly expressed in cancer cells, it allows cancer cells to dodge T-cell mediated immune responses. Therefore, blocking the binding of PD-1 to these ligands can allow T-cells to function normally and prevent tumor cells from bypassing immune surveillance. In mouse tumor models, it was shown that inhibiting PD-1 activity decreased tumor growth.
Efficacy
In the GARNET Trial, dostarlimab achieved favorable results in decreasing the size of the tumor in those with endometrial cancer. The study observed people with endometrial cancer from seven different countries and the size of the tumor was reduced in 42% of the population studied.Dostarlimab exhibits better efficacy than other PD-1 inhibitors, such as avelumab and durvalumab, in dMMR advanced endometrial cancers. Efficacy of the drug is measured by the response rate, which is 47% for dostarlimab.
History
In 2020, dostarlimab, a PD-1inhibitor, was undergoing phase I/II and phase III clinical trials.In 2020, the manufacturer, Tesaro, announced preliminary successful results from the phase I/II GARNET study.In 2020, the GARNET study announced that dostarlimab had promising potential to treat a specific subset of individuals with recurrent or advanced endometrial cancer.In April 2021, dostarlimab was approved for the treatment of recurrent or advanced endometrial cancer with mismatch repair deficient (dMMR), which are genetic abnormalities that disrupt DNA repair, in individuals who had previously been treated with platinum-containing regimens.In April 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GSK). Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in participants with advanced solid tumors.In 2022, an early clinical study of dostarlimab reported a 100% remission rate in 14 patients with rectal cancer who had mismatch repair deficiency, a type of genetic mutation that only affects 5-10% of cases.
Society and culture
Dostarlimab is the international nonproprietary name (INN), and the United States Adopted Name (USAN).
Legal status
In February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Jemperli, intended for the treatment of certain types of recurrent or advanced endometrial cancer. The applicant for this medicinal product is GSK (Ireland) Limited. Dostarlimab was approved for medical use in the European Union in April 2021.
Economics
In the United States, dostarlimab is an expensive medication, costing around US$11,000 per dose.For patients with endometrial cancer it is estimated cost of dostarlimab is $104,000 in the first 6 months. This only includes the cost of accessing the medication and not the doctors fee or infusion cost or imaging. Thus those who are uninsured will most likely have trouble getting treatment with Dostarlimab.
Among those who are insured, those who have Medicaid insurance are less likely to receive full care for gynecologic cancer. Those insured through private insurance still experience economical hardships while getting treatment. Uninsured patients do not tend to get screened regularly, which results in late diagnosis of the disease.
References
External links
"Dostarlimab". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02715284 for "Study of TSR-042, an Anti-programmed Cell Death-1 Receptor (PD-1) Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET)" at ClinicalTrials.gov |
Bethanechol | Bethanechol is a parasympathomimetic choline carbamate that selectively stimulates muscarinic receptors without any effect on nicotinic receptors. Unlike acetylcholine, bethanechol is not hydrolyzed by cholinesterase and will therefore have a long duration of action. Bethanechol is sold under the brand names Duvoid (Roberts), Myotonachol (Glenwood), Urecholine (Merck Frosst) and Urocarb (Hamilton). The name bethanechol refers to its structure as the urethane of beta-methylcholine.
Medical uses
Bethanechol alleviates dry mouth and is sometimes given orally or subcutaneously to treat urinary retention resulting from general anesthetic, diabetic neuropathy of the bladder, or a side effect of antidepressants; or to treat gastrointestinal lack of muscular tone. The muscarinic receptors in the bladder and gastrointestinal tract stimulate contraction of the bladder and expulsion of urine, and increased gastrointestinal motility, respectively. Bethanechol should be used to treat these disorders only after mechanical obstruction is ruled out as a possible cause.
Its potential benefit in the treatment of cerebral palsy has been investigated.Atropine is given preoperatively to prevent voiding of the bowel/bladder during surgery, Bethanechol is then given postoperatively to revert this action.
Contraindications
Use of bethanechol, as well as all other muscarinic receptor agonists, is contraindicated in patients with asthma, coronary insufficiency, peptic ulcers, intestinal obstruction and hyperthyroidism. The parasympathomimetic action of this drug will exacerbate the symptoms of these disorders.
References
External links
"Bethanechol". Drug Information Portal. U.S. National Library of Medicine. |
DTaP-IPV vaccine | DTaP-IPV vaccine is a combination vaccine whose full generic name is diphtheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine (IPV).It is also known as DTaP/IPV, dTaP/IPV, DTPa-IPV, or DPT-IPV. It protects against the infectious diseases diphtheria, tetanus, pertussis, and poliomyelitis.Branded formulations marketed in the USA are Kinrix from GlaxoSmithKline and Quadracel from Sanofi Pasteur.Repevax is available in the UK.Within Japan, the formulation is called 四種混合（shishukongou - "mixture of 4").
Astellas markets it under the クアトロバック (Quattro-back) formulation, while another is available from Mitsubishi Tanabe Pharma named テトラビック (Tetrabic).
A previous product by Takeda Pharmaceutical Company has been withdrawn by the company.
== References == |
Fluoxymesterone | Fluoxymesterone, sold under the brand names Halotestin and Ultandren among others, is an androgen and anabolic steroid (AAS) medication which is used in the treatment of low testosterone levels in men, delayed puberty in boys, breast cancer in women, and anemia. It is taken by mouth.Side effects of fluoxymesterone include symptoms of masculinization like acne, increased hair growth, voice changes, and increased sexual desire. It can also cause liver damage and cardiovascular side effects like high blood pressure. The drug is a synthetic androgen and anabolic steroid and hence is an agonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has strong androgenic effects and moderate anabolic effects, which make it useful for producing masculinization.Fluoxymesterone was first described in 1956 and was introduced for medical use in 1957. In addition to its medical use, fluoxymesterone is used to improve physique and performance. The drug is a controlled substance in many countries and so non-medical use is generally illicit.
Medical uses
Fluoxymesterone is or has been used in the treatment of hypogonadism, delayed puberty, and anemia in males and the treatment of breast cancer in women. It is specifically approved in one or more countries for the treatment of hypogonadism in men, delayed puberty in boys, and breast cancer in women. Current prescribing guidelines in the United States list only the treatment of androgen deficiency in males and breast cancer in females as indications.Fluoxymesterone is less effective in inducing masculinization than testosterone, but is useful for maintaining established masculinization in adults.
Available forms
Fluoxymesterone is available in the form of 2, 5, and 10 mg oral tablets.
Non-medical uses
Fluoxymesterone is used for physique- and performance-enhancing purposes by competitive athletes, bodybuilders, and powerlifters.
Side effects
Side effects that have been associated with fluoxymesterone include acne, edema, seborrhea/seborrheic dermatitis, alopecia, hirsutism, voice deepening, virilization in general, flushing, gynecomastia, breast pain, menstrual disturbances, hypogonadism, testicular atrophy, clitoral enlargement, penile enlargement, priapism, increased aggressiveness, prostate enlargement, cardiovascular toxicity, and hepatotoxicity, among others.
Pharmacology
Pharmacodynamics
As an AAS, fluoxymesterone is an agonist of the androgen receptor (AR), similarly to androgens like testosterone and DHT. It is a substrate for 5α-reductase like testosterone, and so is potentiated in so-called "androgenic" tissues like the skin, hair follicles, and prostate gland via transformation into 5α-dihydrofluoxymesterone. As such, fluoxymesterone has a relatively poor ratio of anabolic to androgenic activity similarly to testosterone and methyltestosterone. However, fluoxymesterone is nonetheless proportionally less androgenic and more anabolic than methyltestosterone and testosterone.Fluoxymesterone has been reported to be non-aromatizable due to steric hindrance by its C11β hydroxyl group, and hence is not considered to have a propensity for producing estrogenic effects such as gynecomastia or fluid retention. However, paradoxically, a case report of severe fluoxymesterone-induced gynecomastia exists, and gynecomastia associated with fluoxymesterone has also been reported in other publications, although this may not be due to estrogenic activity. Fluoxymesterone is thought to possess little or no progestogenic activity.Because of the presence of its 17α-methyl group, the metabolism of fluoxymesterone is impeded, resulting in it being orally active, although also hepatotoxic.
11β-HSD inhibition
Fluoxymesterone has been found to act as a potent inhibitor of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) (IC50 = 60–630 nM), with a potency comparable to that of the 11β-HSD2 inhibitor glycyrrhetinic acid. This action of fluoxymesterone is unique among AAS and is likely related to its 11β-hydroxyl group. 11β-HSD2 is responsible for the inactivation of the glucocorticoids cortisol and corticosterone (into cortisone and 11-dehydrocorticosterone, respectively). Inhibition of 11β-HSD2 by fluoxymesterone may result in mineralocorticoid receptor overactivation and associated side effects such as hypertension and fluid retention, and has been hypothesized to be involved in the cardiovascular and other adverse effects of fluoxymesterone.
Glucocorticoid activity
Unlike other AAS, fluoxymesterone has structural features in common with corticosteroids, including its C9α fluoro and C11β hydroxyl groups. In relation to this, it has weak (micromolar) but potentially clinically significant affinity for the glucocorticoid receptor.
Pharmacokinetics
Fluoxymesterone has approximately 80% oral bioavailability, unlike testosterone, as the C17α methyl group of fluoxymesterone inhibits first-pass metabolism. It has very low affinity for human serum sex hormone-binding globulin (SHBG), less than 5% of that of testosterone and less than 1% of that of DHT. The drug is metabolized in the liver, mainly by 6β-hydroxylation, 5α- and 5β-reduction, 3α- and 3β-keto-oxidation, and 11β-hydroxy-oxidation. Its known active metabolites include 5α-dihydrofluoxymesterone and 11-oxofluoxymesterone. Fluoxymesterone has an elimination half-life of approximately 9.2 hours, which is long relative to that of testosterone. It is eliminated in the urine, with less than 5% excreted unchanged.
Chemistry
Fluoxymesterone, also known as 9α-fluoro-11β-hydroxy-17α-methyltestosterone or as 9α-fluoro-17α-methylandrost-4-en-11β,17β-diol-3-one, is a synthetic androstane steroid and a 17α-alkylated derivative of testosterone (androst-4-en-17β-ol-3-one). It is specifically the derivative of testosterone with a fluorine atom at the C9α position, a hydroxyl group at the C11β position, and a methyl group at the C17α position.
Synthesis
Step one: The first step in the synthesis of fluoxymesterone is the microbiological oxidation of commercially available androstenedione (1.11) by Actinomyces; this introduces a hydroxyl group to the 11α-position (1.12), which is then oxidised to a ketone using Jones reagent, yielding the 3,11,17-triketone, adrenosterone (1.13). Pyrrolidine then reacts to form an enamine (1.14) by reaction with the 3α-keto group, protecting it from alkylation in a subsequent step. The regioselectivity of pyrrolidine for reaction at the 3α-position occurs inherently in the structure of adrenosterone, due to the position of the sterically bulky methyl groups. In subsequent steps, alkylation of the 17-keto group (1.14) using Grignard reagent, addition of hydride at the 11-position (1.15) and regeneration of the protected 3-keto group yields the starting material (1.16) for the final steps of the fluoxymesterone synthesis. This involves more standard synthetic transformations.
Step two: The 11α-hydroxyl of the starting material (1.16) is sulfonylated by p-toluenesulfonyl chloride; addition of trimethylamine (base) deprotonates the 11α-carbon, yielding an (E2) elimination of tosylate (pka - 5) to give olefin (1.17). Stereospecificity of reaction between olefin and hypobromous acid (HOBr) in base, N-bromosuccinimide (NBS), is determined by the formation of a bromonium intermediate; the electrophilic bromonium cation approaches the rings less sterically hindered α-face and is attacked by the π-electron density of the alkene. The hydroxide ion then attacks from above the ring (β-face) at the 11-carbon, resulting in a structure (1.18) by the stereospecific addition of hydroxyl and bromine across the double bond. Addition of sodium hydroxide results in deprotonation of the 11α-hydroxyl, and the subsequent structure undergoes an intramolecular SN2 epoxy ring formation. The epoxy ring of the β-epoxide (1.19) is protonated to give an oxironium ion intermediate. In a concerted process, fluoride attacks the rings α-face from below, as one of the two oxygen-carbon bonds is broken on the opposite face; hence regenerating the 11α-hydroxyl trans to the fluorine substituent. The resulting structure (1.20) is the androgenic steroid, fluoxymesterone.
Detection in body fluids
Detection of halotestin and other such illegal anabolic steroids in sports is achieved by GS-MS identification of urinary excreted anabolic steroids and their metabolites. In a test for halotestin, a dry residue obtained from a urine sample is dissolved in dimethylformamide and a sulfur trioxide-pyridine complex and is heated with 1% potassium carbonate solution. Halotestin and many of its metabolites contain two polar hydroxyl groups, leading to intermolecular hydrogen bonding that increases their boiling point and reduces volatility. In order to attain a gaseous sample for GC-MS, the products of hydrolysis are extracted, dissolved in methanol and derivatised to form volatile trimethylsilyl (TMS) esters by adding N-methyl-N-trimethylsilyl-trifluoroacetamide (MSTFA) and trimethylsilylimidazole (TMSImi).
History
Fluoxymesterone was first described in 1956 and was introduced for medical use in the United States in 1957. Over time the use of fluoxymesterone has become increasingly controversial and limited.
Society and culture
Generic names
Fluoxymesterone is the generic name of the drug and its INN, USP, BAN, DCIT, and JAN, while fluoxymestérone is its DCF.
Brand names
Brand names of fluoxymesterone include Android-F, Androxy, Halotestin, Ora-Testryl, and Ultandren among others.
Availability
United States
Fluoxymesterone is one of the few AAS that remains available for medical use in the United States. The others (as of November 2017) are testosterone, testosterone cypionate, testosterone enanthate, testosterone undecanoate, methyltestosterone, oxandrolone, and oxymetholone.
Other countries
Availability of fluoxymesterone aside from the United States remains scarce, but it is marketed in some other countries such as Mexico, Moldova, and Taiwan.
Legal status
Fluoxymesterone, along with other AAS, is a schedule III controlled substance in the United States under the Controlled Substances Act.
References
== External links == |
Demeclocycline | Demeclocycline (INN, BAN, USAN, brand name Declomycin) is a tetracycline antibiotic which was derived from a mutant strain of Streptomyces aureofaciens.
Uses
Demeclocycline is officially indicated for the treatment of various types of bacterial infections. It is used as an antibiotic in the treatment of Lyme disease, acne, and bronchitis. Resistance, though, is gradually becoming more common, and demeclocycline is now rarely used for treatment of infections.It is widely used (though off-label in many countries including the United States) in the treatment of hyponatremia (low blood sodium concentration) due to the syndrome of inappropriate antidiuretic hormone (SIADH) when fluid restriction alone has been ineffective. Physiologically, this works by reducing the responsiveness of the collecting tubule cells to ADH.The use in SIADH actually relies on a side effect; demeclocycline induces nephrogenic diabetes insipidus (dehydration due to the inability to concentrate urine).The use of demeclocycline in SIADH was first reported in 1975, and, in 1978, a larger study found it to be more effective and better tolerated than lithium carbonate, the only available treatment at the time. Demeclocycline used to be the drug of choice for treating SIADH. Meanwhile it might be superseded, now that vasopressin receptor antagonists, such as tolvaptan, became available.
Contraindications
Like other tetracyclines, demeclocycline is contraindicated in children and pregnant or nursing women. All members of this class interfere with bone development and may discolour teeth.
Side effects and interactions
These are similar to those of other tetracyclines. Skin reactions with sunlight have been reported. Like only few other known tetracycline derivatives, demeclocycline causes nephrogenic diabetes insipidus. Furthermore demeclocycline might have psychotropic side effects similar to lithium.Tetracyclines bind to cations, such as calcium, iron (when given orally), and magnesium, rendering them insoluble and inadsorbable for the gastrointestinal tract. Demeclocycline should not be taken with food (particularly milk and other dairy products) or antacids.
Mechanism of action
As with related tetracycline antibiotics, demeclocycline acts by binding to the 30S ribosomal subunit to inhibit binding of aminoacyl tRNA which impairs protein synthesis by bacteria. It is bacteriostatic (it impairs bacterial growth, but does not kill bacteria directly).Demeclocycline inhibits the renal action of antidiuretic hormone by interfering with the intracellular second messenger cascade (specifically, inhibiting adenylyl cyclase activation) after the hormone binds to vasopressin V2 receptors in the kidney. Exactly how demeclocycline does this has yet to be elucidated, however.
Brand names
Brand names include Declomycin, Declostatin, Ledermycin, Bioterciclin, Deganol, Deteclo, Detravis, Meciclin, Mexocine, and Clortetrin.
== References == |
Fluphenazine | Fluphenazine, sold under the brand name Prolixin among others, is a high-potency typical antipsychotic medication. It is used in the treatment of chronic psychoses such as schizophrenia, and appears to be about equal in effectiveness to low-potency antipsychotics like chlorpromazine. It is given by mouth, injection into a muscle, or just under the skin. There is also a long acting injectable version that may last for up to four weeks. Fluphenazine decanoate, the depot injection form of fluphenazine, should not be used by people with severe depression.Common side effects include movement problems, sleepiness, depression and increased weight. Serious side effects may include neuroleptic malignant syndrome, low white blood cell levels, and the potentially permanent movement disorder tardive dyskinesia. In older people with psychosis as a result of dementia it may increase the risk of dying. It may also increase prolactin levels which may result in milk production, enlarged breasts in males, impotence, and the absence of menstrual periods. It is unclear if it is safe for use in pregnancy.Fluphenazine is a typical antipsychotic of the phenothiazine class. Its mechanism of action is not entirely clear but believed to be related to its ability to block dopamine receptors. In up to 40% of those on long term phenothiazines, liver function tests become mildly abnormal.Fluphenazine came into use in 1959. The injectable form is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. It was discontinued in Australia in 2017.
Medical use
A 2018 Cochrane review found that fluphenazine was an imperfect treatment and other inexpensive drugs less associated with side effects may be an equally effective choice for people with schizophrenia.
Side effects
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Pharmacology
Pharmacodynamics
Fluphenazine acts primarily by blocking post-synaptic D2 receptors in the basal ganglia, cortical and limbic system. It also blocks alpha-1 adrenergic receptors, muscarinic-1 receptors, and histamine-1 receptors.
Pharmacokinetics
History
Fluphenazine came into use in 1959.
Availability
The injectable form is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. It was discontinued in Australia in 2017.
Veterinary
In horses, it is sometimes given by injection as an anxiety-relieving medication, though there are many negative common side effects and it is forbidden by many equestrian competition organizations.
References
External links
"Fluphenazine". Drug Information Portal. U.S. National Library of Medicine. |
Sodium phosphates | Sodium phosphate is a generic term for a variety of salts of sodium (Na+) and phosphate (PO43−). Phosphate also forms families or condensed anions including di-, tri-, tetra-, and polyphosphates. Most of these salts are known in both anhydrous (water-free) and hydrated forms. The hydrates are more common than the anhydrous forms.
Uses
Sodium phosphates have many applications in food and for water treatment. For example, sodium phosphates are often used as emulsifiers (as in processed cheese), thickening agents, and leavening agents for baked goods. They are also used to control pH of processed foods. They are also used in medicine for constipation and to prepare the bowel for medical procedures. Moreover, they are used in detergents for softening water, and as an efficient anti rust solution.
Adverse effects
Sodium phosphates are popular in commerce in part because they are inexpensive and because they are nontoxic at normal levels of consumption. However, oral sodium phosphates when taken at high doses for bowel preparation for colonoscopy may in some individuals carry a risk of kidney injury under the form of phosphate nephropathy. There are several oral phosphate formulations which are prepared extemporaneously. Oral phosphate prep drugs have been withdrawn in the United States, although evidence of causality is equivocal. Since safe and effective replacements for phosphate purgatives are available, several medical authorities have recommended general disuse of oral phosphates.
Monophosphates
Three families of sodium monophosphates are common, those derived from orthophosphate (PO43−), hydrogen phosphate (HPO42−), and dihydrogenphosphate (H2PO4−). Some of the most well known salts are shown in the table.
Di- and polyphosphates
In addition to these phosphates, sodium forms a number of useful salts with pyrophosphates (also called diphosphates), triphosphates and high polymers. Of these salts, those of the diphosphates are particularly common commercially.
Beyond the diphosphates, sodium salts are known triphosphates, e.g. sodium triphosphate and tetraphosphates. The cyclic polyphosphates, called metaphosphates, include the trimer sodium trimetaphosphate and the tetramer, Na3P3O9 and Na4P4O12, respectively.
Polymeric sodium phosphates are formed upon heating mixtures of NaH2PO4 and Na2HPO4, which induces a condensation reaction. The specific polyphosphate generated depends on the details of the heating and annealing. One derivative is the glassy (i.e., amorphous) Grahams salt. It is a linear polyphosphate the average formula NaO(NaPO3)Na2. Crystalline high molecular weight polyphosphates include Kurrols salt and Maddrells salt (CAS#10361-03-2). These species have the formula [NaPO3]n[NaPO3(OH)]2 where n can be as great as 2000. In terms of their structures, these polymers consist of PO3− "monomers", with the chains are terminated by protonated phosphates.
References
External links
Bell, Russel N (April 1973), "Sodium Aluminum Phosphate Cheese Emulsifying Agent", US Patent 3726960
Lien, YH (16 July 2008), "Is bowel preparation before colonoscopy a risky business for the kidney?", Nature Clinical Practice Nephrology, 4 (11): 606–14, doi:10.1038/ncpneph0939, PMID 18797448, S2CID 340122 |
Avapritinib | Avapritinib, sold under the brand name Ayvakit among others, is a medication used for the treatment of advanced systemic mastocytosis and for the treatment of tumors due to one specific rare mutation: it is specifically intended for adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) that harbor a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation.Common side effects include edema (swelling), nausea, fatigue/asthenia (abnormal physical weakness or lack of energy), cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation (secretion of tears), abdominal pain, constipation, rash and dizziness.Avapritinib is a kinase inhibitor.
Medical uses
Avapritinib is indicated for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring the platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.Avapritinib is also indicated for the treatment of adults with advanced systemic mastocytosis, aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, and mast cell leukemia (MCL).
History
The U.S. Food and Drug Administration (FDA) approved avapritinib in January 2020. The application for avapritinib was granted fast track designation, breakthrough therapy designation, and orphan drug designation. The FDA granted approval of Ayvakit to Blueprint Medicines Corporation.Avapritinib was approved based on the results from the Phase I NAVIGATOR clinical trial involving 43 subjects with GIST harboring a PDGFRA exon 18 mutation, including 38 subjects with PDGFRA D842V mutation. Subjects received avapritinib 300 mg or 400 mg orally once daily until disease progression or they experienced unacceptable toxicity. The recommended dose was determined to be 300 mg once daily. The trial measured how many subjects experienced complete or partial shrinkage (by a certain amount) of their tumors during treatment (overall response rate). For subjects harboring a PDGFRA exon 18 mutation, the overall response rate was 84%, with 7% having a complete response and 77% having a partial response. For the subgroup of subjects with PDGFRA D842V mutations, the overall response rate was 89%, with 8% having a complete response and 82% having a partial response. While the median duration of response was not reached, 61% of the responding subjects with exon 18 mutations had a response lasting six months or longer (31% of subjects with an ongoing response were followed for less than six months).The FDA approved avapritinib based on evidence from one clinical trial (NCT02508532) of 204 subjects with GIST. The trial was conducted at 17 sites in the United States, Europe and Asia.Avapritinib showed a median PFS of 4.2 months compared to 5.6 months for regorafenib. The difference in median PFS between the avapritinib and regorafenib groups was not statistically significant. The overall response rate was 17 percent for the avapritinib group and 7 percent for the regorafenib group. The VOYAGER trial evaluated the efficacy and safety of avapritinib (N=240) versus regorafenib (N=236) in patients with third- or fourth-line GIST.Avapritinib was approved for medical use in the European Union in September 2020.Ayvakit was granted approval for advanced systemic mastocytosis by the FDA on June 16th 2021.
References
Further reading
Wu CP, Lusvarghi S, Wang JC, et al. (July 2019). "Avapritinib: A Selective Inhibitor of KIT and PDGFRα that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines". Mol. Pharm. 16 (7): 3040–3052. doi:10.1021/acs.molpharmaceut.9b00274. PMC 6620786. PMID 31117741.
Gebreyohannes YK, Wozniak A, Zhai ME, et al. (January 2019). "Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors". Clin. Cancer Res. 25 (2): 609–618. doi:10.1158/1078-0432.CCR-18-1858. PMID 30274985.
External links
"Avapritinib". Drug Information Portal. U.S. National Library of Medicine (NLM).
"Avapritinib". NCI Dictionary of Cancer Terms. National Cancer Institute.
"Avapritinib". National Cancer Institute. 28 January 2020.
Clinical trial number NCT02508532 for "(NAVIGATOR) Study of BLU-285 in Patients With Gastrointestinal Stromal Tumors (GIST) and Other Relapsed and Refractory Solid Tumors" at ClinicalTrials.gov
Clinical trial number NCT02561988 for "(EXPLORER) Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies" at ClinicalTrials.gov
Clinical trial number NCT03580655 for "(PATHFINDER) Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, in Patients With Advanced Systemic Mastocytosis" at ClinicalTrials.gov |
Sonidegib | Sonidegib (INN), sold under the brand name Odomzo, is a medication used to treat cancer.Sonidegib is Hedgehog signaling pathway inhibitor (via smoothened antagonism).
Approvals and indications
It was approved for medical use in the United States and in the European Union in 2015It is indicated for the treatment of adults with locally advanced basal-cell carcinoma that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy.
Pharmacology
Sonidegib is administered by mouth. Common side effects include muscle spasms, hair loss, fatigue, abdominal pain, nausea, headache, and weight loss.Sonidegib binds to and inhibits smoothened to inhibit activation of the Hedgehog pathway. Sonidegib is primarily metabolized by CYP3A and is eliminated hepatically.
Development
It has been investigated as a potential treatment for:
Pancreatic cancer
Breast cancer
Basal cell carcinoma of the skin
Small cell lung cancer
Medulloblastoma
Advanced solid tumors (including ovarian, breast, pancreatic, stomach, oesophageal cancers and glioblastoma multiforme)
Acute leukemia and chronic myeloid leukemia
Myelofibrosis and essential thrombocythaemiaIt has demonstrated significant efficacy against melanoma in vitro and in vivo. It also demonstrated efficacy in a mouse model of pancreatic cancer.
References
External links
"Sonidegib". Drug Information Portal. U.S. National Library of Medicine.
"Sonidegib phosphate". Drug Information Portal. U.S. National Library of Medicine. |
Avacopan | Avacopan, sold under the brand name Tavneos, is a medication used to treat anti-neutrophil cytoplasmic autoantibody-associated vasculitis.The most common side effects include nausea (feeling sick), headache, decrease in white blood cell count, upper respiratory tract (nose and throat) infection, diarrhea, vomiting, and nasopharyngitis (inflammation of the nose and throat).Avacopan was approved for medical use in Japan in September 2021, and in the United States in October 2021. It is the first orally-administered inhibitor of the complement C5a receptor approved by the U.S. Food and Drug Administration (FDA). Avacopan is a complement 5a receptor antagonist and a cytochrome P450 3A4 (CYP3A4) inhibitor.
Medical uses
In the United States, avacopan is indicated as an adjunctive treatment of adults with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis) in combination with standard therapy including glucocorticoids.In the European Union, avacopan, in combination with a rituximab or cyclophosphamide regimen, is indicated for the treatment of adults with severe, active granulomatosis with polyangiitis or microscopic polyangiitis (MPA).
Society and culture
Legal status
In November 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Tavneos, intended, in combination with a rituximab or cyclophosphamide regimen, for the treatment of adults with severe, active granulomatosis with polyangiitis or microscopic polyangiitis. The applicant for this medicinal product is Vifor Fresenius Medical Care Renal Pharma France. The EMA considers avacopan to be a first-in-class medicine. Avacopan was approved for medical use in the European Union in January 2022.
Names
Avacopan is the international nonproprietary name (INN).
References
Further reading
Jayne DR, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P, et al. (September 2017). "Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis". J Am Soc Nephrol. 28 (9): 2756–2767. doi:10.1681/ASN.2016111179. PMC 5576933. PMID 28400446.
Jayne DR, Merkel PA, Schall TJ, Bekker P (February 2021). "Avacopan for the Treatment of ANCA-Associated Vasculitis". N Engl J Med. 384 (7): 599–609. doi:10.1056/NEJMoa2023386. PMID 33596356.
Merkel PA, Jayne DR, Wang C, Hillson J, Bekker P (April 2020). "Evaluation of the Safety and Efficacy of Avacopan, a C5a Receptor Inhibitor, in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Treated Concomitantly With Rituximab or Cyclophosphamide/Azathioprine: Protocol for a Randomized, Double-Blind, Active-Controlled, Phase 3 Trial". JMIR Res Protoc. 9 (4): e16664. doi:10.2196/16664. PMC 7175182. PMID 32088663.
Merkel PA, Niles J, Jimenez R, Spiera RF, Rovin BH, Bomback A, et al. (November 2020). "Adjunctive Treatment With Avacopan, an Oral C5a Receptor Inhibitor, in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis". ACR Open Rheumatol. 2 (11): 662–671. doi:10.1002/acr2.11185. PMC 7672305. PMID 33128347.
External links
"Avacopan". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02994927 for "A Phase 3 Clinical Trial of CCX168 (Avacopan) in Patients With ANCA-Associated Vasculitis (ADVOCATE)" at ClinicalTrials.gov |
Tranylcypromine | Tranylcypromine, sold under the brand name Parnate among others, is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.
Tranylcypromine is a propylamine formed from the cyclization of amphetamines side chain; therefore, it is classified as a substituted amphetamine.
Medical uses
Tranylcypromine is used to treat major depressive disorder, including atypical depression, especially when there is an anxiety component, typically as a second-line treatment. It is also used in depression that is not responsive to reuptake inhibitor antidepressants, such as the SSRIs, TCAs, or bupropion.Systematic reviews and meta-analyses have reported that tranylcypromine is significantly more effective in the treatment of depression than placebo and has efficacy over placebo similar to that of other antidepressants such as tricyclic antidepressants.
Contraindications
Contraindications include:
Porphyria
Cardiovascular or cerebrovascular disease
Pheochromocytoma
Tyramine, found in several foods, is metabolized by MAO. Ingestion and absorption of tyramine causes extensive release of norepinephrine, which can rapidly increase blood pressure to the point of causing hypertensive crisis.
Concomitant use of serotonin-enhancing drugs, including SSRIs, serotonergic TCAs, dextromethorphan, and meperidine may cause serotonin syndrome.
Concomitant use of MRAs, including fenfluramine, amphetamine, and pseudoephedrine may cause toxicity via serotonin syndrome or hypertensive crisis.
L-DOPA given without carbidopa may cause hypertensive crisis.
Dietary restrictions
Tyramine is a common component in many foods, and is normally rapidly metabolized by MAO-A. Individuals not taking MAOIs may consume at least 2 grams of tyramine in a meal and not experience an increase in blood pressure, whereas those taking MAOIs such as tranylcypromine may experience a sharp increase in blood pressure following consumption of as little as 10 mg of tyramine, which can lead to hypertensive crisis.Foods containing tyramine include aged cheeses, cured meats, tofu and certain red wines. Some, such as yeast extracts, contain enough tyramine to be potentially fatal in a single serving. Spoiled food is also likely to contain dangerous levels of tyramine.
Adverse effects
Incidence of adverse effectsVery common (>10% incidence) adverse effects include:
Dizziness secondary to orthostatic hypotension (17%)Common (1-10% incidence) adverse effects include:
Tachycardia (5–10%)
Hypomania (7%)
Paresthesia (5%)
Weight loss (2%)
Confusion (2%)
Dry mouth (2%)
Sexual function disorders (2%)
Hypertension (1–2 hours after ingestion) (2%)
Rash (2%)
Urinary retention (2%)Other (unknown incidence) adverse effects include:
Increased/decreased appetite
Blood dyscrasias
Chest pain
Diarrhea
Edema
Hallucinations
Hyperreflexia
Insomnia
Jaundice
Leg cramps
Myalgia
Palpitations
Sensation of cold
Suicidal ideation
TremorOf note, there has not been found to be a correlation between sex and age below 65 regarding incidence of adverse effects.Tranylcypromine is not associated with weight gain and has a low risk for hepatotoxicity compared to the hydrazine MAOIs.It is generally recommended that MAOIs be discontinued prior to anesthesia; however, this creates a risk of recurrent depression. In a retrospective observational cohort study, patients on tranylcypromine undergoing general anesthesia had a lower incidence of intraoperative hypotension, while there was no difference between patients not taking an MAOI regarding intraoperative incidence of bradycardia, tachycardia, or hypertension. The use of indirect sympathomimetic drugs or drugs affecting serotonin reuptake, such as meperidine or dextromethorphan poses a risk for hypertension and serotonin syndrome respectively; alternative agents are recommended. Other studies have come to similar conclusions. Pharmacokinetic interactions with anesthetics are unlikely, given that tranylcypromine is a high-affinity substrate for CYP2A6 and does not inhibit CYP enzymes at therapeutic concentrations.Tranylcypromine abuse has been reported at doses ranging from 120 to 600 mg per day. It is thought that higher doses have more amphetamine-like effects and abuse is promoted by the fast onset and short half-life of tranylcypromine.Cases of suicidal ideation and suicidal behaviours have been reported during tranylcypromine therapy or early after treatment discontinuation.Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects.
Interactions
In addition to contraindicated concomitant medications, tranylcypromine inhibits CYP2A6, which may reduce the metabolism and increase the toxicity of substrates of this enzyme, such as:
Dexmedetomidine
nicotine
TSNAs (found in cured tobacco products, including cigarettes)
ValproateNorepinephrine reuptake inhibitors prevent neuronal uptake of tyramine and may reduce its pressor effects.
Pharmacology
Pharmacodynamics
Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase. Regarding the isoforms of monoamine oxidase, it shows slight preference for the MAOB isoenzyme over MAOA. This leads to an increase in the availability of monoamines, such as serotonin, norepinephrine, and dopamine, epinephrine as well as a marked increase in the availability of trace amines, such as tryptamine, octopamine, and phenethylamine. The clinical relevance of increased trace amine availability is unclear.
It may also act as a norepinephrine reuptake inhibitor at higher therapeutic doses. Compared to amphetamine, tranylcypromine shows low potency as a dopamine releasing agent, with even weaker potency for norepinephrine and serotonin release.Tranylcypromine has also been shown to inhibit the histone demethylase, BHC110/LSD1. Tranylcypromine inhibits this enzyme with an IC50 < 2 μM, thus acting as a small molecule inhibitor of histone demethylation with an effect to derepress the transcriptional activity of BHC110/LSD1 target genes. The clinical relevance of this effect is unknown.
Tranylcypromine has been found to inhibit CYP46A1 at nanomolar concentrations. The clinical relevance of this effect is unknown.
Pharmacokinetics
Tranylcypromine reaches its maximum concentration (tmax) within 1–2 hours. After a 20 mg dose, plasma concentrations reach at most 50-200 ng/mL. While its half-life is only about 2 hours, its pharmacodynamic effects last several days to weeks due to irreversible inhibition of MAO.Metabolites of tranylcypromine include 4-hydroxytranylcypromine, N-acetyltranylcypromine, and N-acetyl-4-hydroxytranylcypromine, which are less potent MAO inhibitors than tranylcypromine itself. Amphetamine was once thought to be a metabolite of tranylcypromine, but has not been shown to be.Tranylcypromine inhibits CYP2A6 at therapeutic concentrations.
Chemistry
Synthesis
History
Tranylcypromine was originally developed as an analog of amphetamine. Although it was first synthesized in 1948, its MAOI action was not discovered until 1959. Precisely because tranylcypromine was not, like isoniazid and iproniazid, a hydrazine derivative, its clinical interest increased enormously, as it was thought it might have a more acceptable therapeutic index than previous MAOIs.The drug was introduced by Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961. It was withdrawn from the market in February 1964 due to a number of patient deaths involving hypertensive crises with intracranial bleeding. However, it was reintroduced later that year with more limited indications and specific warnings of the risks.
Research
Tranylcypromine is known to inhibit LSD1, an enzyme that selectively demethylates two lysines found on histone H3. Genes promoted downstream of LSD1 are involved in cancer cell growth and metastasis, and several tumor cells express high levels of LSD1. Tranylcypromine analogues with more potent and selective LSD1 inhibitory activity are being researched in the potential treatment of cancers.Tranylcypromine may have neuroprotective properties applicable to the treatment of Parkinsons disease, similar to the MAO-B inhibitors selegiline and rasagiline. As of 2017, only one clinical trial in Parkinsonian patients has been conducted, which found some improvement initially and only slight worsening of symptoms after a 1.5 year followup.
See also
Tranylcypromine/trifluoperazine
== References == |
Temozolomide | Temozolomide (TMZ), sold under the brand name Temodar among others, is a medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. It is taken by mouth or via intravenous infusion.The most common side effects with temozolomide are nausea, vomiting, constipation, loss of appetite, alopecia (hair loss), headache, fatigue, convulsions (seizures), rash, neutropenia or lymphopenia (low white-blood-cell counts), and thrombocytopenia (low blood platelet counts). People receiving the solution for infusion may also have injection-site reactions, such as pain, irritation, itching, warmth, swelling and redness, as well as bruising.Temozolomide is an alkylating agent used to treat serious brain cancers; most commonly as second-line treatments for astrocytoma and as the first-line treatment for glioblastoma. Olaparib in combination with temozolomide demonstrated substantial clinical activity in relapsed small cell lung cancer.
Medical uses
In the United States temozolomide is indicated for the treatment of adults with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment; or adults with refractory anaplastic astrocytoma who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.In the European Union temozolomide is indicated for adults with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment; or children from the age of three years, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.
Contraindications
Temozolomide is contraindicated in people with hypersensitivity to it or to the similar drug dacarbazine. The use of temozolomide is not recommended in people with severe myelosuppression.
Adverse effects
The most common side effect is bone marrow suppression. The most common non-hematological adverse effects associated with temozolomide are nausea and vomiting, which are either self-limiting or readily controlled with standard antiemetic therapy. These latter effects are usually mild to moderate (grade 1 to 2). The incidence of severe nausea and vomiting is around 4% each. Patients who have pre-existing or a history of severe vomiting may require antiemetic therapy before initiating temozolomide treatment. Temozolomide should be administered in the fasting state, at least one hour before a meal. Antiemetic therapy may be administered before, or following, administration of temozolomide.
Temozolomide is genotoxic, teratogenic and fetotoxic and should not be used during pregnancy.
Lactating women should discontinue nursing while receiving the drug because of the risk of secretion into breast milk.
One study indicated that women that have taken temozolomide without concomitant fertility preservation measures achieve pregnancy to a lesser rate later in life, but the study was too small to show statistical significance in the hypothesis that temozolomide would confer a risk of female infertility.
In male patients, temozolomide can have genotoxic effects. Men are advised not to father a child during or up to six months after treatment and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to temozolomide therapy.
Very rarely temozolomide can cause acute respiratory failure or liver damage.
Interactions
As temozolomide is not metabolized in the liver and has a low affinity to plasma proteins, it is expected to have a low potential for interactions. An analysis of patient data showed no interactions with a range of other drugs; the exception is valproic acid, which slightly slows down temozolomide elimination from the body. Combining the drug with other myelosuppressants may increase the risk of myelosuppression.
Pharmacology
Mechanism of action
The therapeutic benefit of temozolomide depends on its ability to alkylate/methylate DNA, which most often occurs at the N-7 or O-6 positions of guanine residues. This methylation damages the DNA and triggers the death of tumor cells. However, some tumor cells are able to repair this type of DNA damage, and therefore diminish the therapeutic efficacy of temozolomide, by expressing a protein O6-alkylguanine DNA alkyltransferase (AGT) encoded in humans by the O-6-methylguanine-DNA methyltransferase (MGMT) gene. In some tumors, epigenetic silencing of the MGMT gene prevents the synthesis of this enzyme, and as a consequence such tumors are more sensitive to killing by temozolomide. Conversely, the presence of AGT protein in brain tumors predicts poor response to temozolomide and these patients receive little benefit from chemotherapy with temozolomide.
Pharmacokinetics
Temozolomide is quickly and almost completely absorbed from the gut, and readily penetrates the blood–brain barrier; the concentration in the cerebrospinal fluid is 30% of the concentration in the blood plasma. Intake with food decreases maximal plasma concentrations by 33% and the area under the curve by 9%. Only 15% (10–20%) of the substance are bound to blood plasma proteins. Temozolomide is a prodrug; it is spontaneously hydrolyzed at physiological pH to 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC), which further splits into monomethylhydrazine, likely the active methylating agent, and 5-aminoimidazole-4-carboxamide (AIC). Other metabolites include temozolomide acid and unidentified hydrophilic substances.Plasma half-life is 1.8 hours. The substance and its metabolites are mainly excreted via the urine.
Chemical properties
Temozolomide is an imidazotetrazine derivative. It is slightly soluble in water and aqueous acids, and decomposes at 212 °C (414 °F). It was recently discovered that temozolomide is an explosive, tentatively assigned as UN Class 1.Mirroring its medicinal use as an alkylating antineoplastic agent, temozolomide has been reported to be a comparatively safe and stable in situ source of diazomethane in organic synthesis. In particular, its use as a methylating and cyclopropanating reagent was demonstrated.
History
The agent was discovered by Simon Langdon, Niel Gibson and John Hickman at Aston University in Birmingham, England. The molecule was synthesised by PhD student Robert Stone, in a project directed by Malcolm Stevens to find anti-allergens. Its preclinical activity was reported in 1987 in Cancer Research. Stevens then directed its development with the late Edward Newlands at Charing Cross Hospital.It was approved for medical use in the European Union in January 1999, and in the United States in August 1999. The intravenous formulation was approved in the United States in February 2009.
Research
Laboratory studies and clinical trials have started investigating the possibility of increasing the anticancer potency of temozolomide by combining it with other pharmacologic agents. For example, clinical trials have indicated that the addition of chloroquine might be beneficial for the treatment of glioma patients. Laboratory studies found that temozolomide killed brain tumor cells more efficiently when epigallocatechin gallate (EGCG), a component of green tea, was added; however, the efficacy of this effect has not yet been confirmed in brain-tumor patients. Preclinical studies reported in 2010 on investigations into the use of the novel oxygen diffusion-enhancing compound trans sodium crocetinate (TSC) when combined with temozolomide and radiation therapy and a clinical trial was underway as of August 2015.While the above-mentioned approaches have investigated whether the combination of temozolomide with other agents might improve therapeutic outcome, efforts have also started to study whether altering the temozolomide molecule itself can increase its activity. One such approach permanently fused perillyl alcohol, a natural compound with demonstrated therapeutic activity in brain cancer patients, to the temozolomide molecule. The resultant novel compound, called NEO212 or TMZ-POH, revealed anticancer activity that was significantly greater than that of either of its two parent molecules, temozolomide and perillyl alcohol. Although as of 2016, NEO212 has not been tested in humans, it has shown superior cancer therapeutic activity in animal models of glioma, melanoma, and brain metastasis of triple-negative breast cancer.Because tumor cells that express the MGMT gene are more resistant to the effects of temozolomide, researchers investigated whether the inclusion of O6-benzylguanine (O6-BG), an AGT inhibitor, could overcome this resistance and improve the drugs therapeutic effectiveness. In the laboratory, this combination indeed showed increased temozolomide activity in tumor-cell culture in vitro and in animal models in vivo. However, a recently completed phase-II clinical trial with brain-tumor patients yielded mixed outcomes; while there was some improved therapeutic activity when O6-BG and temozolomide were given to patients with temozolomide-resistant anaplastic glioma, there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant glioblastoma multiforme.Some efforts focus on engineering hematopoietic stem cells expressing the MGMT gene prior to transplanting them into brain-tumor patients. This would allow for the patients to receive stronger doses of temozolomide, since the patients hematopoietic cells would be resistant to the drug.High doses of temozolomide in high-grade gliomas have low toxicity, but the results are comparable to the standard doses.Two mechanisms of resistance to temozolomide effects have now been described: 1) intrinsic resistance conferred by MGMT deficiency (MGMTd) and 2) intrinsic or acquired resistance through MMR deficiency (MMRd). The MGMT enzyme is the first line of repair of mismatched bases created by TMZ. Cells are normally MGMT proficient (MGMTp) as they have an unmethylated MGMT promoter allowing the gene to be expressed normally. In this state, TMZ induced DNA damage is able to be efficiently repaired in tumor cells (and normal cells) by the active MGMT enzyme. Cells may grow and pass through the cell cycle normally without arrest or death. However, some tumors cells are MGMT deficient (MGMTd). This is most commonly due to abnormal methylation of the MGMT gene promoter and suppression of gene expression. MGMTd has also been described to occur by promoter rearrangement. In cells with MGMTd, DNA damage by TMZ activates the next stage of repair in cells with a proficient Mismatch Repair enzyme complex (MMRp). In MMRp the MMR protein complex identifies the damage and causes cells to arrest and undergo death which inhibits tumor growth. However, if cells have combined MGMTd and MMR deficiency (MGMTd + MMRd) then cells retain the induced mutations and continue to cycle and are resistant to effects of TMZ.
In gliomas and other cancers MMRd has now been reported to occur as primary MMRd (intrinsic or germline Lynch bMMRd) or as secondary MMRd (acquired - not present in the original untreated tumor). The latter occurs after effective treatment and cytoreduction of tumors with TMZ and then selection or induction of mutant MSH6, MSH2, MLH1, or PMS2 proteins and cells which are MMRd and TMZ resistant. The latter is described as an acquired resistance pathway with hotspot mutations in glioma patients (MSH6 p.T1219I). Other resistance pathways are also likely to exist.
References
Further reading
External links
"Temozolomide". Drug Information Portal. U.S. National Library of Medicine.
"Temozolomide (Temodal)". Cancer Research UK. |
Nitroglycerin (medication) | Nitroglycerin, also known as glyceryl trinitrate (GTN), is a medication used for heart failure, high blood pressure, anal fissures, painful periods, and to treat and prevent chest pain caused by decreased blood flow to the heart (angina) or due to the recreational use of cocaine. This includes chest pain from a heart attack. It is taken by mouth, under the tongue, applied to the skin, or by injection into a vein.Common side effects include headache and low blood pressure. The low blood pressure can be severe. It is unclear if use in pregnancy is safe for the baby. It should not be used together with medications within the sildenafil (PDE5 inhibitor) family due to the risk of low blood pressure. Nitroglycerin is in the nitrate family of medications. While it is not entirely clear how it works, it is believed to function by dilating blood vessels.Nitroglycerin was written about as early as 1846 and came into medical use in 1878. It is on the World Health Organizations List of Essential Medicines. The drug nitroglycerin (GTN) is a dilute form of the same chemical used as the explosive, nitroglycerin. Dilution makes it non-explosive. In 2019, it was the 184th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Medical uses
Nitroglycerin is used for the treatment of angina, acute myocardial infarction, severe hypertension, and acute coronary artery spasms. It may be administered intravenously, as a sublingual spray, or as a patch applied to the skin.
Angina
GTN is useful in decreasing angina attacks, perhaps more so than reversing angina once started, by supplementing blood concentrations of NO, also called endothelium-derived relaxing factor, before the structure of NO as the responsible agent was known. This led to the development of transdermal patches of glyceryl trinitrate, providing 24-hour release. However, the effectiveness of glyceryl trinitrate is limited by development of tolerance/tachyphylaxis within 2–3 weeks of sustained use. Continuous administration and absorption (such as provided by daily pills and especially skin patches) accelerate onset of tolerance and limit the usefulness of the agent. Thus, glyceryl trinitrate works best when used only in short-term, pulse dosing. Glyceryl trinitrate is useful for myocardial infarction (heart attack) and pulmonary edema, again working best if used quickly, within a few minutes of symptom onset, as a pulse dose.It may also be given as a sublingual or buccal dose in the form of a tablet placed under the tongue or a spray into the mouth for the treatment of an angina attack.
Other uses
Tentative evidence indicates efficacy of glyceryl trinitrate in the treatment of various tendinopathies, both in pain management and acceleration of soft tissue repair.GTN is also used in the treatment of anal fissures, though usually at a much lower concentration than that used for angina treatment.GTN has been used to decrease pain associated with dysmenorrhea.GTN was once researched for the prevention and treatment of osteoporosis; however, the researcher Sophie Jamal was found to have falsified the findings, sparking one of the largest scientific misconduct cases in Canada.
Tolerance
After long-term use for chronic conditions, nitrate tolerance—tolerance to agents such as GTN— may develop in a patient, reducing its effectiveness. Tolerance is defined as the loss of symptomatic and hemodynamic effects of GTN and/or the need for higher doses of the drug to achieve the same effects, and was first described soon after the introduction of GTN in cardiovascular therapy. Studies have shown that nitrate tolerance is associated with vascular abnormalities which have the potential to worsen patients prognosis. These include endothelial and autonomic dysfunction.The mechanisms of nitrate tolerance have been investigated over the last 30 years, and several hypotheses to explain tolerance have been offered, including:
plasma volume expansion
impaired transformation of GTN into NO or related species
counteraction of GTN vasodilation by neurohormonal activation
oxidative stressRecent evidence suggests that deleterious GTN-induced production of oxygen free radicals might induce a number of abnormalities, include those described above, so that the oxidative stress hypothesis might represent a unifying principle.
Adverse events
Glyceryl trinitrate can cause severe hypotension, reflex tachycardia, and severe headaches that necessitate analgesic intervention for pain relief, the painful nature of which can have a marked negative effect on patient compliance.
GTN also can cause severe hypotension, circulatory collapse, and death if used together with vasodilator drugs that are used for erectile dysfunction, such as sildenafil, tadalafil, and vardenafil.GTN transdermal patches should be removed before defibrillation due to the risk of explosion and/or burns, but investigations have concluded that GTN patch explosions during defibrillation were due to voltage breakdown involving the metal mesh in some patches.
Mechanism of action
GTN is a prodrug which must be denitrated, with the nitrite anion or a related species further reduced to produce the active metabolite nitric oxide (NO). Organic nitrates that undergo these two steps within the body are called nitrovasodilators, and the denitration and reduction occur via a variety of mechanisms. The mechanism by which such nitrates produce NO is widely disputed. Some believe that organic nitrates produce NO by reacting with sulfhydryl groups, while others believe that enzymes such as glutathione S-transferases, cytochrome P450 (CYP), and xanthine oxidoreductase are the primary source of GTN bioactivation. In recent years, a great deal of evidence has been produced that supports the conclusion that GTNs clinically relevant denitration and reduction produce 1,2-glyceryl dinitrate (GDN) and NO, and that this reaction is catalysed by mitochondrial aldehyde dehydrogenase (ALDH2 or mtALDH).
The NO produced by this process is a potent activator of guanylyl cyclase (GC) by heme-dependent mechanisms; this activation results in formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). Among other roles, cGMP serves as a substrate for a cGMP-dependent protein kinase that activates myosin light chain phosphatase. Thus, production of NO from exogenous sources such as GTN increases the level of cGMP within the cell, and stimulates dephosphorylation of myosin, which initiates relaxation of smooth muscle cells in blood vessels.
History
It was known almost from the time of the first synthesis of GTN by Ascanio Sobrero in 1846 that handling and tasting of nitroglycerin could cause sudden intense headaches, which suggested a vasodilation effect (as suggested by Sobrero). Constantine Hering developed a form of nitroglycerin in 1847 and advocated for its dosing as a treatment of a number of diseases; however, its use as a specific treatment for blood pressure and chest pain was not among these. This is primarily due to his deep rooted focus in homeopathy.Following Thomas Bruntons discovery that amyl nitrite could be used to treat chest pain, William Murrell experimented with the use of nitroglycerin to alleviate angina pectoris and reduce blood pressure, and showed that the accompanying headaches occurred as a result of overdose. Murrell began treating patients with small doses of GTN in 1878, and the substance was widely adopted after he published his results in The Lancet in 1879.The medical establishment used the name "glyceryl trinitrate" or "trinitrin" to avoid alarming patients, because of a general awareness that nitroglycerin was explosive.Overdoses may generate methemoglobinemia.
References
== Further reading == |
Pegaspargase | Pegaspargase, sold under the brand name Oncaspar, is a medication used in the treatment of acute lymphoblastic leukemia (ALL). Often it is used together with anthracycline, vincristine, and corticosteroids (for example prednisone and dexamethasone). Pegaspargase can be administered either via an intravenous infusion or a intramuscular injection.Known side effects include allergic reactions, coagulopathy, high blood sugar, affected liver function, pancreas inflammation, and blood clots in the brain. There is no data regarding the usage of pegaspargase during pregnancy. Therefor caution should be observed and pegaspargase should only be used during pregnancy when the benefits outweigh the possible risks.
Pegaspargase is a modified version of the enzyme asparaginase which has undergone PEGylation. It works by breaking down the amino acid asparagine that are circulating in the bloodstream. The circulating asparagine is essential for the cancer cells to enable growth since they cant produce their own, in contrast to normal cells. The normal cells are therefor less affected by pegaspargase.
Pegaspargase was approved for medical use in the United States in 1994. It is on the World Health Organizations List of Essential Medicines. It is made by Sigma-Tau.
References
External links
"Pegaspargase". Drug Information Portal. U.S. National Library of Medicine. |
Candesartan | Candesartan is an angiotensin receptor blocker used mainly for the treatment of high blood pressure and congestive heart failure. Candesartan has a very low maintenance dose. The metabolism for the drug is unique as it is a cascading pro-drug. Candesartan has good bioavailibility and is more potent among the AT-1 receptor antagonists.
It was patented in 1990 and approved for medical use in 1997.
Medical uses
Hypertension
As with other angiotensin II receptor antagonists, candesartan is indicated for the treatment of hypertension. Candesartan has an additive antihypertensive effect when combined with a diuretic, such as chlorthalidone. It is available in a fixed-combination formulation with a low dose of the thiazide diuretic hydrochlorothiazide. Candesartan/hydrochlorothiazide combination preparations are marketed under various trade names including Atacand Plus, Hytacand, Blopress Plus, Advantec and Ratacand Plus.
Congestive heart failure
Angiotensin receptor blockers such as candesartan and valsartan have been demonstrated in randomised controlled trials to reduce heart failure hospitalisations and cardiovascular deaths for chronic heart failure patients with reduced left ventricular ejection fraction (LVEF ≤40%) and are intolerant to angiotensin-converting enzyme inhibitors.
Prehypertension
In a four-year randomized controlled trial, candesartan was compared to placebo to see whether it could prevent or postpone the development of full-blown hypertension in people with so-called prehypertension. During the first two years of the trial, half of participants were given candesartan while the other half received placebo; candesartan reduced the risk of developing hypertension by nearly two-thirds during this period. In the last two years of the study, all participants were switched to placebo. By the end of the study, candesartan had significantly reduced the risk of hypertension, by more than 15%. Serious adverse effects were more common among participants receiving placebo than in those given candesartan.
Prevention of atrial fibrillation
Results from a meta-analysis completed in 2005 demonstrated a reduction in atrial fibrillation in patients with systolic left ventricular dysfunction treated with candesartan, another angiotensin receptor blocker or an angiotensin converting enzyme inhibitor. Evidence for the use of candesartan specifically is also supported by an analysis of the CHARM study which demonstrated a reduction in atrial fibrillation in patients with systolic left ventricular dysfunction. While these studies have demonstrated a potential additional benefit for candesartan when used in patients with systolic left ventricular dysfunction, additional studies are required to further elucidate the role of candesartan in the prevention of atrial fibrillation in other population groups.
Diabetic retinopathy
Use of antihypertensive drugs has been demonstrated to slow the progression of diabetic retinopathy; the role of candesartan specifically in reducing progression in type 1 and type 2 diabetes is still up for debate. Results from a 2008 study on patients with type 1 diabetes showed there was no benefit in using candesartan to reduce progression of diabetic retinopathy when compared to placebo. Candesartan has been demonstrated to reverse the severity (cause regression) of mild to moderate diabetic retinopathy in patients with type 2 diabetes. The patient populations investigated in these studies were limited to mostly Caucasians and those younger than 75 years of age, so generalization of these findings to other population groups should be done with caution.
Migraine prophylaxis
In two small randomised, controlled cross-over studies, candesartan was shown to be effective for the prophylaxis of migraine; however, further studies would enhance confidence in its use for this indication.
Adverse effects
As with other drugs that inhibit the renin–angiotensin system, if candesartan is taken by pregnant women during the second or third trimester, it can cause injury and in some cases, death of the developing fetus. Symptomatic hypotension may occur in people who take candesartan and are volume-depleted or salt-depleted, as can also occur when diuretics are coadministered. Reduction in renal glomerular filtration rate may occur; people with renal artery stenosis may be at higher risk. Hyperkalemia may occur; people who are also taking spironolactone or eplerenone may be at higher risk.Anemia may occur, due to inhibition of the renin–angiotensin system.As with other angiotensin receptor blockers, candesartan can rarely cause severe liver injury.
Chemistry and pharmacokinetics
Candesartan is marketed as the cyclohexyl 1-hydroxyethyl carbonate (cilexetil) ester, known as candesartan cilexetil. Candesartan cilexetil is metabolised completely by esterases in the intestinal wall during absorption to the active candesartan moiety. The first step that occurs in the cascading pro-drug mechanism of Candesartan is that the carbonate gets hydrolyzed. The carbonate gets hydrolyzed and releases carbon dioxide. The metabolite at this step is cyclohexanol, and this is a relatively non-toxic compound which is advantageous to the design of the drug. The other aspect of the cascading prodrug is the O-CH-CH3 molecule which becomes converted into acetic acid, which is another product from the cascading side reaction. Similar to the insight from cyclohexanol, the metabolite of acetic acid relatively is non-toxic and thus less of a hazard if produced as the drug takes pharmacologic action.
The use of a prodrug form increases the bioavailability of candesartan. Despite this, absolute bioavailability is relatively poor at 15% (candesartan cilexetil tablets) to 40% (candesartan cilexetil solution). Its IC50 is 15 μg/kg. Candesartan is not administered in its active form because the administration of the pro-drug would require greater doses and has an unfavorable adverse event profile.
History
The compound known as TCV-116 (candesartan) was studied by Japanese scientists using standard laboratory rats. Animal studies were published showing the effectiveness of the compound in 1992–1993, with a pilot study on humans published in the summer of 1993.
Names
The prodrug candesartan cilexetil is marketed by AstraZeneca and Takeda Pharmaceuticals, commonly under the trade names Blopress, Atacand, Amias, and Ratacand. It is available in generic form.
== References == |
Potassium chloride | Potassium chloride (KCl, or potassium salt) is a metal halide salt composed of potassium and chlorine. It is odorless and has a white or colorless vitreous crystal appearance. The solid dissolves readily in water, and its solutions have a salt-like taste. Potassium chloride can be obtained from ancient dried lake deposits. KCl is used as a fertilizer, in medicine, in scientific applications, domestic water softeners (as a substitute for sodium chloride salt), and in food processing, where it may be known as E number additive E508.
It occurs naturally as the mineral sylvite, and in combination with sodium chloride as sylvinite.
Uses
Fertilizer
The majority of the potassium chloride produced is used for making fertilizer, called potash, since the growth of many plants is limited by potassium availability. Potassium chloride sold as fertilizer is known as muriate of potash (MOP). The vast majority of potash fertilizer worldwide is sold as MOP.
Medical use
Potassium is vital in the human body, and potassium chloride by mouth is the common means to treat low blood potassium, although it can also be given intravenously. It is on the World Health Organizations List of Essential Medicines. Overdose causes hyperkalemia which can disrupt cell signaling to the extent that the heart will stop, reversibly in the case of some open heart surgeries.
Culinary use
It can be used as a salt substitute for food, but due to its weak, bitter, unsalty flavor, it is often mixed with ordinary table salt (sodium chloride) to improve the taste to form low sodium salt. The addition of 1 ppm of thaumatin considerably reduces this bitterness. Complaints of bitterness or a chemical or metallic taste are also reported with potassium chloride used in food.
Industrial
As a chemical feedstock, it is used for the manufacture of potassium hydroxide and potassium metal. It is also used in medicine, lethal injections, scientific applications, food processing, soaps, and as a sodium-free substitute for table salt for people concerned about the health effects of sodium.
It is used as a supplement in animal feed to boost the potassium level in the feed. As an added benefit, it is known to increase milk production.
It is sometimes used in solution as a completion fluid in petroleum and natural gas operations, as well as being an alternative to sodium chloride in household water softener units.
Glass manufacturers use granular potash as a flux, lowering the temperature at which a mixture melts. Because potash imparts excellent clarity to glass, it is commonly used in eyeglasses, glassware, televisions, and computer monitors.
KCl is useful as a beta radiation source for calibration of radiation monitoring equipment, because natural potassium contains 0.0118% of the isotope 40K. One kilogram of KCl yields 16350 becquerels of radiation, consisting of 89.28% beta and 10.72% gamma, with 1.46083 MeV. In order to use off-the-shelf materials, it needs to be crystallized sequentially, using controlled temperature, in order to extract KCl, which is the subject of ongoing research. It also emits a relatively low level of 511 keV gamma rays from positron annihilation, which can be used to calibrate medical scanners.
Potassium chloride is used in some de-icing products designed to be safer for pets and plants, though these are inferior in melting quality to calcium chloride [lowest usable temperature 12 °F (−11 °C) v. −25 °F (−32 °C)]. It is also used in various brands of bottled water.
Potassium chloride was once used as a fire extinguishing agent, and in portable and wheeled fire extinguishers. Known as Super-K dry chemical, it was more effective than sodium bicarbonate-based dry chemicals and was compatible with protein foam. This agent fell out of favor with the introduction of potassium bicarbonate (Purple-K) dry chemical in the late 1960s, which was much less corrosive, as well as more effective. It is rated for B and C fires.
Along with sodium chloride and lithium chloride, potassium chloride is used as a flux for the gas welding of aluminium.
Potassium chloride is also an optical crystal with a wide transmission range from 210 nm to 20 µm. While cheap, KCl crystals are hygroscopic. This limits its application to protected environments or short-term uses such as prototyping. Exposed to free air, KCl optics will "rot". Whereas KCl components were formerly used for infrared optics, it has been entirely replaced by much tougher crystals such as zinc selenide.
Potassium chloride is used as a scotophor with designation P10 in dark-trace CRTs, e.g. in the Skiatron.
Toxicity
The typical amounts of potassium chloride found in the diet appear to be generally safe. In larger quantities, however, potassium chloride is toxic. The LD50 of orally ingested potassium chloride is approximately 2.5 g/kg, or 190 grams (6.7 oz) for a body mass of 75 kilograms (165 lb). In comparison, the LD50 of sodium chloride (table salt) is 3.75 g/kg.
Intravenously, the LD50 of potassium chloride is far smaller, at about 57.2 mg/kg to 66.7 mg/kg; this is found by dividing the lethal concentration of positive potassium ions (about 30 to 35 mg/kg) by the proportion by mass of potassium ions in potassium chloride (about 0.52445 mg K+/mg KCl).
Chemical properties
Solubility
KCl is soluble in a variety of polar solvents.
Solutions of KCl are common standards, for example for calibration of the electrical conductivity of (ionic) solutions, since KCl solutions are stable, allowing for reproducible measurements. In aqueous solution, it is essentially fully ionized into solvated K+ and Cl− ions.
Redox and the conversion to potassium metal
Although potassium is more electropositive than sodium, KCl can be reduced to the metal by reaction with metallic sodium at 850 °C because the more volatile potassium can be removed by distillation (see Le Chateliers principle):
KCl
(
l
)
+
Na
(
l
)
↽
−
−
⇀
NaCl
(
l
)
+
K
(
g
)
{\displaystyle {\ce {KCl_{(l)}{}+ Na_{(l)}<=> NaCl_{(l)}{}+ K_{(g)}}}}
This method is the main method for producing metallic potassium. Electrolysis (used for sodium) fails because of the high solubility of potassium in molten KCl.
Physical properties
The crystal structure of potassium chloride is like that of NaCl. It adopts a face-centered cubic structure. Its lattice constant is roughly 6.3 Å. Crystals cleave easily in three directions.
Some other properties are
Transmission range: 210 nm to 20 µm
Transmittivity = 92% at 450 nm and rises linearly to 94% at 16 µm
Refractive index = 1.456 at 10 µm
Reflection loss = 6.8% at 10 µm (two surfaces)
dN/dT (expansion coefficient)= −33.2×10−6/°C
dL/dT (refractive index gradient)= 40×10−6/°C
Thermal conductivity = 0.036 W/(cm·K)
Damage threshold (Newman and Novak): 4 GW/cm2 or 2 J/cm2 (0.5 or 1 ns pulse rate); 4.2 J/cm2 (1.7 ns pulse rate Kovalev and Faizullov)As with other compounds containing potassium, KCl in powdered form gives a lilac flame.
Production
Potassium chloride is extracted from minerals sylvite, carnallite, and potash. It is also extracted from salt water and can be manufactured by crystallization from solution, flotation or electrostatic separation from suitable minerals. It is a by-product of the production of nitric acid from potassium nitrate and hydrochloric acid.
The vast majority of potassium chloride is produced as agricultural and industrial grade potash in Saskatchewan, Canada, as well as Russia and Belarus. Saskatchewan alone accounted for over 25% of the worlds potash production in 2017.
Laboratory methods
Potassium chloride is inexpensively available and is rarely prepared intentionally in the laboratory. It can be generated by treating potassium hydroxide (or other potassium bases) with hydrochloric acid:
KOH
+
HCl
⟶
KCl
+
H
2
O
{\displaystyle {\ce {KOH + HCl -> KCl + H2O}}}
This conversion is an acid-base neutralization reaction. The resulting salt can then be purified by recrystallization. Another method would be to allow potassium to burn in the presence of chlorine gas, also a very exothermic reaction:
2
K
+
Cl
2
⟶
2
KCl
{\displaystyle {\ce {2 K + Cl2 -> 2 KCl}}}
References
Further reading
Lide, D. R., ed. (2005). CRC Handbook of Chemistry and Physics (86th ed.). Boca Raton (FL): CRC Press. ISBN 0-8493-0486-5.
Greenwood, Norman N.; Earnshaw, Alan (1984). Chemistry of the Elements. Oxford: Pergamon Press. ISBN 978-0-08-022057-4.
External links
"Potassium chloride". Drug Information Portal. U.S. National Library of Medicine.
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Celecoxib/tramadol | Celecoxib/tramadol sold under the brand name Seglentis, is a fixed-dose combination of the anti-inflammatory celecoxib and the opioid tramadol used for the management and treatment of pain.Developed by Spanish pharmaceutical company Esteve, it was approved for medical use in the United States in October 2021.
References
External links
"Celecoxib". Drug Information Portal. U.S. National Library of Medicine.
"Tramadol hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03108482 for "Co-crystal E-58425 vs Tramadol and Celecoxib for Moderate to Severe Acute Pain After Bunionectomy. Phase III Clinical Trial." at ClinicalTrials.gov |
Guaifenesin | Guaifenesin, sold under the brand name Mucinex, among others, is a medication used as an expectorant, intended to help cough out phlegm from the airways. Chemically it is an ether of guaiacol and glycerine. It is unclear if it decreases coughing. Use is not recommended in children less than six years old. It is often used in combination with other medications. It is taken by mouth.Side effects may include dizziness, sleepiness, skin rash, and nausea. While it has not been properly studied in pregnancy, it appears to be safe. It is believed to work by making airway secretions more liquid.Guaifenesin has been used medically since at least 1933. It is available as a generic medication and over the counter. In 2018, it was the 172nd most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Medical use
Guaifenesin is used to try to help with coughing up thick mucus and is sometimes combined with dextromethorphan, an antitussive (cough suppressant), such as in Mucinex DM or Robitussin DM. It is also combined with ephedrine to produce Primatene and Bronkaid tablets for symptomatic relief of asthma.
Side effects
Side-effects of guaifenesin include nausea, vomiting, formation of kidney stones, diarrhea, and constipation. Nausea and vomiting can be reduced by taking guaifenesin with meals. The risk of forming kidney stones during prolonged use can be reduced by maintaining good hydration and increasing the pH of urine. Rarely, severe allergic reactions may occur, including a rash or swelling of the lips or gums, which may require urgent medical assistance. Mild dry mouth or chapped lips may also occur when taking this medication. Drinking a glass of water is recommended with each dose of guaifenesin.
Pharmacology
Mechanism of action
Guaifenesin is thought to act as an expectorant by increasing the volume and reducing the viscosity of secretions in the trachea and bronchi. It may aid in the flow of respiratory tract secretions, allowing ciliary movement to carry the loosened secretions upward toward the pharynx. Thus, it may increase the efficiency of the cough reflex and facilitate removal of the secretions.
Guaifenesin has muscle relaxant and anticonvulsant properties and may act as an NMDA receptor antagonist.
History
Similar medicines derived from the guaiac tree were in use as a generic remedy by American indigenous peoples when explorers reached North America in the 16th century. The Spanish encountered guaiacum wood "when they conquered Santo Domingo; it was soon brought back to Europe, where it acquired an immense reputation in the sixteenth century as a cure for syphilis and certain other diseases..."The 1955 edition of the Textbook of Pharmacognosy states: "Guaiacum has a local stimulant action which is sometimes useful in sore throat. The resin is used in chronic gout and rheumatism, whilst the wood is an ingredient in the compound concentrated solution of sarsaparilla, which was formerly much used as an alternative in syphilis."In the US, guaifenesin was first approved by the Food and Drug Administration (FDA) in 1952. Although previously deemed "Generally Regarded as Safe" in its original approval, the drug received a New Drug Application for the extended-release version, which received approval on 12 July 2002. Because of this, the FDA then issued letters to other manufacturers of timed-release guaifenesin to stop marketing their unapproved versions, leaving Adams Respiratory Therapeutics in control of the market. In 2007, Adams was acquired by Reckitt Benckiser. The drug is now sold over-the-counter by many companies, alone and in combination.
Availability
Guaifenesin is taken by mouth as pills or syrups. It is available under many brand names, as either the lone active ingredient or as one part of a combination drug. Drugs combined with guaifenesin in over-the-counter preparations include the cough-suppressant dextromethorphan, analgesics such as paracetamol/acetaminophen, and decongestants such as ephedrine, pseudoephedrine, or phenylephrine.
Veterinary use
Guaifenesins neurological properties first became known in the late 1940s. Guaifenesin is a centrally acting muscle relaxant used routinely in large-animal veterinary surgery. Guaifenesin is used in combination with, for example, ketamine, since guaifenesin does not provide analgesia nor does it produce unconsciousness.
Research
The guaifenesin protocol was studied as a method to treat fibromyalgia; a one-year double-blind study found that the treatment performs no better than placebo. Guaifenesin is not approved by the FDA for the treatment of fibromyalgia.
Guaifenesin was studied as a method to improve the possibility of conception, by thinning and increasing the stretchability (improved spinnbarkeit) of the cervical mucus, during the few days before ovulation, thus facilitating sperm penetration.Results from a 2014 study by the Virginia Commonwealth Universitys Department of Pediatrics indicated that guaifenesin did not have significant impact on sputum production or clearance in upper respiratory infections. This was consistent with a 2014 study involving 378 adult and adolescent participants, which indicated guaifenesin had no significant effect as either mucolytic or expectorant compared to placebo: "Although the upper respiratory quality of life improved over the course of the study in both the [guaifenesin] and placebo groups, this improvement was not accompanied by changes in sputum properties".
See also
Guaiacol
Guaifenesin/phenylephrine
Methocarbamol
Mephenoxalone
Oxomemazine/guaifenesin
Plastic bronchitis
References
External links
"Guaifenesin". Drug Information Portal. U.S. National Library of Medicine.
"F.D.A. Study Worries Makers of Drugs". The New York Times. 20 October 1981. |
Ibutilide | Ibutilide is a Class III antiarrhythmic agent that is indicated for acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm. It exerts its antiarrhythmic effect by induction of slow inward sodium current, which prolongs action potential and refractory period (physiology) of myocardial cells. Because of its Class III antiarrhythmic activity, there should not be concomitant administration of Class Ia and Class III agents.
Ibutilide is marketed as Corvert by Pfizer. Administration resulted in successful heart rhythm control in 31-44% of patients within 90 minutes, with sustained polymorphic ventricular tachycardia in 0.9-2.5% of patients. It appears to show better results in atrial flutter as compared to atrial fibrillation.
Mechanism of action
Ibutilide, like other class III antiarrhythmic drugs, blocks delayed rectified potassium current.It does have action on the slow sodium channel and promotes the influx of sodium through these slow channels.
Although potassium current seems to play a role, their interactions are complex and not well understood. Ibutilides unique mechanism works by an activation of a specific inward sodium current, thus producing its therapeutic response in which a prolonged action potential increases myocytes’ cardiac refractoriness in case of atrial fibrillation and flutter.
Pharmacokinetics
Absorption
Ibutilide is intravenously administered. It has a high first-pass metabolism, which results in a poor bioavailability when taken orally. Individual pharmacokinetic properties are highly viable during the clinical trial.
Distribution
Ibutilide has a relatively large volume of distribution among individual subjects, which is about 11L/kg. Approximately 40% of the drug is bound with plasma albumin of healthy volunteers in a trial. This is also approximately close to patients with atrial fibrillation and flutter.
Metabolism
Ibutilide has a high systemic plasma clearance that closes to the hepatic blood flow (29mL/min/kg). Its metabolic pathway is via livers cytochrome P450 system by isoenzymes other than CYP3A4 and CYP2D6 by which the heptyl side chain of ibutilide is oxidized. With eight metabolites are detected in the urine, however, only one is an active metabolite that shares the similar electrophysiologic property of the Class III antiarrhythmic agents. The plasma concentration of this metabolite is only less than 10% of ibutilide.
Excretion
After administration of ibutilide, it is quickly excreted by renal pathway with a half-life of approximately 6 hours. Approximately 82% of a 0.01 mg/kg dose is excreted in the urine during the trial. Among those, around 7% is excreted as unchanged drug. The remainder of the drug is excreted in feces (about 19%).
Adverse effects and contraindications
Like other antiarrhythmics, ibutilide can lead to abnormal heart rhythms due to its ability to prolong the QT interval, which can lead to the potentially fatal abnormal heart rhythm known as torsades de pointes. Consequently, the drug is contraindicated in patients that are likely to develop abnormal heart rhythms; this includes persons that have had polymorphic ventricular tachycardia in the past, have a long QT interval, sick sinus syndrome, or a recent myocardial infarction, among others.
Patient Information
This medication will be given intravenously for your heart disease. You will have continuously ECG monitoring during the infusion and 4 hours after your infusion. Some of the minor side effects are headache and irregular heartbeat. If you experience chest pain and respiratory difficulties, you should report to your doctors immediately.
See also
Sematilide
Risotilide
== References == |
Ephedrine | Ephedrine is a central nervous system (CNS) stimulant that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in nasal congestion. It can be taken by mouth or by injection into a muscle, vein, or just under the skin. Onset with intravenous use is fast, while injection into a muscle can take 20 minutes, and by mouth can take an hour for effect. When given by injection it lasts about an hour and when taken by mouth it can last up to four hours.Common side effects include trouble sleeping, anxiety, headache, hallucinations, high blood pressure, fast heart rate, loss of appetite, and inability to urinate. Serious side effects include stroke and heart attack. While likely safe in pregnancy, its use in this population is poorly studied. Use during breastfeeding is not recommended. Ephedrine works by increasing the activity of the α and β adrenergic receptors.Ephedrine was first isolated in 1885 and came into commercial use in 1926. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. It can normally be found in plants of the Ephedra genus. Dietary supplements containing ephedrine are illegal in the United States, with the exception of those used in traditional Chinese medicine, where its presence is noted by má huáng.
Medical use
Both ephedrine and pseudoephedrine increase blood pressure and act as bronchodilators, with pseudoephedrine having considerably less effect.Ephedrine may decrease motion sickness, but it has mainly been used to decrease the sedating effects of other medications used for motion sickness.Ephedrine is also found to have quick and long-lasting responsiveness in congenital myasthenic syndrome in early childhood and also even in the adults with a novel COLQ mutation.
Weight loss
Ephedrine promotes modest short-term weight loss, specifically fat loss, but its long-term effects are unknown. In mice, ephedrine is known to stimulate thermogenesis in the brown adipose tissue, but because adult humans have only small amounts of brown fat, thermogenesis is assumed to take place mostly in the skeletal muscle. Ephedrine also decreases gastric emptying. Methylxanthines such as caffeine and theophylline have a synergistic effect with ephedrine with respect to weight loss. This led to creation and marketing of compound products. One of them, known as the ECA stack, contains ephedrine with caffeine and aspirin. It is a popular supplement taken by bodybuilders seeking to cut body fat before a competition.
Recreational use
As a phenethylamine, ephedrine has a similar chemical structure to amphetamines and is a methamphetamine analogue having the methamphetamine structure with a hydroxyl group at the β position. Because of ephedrines structural similarity to methamphetamine, it can be used to create methamphetamine using chemical reduction in which ephedrines hydroxyl group is removed; this has made ephedrine a highly sought-after chemical precursor in the illicit manufacture of methamphetamine.
The most popular method for reducing ephedrine to methamphetamine is similar to the Birch reduction, in that it uses anhydrous ammonia and lithium metal in the reaction. The second-most popular method uses red phosphorus and iodine in the reaction with ephedrine. Moreover, ephedrine can be synthesized into methcathinone via simple oxidation. As such, ephedrine is listed as a table-I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.
Detection of use
Ephedrine may be quantified in blood, plasma, or urine to monitor possible abuse by athletes, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Many commercial immunoassay screening tests directed at the amphetamines cross-react appreciably with ephedrine, but chromatographic techniques can easily distinguish ephedrine from other phenethylamine derivatives. Blood or plasma ephedrine concentrations are typically in the 20–200 µg/L range in persons taking the drug therapeutically, 300–3000 µg/L in abusers or poisoned patients and 3–20 mg/L in cases of acute fatal overdosage. The current World Anti-Doping Agency (WADA) limit for ephedrine in an athletes urine is 10 µg/mL.
Contraindications
Ephedrine should not be used in conjunction with certain antidepressants, namely norepinephrine-dopamine reuptake inhibitors (NDRIs), as this increases the risk of symptoms due to excessive serum levels of norepinephrine.
Bupropion is an example of an antidepressant with an amphetamine-like structure similar to ephedrine, and it is an NDRI. Its action bears more resemblance to amphetamine than to fluoxetine in that its primary mode of therapeutic action involves norepinephrine and to a lesser degree dopamine, but it also releases some serotonin from presynaptic clefts. It should not be used with ephedrine, as it may increase the likelihood of side effects.
Ephedrine should be used with caution in patients with inadequate fluid replacement, impaired adrenal function, hypoxia, hypercapnia, acidosis, hypertension, hyperthyroidism, prostatic hypertrophy, diabetes mellitus, cardiovascular disease, during delivery if maternal blood pressure is >130/80 mmHg, and during lactation.Contraindications for the use of ephedrine include: closed-angle glaucoma, phaeochromocytoma, asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis), concomitant or recent (previous 14 days) monoamine oxidase inhibitor (MAOI) therapy, general anaesthesia with halogenated hydrocarbons (particularly halothane), tachyarrhythmias or ventricular fibrillation, or hypersensitivity to ephedrine or other stimulants.
Ephedrine should not be used at any time during pregnancy unless specifically indicated by a qualified physician and only when other options are unavailable.
Adverse effects
Ephedrine is a potentially dangerous natural compound; as of 2004 the US Food and Drug Administration had received over 18,000 reports of adverse effects in people using it.Adverse drug reactions (ADRs) are more common with systemic administration (e.g. injection or oral administration) compared to topical administration (e.g. nasal instillations). ADRs associated with ephedrine therapy include:
Cardiovascular: tachycardia, cardiac arrhythmias, angina pectoris, vasoconstriction with hypertension
Dermatological: flushing, sweating, acne vulgaris
Gastrointestinal: nausea
Genitourinary: decreased urination due to vasoconstriction of renal arteries, difficulty urinating is not uncommon, as alpha-agonists such as ephedrine constrict the internal urethral sphincter, mimicking the effects of sympathetic nervous system stimulation
Nervous system: restlessness, confusion, insomnia, mild euphoria, mania/hallucinations (rare except in previously existing psychiatric conditions), delusions, formication (may be possible, but lacks documented evidence) paranoia, hostility, panic, agitation
Respiratory: dyspnea, pulmonary edema
Miscellaneous: dizziness, headache, tremor, hyperglycemic reactions, dry mouthThe neurotoxicity of l-ephedrine is disputed.
Other uses
In chemical synthesis, ephedrine is used in bulk quantities as a chiral auxiliary group.
In saquinavir synthesis, the half-acid is resolved as its salt with l-ephedrine.
Chemistry and nomenclature
Ephedrine is a sympathomimetic amine and substituted amphetamine. It is similar in molecular structure to phenylpropanolamine, methamphetamine, and epinephrine (adrenaline). Chemically, it is an alkaloid with a phenethylamine skeleton found in various plants in the genus Ephedra (family Ephedraceae). It works mainly by increasing the activity of norepinephrine (noradrenaline) on adrenergic receptors. It is most usually marketed as the hydrochloride or sulfate salt.
Ephedrine exhibits optical isomerism and has two chiral centres, giving rise to four stereoisomers. By convention, the pair of enantiomers with the stereochemistry (1R,2S) and (1S,2R) is designated ephedrine, while the pair of enantiomers with the stereochemistry (1R,2R) and (1S,2S) is called pseudoephedrine.
Ephedrine is a substituted amphetamine and a structural methamphetamine analogue. It differs from methamphetamine only by the presence of a hydroxyl group (—OH).
The isomer which is marketed is (−)-(1R,2S)-ephedrine.Ephedrine hydrochloride has a melting point of 187−188 °C.In the outdated D/L system (+)-ephedrine is also referred to as D-ephedrine and (−)-ephedrine as L-ephedrine (in which case, in the Fisher projection, the phenyl ring is drawn at the bottom).Often, the D/L system (with small caps) and the d/l system (with lower-case) are confused. The result is that the levorotary l-ephedrine is wrongly named L-ephedrine and the dextrorotary d-pseudoephedrine (the diastereomer) wrongly D-pseudoephedrine.
The IUPAC names of the two enantiomers are (1R,2S)- respectively (1S,2R)-2-methylamino-1-phenylpropan-1-ol. A synonym is erythro-ephedrine.
Sources
Agricultural
Ephedrine is obtained from the plant Ephedra sinica and other members of the genus Ephedra, from which the name of the substance is derived. Raw materials for the manufacture of ephedrine and traditional Chinese medicines are produced in China on a large scale. As of 2007, companies produced for export US$13 million worth of ephedrine from 30,000 tons of ephedra annually, or about ten times the amount used in traditional Chinese medicine.
Synthetic
Most of the l-ephedrine produced today for official medical use is made synthetically as the extraction and isolation process from E. sinica is tedious and no longer cost effective.
Biosynthetic
Ephedrine was long thought to come from modifying the amino acid L-phenylalanine. L-Phenylalanine would be decarboxylated and subsequently attacked with ω-aminoacetophenone. Methylation of this product would then produce ephedrine. This pathway has since been disproven. A new pathway proposed suggests that phenylalanine first forms cinnamoyl-CoA via the enzymes phenylalanine ammonia-lyase and acyl CoA ligase. The cinnamoyl-CoA is then reacted with a hydratase to attach the alcohol functional group. The product is then reacted with a retro-aldolase, forming benzaldehyde. Benzaldehyde reacts with pyruvic acid to attach a 2 carbon unit. This product then undergoes transamination and methylation to form ephedrine and its stereoisomer, pseudoephedrine.
Mechanism of action
Ephedrine, a sympathomimetic amine, acts on part of the sympathetic nervous system (SNS). The principal mechanism of action relies on its indirect stimulation of the adrenergic receptor system by increasing the activity of norepinephrine at the postsynaptic α and β receptors. The presence of direct interactions with α receptors is unlikely, but still controversial. L-ephedrine, and particularly its stereoisomer norpseudoephedrine (which is also present in Catha edulis) has indirect sympathomimetic effects and due to its ability to cross the blood-brain barrier, it is a CNS stimulant similar to amphetamines, but less pronounced, as it releases noradrenaline and dopamine in the substantia nigra.The presence of an N-methyl group decreases binding affinities at α receptors, compared with norephedrine. Ephedrine, though, binds better than N-methylephedrine, which has an additional methyl group at the nitrogen atom. Also the steric orientation of the hydroxyl group is important for receptor binding and functional activity.
Compounds with decreasing α-receptor affinity
History
Asia
Ephedrine in its natural form, known as máhuáng (麻黄) in traditional Chinese medicine, has been documented in China since the Han dynasty (206 BC – 220 AD) as an antiasthmatic and stimulant. In traditional Chinese medicine, máhuáng has been used as a treatment for asthma and bronchitis for centuries.In 1885, the chemical synthesis of ephedrine was first accomplished by Japanese organic chemist Nagai Nagayoshi based on his research on traditional Japanese and Chinese herbal medicines.
The industrial manufacture of ephedrine in China began in the 1920s, when Merck began marketing and selling the drug as ephetonin. Ephedrine exports from China to the West grew from 4 to 216 tonnes between 1926 and 1928.
Western medicine
Introduced in 1948 Vicks Vatronol nose drops (now discontinued) contained ephedrine sulfate as the active ingredient for rapid nasal decongestion.
Legality
Canada
In January 2002, Health Canada issued a voluntary recall of all ephedrine products containing more than 8 mg per dose, all combinations of ephedrine with other stimulants such as caffeine, and all ephedrine products marketed for weight-loss or bodybuilding indications, citing a serious risk to health. Ephedrine is still sold as an oral nasal decongestant in 8 mg pills as a natural health product, with a limit of 0.4g per package, the limit established by the Controlled Drugs and Substances Act as it is considered as Class A Precursor.
United States
In 1997, the FDA proposed a regulation on ephedra (the herb from which ephedrine is obtained), which limited an ephedra dose to 8 mg (of active ephedrine) with no more than 24 mg per day. This proposed rule was withdrawn, in part, in 2000 because of "concerns regarding the agencys basis for proposing a certain dietary ingredient level and a duration of use limit for these products." In 2004, the FDA created a ban on ephedrine alkaloids marketed for reasons other than asthma, colds, allergies, other disease, or traditional Asian use. On April 14, 2005, the U.S. District Court for the District of Utah ruled the FDA did not have proper evidence that low dosages of ephedrine alkaloids are actually unsafe, but on August 17, 2006, the U.S. Court of Appeals for the Tenth Circuit in Denver upheld the FDAs final rule declaring all dietary supplements containing ephedrine alkaloids adulterated, and therefore illegal for marketing in the United States. Furthermore, ephedrine is banned by the NCAA, MLB, NFL, and PGA. Ephedrine is, however, still legal in many applications outside of dietary supplements. Purchasing is currently limited and monitored, with specifics varying from state to state.
The House passed the Combat Methamphetamine Epidemic Act of 2005 as an amendment to the renewal of the USA PATRIOT Act. Signed into law by President George W. Bush on March 6, 2006, the act amended the US Code (21 USC 830) concerning the sale of products containing ephedrine and the closely related drug pseudoephedrine. Both substances are used as precursors in the illicit production of methamphetamine, and to discourage that use the federal statute included the following requirements for merchants who sell these products:
A retrievable record of all purchases identifying the name and address of each party to be kept for two years
Required verification of proof of identity of all purchasers
Required protection and disclosure methods in the collection of personal information
Reports to the Attorney General of any suspicious payments or disappearances of the regulated products
Non-liquid dose form of regulated product may only be sold in unit-dose blister packs
Regulated products are to be sold behind the counter or in a locked cabinet in such a way as to restrict access
Daily sales of regulated products not to exceed 3.6 g to a single purchaser, without regard to the number of transactions
Monthly sales to a single purchaser not to exceed 9 g of pseudoephedrine base in regulated productsThe law gives similar regulations to mail-order purchases, except the monthly sales limit is 7.5 g.
As a pure herb or tea, má huáng, containing ephedrine, is still sold legally in the US. The law restricts/prohibits its being sold as a dietary supplement (pill) or as an ingredient/additive to other products, like diet pills.
Australia
Ephedrine and all Ephedra species which contain it are considered Schedule 4 substances under the Poisons Standard (October 2015). A Schedule 4 drug is considered a Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription under the Poisons Standard (October 2015).
South Africa
In South Africa, ephedrine was moved to schedule 6 on 27 May 2008, which makes pure ephedrine tablets prescription only. Pills containing ephedrine up to 30mg per tablet in combination with other medications are still available OTC, schedule 1 and 2, for sinus, head colds and influenza.
Germany
Ephedrine was freely available in pharmacies in Germany until 2001. Afterwards, access was restricted since it was mostly bought for unindicated uses. Similarly, ephedra can only be bought with a prescription. Since April 2006, all products, including plant parts, that contain ephedrine are only available with a prescription.
See also
Amphetamine
Methamphetamine
Phenylephrine
Propylhexedrine
Pyrovalerone
Norephedrine
Halostachine
Metaraminol
Oxyfedrine
Pseudoephedrine
Synephrine
References
External links
"Ephedrine". Drug Information Portal. U.S. National Library of Medicine.
"Ephedrine sulfate". Drug Information Portal. U.S. National Library of Medicine.
"Ephedrine Hhydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Triptorelin | Triptorelin, sold under the brand name Decapeptyl among others, is a medication that acts as an agonist analog of gonadotropin-releasing hormone, repressing expression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).It is a decapeptide (pGlu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2) and a gonadotropin-releasing hormone agonist (GnRH agonist) used as the acetate or pamoate salts.
Primary indications include endometriosis, for the reduction of uterine fibroids, to treat prostate cancer, and to treat male hypersexuality with severe sexual deviation. The drug has also been used off label to delay puberty in patients with gender dysphoria.It was patented in 1975 and approved for medical use in 1986. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Triptorelin is used to treat prostate cancer as part of androgen deprivation therapy.Another common use in the United Kingdom is for hormone replacement therapy to suppress testosterone or estrogen levels in transgender people (in conjunction with estradiol valerate for trans women or testosterone for trans men). Spironolactone and cyproterone acetate are other drugs used by trans people to suppress sex hormones, but these drugs have a completely different mechanism of action. It can also be used as a puberty blocker.Triptorelin has been used as a chemical castration agent for reducing sexual urges in sex offenders.
Drug action
Triptorelin is a gonadorelin analogue, also known as luteinizing hormone releasing analogue (GnRH analogue, LHRH analogue). The drug binds to receptors in the pituitary gland and stimulates secretion of gonadotropins (namely luteinizing hormone LH and follicle-stimulating hormone FSH). This causes an initial phase of LH and FSH stimulation, prior to down-regulation of the gonadotrophin-releasing hormone receptors, thereby reducing the release of gonadotropins in the long term, which in turn leads to the inhibition of androgen and estrogen production.
Side-effects
General side effects can include:
Anaphylaxis
Arthralgia
Asthenia
Asthma
Breast tenderness (males and females)
Changes in blood pressure
Changes in breast size
Depression
Ovarian cysts
Mood changes
Skin rashes
Hot flushes
Weight changes
Society and culture
Brand names
Triptorelin is marketed under the brand names Decapeptyl (Ipsen) and Diphereline and Gonapeptyl (Ferring Pharmaceuticals). In the United States, it is sold by Watson Pharmaceuticals as Trelstar and by Arbor Pharmaceuticals as Triptodur (an extended-release 6-month depot injection). In Iran, triptorelin is marketed under the brand name Variopeptyl. In the UK and Germany, it is sold as Salvacyl.
Research
Triptorelin and other antiandrogens may be effective in the treatment of obsessive–compulsive disorder.
References
Further reading
Lahlou N, Carel JC, Chaussain JL, Roger M (July 2000). "Pharmacokinetics and pharmacodynamics of GnRH agonists: clinical implications in pediatrics". J Pediatr Endocrinol Metab. 13 Suppl 1: 723–37. doi:10.1515/jpem.2000.13.s1.723. PMID 10969915. S2CID 3639804.
Padula AM (August 2005). "GnRH analogues—agonists and antagonists". Anim Reprod Sci. 88 (1–2): 115–26. doi:10.1016/j.anireprosci.2005.05.005. PMID 15955640.
External links
"Triptorelin". Drug Information Portal. U.S. National Library of Medicine. |
Fosinopril | Fosinopril is an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of chronic heart failure. Fosinopril is the only phosphonate-containing ACE inhibitor marketed, by Bristol-Myers Squibb under the trade name Monopril. Fosinopril is a cascading pro-drug. The special niche for the medication that differentiates it from the other members of the ACE Inhibitor drug class is that was specifically developed for the use for patients with renal impairment. This was through manipulation of the metabolism and excretion, and is seen that fifty percent of the drug is hepatobiliary cleared, which can compensate for diminished renal clearance. The remaining fifty percent is excreted in urine. It does not need dose adjustment.
It was patented in 1980 and approved for medical use in 1991.
Medical uses
In congestive heart failure, the ability of the heart to pump enough blood to satisfy the physiological needs of the body is reduced. This condition has a variety of causes, including damaged heart valves, myocardial infarction, hypertension, vitamin B1 deficiency, and genetic mutations. When subsequent blood flow to the kidneys is reduced, the kidneys respond by increasing the secretion of renin from the juxtaglomerular apparatus. Renin converts the inactive angiotensinogen into angiotensin I, which is converted to angiotensin II (AII) by angiotensin converting enzyme (ACE). AII can have negative effects on the cardiovascular system after events such as heart failure and myocardial infarction. AII causes arterial vasoconstriction and hypertension, resulting in an increase in afterload, increasing the resistance against which the heart works. Additionally, chronic increase in production of AII is associated with structural changes to the myocardium which reduces the functionality of the heart.In heart failure patients, fosinopril increases exercise tolerance and lowers the frequency of events associated with worsening heart failure, such as dyspnea, the need for supplemental diuretics, fatigue, and hospitalizations.
Chemistry
Unlike other ACE inhibitors that are primarily excreted by the kidneys, fosinopril is eliminated from the body by both renal and hepatic pathways. This characteristic of fosinopril makes the drug a safer choice than other ACE inhibitors for heart failure patients with impaired kidney function resulting from poor perfusion as fosinopril can still be eliminated by the liver, preventing accumulation of the drug in the body.Fosinopril is de-esterified by the liver or gastrointestinal mucosa and is converted to its active form, fosinoprilat. Fosinoprilat competitively binds to ACE, preventing ACE from binding to and converting angiotensin I to angiotensin II. Inhibiting the production of AII lowers peripheral vascular resistance, decreases afterload, and decreases blood pressure, thus helping to alleviate the negative effects of AII on cardiac performance.
== References == |
Pyrimethamine | Pyrimethamine, sold under the brand name Daraprim among others, is a medication used with leucovorin (leucovorin is used to decrease side effects of pyrimethamine; it does not have intrinsic anti-parasitic activity) to treat the parasitic diseases toxoplasmosis and cystoisosporiasis. It is also used with dapsone as a second-line option to prevent Pneumocystis jiroveci pneumonia in people with HIV/AIDS. It was previously used for malaria but is no longer recommended due to resistance. Pyrimethamine is taken by mouth.Common side effects include gastrointestinal upset, severe allergic reactions, and bone marrow suppression. It should not be used by people with folate deficiency that has resulted in anemia. There is concern that it may increase the risk of cancer. While occasionally used in pregnancy it is unclear if pyrimethamine is safe for the baby. Pyrimethamine is classified as a folic acid antagonist. It works by inhibiting folic acid metabolism and therefore the making of DNA.Pyrimethamine was discovered in 1952 and came into medical use in 1953. It is on the World Health Organizations List of Essential Medicines. It was approved as a generic in the United States in February 2020.
Medical uses
Pyrimethamine is typically given with a sulfonamide and folinic acid.It is used for the treatment of toxoplasmosis, actinomycosis, and isosporiasis, and for the treatment and prevention of Pneumocystis jirovecii pneumonia.
Toxoplasmosis
Pyrimethamine is also used in combination with sulfadiazine to treat active toxoplasmosis. The two drugs bind the same enzymatic targets as the drugs trimethoprim and sulfamethoxazole - dihydrofolate reductase and dihydropteroate synthase, respectively.Pyrimethamine has also been used in several trials to treat retinochoroiditis.
Pregnancy consideration
Pyrimethamine is labeled as pregnancy category C in the United States. To date, not enough evidence on its risks in pregnancy or its effects on the fetus is available.
Malaria
It is primarily active against Plasmodium falciparum, but also against Plasmodium vivax. Due to the emergence of pyrimethamine-resistant strains of P. falciparum, pyrimethamine alone is seldom used now. In combination with a long-acting sulfonamide such as sulfadiazine, it was widely used, such as in Fansidar, though resistance to this combination is increasing.
Contraindications
Pyrimethamine is contraindicated in people with folate-deficiency anaemia.
Side effects
When higher doses are used, as in the treatment of toxoplasmosis, pyrimethamine can cause gastrointestinal symptoms such as nausea, vomiting, glossitis, anorexia, and diarrhea. A rash, which can be indicative of a hypersensitivity reaction, is also seen, particularly in combination with sulfonamides. Central nervous system effects include ataxia, tremors, and seizures. Hematologic side effects such as thrombocytopenia, leukopenia, and anemia can also occur.
Interactions
Other antifolate agents such as methotrexate and trimethoprim may potentiate the antifolate actions of pyrimethamine, leading to potential folate deficiency, anaemia, and other blood dyscrasias.
Mechanism of action
Pyrimethamine interferes with the regeneration of tetrahydrofolic acid from dihydrofolate by competitively inhibiting the enzyme dihydrofolate reductase. Tetrahydrofolic acid is essential for DNA and RNA synthesis in many species, including protozoa. It has also been found to reduce the expression of SOD1, a key protein involved in amyotrophic lateral sclerosis.
Other medications
Pyrimethamine is typically given with folinic acid and sulfadiazine.
Sulfonamides (e.g. sulfadiazine) inhibit dihydropteroate synthetase, an enzyme that participates in folic acid synthesis from para-aminobenzoic acid. Hence, sulfonamides work synergistically with pyrimethamine by blocking a different enzyme needed for folic acid synthesis.
Folinic acid (leucovorin) is a folic acid derivative converted to tetrahydrofolate, the primary active form of folic acid, in vivo, without relying on dihydrofolate reductase. Folinic acid reduces side effects related to folate deficiency in the patient.
Mechanism of resistance
Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce its effectiveness. These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of hydrogen bonds and steric interactions.
History
Nobel Prize-winning American scientist Gertrude Elion developed the drug at Burroughs-Wellcome (now part of GlaxoSmithKline) to combat malaria. Pyrimethamine has been available since 1953. In 2010, GlaxoSmithKline sold the marketing rights for Daraprim to CorePharma. Impax Laboratories sought to buy CorePharma in 2014, and completed the acquisition, including Daraprim, in March 2015. In August 2015, the rights were bought by Turing Pharmaceuticals. Turing subsequently became infamous for a price hike controversy when it raised the price of a dose of the drug in the U.S. market from US$13.50 to US$750, a 5,500% increase.
Society and culture
Economics
In the United States in 2015, Turing Pharmaceuticals was criticized for increasing the price 50-fold, from US$13.50 to $750 a tablet, leading to a cost of $75,000 for a course of treatment reported at one hospital.
United States
In the United States, in 2015, with Turing Pharmaceuticals acquisition of the US marketing rights for Daraprim tablets, Daraprim became a single-source and specialty pharmacy item, and the price was increased. The cost of a monthly course for a person on 75 mg dose rose to about $75,000/month at one hospital, or $750 per tablet while it was previously priced at 13.50.Outpatients could no longer obtain the medication from a community pharmacy, but only through a single dispensing pharmacy, Walgreens Specialty Pharmacy, and institutions could no longer order from their general wholesaler, but had to set up an account with the Daraprim Direct program. Presentations from Retrophin, a company formerly headed by Martin Shkreli, CEO of Turing, from which Turing acquired the rights to Daraprim, suggested that a closed distribution system could prevent generic competitors from legally obtaining the drugs for the bioequivalence studies required for FDA approval of a generic drug.Shkreli defended the price hike by saying, "If there was a company that was selling an Aston Martin at the price of a bicycle, and we buy that company and we ask to charge Toyota prices, I dont think that that should be a crime." As a result of the backlash, Shkreli hired a crisis public relations firm to help explain his funds move. Turing Pharmaceuticals announced on 24 November 2015, "that it would not reduce the list price of that drug after all", but they would offer patient assistance programs. New York Times journalist Andrew Pollack noted that these programs "are standard for companies selling extremely high-priced drugs. They enable the patients to get the drug while pushing most of the costs onto insurance companies and taxpayers."The price increase was criticized by physician groups such as HIV Medicine Associates and Infectious Diseases Society of America.In 2016, a group of high school students from Sydney Grammar supported by the University of Sydney prepared pyrimethamine as an illustration that the synthesis is comparatively easy and the price-hike unjustifiable. His team produced 3.7 g for US$20, which would have been worth between US$35,000 and US$110,000 in the United States at the time. Shkreli said the schoolboys were not competition, likely because the necessary bioequivalence studies require a sample of the existing medication provided directly by the company, and not simply purchased from a pharmacy, which Turing could decline to provide. Nonetheless, the students work was featured in The Guardian and Time magazine, and on ABC Australia, the BBC, and CNN.On 22 October 2015, Imprimis Pharmaceuticals announced it had made available compounded and customizable formulations of pyrimethamine and leucovorin in capsules to be taken by mouth starting as low as $99 for a 100-count bottle in the United States. Pyrimethamine was approved as a generic in the United States in February 2020.In January 2020 the FTC filed a case against Vyera "alleging an elaborate anticompetitive scheme to preserve a monopoly for the life-saving drug, Daraprim". A settlement was reached in December 2021. According to AP News, the settlement "requires Vyera and Phoenixus to provide up to $40 million in relief over 10 years to consumers who allegedly were fleeced by their actions and requires them to make Daraprim available to any potential generic competitor at the cost of producing the drug." According to Law360, company executive Kevin Mulleady "agreed to a seven-year ban on working for or holding more than an 8% share in most pharmaceutical companies."
Other countries
In India, over a dozen manufacturers sell pyrimethamine tablets, and multiple combinations of generic pyrimethamine are available for a price ranging from US$0.04 to US$0.10 each (3–7 rupees).In the UK, the same drug is available from GSK at a cost of US$20 (£13) for 30 tablets (about $0.66 each).In Australia, the drug is available in most pharmacies at a cost of US$9.35 (A$12.99) for 50 tablets (around US$0.18 each).In Brazil, the drug is available for R$0.07 a pill, or about US$0.02.In Canada, the drug was reportedly discontinued in 2013, but hospitals may make the drug in-house when it is needed. As of December 2015, Daraprim imported into Canada directly from GSK UK is available from an online pharmacy for US$2.20 per tablet.In Switzerland, the drug is available for US$9.45 (CHF9.05) for 30 tablets (around US$0.32 a piece).
Research
In 2011, researchers discovered that pyrimethamine can increase β-hexosaminidase activity, thus potentially slowing down the progression of late-onset Tay–Sachs disease. It is being evaluated in clinical trials as a treatment for amyotrophic lateral sclerosis.
See also
Sulfadoxine/pyrimethamine
References
External links
"Pyrimethamine". Drug Information Portal. U.S. National Library of Medicine. |
Valproate | Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.Common side effects of valproate include nausea, vomiting, somnolence, and dry mouth. Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended. Other serious risks include pancreatitis and an increased suicide risk. Valproate is known to cause serious abnormalities in fetuses if taken during pregnancy, and is contra-indicated for women of childbearing age unless the drug is essential to their medical condition. As of 2022 the drug was still prescribed in the UK to potentially pregnant women, but use declined by 51% from 2018–19 to 2020–21.Valproates precise mechanism of action is unclear. Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, and inhibiting histone deacetylases. Valproic acid is a branched short-chain fatty acid (SCFA) made from valeric acid.Valproate was first made in 1881 and came into medical use in 1962. It is on the World Health Organizations List of Essential Medicines and is available as a generic medication. In 2019, it was the 114th most commonly prescribed medication in the United States, with more than 5 million prescriptions.
Terminology
Valproic acid (VPA) is an organic weak acid. The conjugate base is valproate. The sodium salt of the acid is sodium valproate and a coordination complex of the two is known as valproate semisodium.
Medical uses
It is used primarily to treat epilepsy and bipolar disorder. It is also used to prevent migraine headaches.
Epilepsy
Valproate has a broad spectrum of anticonvulsant activity, although it is primarily used as a first-line treatment for tonic–clonic seizures, absence seizures and myoclonic seizures and as a second-line treatment for partial seizures and infantile spasms. It has also been successfully given intravenously to treat status epilepticus.
Mental illness
Bipolar disorder
Valproate products are also used to treat manic or mixed episodes of bipolar disorder.
Schizophrenia
A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:
Dopamine dysregulation syndrome
Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of the dopamine dysregulation syndrome that arise from the treatment of Parkinsons disease with levodopa.
Migraines
Valproate is also used to prevent migraine headaches.
Other
The medication has been tested in the treatment of AIDS and cancer, owing to its histone-deacetylase-inhibiting effects.
Contraindications
Contraindications include:
Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related.
Known hypersensitivity to valproate or any of the ingredients used in the preparation
Urea cycle disorders
Hepatic porphyria
Hepatotoxicity
Mitochondrial disease
Pancreatitis
Porphyria
Adverse effects
Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.It is worthy of mentioning that some adverse effects related to valproic acid may be dose-dependent such as pancytopenia.There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height. Valproic acid can also cause mydriasis, a dilation of the pupils. There is evidence that shows valproic acid may increase the chance of polycystic ovary syndrome (PCOS) in women with epilepsy or bipolar disorder. Studies have shown this risk of PCOS is higher in women with epilepsy compared to those with bipolar disorder. Weight gain is also possible.
Pregnancy
Valproate causes birth defects; exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida with the risks being related to the strength of medication used and use of more than one drug. More rarely, with several other defects, including a "valproate syndrome". Characteristics of this valproate syndrome include facial features that tend to evolve with age, including a triangle-shaped forehead, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth. While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.Children of mothers taking valproate during pregnancy are at risk for lower IQs. Maternal valproate use during pregnancy increased the probability of autism in the offspring compared to mothers not taking valproate from 1.5% to 4.4%. A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%. The normal incidence for autism in the general population is estimated at 1 in 44 (2.3%). A 2009 study found that the 3-year-old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.Sodium valproate has been associated with paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate. Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have worse outcomes for the fetus than exposure to valproate). Studies have shown that taking folic acid supplements can reduce the risk of congenital neural tube defects. The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the European Union, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.
Elderly
Valproate may cause increased somnolence in the elderly. In a trial of valproate in elderly patients with dementia, a significantly higher portion of valproate patients had somnolence compared to placebo. In approximately one-half of such patients, there was associated reduced nutritional intake and weight loss.
Overdose and toxicity
Excessive amounts of valproic acid can result in somnolence, tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/L during controlled therapy, but may reach 150–1500 mg/L following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography.
In contrast to other antiepileptic drugs, at present there is little favorable evidence for salivary therapeutic drug monitoring. Salivary levels of valproic acid correlate poorly with serum levels, partly due to valproates weak acid property (pKa of 4.9).In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body. Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored. Supplemental L-carnitine is indicated in patients having an acute overdose and also prophylactically in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly than L-carnitine.
Interactions
Valproate inhibits CYP2C9, glucuronyl transferase, and epoxide hydrolase and is highly protein bound and hence may interact with drugs that are substrates for any of these enzymes or are highly protein bound themselves. It may also potentiate the CNS depressant effects of alcohol. It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics (including carbamazepine, lamotrigine, phenytoin and phenobarbitone) and itself. It may also interact with:
Aspirin: may increase valproate concentrations. May also interfere with valproates metabolism.
Benzodiazepines: may cause CNS depression and there are possible pharmacokinetic interactions.
Carbapenem antibiotics: reduce valproate levels, potentially leading to seizures.
Cimetidine: inhibits valproates metabolism in the liver, leading to increased valproate concentrations.
Erythromycin: inhibits valproates metabolism in the liver, leading to increased valproate concentrations.
Ethosuximide: valproate may increase ethosuximide concentrations and lead to toxicity.
Felbamate: may increase plasma concentrations of valproate.
Mefloquine: may increase valproate metabolism combined with the direct epileptogenic effects of mefloquine.
Oral contraceptives: may reduce plasma concentrations of valproate.
Primidone: may accelerate metabolism of valproate, leading to a decline of serum levels and potential breakthrough seizure.
Rifampicin: increases the clearance of valproate, leading to decreased valproate concentrations
Warfarin: valproate may increase free warfarin concentration and prolong bleeding time.
Zidovudine: valproate may increase zidovudine serum concentration and lead to toxicity.
Pharmacology
Pharmacodynamics
Although the mechanism of action of valproate is not fully understood, traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA). The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate. In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells.Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism. Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.It also has histone-deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.
Endocrine actions
Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence as a nonsteroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels. In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations. These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.Valproic acid has been found to directly stimulate androgen biosynthesis in the gonads via inhibition of histone deacetylases and has been associated with hyperandrogenism in women and increased 4-androstenedione levels in men. High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.
Pharmacokinetics
Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut. When in the bloodstream, 80–90% of the substance are bound to plasma proteins, mainly albumin. Protein binding is saturable: it decreases with increasing valproate concentration, low albumin concentrations, the patients age, additional use of other drugs such as aspirin, as well as liver and kidney impairment. Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.The vast majority of valproate metabolism occurs in the liver. Valproate is known to be metabolized by the cytochrome P450 enzymes CYP2A6, CYP2B6, CYP2C9, and CYP3A5. It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15. Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):
via glucuronidation (30–50%): valproic acid β-O-glucuronide
via beta oxidation (>40%): 2E-ene-valproic acid, 2Z-ene-valproic acid, 3-hydroxyvalproic acid, 3-oxovalproic acid
via omega oxidation: 5-hydroxyvalproic acid, 2-propyl-glutaric acid
some others: 3E-ene-valproic acid, 3Z-ene-valproic acid, 4-ene-valproic acid, 4-hydroxyvalproic acidAll in all, over 20 metabolites are known.In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as the glucuronide conjugate. The other major pathway in the metabolism of valproate is mitochondrial beta oxidation, which typically accounts for over 40% of an administered dose. Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine. Only a small amount is excreted via the faeces. Elimination half-life is 16±3 hours and can decrease to 4–9 hours when combined with enzyme inducers.
Chemistry
Valproic acid is a branched short-chain fatty acid and the 2-n-propyl derivative of valeric acid.
History
Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian. Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented pentylenetetrazol-induced convulsions in laboratory rats. It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide. Valproic acid has also been used for migraine prophylaxis and bipolar disorder.
Society and culture
Valproate is available as a generic medication.
Approval status
Off-label uses
In 2012, pharmaceutical company Abbott paid $1.6 billion in fines to US federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents.Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.
Formulations
Valproate exists in two main molecular variants: sodium valproate and valproic acid without sodium (often implied by simply valproate). A mixture between these two is termed semisodium valproate. It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more mass of sodium valproate is needed than valproic acid without sodium to compensate for the sodium itself.
Brand names of valproic acid
Branded products include:
Brand names of sodium valproate
Portugal
Tablets – Diplexil-R by Bial.
United States
Intravenous injection – Depacon by Abbott Laboratories.
Syrup – Depakene by Abbott Laboratories. (Note Depakene capsules are valproic acid).
Depakote tablets are a mixture of sodium valproate and valproic acid.
Tablets – Eliaxim by Bial.
Australia
Epilim Crushable Tablets Sanofi
Epilim Sugar Free Liquid Sanofi
Epilim Syrup Sanofi
Epilim Tablets Sanofi
Sodium Valproate Sandoz Tablets Sanofi
Valpro Tablets Alphapharm
Valproate Winthrop Tablets Sanofi
Valprease tablets Sigma
New Zealand
Epilim by Sanofi-AventisAll the above formulations are Pharmac-subsidised.
UK
Depakote Tablets (as in USA)
Tablets – Orlept by Wockhardt and Epilim by Sanofi
Oral solution – Orlept Sugar Free by Wockhardt and Epilim by Sanofi
Syrup – Epilim by Sanofi-Aventis
Intravenous injection – Epilim Intravenous by Sanofi
Extended release tablets – Epilim Chrono by Sanofi is a combination of sodium valproate and valproic acid in a 2.3:1 ratio.
Enteric-coated tablets – Epilim EC200 by Sanofi is a 200-mg sodium valproate enteric-coated tablet.
UK only
Capsules – Episenta prolonged release by Beacon
Sachets – Episenta prolonged release by Beacon
Intravenous solution for injection – Episenta solution for injection by Beacon
Germany, Switzerland, Norway, Finland, Sweden
Tablets – Orfiril by Desitin Pharmaceuticals
Intravenous injection – Orfiril IV by Desitin Pharmaceuticals
South Africa
Syrup – Convulex by Byk Madaus
Tablets – Epilim by Sanofi-synthelabo
Malaysia
Tablets – Epilim by Sanofi-Aventis
Romania
Companies are SANOFI-AVENTIS FRANCE, GEROT PHARMAZEUTIKA GMBH and DESITIN ARZNEIMITTEL GMBH
Types are Syrup, Extended release mini tablets, Gastric resistant coated tablets, Gastric resistant soft capsules, Extended release capsules, Extended release tablets and Extended release coated tablets
Canada
Intravenous injection – Epival or Epiject by Abbott Laboratories.
Syrup – Depakene by Abbott Laboratories its generic formulations include Apo-Valproic and ratio-Valproic.
Japan
Tablets – Depakene by Kyowa Hakko Kirin
Extended release tablets – Depakene-R by Kyowa Hakko Kogyo and Selenica-R by Kowa
Syrup – Depakene by Kyowa Hakko Kogyo
Europe
In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.
Taiwan
Tablets (white round tablet) – Depakine (Chinese: 帝拔癲; pinyin: di-ba-dian) by Sanofi Winthrop Industrie (France)
Iran
Tablets – Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo
Slow release tablets – Depakine Chrono by Sanofi Winthrop Industrie (France)
Israel
Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by Sanofi-Aventis.
India, Russia and CIS countries
Valparin Chrono by Sanofi India
Valprol CR by Intas Pharmaceutical (India)
Encorate Chrono by Sun Pharmaceutical (India)
Serven Chrono by Leeven APL Biotech (India)
Brand names of valproate semisodium
Brazil – Depakote by Abbott Laboratories and Torval CR by Torrent do Brasil
Canada – Epival by Abbott Laboratories
Mexico – Epival and Epival ER (extended release) by Abbott Laboratories
United Kingdom – Depakote (for psychiatric conditions) and Epilim (for epilepsy) by Sanofi-Aventis and generics
United States – Depakote and Depakote ER (extended release) by Abbott Laboratories and generics
India – Valance and Valance OD by Abbott Healthcare Pvt Ltd, Divalid ER by Linux laboratories Pvt Ltd, Valex ER by Sigmund Promedica, Dicorate by Sun Pharma
Germany – Ergenyl Chrono by Sanofi-Aventis and generics
Chile – Valcote and Valcote ER by Abbott Laboratories
France and other European countries — Depakote
Peru – Divalprax by AC Farma Laboratories
China – Diprate OD
References
External links
"Valproic acid". Drug Information Portal. U.S. National Library of Medicine.
"Valproate sodium". Drug Information Portal. U.S. National Library of Medicine.
"Divalproex sodium". Drug Information Portal. U.S. National Library of Medicine. |
Viltolarsen | Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen is a Morpholino antisense oligonucleotide.The most common side effects include upper respiratory tract infection, injection site reaction, cough, and pyrexia (fever).Viltolarsen was approved for medical use in the United States in August 2020. After golodirsen was approved in December 2019, viltolarsen is the second approved targeted treatment for people with this type of mutation in the United States. Approximately 8% of people with DMD have a mutation that is amenable to exon 53 skipping.
Medical uses
Viltolarsen is indicated for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness. It is the most common type of muscular dystrophy. DMD is caused by mutations in the DMD gene that results in an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between three and five years of age and worsen over time. DMD occurs in approximately one out of every 3,600 male infants worldwide; in rare cases, it can affect females.
Adverse effects
The most common side effects include upper respiratory tract infection, injection site reaction, cough, and pyrexia (fever).Although kidney toxicity was not observed in the clinical studies, the clinical experience is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides.
History
Viltolarsen was developed by Nippon Shinyaku and the NCNP based on pre-clinical study conducted by Toshifumi Yokota and colleagues, and evaluated in two clinical studies with a total of 32 participants, all of whom were male and had genetically confirmed DMD. The increase in dystrophin production was established in one of those two studies, a study that included sixteen DMD participants, with eight participants receiving viltolarsen at the recommended dose. In the study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25. Trial 1 provided data for evaluation of the benefits of viltolarsen. The combined populations from both trials provided data for evaluation of the side effects of viltolarsen. Trial 1 was conducted at six sites in the United States and Canada and Trial 2 was conducted at five sites in Japan. All participants in both trials were on a stable dose of corticosteroids for at least three months before entering the trials.The U.S. Food and Drug Administration (FDA) concluded that the applicants data demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in people with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping. A clinical benefit of the drug has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.The application for viltolarsen was granted priority review designation and the FDA granted the approval to NS Pharma, Inc.
Society and culture
Economics
Viltolarsen costs around US$733,000 per year for a person that weighs 30 kilograms (66 lb).
References
Further reading
Dhillon S (July 2020). "Viltolarsen: First Approval". Drugs. 80 (10): 1027–1031. doi:10.1007/s40265-020-01339-3. PMID 32519222. S2CID 219542850.
Dzierlega K, Yokota T (June 2020). "Optimization of antisense-mediated exon skipping for Duchenne muscular dystrophy". Gene Ther. 27 (9): 407–416. doi:10.1038/s41434-020-0156-6. PMID 32483212. S2CID 219157034.
Hwang J, Yokota T (October 2019). "Recent advancements in exon-skipping therapies using antisense oligonucleotides and genome editing for the treatment of various muscular dystrophies". Expert Rev Mol Med. 21: e5. doi:10.1017/erm.2019.5. PMID 31576784. S2CID 203641010.
Roshmi RR, Yokota T (October 2019). "Viltolarsen for the treatment of Duchenne muscular dystrophy". Drugs Today. 55 (10): 627–639. doi:10.1358/dot.2019.55.10.3045038. PMID 31720560. S2CID 207935659.
External links
"Viltolarsen". Drug Information Portal. U.S. National Library of Medicine (NLM).
Clinical trial number NCT02740972 for "Safety and Dose Finding Study of NS-065/NCNP-01 in Boys With Duchenne Muscular Dystrophy (DMD)" at ClinicalTrials.gov |
Brinzolamide/brimonidine | Brinzolamide/brimonidine, sold under the brand name Simbrinza, is a fixed-dose combination medication used to reduce intra-ocular pressure (pressure inside the eye) in adults with ocular hypertension (high intra-ocular pressure) or in those with an eye condition known as open-angle glaucoma. It contains brinzolamide and brimonidine tartrate. It is used as an eye drop.The most common side effects include ocular hyperaemia (red eye), allergic reactions in the eye, and dysgeusia (taste disturbances).Open-angle glaucoma (a condition where the aqueous humour, the watery fluid inside the eyeball, cannot drain away properly) and other causes of high pressure in the eye increase the risk of damage to the retina and the optic nerve (the nerve that sends signals from the eye to the brain). This can result in serious vision loss and even blindness.The active substances, brinzolamide and brimonidine tartrate, help to reduce intra-ocular pressure by reducing the production of aqueous humour. Brinzolamide works by blocking an enzyme called carbonic anhydrase, which produces bicarbonate needed for the production of the aqueous humour, while brimonidine tartrate blocks another enzyme known as adenylate cyclase, which is also involved in the production of the aqueous humour. Brimonidine also increases the drainage of aqueous humour from the front of the eye.Brinzolamide/brimonidine was approved for medical use in the United States in April 2013, and in the European Union in July 2014.
Medical uses
Brinzolamide/brimonidine is indicated to decrease of elevated intraocular pressure (IOP) in adults with open-angle glaucoma or ocular hypertension for whom monotherapy provides insufficient IOP reduction.
History
Brinzolamide/brimonidine was approved for medical use in the United States in April 2013, and in the European Union in July 2014.
References
Further reading
Li T, Lindsley K, Rouse B, Hong H, Shi Q, Friedman DS, Wormald R, Dickersin K (January 2016). "Comparative Effectiveness of First-Line Medications for Primary Open-Angle Glaucoma: A Systematic Review and Network Meta-analysis". Ophthalmology. 123 (1): 129–40. doi:10.1016/j.ophtha.2015.09.005. PMC 4695285. PMID 26526633.
Lusthaus JA, Goldberg I (September 2017). "Brimonidine and brinzolamide for treating glaucoma and ocular hypertension; a safety evaluation". Expert Opin Drug Saf. 16 (9): 1071–1078. doi:10.1080/14740338.2017.1346083. PMID 28656780. S2CID 205825340.
External links
"Brinzolamide". Drug Information Portal. U.S. National Library of Medicine.
"Brimonidine". Drug Information Portal. U.S. National Library of Medicine.
"Brimonidine tartrate". Drug Information Portal. U.S. National Library of Medicine. |
Torasemide | Torasemide, also known as torsemide, is a diuretic medication used to treat fluid overload due to heart failure, kidney disease, and liver disease and high blood pressure. It is a less preferred treatment for high blood pressure. It is taken by mouth or by injection into a vein.Common side effects include headache, increased urination, diarrhea, cough, and dizziness. Other side effects may include hearing loss and low blood potassium. Torasemide is a sulfonamide and loop diuretic. Use is not recommended in pregnancy or breastfeeding. It works by decreasing the reabsorption of sodium by the kidneys.Torasemide was patented in 1974 and came into medical use in 1993. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 227th most commonly prescribed medication in the United States, with more than 2 million prescriptions.
Medical uses
It is used to treat fluid overload due to heart failure. It is sometimes used to treat high blood pressure. Compared with furosemide, torasemide is associated with a lower risk of rehospitalization for heart failure and an improvement in New York Heart Association class of heart failure. In heart failure it may be safer and more effective than furosemide. Long-term outcomes with torasemide may be better than with furosemide in patients with heart failure.
Adverse effects
No evidence of torasemide-induced ototoxicity has been demonstrated in humans.Loop diuretics, including torsemide, may decrease total body thiamine, particularly in people with poor thiamine intake, and this depletion may worsen heart failure. It is therefore reasonable to either also give thiamine supplements or to check blood thiamine levels in those being treated with chronic loop diuretics.
Chemistry
Compared with other loop diuretics, torasemide has a more prolonged diuretic effect than equipotent doses of furosemide and relatively decreased potassium loss.
Names
Torasemide is the recommended name of the drug (rINN) according to the (INN), which is the drug naming system coordinated by the World Health Organization. Torsemide is the official name of the drug according to the (USAN), which is the drug naming system coordinated by the USAN Council, which is co-sponsored by the American Medical Association (AMA), the United States Pharmacopeial Convention (USP), and the American Pharmacists Association (APhA).
References
External links
"Torasemide". Drug Information Portal. U.S. National Library of Medicine. |
Lincomycin | Lincomycin is a lincosamide antibiotic that comes from the actinomycete Streptomyces lincolnensis. A related compound, clindamycin, is derived from lincomycin by using thionyl chloride to replace the 7-hydroxy group with a chlorine atom with inversion of chirality. It was released for medical use in September 1964.
Uses
Although similar in antibacterial spectrum and mechanism of action to macrolides, lincomycin is also effective against other organisms including actinomycetes and some species of Mycoplasma and Plasmodium.However, because of its adverse effects and toxicity, it is rarely used today and reserved for patients allergic to penicillin or where bacteria have developed resistance.
Clinical pharmacology
Intramuscular administration of a single dose of 600 mg of Lincomycin produces average peak serum levels of 11.6 µg/mL at 60 min, and maintains therapeutic levels for 17 h to 20 h, for most susceptible gram-positive organisms. Urinary excretion after this dose ranges from 1.8% to 24.8% (mean: 17.3%).
A two-hour intravenous infusion of 600 mg of Lincomycin achieves average peak serum levels of 15.9 µg/mL and yields therapeutic levels for 14 h for most susceptible gram-positive organisms. Urinary excretion ranges from 4.9% to 30.3% (mean: 13.8%).
The biological half-life after IM or IV administration is 5.4 ± 1.0 h. The serum half-life of lincomycin may be prolonged in patients with severe impairment of renal function, compared to patients with normal renal function. In patients with abnormal hepatic function, serum half-life may be twofold longer than in patients with normal hepatic function. Hemodialysis and peritoneal dialysis are not effective in removing lincomycin from the serum.
Tissue level studies indicate that bile is an important route of excretion. Significant levels have been demonstrated in the majority of body tissues. Although lincomycin appears to diffuse in the cerebrospinal fluid (CSF), levels of lincomycin in the CSF appear inadequate for the treatment of meningitis.
Biosynthesis
Lincomycin is an antibiotic classified as a member of the lincosamide class, which typically features a L-proline amino acid derivative linked through amide group with an eight-carbon aminothio sugar. The two units 4-propyl-L-proline and the amino-octose, are each synthesized separately, and are then condensed by LmbD protein, and then further postcondensation reactions involving cleaving of mycothiol, deacetylation, and S-methylation finally yield lincomycin.
The biosynthesis of the amino acid moiety of lincomycin, starts with tyrosine which is transformed to 4-propyl-L-proline by the consecutive action of LmbB1, LmbB2, LmbW, LmbA and LmbX proteins. 4-Propyl-L-proline is activated by LmbC and loaded into LmbN, a bifunctional peptidyl carrier protein, and is ready for condensation by LmbD.
The biosynthetic pathway for production of the amino-octose moiety is almost fully elucidated although the order of the steps still needs further research. Condensation through a transaldolase (LmbR) of ribose 5-phosphate (C5) with fructose 6-phosphate or sedoheptulose-7-phosphate (providing a C3 unit) forms the octose (C8). Further transformations involving isomerization (LmbN), 1-phosphorylation (LmbP), 8-dephosphorylation (LmbK), guanosine diphosphate attachment at position 1 (LmbO), 4-epimerization (LmbM), 6-oxidation (LmbL), amination (LmbS), imine reduction (LmbZ) and 8-reduction, are performed to construct the amino-octose unit. LmbT protein exchange GDP by ergothioneine and the condensation with 4-propyl-L-proline and catalysed by LmbD can occur. The amide-linked product between the amino acid and the amino-octose bound to ergothioneine is then the substrate of LmbV, which substitute ergothioneine by mycothiol. The mycothiol moiety is then cleaved by LmbE, and the product is further processed by LmbIH, LmbQ, LmbJ, LmbF and is finally sulphur methylated by LmbG, to afford lincomycin.
Spectrum of susceptibility
Lincomycin is a narrow spectrum antibiotic with activity against Gram-positive and cell wall-less bacteria including pathogenic species of Streptococcus, Staphylococcus, and Mycoplasma. Lincomycin is used to treat severe bacterial infections in patients who cannot use penicillin antibiotics. Lincomycin shows weak activity against most Gram-negative bacteria. The following represents susceptibility (MIC) data for a few pathogenic bacteria:
Staphylococcus aureus - 0.2 µg/mL - 32 µg/mL
Streptococcus pneumoniae - 0.05 µg/mL - 0.4 µg/mL
Streptococcus pyogenes - 0.04 µg/mL - 0.8 µg/mL
See also
Lincosamides
== References == |
Osilodrostat | Osilodrostat, sold under the brand name Isturisa, is a medication for the treatment of adults with Cushings disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. It is taken by mouth.The most common side effects are adrenal insufficiency, headache, vomiting, nausea, fatigue, and edema (swelling caused by fluid retention).Hypocortisolism (low cortisol levels), QTc prolongation (a heart rhythm condition) and elevations in adrenal hormone precursors (inactive substance converted into a hormone) and androgens (hormone that regulates male characteristics) may also occur in people taking osilodrostat.Osilodrostat was approved for medical use in the European Union in January 2020, and for medical use in the United States in March 2020. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.Osilodrostat is an orally active, nonsteroidal corticosteroid biosynthesis inhibitor which was developed by Novartis for the treatment of Cushings syndrome and pituitary ACTH hypersecretion (a specific subtype of Cushings syndrome). It specifically acts as a potent and selective inhibitor of aldosterone synthase (CYP11B2) and at higher dosages of 11β-hydroxylase (CYP11B1).
History
In October 2014, an orphan designation was granted by the European Commission for osilodrostat for the treatment of Cushings syndrome.Osilodrostat was approved for medical use in the European Union in January 2020, and for medical use in the United States in March 2020.Osilodrostats safety and effectiveness for treating Cushings disease among adults was evaluated in a study of 137 adult subjects (about three-quarters women) with a mean age of 41 years. The majority of subjects either had undergone pituitary surgery that did not cure Cushings disease or were not surgical candidates. In the 24-week, single-arm, open-label period, all subjects received a starting dose of 2 milligrams (mg) of osilodrostat twice a day that could be increased every two weeks up to 30 mg twice a day. At the end of this 24-week period, about half of subjects had cortisol levels within normal limits. After this point, 71 subjects who did not need further dose increases and tolerated the drug for the last 12 weeks entered an eight-week, double-blind, randomized withdrawal study where they either received osilodrostat or a placebo (inactive treatment). At the end of this withdrawal period, 86% of subjects receiving osilodrostat maintained cortisol levels within normal limits compared to 30% of subjects taking the placebo.The U.S. Food and Drug Administration (FDA) approved osilodrostat based on the evidence from one clinical trial (NCT02180217) of 137 subjects with Cushings disease. The trial was conducted at 66 sites across 19 countries (United States, Argentina, Austria, Bulgaria, Canada, China, Columbia, Germany, Spain, France, Great Britain, India, Italy, Japan, Korea, Netherlands, Russia, Thailand, and Turkey).There was one trial of 48 weeks duration that assessed the benefits and side effects of osilodrostat. The trial enrolled subjects with Cushings disease for whom pituitary gland surgery was not an option or did not work. The trial was divided in four periods. Subjects received osilodrostat two times a day in all four periods. After the first two periods (24 weeks), the benefit of osilodrostat was assessed by the percentage of subjects who had 24-hour urinary free cortisol levels within normal limits.In the third period (which lasted eight weeks), half of the subjects who had normal urinary free cortisol levels after 24 weeks of treatment continued taking osilodrostat and the other half was switched to placebo. Neither the subjects nor the healthcare providers know which treatment was given during this period. The benefit of osilodrostat was assessed on the percentage of subjects who had normal cortisol levels at the end of this period versus the subjects who received placebo.The FDA granted osilodrostat an orphan drug designation and granted the approval of Isturisa to Novartis.
See also
Levoketoconazole
References
Further reading
Turcu A, Smith JM, Auchus R, et al. (October 2014). "Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions". Compr Physiol. 4 (4): 1369–81. doi:10.1002/cphy.c140006. ISBN 9780470650714. PMC 4437668. PMID 25428847. NIHMSID: NIHMS689229.
External links
"Osilodrostat". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02697734 for "Efficacy and Safety Evaluation of Osilodrostat in Cushings Disease (LINC-4)" at ClinicalTrials.gov |
Cocaine | Cocaine (from French: cocaïne, from Spanish: coca, ultimately from Quechua: kúka) is a stimulant drug obtained from the leaves of two Coca species native to South America, Erythroxylum coca and Erythroxylum novogranatense. After extraction from coca leaves and further processing into cocaine hydrochloride (powdered cocaine), the drug may be snorted, heated until sublimated and then inhaled, or dissolved and injected into a vein. Cocaine stimulates the reward pathway in the brain. Mental effects may include an intense feeling of happiness, sexual arousal, loss of contact with reality, or agitation. Physical effects may include a fast heart rate, sweating, and dilated pupils. High doses can result in high blood pressure or high body temperature. Effects begin within seconds to minutes of use and last between five and ninety minutes. As cocaine also has numbing and blood vessel constriction properties, it is occasionally used during surgery on the throat or inside of the nose to control pain, bleeding, and vocal cord spasm.Cocaine crosses the blood-brain barrier via a proton-coupled organic cation antiporter and (to a lesser extent) via passive diffusion across cell membranes. Cocaine blocks the dopamine transporter, inhibiting reuptake of dopamine from the synaptic cleft into the pre-synaptic axon terminal; the higher dopamine levels in the synaptic cleft increase dopamine receptor activation in the post-synaptic neuron, causing euphoria and arousal. Cocaine also blocks the serotonin transporter and norepinephrine transporter, inhibiting reuptake of serotonin and norepinephrine from the synaptic cleft into the pre-synaptic axon terminal and increasing activation of serotonin receptors and norepinephrine receptors in the post-synaptic neuron, contributing to the mental and physical effects of cocaine exposure.A single dose of cocaine induces tolerance to the drugs effects. Repeated use is likely to result in cocaine addiction. Addicts who abstain from cocaine experience cocaine craving and drug withdrawal, with depression, decreased libido, decreased ability to feel pleasure and fatigue. Use of cocaine increases the overall risk of death and intravenous use particularly increases the risk of trauma and infectious diseases such as blood infections and HIV. It also increases risk of stroke, heart attack, cardiac arrhythmia, lung injury (when smoked), and sudden cardiac death. Illicitly sold cocaine is commonly adulterated with local anesthetics, levamisole, cornstarch, quinine, or sugar, which can result in additional toxicity. In 2017, the Global Burden of Disease study found that cocaine use caused around 7300 deaths annually world-wide.
Uses
Coca leaves have been used by Andean civilizations since ancient times. In ancient Wari culture, Incan culture, and through modern successor indigenous cultures of the Andes mountains, coca leaves are chewed, taken orally in the form of a tea, or alternatively, prepared in a sachet wrapped around alkaline burnt ashes, and held in the mouth against the inner cheek; it has traditionally been used to combat the effects of cold, hunger, and altitude sickness. Cocaine was first isolated from the leaves in 1860.Globally, in 2019, cocaine was used by an estimated 20 million people (0.4% of adults aged 15 to 64 years). The highest prevalence of cocaine use was in Australia and New Zealand (2.1%), followed by North America (2.1%), Western and Central Europe (1.4%), and South and Central America (1.0%). Since 1961, the international Single Convention on Narcotic Drugs has required countries to make recreational use of cocaine a crime. In the United States, cocaine is regulated as a Schedule II drug under the Controlled Substances Act, meaning that it has a high potential for abuse and has an accepted medical use for treatment. While rarely used medically today, its accepted uses are as a topical local anesthetic for the upper respiratory tract as well as to reduce bleeding in the mouth, throat and nasal cavities.
Medical
Topical cocaine is sometimes used as a local numbing agent and vasoconstrictor to help control pain and bleeding with surgery of the nose, mouth, throat or lacrimal duct. Although some absorption and systemic effects may occur, the use of cocaine as a topical anesthetic and vasoconstrictor is generally safe, rarely causing cardiovascular toxicity, glaucoma, and pupil dilation. Occasionally, cocaine is mixed with adrenaline and sodium bicarbonate and used topically for surgery, a formulation called Moffetts solution.Cocaine hydrochloride (Goprelto), an ester local anesthetic, was approved for medical use in the United States in December 2017, and is indicated for the introduction of local anesthesia of the mucous membranes for diagnostic procedures and surgeries on or through the nasal cavities of adults. Cocaine hydrochloride (Numbrino) was approved for medical use in the United States in January 2020.The most common adverse reactions in people treated with Goprelto are headache and epistaxis. The most common adverse reactions in people treated with Numbrino are hypertension, tachycardia, and sinus tachycardia.
Recreational
Cocaine is a central nervous system stimulant. Its effects can last from 15 minutes to an hour. The duration of cocaines effects depends on the amount taken and the route of administration. Cocaine can be in the form of fine white powder, bitter to the taste. Crack cocaine is a smokeable form of cocaine made into small "rocks" by processing cocaine with sodium bicarbonate (baking soda) and water. Crack cocaine is referred to as "crack" because of the crackling sounds it makes when heated.Cocaine use leads to increases in alertness, feelings of well-being and euphoria, increased energy and motor activity, and increased feelings of competence and sexuality.Analysis of the correlation between the use of 18 various psychoactive substances shows that cocaine use correlates with other "party drugs" (such as ecstasy or amphetamines), as well as with heroin and benzodiazepines use, and can be considered as a bridge between the use of different groups of drugs.
Coca leaves
It is legal for people to use Coca leaves in some Andean nations, such as Peru and Bolivia, where they are chewed, consumed in the form of tea, or are sometimes incorporated into food products. Coca leaves are typically mixed with an alkaline substance (such as lime) and chewed into a wad that is retained in the buccal pouch (mouth between gum and cheek, much the same as chewing tobacco is chewed) and sucked of its juices. The juices are absorbed slowly by the mucous membrane of the inner cheek and by the gastrointestinal tract when swallowed. Alternatively, coca leaves can be infused in liquid and consumed like tea. Coca tea, an infusion of coca leaves, is also a traditional method of consumption. The tea has often been recommended for travelers in the Andes to prevent altitude sickness. Its actual effectiveness has never been systematically studied.In 1986 an article in the Journal of the American Medical Association revealed that U.S. health food stores were selling dried coca leaves to be prepared as an infusion as "Health Inca Tea". While the packaging claimed it had been "decocainized", no such process had actually taken place. The article stated that drinking two cups of the tea per day gave a mild stimulation, increased heart rate, and mood elevation, and the tea was essentially harmless.
Insufflation
Nasal insufflation (known colloquially as "snorting", "sniffing", or "blowing") is a common method of ingestion of recreational powdered cocaine. The drug coats and is absorbed through the mucous membranes lining the nasal passages. Cocaines desired euphoric effects are delayed when snorted through the nose by about five minutes. This occurs because cocaines absorption is slowed by its constricting effect on the blood vessels of the nose. Insufflation of cocaine also leads to the longest duration of its effects (60–90 minutes). When insufflating cocaine, absorption through the nasal membranes is approximately 30–60%In a study of cocaine users, the average time taken to reach peak subjective effects was 14.6 minutes. Any damage to the inside of the nose is because cocaine highly constricts blood vessels – and therefore blood and oxygen/nutrient flow – to that area.
Rolled up banknotes, hollowed-out pens, cut straws, pointed ends of keys, specialized spoons, long fingernails, and (clean) tampon applicators are often used to insufflate cocaine. The cocaine typically is poured onto a flat, hard surface (such as a mobile phone screen, mirror, CD case or book) and divided into "bumps", "lines" or "rails", and then insufflated. A 2001 study reported that the sharing of straws used to "snort" cocaine can spread blood diseases such as hepatitis C.
Injection
Subjective effects not commonly shared with other methods of administration include a ringing in the ears moments after injection (usually when over 120 milligrams) lasting two to 5 minutes including tinnitus and audio distortion. This is colloquially referred to as a "bell ringer". In a study of cocaine users, the average time taken to reach peak subjective effects was 3.1 minutes. The euphoria passes quickly. Aside from the toxic effects of cocaine, there is also the danger of circulatory emboli from the insoluble substances that may be used to cut the drug. As with all injected illicit substances, there is a risk of the user contracting blood-borne infections if sterile injecting equipment is not available or used.
An injected mixture of cocaine and heroin, known as "speedball", is a particularly dangerous combination, as the converse effects of the drugs actually complement each other, but may also mask the symptoms of an overdose. It has been responsible for numerous deaths, including celebrities such as comedians/actors John Belushi and Chris Farley, Mitch Hedberg, River Phoenix, grunge singer Layne Staley and actor Philip Seymour Hoffman. Experimentally, cocaine injections can be delivered to animals such as fruit flies to study the mechanisms of cocaine addiction.
Inhalation
The onset of cocaines euphoric effects is fastest with inhalation, beginning after 3–5 seconds. However, inhalation gives the shortest duration of euphoria (5–15 minutes). Cocaine is smoked by inhaling the vapor produced when free base cocaine is heated to the point of sublimation. In a 2000 Brookhaven National Laboratory medical department study, based on self-reports of 32 people who used cocaine who participated in the study, "peak high" was found at a mean of 1.4min +/- 0.5 minutes. Pyrolysis products of cocaine that occur only when heated/smoked have been shown to change the effect profile, i.e. anhydroecgonine methyl ester, when co-administered with cocaine, increases the dopamine in CPu and NAc brain regions, and has M1- and M3- receptor affinity.Smoking freebase cocaine is often accomplished using a pipe made from a small glass tube, often taken from "love roses", small glass tubes with a paper rose that are promoted as romantic gifts. These are sometimes called "stems", "horns", "blasters" and "straight shooters". A small piece of clean heavy copper or occasionally stainless steel scouring pad – often called a "brillo" (actual Brillo Pads contain soap, and are not used) or "chore" (named for Chore Boy brand copper scouring pads) – serves as a reduction base and flow modulator in which the "rock" can be melted and boiled to vapor. Crack is smoked by placing it at the end of the pipe; a flame held close to it produces vapor, which is then inhaled by the smoker. The effects felt almost immediately after smoking, are very intense and do not last long – usually 2 to 10 minutes. When smoked, cocaine is sometimes combined with other drugs, such as cannabis, often rolled into a joint or blunt.
Effects
Acute
Acute exposure to cocaine has many effects on humans, including euphoria, increases in heart rate and blood pressure, and increases in cortisol secretion from the adrenal gland. In humans with acute exposure followed by continuous exposure to cocaine at a constant blood concentration, the acute tolerance to the chronotropic cardiac effects of cocaine begins after about 10 minutes, while acute tolerance to the euphoric effects of cocaine begins after about one hour. With excessive or prolonged use, the drug can cause itching, fast heart rate, and paranoid delusions or sensations of insects crawling on the skin. Intranasal cocaine and crack use are both associated with pharmacological violence. Aggressive behavior may be displayed by both addicts and casual users. Cocaine can induce psychosis characterized by paranoia, impaired reality testing, hallucinations, irritability, and physical aggression. Cocaine intoxication can cause hyperawareness, hypervigilance, and psychomotor agitation and delirium. Consumption of large doses of cocaine can cause violent outbursts, especially by those with preexisting psychosis. Crack-related violence is also systemic, relating to disputes between crack dealers and users. Acute exposure may induce cardiac arrhythmias, including atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, and ventricular fibrillation. Acute exposure may also lead to angina, heart attack, and congestive heart failure. Cocaine overdose may cause seizures, abnormally high body temperature and a marked elevation of blood pressure, which can be life-threatening, abnormal heart rhythms, and death. Anxiety, paranoia, and restlessness can also occur, especially during the comedown. With excessive dosage, tremors, convulsions and increased body temperature are observed. Severe cardiac adverse events, particularly sudden cardiac death, become a serious risk at high doses due to cocaines blocking effect on cardiac sodium channels. Incidental exposure of the eye to sublimated cocaine while smoking crack cocaine can cause serious injury to the cornea and long-term loss of visual acuity.
Chronic
Although it has been commonly asserted, the available evidence does not show that chronic use of cocaine is associated with broad cognitive deficits. Research is inconclusive on age-related loss of striatal dopamine transporter (DAT) sites, suggesting cocaine has neuroprotective or neurodegenerative properties for dopamine neurons. Exposure to cocaine may lead to the breakdown of the blood-brain barrier.Physical side effects from chronic smoking of cocaine include coughing up blood, bronchospasm, itching, fever, diffuse alveolar infiltrates without effusions, pulmonary and systemic eosinophilia, chest pain, lung trauma, sore throat, asthma, hoarse voice, dyspnea (shortness of breath), and an aching, flu-like syndrome. Cocaine constricts blood vessels, dilates pupils, and increases body temperature, heart rate, and blood pressure. It can also cause headaches and gastrointestinal complications such as abdominal pain and nausea. A common but untrue belief is that the smoking of cocaine chemically breaks down tooth enamel and causes tooth decay. Cocaine can cause involuntary tooth grinding, known as bruxism, which can deteriorate tooth enamel and lead to gingivitis. Additionally, stimulants like cocaine, methamphetamine, and even caffeine cause dehydration and dry mouth. Since saliva is an important mechanism in maintaining ones oral pH level, people who use cocaine over a long period of time who do not hydrate sufficiently may experience demineralization of their teeth due to the pH of the tooth surface dropping too low (below 5.5). Cocaine use also promotes the formation of blood clots. This increase in blood clot formation is attributed to cocaine-associated increases in the activity of plasminogen activator inhibitor, and an increase in the number, activation, and aggregation of platelets.Chronic intranasal usage can degrade the cartilage separating the nostrils (the septum nasi), leading eventually to its complete disappearance. Due to the absorption of the cocaine from cocaine hydrochloride, the remaining hydrochloride forms a dilute hydrochloric acid.Illicitly-sold cocaine may be contaminated with levamisole. Levamisole may accentuate cocaines effects. Levamisole-adulterated cocaine has been associated with autoimmune disease.Cocaine use leads to an increased risk of hemorrhagic and ischemic strokes. Cocaine use also increases the risk of having a heart attack.
Addiction
Relatives of persons with cocaine addiction have an increased risk of cocaine addiction. Cocaine addiction occurs through ΔFosB overexpression in the nucleus accumbens, which results in altered transcriptional regulation in neurons within the nucleus accumbens. ΔFosB levels have been found to increase upon the use of cocaine. Each subsequent dose of cocaine continues to increase ΔFosB levels with no ceiling of tolerance. Elevated levels of ΔFosB leads to increases in brain-derived neurotrophic factor (BDNF) levels, which in turn increases the number of dendritic branches and spines present on neurons involved with the nucleus accumbens and prefrontal cortex areas of the brain. This change can be identified rather quickly, and may be sustained weeks after the last dose of the drug.
Transgenic mice exhibiting inducible expression of ΔFosB primarily in the nucleus accumbens and dorsal striatum exhibit sensitized behavioural responses to cocaine. They self-administer cocaine at lower doses than control, but have a greater likelihood of relapse when the drug is withheld. ΔFosB increases the expression of AMPA receptor subunit GluR2 and also decreases expression of dynorphin, thereby enhancing sensitivity to reward.DNA damage is increased in the brain of rodents by administration of cocaine. During DNA repair of such damages, persistent chromatin alterations may occur such as methylation of DNA or the acetylation or methylation of histones at the sites of repair. These alterations can be epigenetic scars in the chromatin that contribute to the persistent epigenetic changes found in cocaine addiction.
Dependence and withdrawal
Cocaine dependence develops after even brief periods of regular cocaine use and produces a withdrawal state with emotional-motivational deficits upon cessation of cocaine use.
During pregnancy
Crack baby is a term for a child born to a mother who used crack cocaine during her pregnancy. The threat that cocaine use during pregnancy poses to the fetus is now considered exaggerated. Studies show that prenatal cocaine exposure (independent of other effects such as, for example, alcohol, tobacco, or physical environment) has no appreciable effect on childhood growth and development.
However, the official opinion of the National Institute on Drug Abuse of the United States warns about health risks while cautioning against stereotyping:
Many recall that "crack babies", or babies born to mothers who used crack cocaine while pregnant, were at one time written off by many as a lost generation. They were predicted to suffer from severe, irreversible damage, including reduced intelligence and social skills. It was later found that this was a gross exaggeration. However, the fact that most of these children appear normal should not be over-interpreted as indicating that there is no cause for concern. Using sophisticated technologies, scientists are now finding that exposure to cocaine during fetal development may lead to subtle, yet significant, later deficits in some children, including deficits in some aspects of cognitive performance, information-processing, and attention to tasks—abilities that are important for success in school.
There are also warnings about the threat of breastfeeding: The March of Dimes said "it is likely that cocaine will reach the baby through breast milk," and advises the following regarding cocaine use during pregnancy:
Cocaine use during pregnancy can affect a pregnant woman and her unborn baby in many ways. During the early months of pregnancy, it may increase the risk of miscarriage. Later in pregnancy, it can trigger preterm labor (labor that occurs before 37 weeks of pregnancy) or cause the baby to grow poorly. As a result, cocaine-exposed babies are more likely than unexposed babies to be born with low birth weight (less than 5.5 lb or 2.5 kg). Low-birthweight babies are 20 times more likely to die in their first month of life than normal-weight babies, and face an increased risk of lifelong disabilities such as mental retardation and cerebral palsy. Cocaine-exposed babies also tend to have smaller heads, which generally reflect smaller brains. Some studies suggest that cocaine-exposed babies are at increased risk of birth defects, including urinary tract defects and, possibly, heart defects. Cocaine also may cause an unborn baby to have a stroke, irreversible brain damage, or a heart attack.
Mortality
Persons with regular or problematic use of cocaine have a significantly higher rate of death, and are specifically at higher risk of traumatic deaths and deaths attributable to infectious disease.
Pharmacology
Pharmacokinetics
The extent of absorption of cocaine into the systemic circulation after nasal insufflation is similar to that after oral ingestion. The rate of absorption after nasal insufflation is limited by cocaine-induced vasoconstriction of capillaries in the nasal mucosa. Onset of absorption after oral ingestion is delayed because cocaine is a weak base with a pKa of 8.6, and is thus in an ionized form that is poorly absorbed from the acidic stomach and easily absorbed from the alkaline duodenum. The rate and extent of absorption from inhalation of cocaine is similar or greater than with intravenous injection, as inhalation provides access directly to the pulmonary capillary bed. The delay in absorption after oral ingestion may account for the popular belief that cocaine bioavailability from the stomach is lower than after insufflation. Compared with ingestion, the faster absorption of insufflated cocaine results in quicker attainment of maximum drug effects. Snorting cocaine produces maximum physiological effects within 40 minutes and maximum psychotropic effects within 20 minutes. Physiological and psychotropic effects from nasally insufflated cocaine are sustained for approximately 40–60 minutes after the peak effects are attained.Cocaine crosses the blood-brain barrier via both a proton-coupled organic cation antiporter and (to a lesser extent) via passive diffusion across cell membranes. As of September 2022, the gene or genes encoding the human proton-organic cation antiporter had not been identified.Cocaine has a short elimination half life of 0.7–1.5 hours and is extensively metabolized by plasma esterases and also by liver cholinesterases, with only about 1% excreted unchanged in the urine. The metabolism is dominated by hydrolytic ester cleavage, so the eliminated metabolites consist mostly of benzoylecgonine (BE), the major metabolite, and other metabolites in lesser amounts such as ecgonine methyl ester (EME) and ecgonine. Further minor metabolites of cocaine include norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE), and m-hydroxybenzoylecgonine. If consumed with alcohol, cocaine combines with alcohol in the liver to form cocaethylene. Studies have suggested cocaethylene is more euphoric, and has a higher cardiovascular toxicity than cocaine by itself.Depending on liver and kidney function, cocaine metabolites are detectable in urine. Benzoylecgonine can be detected in urine within four hours after cocaine intake and remains detectable in concentrations greater than 150 ng/mL typically for up to eight days after cocaine is used. Detection of cocaine metabolites in hair is possible in regular users until after the sections of hair grown during the period of cocaine use are cut or fall out.
Pharmacodynamics
The pharmacodynamics of cocaine involve the complex relationships of neurotransmitters (inhibiting monoamine uptake in rats with ratios of about: serotonin:dopamine = 2:3, serotonin:norepinephrine = 2:5). The most extensively studied effect of cocaine on the central nervous system is the blockade of the dopamine transporter protein. Dopamine neurotransmitter released during neural signaling is normally recycled via the transporter; i.e., the transporter binds the transmitter and pumps it out of the synaptic cleft back into the presynaptic neuron, where it is taken up into storage vesicles. Cocaine binds tightly at the dopamine transporter forming a complex that blocks the transporters function. The dopamine transporter can no longer perform its reuptake function, and thus dopamine accumulates in the synaptic cleft. The increased concentration of dopamine in the synapse activates post-synaptic dopamine receptors, which makes the drug rewarding and promotes the compulsive use of cocaine.Cocaine affects certain serotonin (5-HT) receptors; in particular, it has been shown to antagonize the 5-HT3 receptor, which is a ligand-gated ion channel. An overabundance of 5-HT3 receptors is reported in cocaine-conditioned rats, though 5-HT3s role is unclear. The 5-HT2 receptor (particularly the subtypes 5-HT2A, 5-HT2B and 5-HT2C) are involved in the locomotor-activating effects of cocaine.Cocaine has been demonstrated to bind as to directly stabilize the DAT transporter on the open outward-facing conformation. Further, cocaine binds in such a way as to inhibit a hydrogen bond innate to DAT. Cocaines binding properties are such that it attaches so this hydrogen bond will not form and is blocked from formation due to the tightly locked orientation of the cocaine molecule. Research studies have suggested that the affinity for the transporter is not what is involved in the habituation of the substance so much as the conformation and binding properties to where and how on the transporter the molecule binds.Sigma receptors are affected by cocaine, as cocaine functions as a sigma ligand agonist. Further specific receptors it has been demonstrated to function on are NMDA and the D1 dopamine receptor.Cocaine also blocks sodium channels, thereby interfering with the propagation of action potentials; thus, like lignocaine and novocaine, it acts as a local anesthetic. It also functions on the binding sites to the dopamine and serotonin sodium dependent transport area as targets as separate mechanisms from its reuptake of those transporters; unique to its local anesthetic value which makes it in a class of functionality different from both its own derived phenyltropanes analogues which have that removed. In addition to this, cocaine has some target binding to the site of the Kappa-opioid receptor. Cocaine also causes vasoconstriction, thus reducing bleeding during minor surgical procedures. Recent research points to an important role of circadian mechanisms and clock genes in behavioral actions of cocaine.
Cocaine is known to suppress hunger and appetite by increasing co-localization of sigma σ1R receptors and ghrelin GHS-R1a receptors at the neuronal cell surface, thereby increasing ghrelin-mediated signaling of satiety and possibly via other effects on appetitive hormones. Chronic users may lose their appetite and can experience severe malnutrition and significant weight loss.
Cocaine effects, further, are shown to be potentiated for the user when used in conjunction with new surroundings and stimuli, and otherwise novel environs.
Chemistry
Appearance
Cocaine in its purest form is a white, pearly product. Cocaine appearing in powder form is a salt, typically cocaine hydrochloride. Street cocaine is often adulterated or "cut" with talc, lactose, sucrose, glucose, mannitol, inositol, caffeine, procaine, phencyclidine, phenytoin, lignocaine, strychnine, levamisole, amphetamine, or heroin.The color of "crack" cocaine depends upon several factors including the origin of the cocaine used, the method of preparation – with ammonia or baking soda – and the presence of impurities. It will generally range from white to a yellowish cream to a light brown. Its texture will also depend on the adulterants, origin, and processing of the powdered cocaine, and the method of converting the base. It ranges from a crumbly texture, sometimes extremely oily, to a hard, almost crystalline nature.
Forms
Salts
Cocaine – a tropane alkaloid – is a weakly alkaline compound, and can therefore combine with acidic compounds to form salts. The hydrochloride (HCl) salt of cocaine is by far the most commonly encountered, although the sulfate (SO42-) and the nitrate (NO3−) salts are occasionally seen. Different salts dissolve to a greater or lesser extent in various solvents – the hydrochloride salt is polar in character and is quite soluble in water.
Base
As the name implies, "freebase" is the base |
Cocaine | form of cocaine, as opposed to the salt form. It is practically insoluble in water whereas hydrochloride salt is water-soluble.
Smoking freebase cocaine has the additional effect of releasing methylecgonidine into the users system due to the pyrolysis of the substance (a side effect which insufflating or injecting powder cocaine does not create). Some research suggests that smoking freebase cocaine can be even more cardiotoxic than other routes of administration because of methylecgonidines effects on lung tissue and liver tissue.Pure cocaine is prepared by neutralizing its compounding salt with an alkaline solution, which will precipitate non-polar basic cocaine. It is further refined through aqueous-solvent liquid–liquid extraction.
Crack cocaine
Crack is usually smoked in a glass pipe, and once inhaled, it passes from the lungs directly to the central nervous system, producing an almost immediate "high" that can be very powerful – this initial crescendo of stimulation is known as a "rush". This is followed by an equally intense low, leaving the user craving more drug. Addiction to crack usually occurs with four to six weeks; much more rapidly than with regular cocaine.Powder cocaine (cocaine hydrochloride) must be heated to a high temperature (about 197 °C), and considerable decomposition/burning occurs at these high temperatures. This effectively destroys some of the cocaine and yields a sharp, acrid, and foul-tasting smoke. Cocaine base/crack can be smoked because it vaporizes with little or no decomposition at 98 °C (208 °F), which is below the boiling point of water.
Crack is a lower purity form of free-base cocaine that is usually produced by neutralization of cocaine hydrochloride with a solution of baking soda (sodium bicarbonate, NaHCO3) and water, producing a very hard/brittle, off-white-to-brown colored, amorphous material that contains sodium carbonate, entrapped water, and other by-products as the main impurities. The origin of the name "crack" comes from the "crackling" sound (and hence the onomatopoeic moniker "crack") that is produced when the cocaine and its impurities (i.e. water, sodium bicarbonate) are heated past the point of vaporization.
Coca leaf infusions
Coca herbal infusion (also referred to as coca tea) is used in coca-leaf producing countries much as any herbal medicinal infusion would elsewhere in the world. The free and legal commercialization of dried coca leaves under the form of filtration bags to be used as "coca tea" has been actively promoted by the governments of Peru and Bolivia for many years as a drink having medicinal powers. In Peru, the National Coca Company, a state-run corporation, sells cocaine-infused teas and other medicinal products and also exports leaves to the U.S. for medicinal use.Visitors to the city of Cuzco in Peru, and La Paz in Bolivia are greeted with the offering of coca leaf infusions (prepared in teapots with whole coca leaves) purportedly to help the newly arrived traveler overcome the malaise of high altitude sickness. The effects of drinking coca tea are mild stimulation and mood lift. It has also been promoted as an adjuvant for the treatment of cocaine dependence. One study on coca leaf infusion used with counseling in the treatment of 23 addicted coca-paste smokers in Lima, Peru found that the relapses rate fell from 4.35 times per month on average before coca tea treatment to one during treatment. The duration of abstinence increased from an average of 32 days before treatment to 217.2 days during treatment. This suggests that coca leaf infusion plus counseling may be effective at preventing relapse during cocaine addiction treatment.There is little information on the pharmacological and toxicological effects of consuming coca tea. A chemical analysis by solid-phase extraction and gas chromatography–mass spectrometry (SPE-GC/MS) of Peruvian and Bolivian tea bags indicated the presence of significant amounts of cocaine, the metabolite benzoylecgonine, ecgonine methyl ester and trans-cinnamoylcocaine in coca tea bags and coca tea. Urine specimens were also analyzed from an individual who consumed one cup of coca tea and it was determined that enough cocaine and cocaine-related metabolites were present to produce a positive drug test.
Biosynthesis
The first synthesis and elucidation of the cocaine molecule was by Richard Willstätter in 1898. Willstätters synthesis derived cocaine from tropinone. Since then, Robert Robinson and Edward Leete have made significant contributions to the mechanism of the synthesis. (-NO3)
The additional carbon atoms required for the synthesis of cocaine are derived from acetyl-CoA, by addition of two acetyl-CoA units to the N-methyl-Δ1-pyrrolinium cation. The first addition is a Mannich-like reaction with the enolate anion from acetyl-CoA acting as a nucleophile towards the pyrrolinium cation. The second addition occurs through a Claisen condensation. This produces a racemic mixture of the 2-substituted pyrrolidine, with the retention of the thioester from the Claisen condensation. In formation of tropinone from racemic ethyl [2,3-13C2]4(Nmethyl-2-pyrrolidinyl)-3-oxobutanoate there is no preference for either stereoisomer. In cocaine biosynthesis, only the (S)-enantiomer can cyclize to form the tropane ring system of cocaine. The stereoselectivity of this reaction was further investigated through study of prochiral methylene hydrogen discrimination. This is due to the extra chiral center at C-2. This process occurs through an oxidation, which regenerates the pyrrolinium cation and formation of an enolate anion, and an intramolecular Mannich reaction. The tropane ring system undergoes hydrolysis, SAM-dependent methylation, and reduction via NADPH for the formation of methylecgonine. The benzoyl moiety required for the formation of the cocaine diester is synthesized from phenylalanine via cinnamic acid. Benzoyl-CoA then combines the two units to form cocaine.
N-methyl-pyrrolinium cation
The biosynthesis begins with L-Glutamine, which is derived to L-ornithine in plants. The major contribution of L-ornithine and L-arginine as a precursor to the tropane ring was confirmed by Edward Leete. Ornithine then undergoes a pyridoxal phosphate-dependent decarboxylation to form putrescine. In some animals, the urea cycle derives putrescine from ornithine. L-ornithine is converted to L-arginine, which is then decarboxylated via PLP to form agmatine. Hydrolysis of the imine derives N-carbamoylputrescine followed with hydrolysis of the urea to form putrescine. The separate pathways of converting ornithine to putrescine in plants and animals have converged. A SAM-dependent N-methylation of putrescine gives the N-methylputrescine product, which then undergoes oxidative deamination by the action of diamine oxidase to yield the aminoaldehyde. Schiff base formation confirms the biosynthesis of the N-methyl-Δ1-pyrrolinium cation.
Robert Robinsons acetonedicarboxylate
The biosynthesis of the tropane alkaloid is still not understood. Hemscheidt proposes that Robinsons acetonedicarboxylate emerges as a potential intermediate for this reaction. Condensation of N-methylpyrrolinium and acetonedicarboxylate would generate the oxobutyrate. Decarboxylation leads to tropane alkaloid formation.
Reduction of tropinone
The reduction of tropinone is mediated by NADPH-dependent reductase enzymes, which have been characterized in multiple plant species. These plant species all contain two types of the reductase enzymes, tropinone reductase I and tropinone reductase II. TRI produces tropine and TRII produces pseudotropine. Due to differing kinetic and pH/activity characteristics of the enzymes and by the 25-fold higher activity of TRI over TRII, the majority of the tropinone reduction is from TRI to form tropine.
Detection in body fluids
Cocaine and its major metabolites may be quantified in blood, plasma, or urine to monitor for use, confirm a diagnosis of poisoning, or assist in the forensic investigation of a traffic or other criminal violation or sudden death. Most commercial cocaine immunoassay screening tests cross-react appreciably with the major cocaine metabolites, but chromatographic techniques can easily distinguish and separately measure each of these substances. When interpreting the results of a test, it is important to consider the cocaine usage history of the individual, since a chronic user can develop tolerance to doses that would incapacitate a cocaine-naive individual, and the chronic user often has high baseline values of the metabolites in his system. Cautious interpretation of testing results may allow a distinction between passive or active usage, and between smoking versus other routes of administration.
Field analysis
Cocaine may be detected by law enforcement using the Scott reagent. The test can easily generate false positives for common substances and must be confirmed with a laboratory test.Approximate cocaine purity can be determined using 1 mL 2% cupric sulfate pentahydrate in dilute HCl, 1 mL 2% potassium thiocyanate and 2 mL of chloroform. The shade of brown shown by the chloroform is proportional to the cocaine content. This test is not cross sensitive to heroin, methamphetamine, benzocaine, procaine and a number of other drugs but other chemicals could cause false positives.
Usage
According to a 2016 United Nations report, England and Wales are the countries with the highest rate of cocaine usage (2.4% of adults in the previous year). Other countries where the usage rate meets or exceeds 1.5% are Spain and Scotland (2.2%), the United States (2.1%), Australia (2.1%), Uruguay (1.8%), Brazil (1.75%), Chile (1.73%), the Netherlands (1.5%) and Ireland (1.5%).
Europe
Cocaine is the second most popular illegal recreational drug in Europe (behind cannabis). Since the mid-1990s, overall cocaine usage in Europe has been on the rise, but usage rates and attitudes tend to vary between countries. European countries with the highest usage rates are the United Kingdom, Spain, Italy, and the Republic of Ireland.
Approximately 17 million Europeans (5.1%) have used cocaine at least once and 3.5 million (1.1%) in the last year. About 1.9% (2.3 million) of young adults (15–34 years old) have used cocaine in the last year (latest data available as of 2018).Usage is particularly prevalent among this demographic: 4% to 7% of males have used cocaine in the last year in Spain, Denmark, the Republic of Ireland, Italy, and the United Kingdom. The ratio of male to female users is approximately 3.8:1, but this statistic varies from 1:1 to 13:1 depending on country.In 2014 London had the highest amount of cocaine in its sewage out of 50 European cities.
United States
Cocaine is the second most popular illegal recreational drug in the United States (behind cannabis) and the U.S. is the worlds largest consumer of cocaine. Its users span over different ages, races, and professions. In the 1970s and 1980s, the drug became particularly popular in the disco culture as cocaine usage was very common and popular in many discos such as Studio 54.
Dependence treatment
Treatment with contingency management, such as providing vouchers for retail items contingent upon objectively-verified abstinence from recent drug use, has been shown in randomized clinical trials to significantly reduce the likelihood of having a positive test for the presence of cocaine.
Vaccine
TA-CD is an active vaccine developed by the Xenova Group which is used to negate the effects of cocaine, making it suitable for use in treatment of addiction. It is created by combining norcocaine with inactivated cholera toxin.
History
Discovery
Indigenous peoples of South America have chewed the leaves of Erythroxylon coca – a plant that contains vital nutrients as well as numerous alkaloids, including cocaine – for over a thousand years. The coca leaf was, and still is, chewed almost universally by some indigenous communities. The remains of coca leaves have been found with ancient Peruvian mummies, and pottery from the time period depicts humans with bulged cheeks, indicating the presence of something on which they are chewing. There is also evidence that these cultures used a mixture of coca leaves and saliva as an anesthetic for the performance of trepanation.When the Spanish arrived in South America, the conquistadors at first banned coca as an "evil agent of devil". But after discovering that without the coca the locals were barely able to work, the conquistadors legalized and taxed the leaf, taking 10% off the value of each crop. In 1569, Spanish botanist Nicolás Monardes described the indigenous peoples practice of chewing a mixture of tobacco and coca leaves to induce "great contentment":
When they wished to make themselves drunk and out of judgment they chewed a mixture of tobacco and coca leaves which make them go as they were out of their wittes.
In 1609, Padre Blas Valera wrote:
Coca protects the body from many ailments, and our doctors use it in powdered form to reduce the swelling of wounds, to strengthen broken bones, to expel cold from the body or prevent it from entering, and to cure rotten wounds or sores that are full of maggots. And if it does so much for outward ailments, will not its singular virtue have even greater effect in the entrails of those who eat it?
Isolation and naming
Although the stimulant and hunger-suppressant properties of coca had been known for many centuries, the isolation of the cocaine alkaloid was not achieved until 1855. Various European scientists had attempted to isolate cocaine, but none had been successful for two reasons: the knowledge of chemistry required was insufficient at the time, and contemporary conditions of sea-shipping from South America could degrade the cocaine in the plant samples available to European chemists.The cocaine alkaloid was first isolated by the German chemist Friedrich Gaedcke in 1855. Gaedcke named the alkaloid "erythroxyline", and published a description in the journal Archiv der Pharmazie.In 1856, Friedrich Wöhler asked Dr. Carl Scherzer, a scientist aboard the Novara (an Austrian frigate sent by Emperor Franz Joseph to circle the globe), to bring him a large amount of coca leaves from South America. In 1859, the ship finished its travels and Wöhler received a trunk full of coca. Wöhler passed on the leaves to Albert Niemann, a PhD student at the University of Göttingen in Germany, who then developed an improved purification process.Niemann described every step he took to isolate cocaine in his dissertation titled Über eine neue organische Base in den Cocablättern (On a New Organic Base in the Coca Leaves), which was published in 1860 and earned him his Ph.D. He wrote of the alkaloids "colourless transparent prisms" and said that "Its solutions have an alkaline reaction, a bitter taste, promote the flow of saliva and leave a peculiar numbness, followed by a sense of cold when applied to the tongue." Niemann named the alkaloid "cocaine" from "coca" (from Quechua "kúka") + suffix "ine".The first synthesis and elucidation of the structure of the cocaine molecule was by Richard Willstätter in 1898. It was the first biomimetic synthesis of an organic structure recorded in academic chemical literature. The synthesis started from tropinone, a related natural product and took five steps.
Because of the former use of cocaine as a local anesthetic, a suffix "-caine" was later extracted and used to form names of synthetic local anesthetics.
Medicalization
With the discovery of this new alkaloid, Western medicine was quick to exploit the possible uses of this plant.
In 1879, Vassili von Anrep, of the University of Würzburg, devised an experiment to demonstrate the analgesic properties of the newly discovered alkaloid. He prepared two separate jars, one containing a cocaine-salt solution, with the other containing merely saltwater. He then submerged a frogs legs into the two jars, one leg in the treatment and one in the control solution, and proceeded to stimulate the legs in several different ways. The leg that had been immersed in the cocaine solution reacted very differently from the leg that had been immersed in saltwater.Karl Koller (a close associate of Sigmund Freud, who would write about cocaine later) experimented with cocaine for ophthalmic usage. In an infamous experiment in 1884, he experimented upon himself by applying a cocaine solution to his own eye and then pricking it with pins. His findings were presented to the Heidelberg Ophthalmological Society. Also in 1884, Jellinek demonstrated the effects of cocaine as a respiratory system anesthetic. In 1885, William Halsted demonstrated nerve-block anesthesia, and James Leonard Corning demonstrated peridural anesthesia. 1898 saw Heinrich Quincke use cocaine for spinal anesthesia.
Popularization
In 1859, an Italian doctor, Paolo Mantegazza, returned from Peru, where he had witnessed first-hand the use of coca by the local indigenous peoples. He proceeded to experiment on himself and upon his return to Milan, he wrote a paper in which he described the effects. In this paper, he declared coca and cocaine (at the time they were assumed to be the same) as being useful medicinally, in the treatment of "a furred tongue in the morning, flatulence, and whitening of the teeth."
A chemist named Angelo Mariani who read Mantegazzas paper became immediately intrigued with coca and its economic potential. In 1863, Mariani started marketing a wine called Vin Mariani, which had been treated with coca leaves, to become coca wine. The ethanol in wine acted as a solvent and extracted the cocaine from the coca leaves, altering the drinks effect. It contained 6 mg cocaine per ounce of wine, but Vin Mariani which was to be exported contained 7.2 mg per ounce, to compete with the higher cocaine content of similar drinks in the United States. A "pinch of coca leaves" was included in John Styth Pembertons original 1886 recipe for Coca-Cola, though the company began using decocainized leaves in 1906 when the Pure Food and Drug Act was passed.
In 1879 cocaine began to be used to treat morphine addiction. Cocaine was introduced into clinical use as a local anesthetic in Germany in 1884, about the same time as Sigmund Freud published his work Über Coca, in which he wrote that cocaine causes:
Exhilaration and lasting euphoria, which in no way differs from the normal euphoria of the healthy person. You perceive an increase of self-control and possess more vitality and capacity for work. In other words, you are simply normal, and it is soon hard to believe you are under the influence of any drug. Long intensive physical work is performed without any fatigue. This result is enjoyed without any of the unpleasant after-effects that follow exhilaration brought about by alcoholic beverages. No craving for the further use of cocaine appears after the first, or even after repeated taking of the drug.
By 1885 the U.S. manufacturer Parke-Davis sold coca-leaf cigarettes and cheroots, a cocaine inhalant, a Coca Cordial, cocaine crystals, and cocaine solution for intravenous injection. The company promised that its cocaine products would "supply the place of food, make the coward brave, the silent eloquent and render the sufferer insensitive to pain."
By the late Victorian era, cocaine use had appeared as a vice in literature. For example, it was injected by Arthur Conan Doyles fictional Sherlock Holmes, generally to offset the boredom he felt when he was not working on a case.
In early 20th-century Memphis, Tennessee, cocaine was sold in neighborhood drugstores on Beale Street, costing five or ten cents for a small boxful. Stevedores along the Mississippi River used the drug as a stimulant, and white employers encouraged its use by black laborers.In 1909, Ernest Shackleton took "Forced March" brand cocaine tablets to Antarctica, as did Captain Scott a year later on his ill-fated journey to the South Pole.In the 1931 song "Minnie the Moocher", Cab Calloway heavily references cocaine use. He uses the phrase "kicking the gong around", slang for cocaine use; describes titular character Minnie as "tall and skinny;" and describes Smokey Joe as "cokey". In the 1932 comedy musical film The Big Broadcast, Cab Calloway performs the song with his orchestra and mimes snorting cocaine in between verses.During the mid-1940s, amidst World War II, cocaine was considered for inclusion as an ingredient of a future generation of pep pills for the German military, code named D-IX.In modern popular culture, references to cocaine are common. The drug has a glamorous image associated with the wealthy, famous and powerful, and is said to make users "feel rich and beautiful". In addition the pace of modern society − such as in finance − gives many the incentive to make use of the drug.
Modern usage
In many countries, cocaine is a popular recreational drug. In the United States, the development of "crack" cocaine introduced the substance to a generally poorer inner-city market. The use of the powder form has stayed relatively constant, experiencing a new height of use during the late 1990s and early 2000s in the U.S., and has become much more popular in the last few years in the UK.Cocaine use is prevalent across all socioeconomic strata, including age, demographics, economic, social, political, religious, and livelihood.The estimated U.S. cocaine market exceeded US$70 billion in street value for the year 2005, exceeding revenues by corporations such as Starbucks. Cocaines status as a club drug shows its immense popularity among the "party crowd".In 1995 the World Health Organization (WHO) and the United Nations Interregional Crime and Justice Research Institute (UNICRI) announced in a press release the publication of the results of the largest global study on cocaine use ever undertaken. An American representative in the World Health Assembly banned the publication of the study, because it seemed to make a case for the positive uses of cocaine. An excerpt of the report strongly conflicted with accepted paradigms, for example, "that occasional cocaine use does not typically lead to severe or even minor physical or social problems." In the sixth meeting of the B committee, the US representative threatened that "If World Health Organization activities relating to drugs failed to reinforce proven drug control approaches, funds for the relevant programs should be curtailed". This led to the decision to discontinue publication. A part of the study was recuperated and published in 2010, including profiles of cocaine use in 20 countries, but are unavailable as of 2015.In October 2010 it was reported that the use of cocaine in Australia has doubled since monitoring began in 2003.A problem with illegal cocaine use, especially in the higher volumes used to combat fatigue (rather than increase euphoria) by long-term users, is the risk of ill effects or damage caused by the compounds used in adulteration. Cutting or "stepping on" the drug is commonplace, using compounds which simulate ingestion effects, such as Novocain (procaine) producing temporary anesthesia, as many users believe a strong numbing effect is the result of strong and/or pure cocaine, ephedrine or similar stimulants that are to produce an increased heart rate. The normal adulterants for profit are inactive sugars, usually mannitol, creatine, or glucose, so introducing active adulterants gives the illusion of purity and to stretch or make it so a dealer can sell more product than without the adulterants. The adulterant of sugars allows the dealer to sell the product for a higher price because of the illusion of purity and allows the sale of more of the product at that higher price, enabling dealers to significantly increase revenue with little additional cost for the adulterants. A 2007 study by the European Monitoring Centre for Drugs and Drug Addiction showed that the purity levels for street purchased cocaine was often under 5% and on average under 50% pure.
Society and culture
Legal status
The production, distribution, and sale of cocaine products is restricted (and illegal in most contexts) in most countries as regulated by the Single Convention on Narcotic Drugs, and the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances. In the United States the manufacture, importation, possession, and distribution of cocaine are additionally regulated by the 1970 Controlled Substances Act.
Some countries, such as Peru and Bolivia, permit the cultivation of coca leaf for traditional consumption by the local indigenous population, but nevertheless, prohibit the production, sale, and consumption of cocaine. The provisions as to how much a coca farmer can yield annually is protected by laws such as the Bolivian Cato accord. In addition, some parts of Europe, the United States, and Australia allow processed cocaine for medicinal uses only.
Australia
Cocaine is a Schedule 8 prohibited substance in Australia under the Poisons Standard (July 2016). A schedule 8 substance is a controlled Drug – Substances which should be available for use but require the restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse, and physical or psychological dependence.In Western Australia under the Misuse of Drugs Act 1981 4.0g of cocaine is the amount of prohibited drugs determining a court of trial, 2.0g is the amount of cocaine required for the presumption of intention to sell or supply and 28.0g is the amount of cocaine required for purposes of drug trafficking.
United States
The US federal government instituted a national labeling requirement for cocaine and cocaine-containing products through the Pure Food and Drug Act of 1906. The next important federal regulation was the Harrison Narcotics Tax Act of 1914. While this act is often seen as the start of prohibition, the act itself was not actually a prohibition on cocaine, but instead set up a regulatory and licensing regime. The Harrison Act did not recognize addiction as a treatable condition and therefore the therapeutic use of cocaine, heroin, or morphine to such individuals was outlawed – leading a 1915 editorial in the journal American Medicine to remark that the addict "is denied the medical care he urgently needs, open, above-board sources from which he formerly obtained his drug supply are closed to him, and he is driven to the underworld where he can get his drug, but of course, surreptitiously and in violation of the law." The Harrison Act left manufacturers of cocaine untouched so long as they met certain purity and labeling standards. Despite that cocaine was typically illegal to sell and legal outlets were rarer, the quantities of legal cocaine produced declined very little. Legal cocaine quantities did not decrease until the Jones–Miller Act of 1922 put serious restrictions on cocaine manufactures.Before the early 1900s, the primary problem caused by cocaine use was portrayed by newspapers to be addiction, not violence or crime, and the cocaine user was represented as an upper- or middle-class White person. In 1914, The New York Times published an article titled "Negro Cocaine Fiends Are a New Southern Menace", portraying Black cocaine users as dangerous and able to withstand wounds that would normally be fatal. The Anti-Drug Abuse Act of 1986 mandated prison sentences for 500 grams of powdered cocaine and 5 grams of crack cocaine. In the National Survey on Drug Use and Health, Whites reported a higher rate of powdered cocaine use, and Blacks reported a higher rate of crack cocaine use.
Interdiction
In 2004, according to the United Nations, 589 tonnes of cocaine were seized globally by law enforcement authorities |
Cocaine | . Colombia seized 188 t, the United States 166 t, Europe 79 t, Peru 14 t, Bolivia 9 t, and the rest of the world 133 t.
Production
Colombia is as of 2019 the worlds largest cocaine producer, with production more than tripling since 2013. Three-quarters of the worlds annual yield of cocaine has been produced in Colombia, both from cocaine base imported from Peru (primarily the Huallaga Valley) and Bolivia and from locally grown coca. There was a 28% increase in the amount of potentially harvestable coca plants which were grown in Colombia in 1998. This, combined with crop reductions in Bolivia and Peru, made Colombia the nation with the largest area of coca under cultivation after the mid-1990s. Coca grown for traditional purposes by indigenous communities, a use which is still present and is permitted by Colombian laws, only makes up a small fragment of total coca production, most of which is used for the illegal drug trade.An interview with a coca farmer published in 2003 described a mode of production by acid-base extraction that has changed little since 1905. Roughly 625 pounds (283 kg) of leaves were harvested per hectare, six times per year. The leaves were dried for half a day, then chopped into small pieces with a string trimmer and sprinkled with a small amount of powdered cement (replacing sodium carbonate from former times). Several hundred pounds of this mixture were soaked in 50 US gallons (190 L) of gasoline for a day, then the gasoline was removed and the leaves were pressed for the remaining liquid, after which they could be discarded. Then battery acid (weak sulfuric acid) was used, one bucket per 55 lb (25 kg) of leaves, to create a phase separation in which the cocaine free base in the gasoline was acidified and extracted into a few buckets of "murky-looking smelly liquid". Once powdered caustic soda was added to this, the cocaine precipitated and could be removed by filtration through a cloth. The resulting material, when dried, was termed pasta and sold by the farmer. The 3750 pound yearly harvest of leaves from a hectare produced 6 lb (2.5 kg) of pasta, approximately 40–60% cocaine. Repeated recrystallization from solvents, producing pasta lavada and eventually crystalline cocaine were performed at specialized laboratories after the sale.Attempts to eradicate coca fields through the use of defoliants have devastated part of the farming economy in some coca-growing regions of Colombia, and strains appear to have been developed that are more resistant or immune to their use. Whether these strains are natural mutations or the product of human tampering is unclear. These strains have also shown to be more potent than those previously grown, increasing profits for the drug cartels responsible for the exporting of cocaine. Although production fell temporarily, coca crops rebounded in numerous smaller fields in Colombia, rather than the larger plantations.The cultivation of coca has become an attractive economic decision for many growers due to the combination of several factors, including the lack of other employment alternatives, the lower profitability of alternative crops in official crop substitution programs, the eradication-related damages to non-drug farms, the spread of new strains of the coca plant due to persistent worldwide demand.
The latest estimate provided by the U.S. authorities on the annual production of cocaine in Colombia refers to 290 metric tons.
As of the end of 2011, the seizure operations of Colombian cocaine carried out in different countries have totaled 351.8 metric tons of cocaine, i.e. 121.3% of Colombias annual production according to the U.S. Department of States estimates.
Synthesis
Synthesizing cocaine could eliminate the high visibility and low reliability of offshore sources and international smuggling, replacing them with clandestine domestic laboratories, as are common for illicit methamphetamine, but is rarely done. Natural cocaine remains the lowest cost and highest quality supply of cocaine. Formation of inactive stereoisomers (cocaine has four chiral centres – 1R 2R, 3S, and 5S, two of them dependent, hence eight possible stereoisomers) plus synthetic by-products limits the yield and purity.
Trafficking and distribution
Organized criminal gangs operating on a large scale dominate the cocaine trade. Most cocaine is grown and processed in South America, particularly in Colombia, Bolivia, Peru, and smuggled into the United States and Europe, the United States being the worlds largest consumer of cocaine, where it is sold at huge markups; usually in the US at $80–120 for 1 gram, and $250–300 for 3.5 grams (1/8 of an ounce, or an "eight ball").
Caribbean and Mexican routes
The primary cocaine importation points in the United States have been in Arizona, southern California, southern Florida, and Texas. Typically, land vehicles are driven across the U.S.–Mexico border. Sixty-five percent of cocaine enters the United States through Mexico, and the vast majority of the rest enters through Florida. As of 2015, the Sinaloa Cartel is the most active drug cartel involved in smuggling illicit drugs like cocaine into the United States and trafficking them throughout the United States.Cocaine traffickers from Colombia and Mexico have established a labyrinth of smuggling routes throughout the Caribbean, the Bahama Island chain, and South Florida. They often hire traffickers from Mexico or the Dominican Republic to transport the drug using a variety of smuggling techniques to U.S. markets. These include airdrops of 500 to 700 kg (1,100 to 1,500 lb) in the Bahama Islands or off the coast of Puerto Rico, mid-ocean boat-to-boat transfers of 500 to 2,000 kg (1,100 to 4,400 lb), and the commercial shipment of tonnes of cocaine through the port of Miami.
Chilean route
Another route of cocaine traffic goes through Chile, which is primarily used for cocaine produced in Bolivia since the nearest seaports lie in northern Chile. The arid Bolivia–Chile border is easily crossed by 4×4 vehicles that then head to the seaports of Iquique and Antofagasta. While the price of cocaine is higher in Chile than in Peru and Bolivia, the final destination is usually Europe, especially Spain where drug dealing networks exist among South American immigrants.
Techniques
Cocaine is also carried in small, concealed, kilogram quantities across the border by couriers known as "mules" (or "mulas"), who cross a border either legally, for example, through a port or airport, or illegally elsewhere. The drugs may be strapped to the waist or legs or hidden in bags, or hidden in the body. If the mule gets through without being caught, the gangs will reap most of the profits. If caught, gangs will sever all links and the mule will usually stand trial for trafficking alone.Bulk cargo ships are also used to smuggle cocaine to staging sites in the western Caribbean–Gulf of Mexico area. These vessels are typically 150–250-foot (50–80 m) coastal freighters that carry an average cocaine load of approximately 2.5 tonnes. Commercial fishing vessels are also used for smuggling operations. In areas with a high volume of recreational traffic, smugglers use the same types of vessels, such as go-fast boats, like those used by the local populations.Sophisticated drug subs are the latest tool drug runners are using to bring cocaine north from Colombia, it was reported on 20 March 2008. Although the vessels were once viewed as a quirky sideshow in the drug war, they are becoming faster, more seaworthy, and capable of carrying bigger loads of drugs than earlier models, according to those charged with catching them.
Sales to consumers
Cocaine is readily available in all major countries metropolitan areas. According to the Summer 1998 Pulse Check, published by the U.S. Office of National Drug Control Policy, cocaine use had stabilized across the country, with a few increases reported in San Diego, Bridgeport, Miami, and Boston. In the West, cocaine usage was lower, which was thought to be due to a switch to methamphetamine among some users; methamphetamine is cheaper, three and a half times more powerful, and lasts 12–24 times longer with each dose. Nevertheless, the number of cocaine users remain high, with a large concentration among urban youth.
In addition to the amounts previously mentioned, cocaine can be sold in "bill sizes": As of 2007 for example, $10 might purchase a "dime bag", a very small amount (0.1–0.15 g) of cocaine. These amounts and prices are very popular among young people because they are inexpensive and easily concealed on ones body. Quality and price can vary dramatically depending on supply and demand, and on geographic region.In 2008, the European Monitoring Centre for Drugs and Drug Addiction reports that the typical retail price of cocaine varied between €50 and €75 per gram in most European countries, although Cyprus, Romania, Sweden, and Turkey reported much higher values.
Consumption
World annual cocaine consumption, as of 2000, stood at around 600 tonnes, with the United States consuming around 300 t, 50% of the total, Europe about 150 t, 25% of the total, and the rest of the world the remaining 150 t or 25%. It is estimated that 1.5 million people in the United States used cocaine in 2010, down from 2.4 million in 2006. Conversely, cocaine use appears to be increasing in Europe with the highest prevalences in Spain, the United Kingdom, Italy, and Ireland.The 2010 UN World Drug Report concluded that "it appears that the North American cocaine market has declined in value from US$47 billion in 1998 to US$38 billion in 2008. Between 2006 and 2008, the value of the market remained basically stable".
See also
References
General bibliography
Further reading
External links
"Cocaine". Drug Information Portal. U.S. National Library of Medicine.
"Cocaine". European Monitoring Centre for Drugs.
"Cocaine Information". Erowid. — A collection of data about cocaine including dose, effects, chemistry, legal status, images and more.
"Cocaine". Slang Dictionary. Archived from the original on 23 March 2011.
"Cocaine Market Data and Value-Havocscope Black Markets". Archived from the original on 23 March 2011. Data on cocaine trafficking worldwide. |
Phenoxybenzamine | Phenoxybenzamine (marketed under the trade names Dibenzyline and Dibenyline) is a non-selective, irreversible alpha blocker.
Uses
It is used in the treatment of hypertension, and specifically that caused by pheochromocytoma. It has a slower onset and a longer-lasting effect compared with other alpha blockers.
It was also the first alpha blocker to be used for treatment of benign prostatic hyperplasia, although it is currently seldom used for that indication due to unfavourable side effects.
It has been used in the treatment of hypoplastic left heart syndrome.It is also used in complex regional pain syndrome (CRPS) type 1 due to its antiadrenergic effects. It has shown to be beneficial if used in the first 3 months of the CRPS diagnosis.
Investigational
Phenoxybenzamine has long been known to block ejaculation without affecting semen quality or ability to achieve orgasm, which could make it an effective male contraceptive. This effect is completely reversible, and is believed to be the result of alpha-1 adrenoceptor blockade in the longitudinal muscles of the vas deferens. A dose of 20 mg/day results in aspermia due to reversible paralyzing effects on the vas deferens, ampulla, and ejaculatory ducts. Due to these actions, phenoxybenzamine is also useful for the treatment of premature ejaculation in men.
Pharmacology
Phenoxybenzamine is used as an anti-hypertensive due to its efficacy in reducing the vasoconstriction caused by epinephrine (adrenaline) and norepinephrine. Phenoxybenzamine forms a permanent covalent bond with adrenergic receptors. Based on known information about the structures of these receptors, it likely involves attack by the cysteine at position 3.36 in transmembrane helix 3 to form a stable linkage. Thus, it remains permanently bound to the receptor, preventing adrenaline and noradrenaline from binding. This causes vasodilation in blood vessels, due to its antagonistic effect at the alpha-1 adrenoceptor found in the walls of blood vessels, resulting in a drop in blood pressure. A side effect of phenoxybenzamine is reflex tachycardia.
As a non-selective alpha receptor antagonist, it will also affect both the postsynaptic alpha 1 and presynaptic alpha 2 receptors in the nervous system, and so reduce sympathetic activity. This results in further vasodilation, pupil constriction, an increase in GI tract motility and secretions, and glycogen synthesis.
Clinically, non-selective alpha antagonists block alpha receptors (but do not differentiate between alpha-1 and alpha-2). They are used as antihypertensives because they block alpha-receptor-mediated vasoconstriction. The block on alpha-2 receptors further potentiates beta-effects, increasing cardiac output.
Phenoxybenzamine has a long-lasting action, binding covalently to the alpha receptors. Its only current clinical use is in preparing patients with pheochromocytoma for surgery; its irreversible antagonism and the resultant depression in the maximum of the agonist dose-response curve are desirable in a situation where surgical manipulation of the tumour may release a large bolus of pressor amine into the circulation. Typically, phenoxybenzamine is not used in the long term, as new receptors are made to upregulate alpha stimulation. The main limiting side-effects of alpha antagonists is that the baroreceptor reflex is disrupted and thus this can cause postural hypotension.
Phenoxybenzamine also has irreversible antagonist/weak partial agonist properties at the serotonin 5-HT2A receptor. Due to its 5-HT2A receptor antagonism, phenoxybenzamine is useful in the treatment of carcinoid tumor, a neoplasm that secretes large amounts of serotonin and causes diarrhea, bronchoconstriction, and flushing.
Stereoisomerism
Phenoxybenzamine contains a stereocenter, so there are two enantiomers, the (R)- and the (S)-forms. All commercial preparations contain the drug as racemate.
See also
Ketanserin
Pindobind
Phentolamine
References
External links
Media related to Phenoxybenzamine at Wikimedia Commons |
Dexlansoprazole | Dexlansoprazole, sold under the trade names Dexilant and Biozodex among others, is a medication which reduces stomach acid. It is used to treat gastroesophageal reflux disease. Effectiveness is similar to other proton pump inhibitors (PPIs). It is taken by mouth.Common side effects include diarrhea, abdominal pain, and nausea. Serious side effects may include osteoporosis, low blood magnesium, Clostridium difficile infection, anaphylaxis, and pneumonia. Use in pregnancy and breastfeeding is of unclear safety. It works by blocking H+/K+-ATPase in the parietal cells of the stomach.Dexlansoprazole was approved for medical use in the United States in 2009. In Canada in 2016, it was the most expensive PPI available. In 2019, it was the 218th most commonly prescribed medication in the United States, with more than 2 million prescriptions.
Medical use
Dexlansoprazole is used to heal and maintain healing of erosive esophagitis and to treat heartburn associated with gastroesophageal reflux disease (GERD). It lasts longer than lansoprazole, to which it is chemically related, and needs to be taken less often. There is no good evidence that it works better than other PPIs.
Adverse effects
The most significant adverse reactions (≥2%) reported in clinical trials were diarrhea, abdominal pain, bloating, nausea, upper respiratory tract infection, vomiting, and flatulence.
Mechanism of action
Like lansoprazole, dexlansoprazole permanently binds to the proton pump and blocks it, preventing the formation of gastric acid.
Chemistry
Dexlansoprazole is the (R)-(+)-enantiomer of lansoprazole, which is a racemic mixture of its (R)-(+) and (S)-(−)-enantiomers. The Takeda drug has a dual release pharmaceutical formulation, with two types of granules of dexlansoprazole, each with a coating that dissolves at a different pH level.
Pharmacokinetics
Dexlansoprazole ((R)-(+)-lansoprazole) has the same binding affinity to the proton pump as the (S)-enantiomer, but is associated with a three- to five-fold greater area under the plasma drug concentration time curve (AUC) compared with (S)-lansoprazole. With its dual release pharmaceutical formulation, the first quick release produces a plasma peak concentration about one hour after application, with a second delayed release producing another peak about four hours later.
History
Dexlansoprazole was approved by the U.S. Food and Drug Administration (FDA) in 2009, and was approved in Canada in 2010 and in Mexico in 2011.Since Kapidex was approved in 2009, there have been reports of dispensing errors because of confusion with the drugs Casodex (bicalutamide) and Kadian (morphine), which have very different uses from Kapidex and from each other. In 2010, the FDA approved a name change for Kapidex to avoid confusion with the two other medications and Takeda began marketing it under the new name Dexilant. It is also available in Bangladesh for the first time as Dexlan by IBN SINA Pharmaceuticals Ltd. in April 2014 and after them DEXILEND by Ziska Pharmaceuticals Ltd., Desopra by Alco Pharma, Delanix by Incepta Pharmaceuticals, Dexogut by Popular Pharmaceuticals Ltd. also introduced it in BD market. In 2020 many other Pharmaceuticals have launched Dexlansoprazole.
References
External links
"Dexlansoprazole". Drug Information Portal. U.S. National Library of Medicine. |
Buprenorphine/naloxone | Buprenorphine/naloxone, sold under the brand name Suboxone among others, is a fixed-dose combination medication that includes buprenorphine and naloxone. It is used to treat opioid use disorder, and reduces the mortality of opioid use disorder by 50% (by reducing the risk of overdose on full-agonist opioids such as heroin or fentanyl). It relieves cravings to use and withdrawal symptoms. Buprenorphine/naloxone is available for use in two different forms, under the tongue or in the cheek.Side effects may include respiratory depression (decreased breathing), small pupils, sleepiness, and low blood pressure. The risk of overdose with buprenorphine/naloxone (unless combined with other sedating substances) is exceedingly low, and lower than with methadone, but people are more likely to stop treatment on buprenorphine/naloxone than methadone. Buprenorphine (like methadone) is a treatment option during pregnancy.
At lower doses, buprenorphine results in the usual opioid effects; high doses beyond a certain level do not result in greater effects. This is believed to result in a lower risk of overdose than some other opioids. Naloxone is an opioid antagonist that competes with and blocks the effect of other opioids (including buprenorphine) if given by injection. Naloxone is poorly absorbed when taken by mouth and is added to decrease the risk that people will misuse the medication by injection. Misuse by injection or use in the nose still occurs. Rates of misuse in the U.S. appear to be lower than with other opioids.The combination formulation was approved for medical use in the U.S. in 2002, and in the European Union in 2017. A generic version was approved in the U.S. in 2018. In 2017, it was the 288th most commonly prescribed medication in the U.S., with more than one million prescriptions.
Medical uses
Buprenorphine/naloxone is used for the treatment of opioid use disorder. Long-term outcomes are generally better with use of buprenorphine/naloxone than attempts at stopping opioid use altogether. This includes a lower risk of overdose with medication use. Due to the high binding affinity and low activation at the opioid receptor, cravings and withdrawal for opioids are decreased while preventing a person from getting high and relapsing on another opioid. The combination of the two medications is preferred over buprenorphine alone for maintenance treatment due to the presence of naloxone in the formulation, which helps discourage intravenous use.Buprenorphine/naloxone has been found to be effective for treating opioid dependence, and serves as a recommended first-line medication according to the U.S. National Institute on Drug Abuse. The medication is an effective maintenance therapy for opioid dependence and has generally similar efficacy to methadone. Both treatments — buprenorphine/naloxone and methadone — are substantially more effective than abstinence-based treatment. Prescribers need a Drug Addiction Treatment Act (DATA 2000) waiver to prescribe buprenorphine/nalaxone for opioid dependence.Because it may be prescribed out of an office setting (as opposed to methadone, which requires specialized centers), buprenorphine/naloxone allows people more freedom of administration. It also thus comes with more risks in this vulnerable population. Buprenorphine/naloxone may be recommended for socially stable people who use opioids who cannot retrieve medications from a center daily, who have another condition requiring regular primary care visits, or who have jobs or daily lives that require they maintain all their faculties and cannot take a sedating medication. Buprenorphine/naloxone is also recommended over methadone for people who at high risk of methadone toxicity, such as the elderly, those taking high doses of benzodiazepines or other sedating substances, concomitant alcohol use disorder, those with a lower level of opioid tolerance, and those at high risk of prolonged QT interval. It is also helpful to use the medication in combination with psychosocial support and counseling.
Available forms
Buprenorphine/naloxone is available in sublingual formulations (that is, products that are dissolved under the tongue). There is no evidence that the tablet formulation is easier to divert and use in ways other than intended by the prescriber compared to the film formulation, or that the tablet formulation has a higher risk for accidental ingestion by children. There are various pharmacokinetic differences between sublingual formulations.
Contraindications
Contraindications are severe respiratory or liver impairment and acute alcoholism. There are limited accounts of cross-reactivity with opioids, but there is a possibility. Serious central nervous system (CNS) and respiratory depression may also occur with concurrent use of CNS depressants, ingesting alcohol, or other CNS-depressing factors while on buprenorphine/naloxone.
Adverse effects
Side effects are similar to those of buprenorphine and other opioids. In addition, naloxone can induce withdrawal symptoms in people who are addicted to opioids. The most common side effects (in order of most to least common) of sublingual tablets include headaches, opioid withdrawal syndrome, pain, nausea, increased sweating, and difficulty sleeping. The most common side effects seen in film formulations are tongue pain, decreased sensation and redness in the mouth, headache, nausea, vomiting, excessive sweating, constipation, signs and symptoms of opioid withdrawal, sleeping difficulties, pain, and swelling of the extremities.Buprenorphine/naloxone has a milder side effect profile than methadone and limited respiratory effects, due to both agonist/antagonist effects. But buprenorphine/naloxone may be less safe than methadone in people with stable liver disease, since it can elevate liver enzymes.
Dependence and withdrawal
When taken in excess, buprenorphine/naloxone can produce dysphoric symptoms for non opioid-dependent/tolerant people because buprenorphine is a partial opioid agonist. The sublingual formulation of the buprenorphine/naloxone combination was designed to reduce the potential to inject the medication in comparison to buprenorphine alone. If the combination is taken sublingually, as directed, the addition of naloxone does not diminish buprenorphines effects. When an opioid-dependent person dissolves and injects a combination sublingual tablet, a withdrawal effect may be triggered because of naloxones high parenteral bioavailability. While this mechanism can act to deter intravenous injection, the Suboxone formulation can still produce an opioid agonist "high" if used sublingually by non-dependent persons, leading to opioid dependence.
Interactions
Buprenorphines sedating/narcotic effect is increased by other sedating substances, such as other opioids, benzodiazepines, first-generation antihistamines, alcohol, and antipsychotics. Opioids and especially benzodiazepines also increase the risk of potentially lethal respiratory depression.Strong inhibitors of the liver enzyme CYP3A4, such as ketoconazole, moderately increase buprenorphine concentrations; CYP3A4 inducers can theoretically decrease concentrations of buprenorphine.
Pharmacology
Mechanism of action
Buprenorphine binds strongly to opioid receptors and acts as a pain-reducing medication in the central nervous system (CNS). It binds to the μ-opioid receptor with high affinity, which produces the analgesic effects in the CNS. It is a partial μ-opioid receptor agonist and a weak κ-opioid receptor antagonist. As the dose of buprenorphine increases, its analgesic effects reach a plateau, and then it starts to act like an antagonist. As a partial agonist, buprenorphine binds and activates the opioid receptors, but has only partia efficacy at the receptor relative to a full agonist, even at maximal receptor occupancy. It is thus well-suited to treat opioid dependence, as it produces milder effects on the opioid receptor with lower dependence and habit-forming potential.
Naloxone is a pure opioid antagonist that competes with opioid molecules in the CNS and prevents them from binding to the opioid receptors. Naloxones binding affinity is highest for the μ-opioid receptor, then the δ-opioid receptor, and lowest for the κ-opioid receptor. Naloxone has poor bioavailability, and is rapidly inactivated following oral administration. When injected, it exerts its full effects.
The principle behind its function as a deterrent is as follows: when taken sublingually as prescribed, buprenorphines effects at the opioid receptor dominate, while naloxones effects are negligible due to the low oral absorption. But when someone attempts to misuse the medication via either injection or inhalation, the naloxone is intended to act as an antagonist and either reduce the opioids euphoric effects or even precipitate withdrawal in those dependent on opioids. This helps reduce the potential for deviating from the prescribers intended use relative to buprenorphine, though it does not eradicate it. One reason that naloxone might have limited efficacy as an abuse deterrent is that buprenorphine binds more tightly to the mu-opioid receptor than naloxone.
Pharmacokinetics
There are small differences in the pharmacokinetics between different sublingual buprenorphine/naloxone products. These differences may require changes in dose when a person switches from one product to another. The buprenorphine/naloxone sublingual film (e.g. trade name Suboxone) achieves higher buprenorphine maximum plasma concentrations (Cmax) and area under the curve (AUC, a measure of total drug exposure) than the original buprenorphine/naloxone sublingual tablets at equal doses. For example, at a buprenorphine/naloxone dose of 8 mg/2 mg, the buprenorphine Cmax after a single dose of the original tablet formulation is around 3 ng/mL whereas that of the 8 mg/2 mg film formulation is around 3.55 ng/mL. The Zubsolv trade name sublingual tablets have higher buprenorphine bioavailability than the original sublingual tablets, while the Bunavail trade name buccal films have the highest bioavailability. For example, a single dose of Bunavail 4.2 mg/0.7 mg achieves a Cmax around 3.41 ng/mL.
Buprenorphine
Buprenorphine is metabolized by the liver, primarily via the cytochrome P450 (CYP) isozyme CYP3A4, into norbuprenorphine. The glucuronidation of buprenorphine is primarily carried out by the UDP-glucuronosyltransferases (UGTs) UGT1A1 and UGT2B7, while norbuprenorphine is glucuronidated by UGT1A1 and UGT1A3. These glucuronides are then eliminated mainly through excretion into bile. The elimination half-life of buprenorphine is 20 to 73 hours (mean 37 hours). Due to the mainly hepatic elimination, there is no risk of accumulation in people with kidney problems.
Naloxone
Naloxone is extensively inactivated by first-pass metabolism in the liver, meaning that use of buprenorphine/naloxone as prescribed should not lead to active naloxone in the blood (which, as an opioid antagonist, would reverse the effect of buprenorphine or other opioids).
Society and culture
Cost
While the cost of the medication buprenorphine/naloxone is greater than buprenorphine alone, one analysis predicted the overall costs would be less in the United States due to a lower risk of misuse.
Access in the United States
Before the Drug Addiction Treatment Act of 2000 (DATA), physicians were not allowed to prescribe narcotics to treat opioid dependence. People with narcotic dependence had to go to registered clinics to receive treatment. With DATA, Suboxone was the first medication approved for office-based treatment for opioid dependence. Suboxone has thus become widely used as a replacement for methadone as it can be prescribed by doctors in their offices, while methadone can only be provided at specialized addiction centers, of which there are a limited number, often making access difficult. Integrating Medication-Assisted Treatment into outpatient primary care practices improves patient access to Suboxone. Some physicians are also leading a movement to begin prescribing it out of the emergency department (ED), as some small studies have shown ED-initiated Suboxone to be effective with people more likely to remain in addiction treatment compared to those either referred to addiction treatment programs or those receiving just a brief intervention in the department.Access to Suboxone can be limited due to varying prior authorization requirements across different insurers. Prior authorization is used by insurance companies to limit certain medications use by requiring approval before the insurance company will pay for them. This can influence a persons financial access and adherence. Financial access is determined through prior authorization approval, which the prescriber must request before the person can start the medication. The time it takes to have the request approved can delay the person in starting the medication. The prior authorization process can also affect adherence, because the approval is needed for every prescription. This presents the potential for a gap in treatment and withdrawal symptoms as the person waits for approval. Several insurance companies, as well as Medicaid in various states, have removed the use of prior authorization for Suboxone in an attempt to increase access to this treatment.
Controversies
In July 2019, the British company Reckitt Benckiser Group (RB Group) and its current/former affiliated entities (notably Indivior, which split from RB Group in 2014) settled with the US Department of Justice (DOJ) regarding the sale and marketing of brand name Suboxone (buprenorphine/naloxone). The non-prosecution agreement involves RB Group paying up to $1.4 billion, the largest settlement payment in U.S. history involving an opioid-class medication. This record was surpassed in October 2020, when Purdue Pharma reached an $8 billion settlement for claims related to injuries and deaths caused by the opioid epidemic, which includes criminal fines, forfeiture, and civil damages. The 2019 case alleged anti-competitive behavior by RB Group and Indivior surrounding the expiration of their regulatory exclusivity for Suboxone sublingual tablets. The DOJ alleged that RB Group and Indivior employed a "product hopping" scheme (when a firm ceases production of a product upon expiration of regulatory exclusivity in favor of another product that still has regulatory exclusivity in order to prevent generic manufacturer competition) by misrepresenting that the Suboxone sublingual film formulation was safer than the sublingual tablet formulation because "children are less likely to be accidentally exposed to the film product". There was no scientific evidence for that claim. The company also sponsored a complaint to the FDA, expressing concern that buprenorphine/naloxone sublingual tablets (the very product they formerly produced) were unsafe, requesting that applications for regulatory approval of generic products by other pharmaceutical companies (their competitors) be rejected by the US Food and Drug Administration.Some members of the abstinence-based recovery community argue against the medications effectiveness. In March 2022, Evan Massey said, "On the matter of Medical Detox with M.A.T its a question of how you want the pain of withdrawal. Do you want lots of pain over a short time? Or less pain over a longer time?"
See also
Buprenorphine/samidorphan
Methadone
References
External links
"Buprenorphine mixture with Naloxone". Drug Information Portal. U.S. National Library of Medicine. |
Flurbiprofen | Flurbiprofen is a member of the phenylalkanoic acid derivative family of nonsteroidal anti-inflammatory drugs (NSAIDs). It is primarily indicated as a pre-operative anti-miotic (in an ophthalmic solution) as well as orally for arthritis or dental pain. Side effects are analogous to those of ibuprofen.It was derived from propionic acid by the research arm of Boots UK during the 1960s, a period which also included the discovery of ibuprofen, indometacin, diclofenac, naproxen, ketoprofen, and sulindac.: 34 It was patented in 1964 by Boots UK and approved for medical use in 1987. It was approved in the US in 1988; the first generic was approved in 1994.: 158
Adverse effects
In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.
Society and culture
Brand names
As of 2016 the drug was available worldwide as drops for ophthalmic use and as tablets, both in various strengths, under many brand names which include: Acustop Cataplasma, Adofeed, Anazin, Anflupin, Anorcid, Ansaid, Antadys, Antafen, Antipain, Baenazin, Benactiv, Biprofin, Biprotec, Bro-Z, Brufen, Brufoz, Cebutid, Clinadol, Coryfin, Dispain, Edolfene, Eyeflur, Falken, Fiera, Flu Ro Fen, Flubifix, Flufen, Flugalin, Flupe, Flur di fen, Fluractive, Fluran, Flurbi Pap, Flurbic, Flurbiprofen, Flurbiprofène, Flurbiprofeno, Flurflex, Flurofen, Fluroptic, Fo Bi Pu Luo Fun, Forphen, Fortine, Froben, Frolix, Fubifen, Fubiprofen, Fubofen, Fukon, Fulruban, Furofen, Kai Fen, Kavoflog, Kotton, Lefenine, Majezik, Maprofen, Maxaljin, Maximus, Meiprofen, Neliacan, Nibelon, Nirolex Gola, Ocufen, Ocuflur, Optifen, Orofaringeo, Painil, Profen, Projezik, Ropion, Sigmaprofen, Stayban, Strefen, Strepfen, Strepflam, Strepsils (various formulations), Sulan, Tie Shr Shu, TransAct, Upnon, Urbifen, Yakuban, Zepolas, Zeralgo, Zero-P, and Zeton.
References
Further reading
Dean L (2019). "Flurbiprofen Therapy and CYP2C9 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 30742399. Bookshelf ID: NBK537365. |
Cefprozil | Cefprozil is a second-generation cephalosporin antibiotic. Originally discovered in 1983, and approved in 1992, it was sold under the tradename Cefzil by Bristol Meyers Squibb until 2010 when the brand name version was discontinued. It continues to be available from various companies in its generic form. It is used in the treatment of pharyngitis, tonsillitis, ear infections, acute sinusitis, bacterial exacerbation of chronic bronchitis, and skin and skin structure infections. It is currently available as a tablet and as a liquid suspension.
Adverse Effects
Although there is a widely quoted cross-allergy risk of 10% between cephalosporins and penicillin, research has shown no increased risk for cross-allergy for cefprozil and several other second-generation or later cephalosporins. The most common side effects were increased hepatic lab values (including AST and ALGT), dizziness, eosinophilia, diaper rash and superinfection, genital pruritus, vaginitis, diarrhea, nausea, vomiting, and abdominal pain.
Spectrum of bacterial susceptibility and resistance
Currently bacteria like Enterobacter aerogenes, Morganella morganii and Pseudomonas aeruginosa are resistant to cefprozil, while Salmonella enterica serotype Agona and streptococci are susceptible to cefprozil. Some bacteria like Brucella abortus, Moraxella catarrhalis and Streptococcus pneumoniae have developed resistance towards cefprozil in varying degrees. Detailed minimum inhibition concentration information is given by the Cefprozil Susceptibility and Resistance Data sheet.
Synthesis
This is not a direct copy of Lednicer book like at first glance, but is sourced from the primary reference material.
Displacement of the allylic chloride in intermediate (1) with triphenylphosphine gives the phosphonium salt (2). This functionality is then converted to its ylide; condensation with acetaldehyde then leads to the vinyl derivative (3); deprotection then gives cefprozil. Semisynthetic oral cephalosporin consisting of ~90:10 Z/E isomeric mixture.
References
External links
Cefprozil MedlinePlus Drug Information |
Ethinylestradiol/norethisterone | Ethinylestradiol/norethisterone (EE/NET), or ethinylestradiol/norethindrone, is a combination birth control pill which contains ethinylestradiol (EE), an estrogen and norethisterone (NET), a progestin. It is used for birth control, symptoms of menstruation, endometriosis, and menopausal symptoms. Other uses include acne. It is taken by mouth. Some preparations of EE/NET additionally contain an iron supplement in the form of ferrous fumarate.Side effects can include nausea, headache, blood clots, breast pain, depression, and liver problems. Use is not recommended during pregnancy, the initial three weeks after childbirth, and in those at high risk of blood clots. It, however, may be started immediately after a miscarriage or abortion. Smoking while using combined birth control pills is not recommended. It works by stopping ovulation, making the uterus not suitable for implantation, and making the mucus at the opening to the cervix thick.This combination pill was approved for medical use in the United States in 1964. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. It is marketed under a large number of brand names. In 2020, it was the 45th most commonly prescribed medication in the United States, with more than 14 million prescriptions.
See also
Mestranol/norethisterone
Oral contraceptive formulations
List of combined sex-hormonal preparations
== References == |
Aciclovir | Aciclovir (ACV), also known as acyclovir, is an antiviral medication. It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include prevention of cytomegalovirus infections following transplant and severe complications of Epstein–Barr virus infection. It can be taken by mouth, applied as a cream, or injected.Common side effects include nausea and diarrhea. Potentially serious side effects include kidney problems and low platelets. Greater care is recommended in those with poor liver or kidney function. It is generally considered safe for use in pregnancy with no harm having been observed. It appears to be safe during breastfeeding. Aciclovir is a nucleoside analogue that mimics guanosine. It works by decreasing the production of the viruss DNA.Aciclovir was patented in 1974, and approved for medical use in 1981. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication and is marketed under many brand names worldwide. In 2019, it was the 157th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Medical use
Aciclovir is used for the treatment of herpes simplex virus (HSV) and varicella zoster virus infections, including:
Genital herpes simplex (treatment and prevention)
Neonatal herpes simplex
Herpes simplex labialis (cold sores)
Shingles
Acute chickenpox in immunocompromised patients
Herpes simplex encephalitis
Acute mucocutaneous HSV infections in immunocompromised patients
Herpes of the eye and herpes simplex blepharitis (a chronic (long-term) form of herpes eye infection)
Prevention of herpes viruses in immunocompromised people (such as people undergoing cancer chemotherapy)Its effectiveness in treating Epstein–Barr virus (EBV) infections is less clear. It has not been found to be useful for infectious mononucleosis due to EBV. Valaciclovir and acyclovir act by inhibiting viral DNA replication, but as of 2016 there was little evidence that they are effective against Epstein–Barr virus, they are expensive, they risk causing resistance to antiviral agents, and (in 1% to 10% of cases) can cause unpleasant side effects.Aciclovir taken by mouth does not appear to decrease the risk of pain after shingles. In those with herpes of the eye, aciclovir may be more effective and safer than idoxuridine. It is not clear if aciclovir eye drops are more effective than brivudine eye drops.Intravenous aciclovir is effective to treat severe medical conditions caused by different species of the herpes virus family, including severe localized infections of herpes virus, severe genital herpes, chickenpox and herpesviral encephalitis. It is also effective in systemic or traumatic herpes infections, eczema herpeticum and herpesviral meningitis.
Reviews of research dating from the 1980s show there is some effect in reducing the number and duration of lesions if aciclovir is applied at an early stage of an outbreak. Research shows effectiveness of topical aciclovir in both the early and late stages of the outbreak as well as improving methodologically and in terms of statistical certainty from previous studies. Aciclovir trials show that this agent has no role in preventing HIV transmission, but it can help slow HIV disease progression in people not taking anti-retroviral therapy (ART). This finding emphasizes the importance of testing simple, inexpensive non-ART strategies, such as aciclovir and cotrimoxazole, in people with HIV.
Pregnancy
Classified as a Category B drug, the CDC and others have declared that during severe recurrent or first episodes of genital herpes, aciclovir may be used. For severe HSV infections (especially disseminated HSV), IV aciclovir may also be used. Studies in mice, rabbits and rats (with doses more than 10 times the equivalent of that used in humans) given during organogenesis have failed to demonstrate birth defects. Studies in rats in which they were given the equivalent to 63 times the standard steady-state humans concentrations of the drug on day 10 of gestation showed head and tail anomalies.Aciclovir is recommended by the CDC for treatment of varicella during pregnancy, especially during the second and third trimesters.Aciclovir is excreted in the breast milk, therefore it is recommended that caution should be used in breast-feeding women. It has been shown in limited test studies that the nursing infant is exposed to approximately 0.3 mg/kg/day following oral administration of aciclovir to the mother. If nursing mothers have herpetic lesions near or on the breast, breast-feeding should be avoided.
Adverse effects
Systemic therapy
Common adverse drug reactions (≥1% of patients) associated with systemic aciclovir therapy (oral or IV) include nausea, vomiting, diarrhea, encephalopathy (with IV use only), injection site reactions (with IV use only) and headache. In high doses, hallucinations have been reported. Infrequent adverse effects (0.1–1% of patients) include agitation, vertigo, confusion, dizziness, oedema, arthralgia, sore throat, constipation, abdominal pain, hair loss, rash and weakness. Rare adverse effects (<0.1% of patients) include coma, seizures, neutropenia, leukopenia, crystalluria, anorexia, fatigue, hepatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis, thrombotic thrombocytopenic purpura and anaphylaxis.Intravenous aciclovir may cause reversible nephrotoxicity in up to 5% to 10% of patients because of precipitation of aciclovir crystals in the kidney. Aciclovir crystalline nephropathy is more common when aciclovir is given as a rapid infusion and in patients with dehydration and preexisting renal impairment. Adequate hydration, a slower rate of infusion, and dosing based on renal function may reduce this risk.The aciclovir metabolite 9-Carboxymethoxymethylguanine (9-CMMG) has been shown to play a role in neurological adverse events, particularly in older people and those with reduced renal function.
Topical therapy
Aciclovir topical cream is commonly associated (≥1% of patients) with: dry or flaking skin or transient stinging/burning sensations. Infrequent adverse effects include erythema or itch. When applied to the eye, aciclovir is commonly associated (≥1% of patients) with transient mild stinging. Infrequently (0.1–1% of patients), ophthalmic aciclovir is associated with superficial punctate keratitis or allergic reactions.
Drug interactions
Ketoconazole: In-vitro replication studies have found a synergistic, dose-dependent antiviral activity against HSV-1 and HSV-2 when given with aciclovir. However, this effect has not been clinically established and more studies need to be done to evaluate the true potential of this synergy.Probenecid: Reports of increased half life of aciclovir, as well as decreased urinary excretion and renal clearance have been shown in studies where probenecid is given simultaneously with aciclovir.Interferon: Synergistic effects when administered with aciclovir and caution should be taken when administering aciclovir to patients receiving IV interferon.Zidovudine: Although administered often with aciclovir in HIV patients, neurotoxicity has been reported in at least one patient who presented with extreme drowsiness and lethargy 30–60 days after receiving IV aciclovir; symptoms resolved when aciclovir was discontinued.
Detection in biological fluids
Aciclovir may be quantitated in plasma or serum to monitor for drug accumulation in patients with renal dysfunction or to confirm a diagnosis of poisoning in acute overdose victims.
Mechanism of action
Aciclovir is converted by viral thymidine kinase to aciclovir monophosphate, which is then converted by host cell kinases to aciclovir triphosphate (ACV-TP, also known as aciclo-GTP). ACV-TP is a very potent inhibitor of viral DNA replication. ACV-TP competitively inhibits and inactivates the viral DNA polymerase. Its monophosphate form also incorporates into the viral DNA, resulting in chain termination.
Resistance
Resistance to aciclovir is rare in people with healthy immune systems, but is more common (up to 10%) in people with immunodeficiencies on chronic antiviral prophylaxis (transplant recipients, people with acquired immunodeficiency syndrome due to HIV infection). Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase or DNA polymerase, altering substrate sensitivity.
Microbiology
Aciclovir is active against most species in the herpesvirus family. In descending order of activity:
Herpes simplex virus type I (HSV-1)
Herpes simplex virus type II (HSV-2)
Varicella zoster virus (VZV)
Epstein–Barr virus (EBV)
Human cytomegalovirus (HCMV) – least activity
Pharmacokinetics
Aciclovir is poorly water-soluble and has poor oral bioavailability (15–30%), hence intravenous administration is necessary if high concentrations are required. When orally administered, peak plasma concentration occurs after 1–2 hours. According to the Biopharmaceutical Classification System (BCS), aciclovir falls under the BCS Class III drug i.e. soluble with low intestinal permeability. Aciclovir has a high distribution rate; protein binding is reported to range from 9 to 33%. The elimination half-life (t1/2) of aciclovir depends according to age group; neonates have a t1/2 of 4 hours, children 1–12 years have a t1/2 of 2–3 hours whereas adults have a t1/2 of 3 hours.
Chemistry
Details of the synthesis of aciclovir were first published by scientists from the University at Buffalo.
In the first step shown, 2,6-dichloropurine was alkylated with 1-benzoyloxy-2-chloromethoxyethane. The chlorine group at the 6-position of the heterocyclic ring is more reactive than the chlorine at the 2-position, hence it can be selectively replaced by an amino group, which was then converted to an amide using nitrous acid. Finally, the remaining chlorine was replaced by the amino group of aciclovir using ammonia in methanol. This synthesis and other methods for preparing the compound have been reviewed.
History
Aciclovir was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in cytotoxicity. Since discovery in mid 1970s, it has been used as an effective drug for the treatment of infections caused by most known species of the herpesvirus family, including herpes simplex and varicella zoster viruses. Nucleosides isolated from a Caribbean sponge, Cryptotethya crypta, were the basis for the synthesis of aciclovir. It was codiscovered by Howard Schaeffer following his work with Robert Vince, S. Bittner and S. Gurwara on the adenosine analog acycloadenosine which showed promising antiviral activity. Later, Schaeffer joined Burroughs Wellcome and continued the development of aciclovir with pharmacologist Gertrude B. Elion. A U.S. patent on aciclovir listing Schaeffer as inventor was issued in 1979. Vince later invented abacavir, an nRTI drug for HIV patients. Elion was awarded the 1988 Nobel Prize in Medicine, partly for the development of aciclovir.
A related prodrug form, valaciclovir came into medical use in 1995. It is converted to aciclovir in the body after absorption.In 2009, acyclovir in combination with hydrocortisone cream, marketed as Xerese, was approved in the United States for the early treatment of recurrent herpes labialis (cold sores) to reduce the likelihood of ulcerative cold sores and to shorten the lesion healing time in adults and children (six years of age and older).
Society and culture
Names
Aciclovir is the international nonproprietary name (INN) and British Approved Name (BAN) while acyclovir is the United States Adopted Name (USAN) and former British Approved Name.It was originally marketed as Zovirax; patents expired in the 1990s and since then it is generic and is marketed under many brand names worldwide.
Notes
References
Further reading
Hazra, S; Konrad, M; Lavie, A (2010). "The sugar ring of the nucleoside is required for productive substrate positioning in the active site of human deoxycytidine kinase (dCK): Implications for the development of dCK-activated acyclic guanine analogues". Journal of Medicinal Chemistry. 53 (15): 5792–800. doi:10.1021/jm1005379. PMC 2936711. PMID 20684612.
Harvey Stewart C. in Remingtons Pharmaceutical Sciences 18th edition: (ed. Gennard, Alfonso R.) Mack Publishing Company, 1990. ISBN 0-912734-04-3.
Huovinen P., Valtonen V. in Kliininen Farmakologia (ed. Neuvonen et al.). Kandidaattikustannus Oy, 1994. ISBN 951-8951-09-8.
Périgaud C.; Gosselin G.; Imbach J.-L. (1992). "Nucleoside analogues as chemotherapeutic agents: a review". Nucleosides and Nucleotides. 11 (2–4): 903–945. doi:10.1080/07328319208021748.
Rang H.P., Dale M.M., Ritter J.M.: Pharmacology, 3rd edition. Pearson Professional Ltd, 1995. 2003 (5th) edition ISBN 0-443-07145-4; 2001 (4th) edition ISBN 0-443-06574-8; 1990 edition ISBN 0-443-03407-9.
External links
"Acyclovir". Drug Information Portal. U.S. National Library of Medicine. |
Casimersen | Casimersen, sold under the brand name Amondys 45, is an antisense oligonucleotide medication used for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the dystrophin gene that is amenable to exon 45 skipping. It is an antisense oligonucleotide of phosphorodiamidate morpholino oligomer (PMO).The most common side effects include upper respiratory tract infections, cough, fever, headache, joint pain and throat pain.Casimersen was approved for medical use in the United States in February 2021, and it is the first FDA-approved targeted treatment for people who have a confirmed mutation of the DMD gene that is amenable to skipping exon 45.
Medical uses
Casimersen is indicated for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping.
History
Casimersen was evaluated in a double-blind, placebo-controlled study in which 43 participants were randomized 2:1 to receive either intravenous casimersen or placebo. All participants were male, between 7 and 20 years of age, and had a genetically confirmed mutation of the DMD gene that is amenable to exon 45 skipping.The U.S. Food and Drug Administration (FDA) granted the application for casimersen fast track, priority review, and orphan drug designations. The FDA granted the approval of Amondys 45 to Sarepta Therapeutics, Inc.
Pharmacodynamics
Duchenne Muscular Dystrophy is an X-linked recessive disorder that results in the absence of a functional dystrophin protein. Dystrophin protein is a protein that consists of an N-terminal actin-binding domain, C-terminal B-dystroglycan- binding domain, and 24 internal spectrum-like repeats. Dystrophin plays a role in muscle function and without dystrophin, muscle tissue will be replaced with fibrous and adipose tissue. Casimersen is an antisense phosphorodiamidate morpholino oligonucleotide designed to bind to the exon 45 of the DMD pre-MRNA, which prevents its exclusion into the mature RNA before translation. This change causes the production of an internally truncated dysphotrophin protein.
Dosage and administration
The usual pediatric and adult dose for Casimersen, for treatment of muscular dystrophy is 30 mg/kg via IV infusion once a week.
Adverse effects
Patients on Casimersen are advised to immediately contact their healthcare team if they experience the following side effects: pink, brown, or foamy urine or swelling of the hands and feet. Common side effects include: headache, fever, joint pain, cough and cold symptoms.
References
External links
"Casimersen". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02500381 for "Study of SRP-4045 and SRP-4053 in DMD Patients (ESSENCE)" at ClinicalTrials.gov |
Flibanserin | Flibanserin, sold under the brand name Addyi, is a medication approved for the treatment of pre-menopausal women with hypoactive sexual desire disorder (HSDD). The medication increases the number of satisfying sexual events per month by about one half over placebo from a starting point of about two to three. The certainty of the estimate is low. The side effects of dizziness, sleepiness, and nausea occur about three to four times more often.Development by Boehringer Ingelheim was halted in October 2010, following a negative evaluation by the US Food and Drug Administration (FDA). The rights to the drug were then transferred to Sprout Pharmaceuticals, which achieved approval of the drug by the US FDA in August 2015.HSDD was recognized as a distinct sexual function disorder for more than 30 years, but was removed from the Diagnostic and Statistical Manual of Mental Disorders in 2013, and replaced with a new diagnosis called female sexual interest/arousal disorder (FSIAD).
Medical uses
Flibanserin is used for hypoactive sexual desire disorder among women. Those receiving flibanserin report a 0.5 increase compared to placebo in the number of times they had "satisfying sexual events". In those on flibanserin it rose from 2.8 to 4.5 times a month while women receiving placebo reported also an increase of "satisfying sexual events" from 2.7 to 3.7 times a month. The onset of the flibanserin effect was seen from the first timepoint measured after 4 weeks of treatment and maintained throughout the treatment period.The effectiveness of flibanserin was evaluated in three phase 3 clinical trials. Each of the three trials had two co-primary endpoints, one for satisfying sexual events (SSEs) and the other for sexual desire. Each of the 3 trials also had a secondary endpoint that measured distress related to sexual desire. All three trials showed that flibanserin produced an increase in the number of SSEs and reduced distress related to sexual desire. The first two trials used an electronic diary to measure sexual desire, and did not find an increase. These two trials also measured sexual desire using the Female Sexual Function Index (FSFI) as a secondary endpoint, and an increase was observed using this latter measure. The FSFI was used as the co-primary endpoint for sexual desire in the third trial, and again showed a statistically significant increase.Womens overall feeling of improvement was small to none. The overall quality of the evidence was low.
Side effects
Adverse events are more common among women taking flibanserin. The majority of adverse events were mild to moderate. The most commonly reported adverse events included dizziness, nausea, feeling tired, sleepiness, and trouble sleeping.Drinking alcohol while on flibanserin may result in severely low blood pressure (low blood pressure that produced symptoms after two glasses of wine occurred in 17%).
Mechanism of action
Activity profile
Flibanserin acts as a full agonist in the frontal cortex and the raphe dorsalis, but only as a partial agonist in the CA3 region of the hippocampus of the 5-HT1A receptor (serotonin receptor) (Ki = 1 nM in CHO cells, but only 15–50 nM in cortex, hippocampus and dorsal raphe) and, with lower affinity, as an antagonist of the 5-HT2A receptor (Ki = 49 nM) and antagonist or very weak partial agonist of the D4 receptor (Ki = 4–24 nM). Despite the much greater affinity of flibanserin for the 5-HT1A receptor, and for reasons that are unknown (although it might be caused by the competition with endogenous serotonin), flibanserin occupies the 5-HT1A and 5-HT2A receptors in vivo with similar percentages. Flibanserin also has low affinity for the 5-HT2B receptor (Ki = 89.3 nM) and the 5-HT2C receptor (Ki = 88.3 nM), both of which it behaves as an antagonist of. Flibanserin preferentially activates 5-HT1A receptors in the prefrontal cortex, demonstrating regional selectivity, and has been found to increase dopamine and norepinephrine levels and decrease serotonin levels in the rat prefrontal cortex, actions that were determined to be mediated by activation of the 5-HT1A receptor. As such, flibanserin has been described as a norepinephrine–dopamine disinhibitor (NDDI).The proposed mechanism of action refers to the Kinsey dual control model of sexual response. Various neurotransmitters, sex steroids, and other hormones have important excitatory or inhibitory effects on the sexual response. Among neurotransmitters, excitatory activity is driven by dopamine and norepinephrine, while inhibitory activity is driven by serotonin. The balance between these systems is of significance for a normal sexual response. By modulating serotonin and dopamine activity in certain parts of the brain, flibanserin may improve the balance between these neurotransmitter systems in the regulation of sexual response.
Society and culture
Flibanserin was originally developed as an antidepressant, before being repurposed for the treatment of HSDD.
Names
Former proposed but abandoned brand names of flibanserin include Ectris and Girosa, and its former developmental code name was BIMT-17. The brand name is Addyi.
Approval process and advocacy
On June 18, 2010, a federal advisory panel to the US Food and Drug Administration (FDA) unanimously voted against recommending approval of flibanserin, citing an inadequate risk-benefit ratio. The Committee acknowledged the validity of hypoactive sexual desire as a diagnosis, but expressed concern with the drugs side effects and insufficient evidence for efficacy, especially the drugs failure to show a statistically significant effect on the co-primary endpoint of sexual desire. Earlier in the week, a FDA staff report also recommended non-approval of the drug. Ahead of the votes, Boehringer Ingelheim had mounted a publicity campaign to promote the controversial disorder of "hypoactive sexual desire". In 2010 the FDA issued a Complete Response Letter, stating that the New Drug Application could not be approved in its current form. The letter cited several concerns, including the failure to demonstrate a statistical effect on the co-primary endpoint of sexual desire and overly restrictive entry criteria for the two Phase 3 trials. The Agency recommended performing a new Phase 3 trial with less restrictive entry criteria. On October 8, 2010, Boehringer announced that it would discontinue its development of flibanserin in light of the FDAs decision.Sprout responded to the FDAs cited deficiencies and refiled the NDA in 2013. The submission included data from a new Phase 3 trial and several Phase 1 drug-drug interaction studies. The FDA again refused the application, citing an uncertain risk/benefit ratio. In December 2013, a Formal Dispute Resolution was filed, which contained the requirements of the FDA for further studies. These include two studies in healthy subjects to determine if flibanserin impairs their ability to drive, and to determine if it interferes with other biochemical pathways. The Agency agreed to call a new Advisory Committee meeting to consider whether the risk-benefit ratio of flibanserin was favorable after this additional data was obtained. Sprout expected to resubmit the New Drug Application (NDA) in the 3rd quarter of 2014.On June 4, 2015, the US FDA Advisory Committee, which includes the Bone, Reproductive, and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management Advisory Committee (DSRM), recommended approval of the drug by 18–6, with the proviso that measures be taken to inform women of the drugs side effects. On August 18, 2015, the FDA approved Addyi (Flibanserin) for the treatment of premenopausal women with low sexual desire that causes personal distress or relationship difficulties. The approval specified that flibanserin should not be used to treat low sexual desire caused by co-existing psychiatric or medical problems; low sexual desire caused by problems in the relationship; or low sexual desire due to medication side effects.As of 21 August 2015, The Pharmaceutical Journal reported that Sprout Pharmaceuticals had not yet made an application to the European Medicines Agency for a marketing authorisation.
Advocacy groups
Even the Score, a coalition of womens groups brought together by a Sprout consultant, actively campaigned for the approval of flibanserin. The campaign emphasized that several approved treatments for male sexual dysfunction exist, while no such treatment for women was available. The group successfully obtained letters of support from the President of the National Organization for Women, the editor of the Journal of Sexual Medicine, and several members of Congress.Other organizations supporting the approval of flibanserin included the National Council of Womens Organizations, the Black Womens Health Imperative, the Association of Reproductive Health Professionals, National Consumers League, and the American Sexual Health Association.The approval was opposed by the National Womens Health Network, the National Center for Health Research and Our Bodies Ourselves. A representative of PharmedOut said "To approve this drug will set the worst kind of precedent — that companies that spend enough money can force the FDA to approve useless or dangerous drugs." An editorial in JAMA noted that, "Although flibanserin is not the first product to be supported by a consumer advocacy group in turn supported by pharmaceutical manufacturers, claims of gender bias regarding the FDAs regulation have been particularly noteworthy, as have the extent of advocacy efforts ranging from social media campaigns to letters from members of Congress".The Even the Score campaign was managed by Blue Engine Message & Media, a public relations firm, and received funding from Sprout.
Acquisition by Valeant Pharmaceuticals
On 20 August 2015 Valeant Pharmaceuticals and Sprout Pharmaceuticals announced that Valeant will acquire Sprout, on a debt-free basis, for approximately $1 billion in cash, plus a share of future profits based upon the achievement of certain milestones.
Reception
The initial response since the 2015 introduction of flibanserin to the U.S. market was slow with 227 prescriptions written during the first three weeks. The slow response may be related to a number of factors: physicians require about 10 minutes of online training to get certified; the medication has to be taken daily and costs about US$400 per month; and questions about the drugs efficacy and need. Prescriptions for the drug continue to be few with less than 4,000 being made as of February 2016.
References
Further reading
Dean L (September 2019). "Flibanserin Therapy and CYP2C19 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 31550099.
Aubert, Yves (December 2012). Sex, aggression and pair-bond : a study on the serotonergic regulation of female sexual function in the marmoset monkey (Thesis). Leiden University. hdl:1887/20268. ISBN 9789461821959.</ref>
Marazziti D, Palego L, Giromella A, et al. (June 2002). "Region-dependent effects of flibanserin and buspirone on adenylyl cyclase activity in the human brain". Int. J. Neuropsychopharmacol. 5 (2): 131–40. doi:10.1017/S1461145702002869. PMID 12135537.
Podhorna J, Brown RE (June 2000). "Flibanserin has anxiolytic effects without locomotor side effects in the infant rat ultrasonic vocalization model of anxiety". Br J Pharmacol. 130 (4): 739–746. doi:10.1038/sj.bjp.0703364. PMC 1572126. PMID 10864879.
Brambilla A, Baschirotto A, Grippa N, Borsini F (December 1999). "Effect of flibanserin (BIMT 17), fluoxetine, 8-OH-DPAT and buspirone on serotonin synthesis in rat brain". Eur Neuropsychopharmacol. 10 (1): 63–7. doi:10.1016/S0924-977X(99)00056-5. PMID 10647099. S2CID 1470166.
External links
"Flibanserin". Drug Information Portal. U.S. National Library of Medicine.
"FDA orders important safety labeling changes for Addyi". U.S. Food and Drug Administration (FDA). 11 April 2019.
"The Company Behind Female Viagra Just Raised $20 Million in Funding". Fortune. 4 September 2019.
"The Womens Libido Pill Is Back, and So Is the Controversy". Bloomberg. 13 June 2018. |
Loperamide/simethicone | Loperamide/simethicone is combination medication marketed under the trade name Imodium Multi-Symptom Relief (formerly Imodium A-D Advanced) used to treat diarrhea and gas simultaneously. It is manufactured by the McNeil Consumer Healthcare Division of McNeil PPC, Inc. It contains loperamide and simethicone.
Loperamide is a μ-opioid receptor agonist that works in the intestines. Although it is an opioid, it has no effects on the central nervous system. It reduces diarrhea by slowing the transit time of contents through the intestinal tract thereby allowing more water to be reabsorbed from the intestinal lumen.
Simethicone reduces gas by allowing smaller gas bubbles to coalesce into larger bubbles in the intestinal tract, making them easier to pass. Simethicone is not absorbed from the gastrointestinal tract so there are no systemic side effects.
Precautions
Anti-diarrheal medications should be avoided if diarrhea is secondary to an infection. Avoid using such products in the presence of fever, black stools, bloody stools, or stools containing mucus.
References
External links
"Loperamide hydrochloride mixture with simethicone". Drug Information Portal. U.S. National Library of Medicine. |
Amphotericin B | Amphotericin B is an antifungal medication used for serious fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, and cryptococcosis. For certain infections it is given with flucytosine. It is typically given by injection into a vein.Common side effects include a reaction with fever, chills, and headaches soon after the medication is given, as well as kidney problems. Allergic symptoms including anaphylaxis may occur. Other serious side effects include low blood potassium and inflammation of the heart. It appears to be relatively safe in pregnancy. There is a lipid formulation that has a lower risk of side effects. It is in the polyene class of medications and works in part by interfering with the cell membrane of the fungus.Amphotericin B was isolated from Streptomyces nodosus in 1955 at the Squibb For Medical Research Institute from cultures isolated from the streptomycete obtained from the river bed of Orinoco in that region of Venezuela and came into medical use in 1958. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication.
Medical uses
Antifungal
One of the main uses of amphotericin B is treating a wide range of systemic fungal infections. Due to its extensive side effects, it is often reserved for severe infections in critically ill, or immunocompromised patients. It is considered first line therapy for invasive mucormycosis infections, cryptococcal meningitis, and certain aspergillus and candidal infections. It has been a highly effective drug for over fifty years in large part because it has a low incidence of drug resistance in the pathogens it treats. This is because amphotericin B resistance requires sacrifices on the part of the pathogen that make it susceptible to the host environment, and too weak to cause infection.
Antiprotozoal
Amphotericin B is used for life-threatening protozoan infections such as visceral leishmaniasis and primary amoebic meningoencephalitis.
Spectrum of susceptibility
The following table shows the amphotericin B susceptibility for a selection of medically important fungi.
Available formulations
Intravenous
Amphotericin B alone is insoluble in normal saline at a pH of 7. Therefore, several formulations have been devised to improve its intravenous bioavailability. Lipid-based formulations of amphotericin B are no more effective than conventional formulations, although there is some evidence that lipid-based formulations may be better tolerated by patients and may have fewer adverse effects.
Deoxycholate
The original formulation uses sodium deoxycholate to improve solubility. Amphotericin B deoxycholate (ABD) is administered intravenously. As the original formulation of amphotericin, it is often referred to as "conventional" amphotericin.
Liposomal
In order to improve the tolerability of amphotericin and reduce toxicity, several lipid formulations have been developed. Liposomal formulations have been found to have less renal toxicity than deoxycholate, and fewer infusion-related reactions. They are more expensive than amphotericin B deoxycholate.AmBisome (LAMB) is a liposomal formulation of amphotericin B for injection and consists of a mixture of phosphatidylcholine, cholesterol and distearoyl phosphatidylglycerol that in aqueous media spontaneously arrange into unilamellar vesicles that contain amphotericin B. It was developed by NeXstar Pharmaceuticals (acquired by Gilead Sciences in 1999). It was approved by the FDA in 1997. It is marketed by Gilead in Europe and licensed to Astellas Pharma (formerly Fujisawa Pharmaceuticals) for marketing in the US, and Sumitomo Pharmaceuticals in Japan.
Lipid complex formulations
A number of lipid complex preparations are also available. Abelcet was approved by the FDA in 1995. It consists of amphotericin B and two lipids in a 1:1 ratio that form large ribbon-like structures. Amphotec is a complex of amphotericin and sodium cholesteryl sulfate in a 1:1 ratio. Two molecules of each form a tetramer that aggregate into spiral arms on a disk-like complex. It was approved by the FDA in 1996.
By mouth
An oral preparation exists but is not widely available. The amphipathic nature of amphotericin along with its low solubility and permeability has posed major hurdles for oral administration given its low bioavailability. In the past it had been used for fungal infections of the surface of the GI tract such as thrush, but has been replaced by other antifungals such as nystatin and fluconazole.However, recently novel nanoparticulate drug delivery systems such as AmbiOnp, nanosuspensions, lipid-based drug delivery systems including cochleates, self-emulsifying drug delivery systems, solid lipid nanoparticles and polymeric nanoparticles—such as Amphotericin B in pegylated polylactide coglycolide copolymer nanoparticles—have demonstrated potential for oral formulation of amphotericin B.
Side effects
Amphotericin B is well known for its severe and potentially lethal side effects. Very often, it causes a serious reaction soon after infusion (within 1 to 3 hours), consisting of high fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea and tachypnea, drowsiness, and generalized weakness. The violent chills and fevers have caused the drug to be nicknamed "shake and bake". The precise etiology of the reaction is unclear, although it may involve increased prostaglandin synthesis and the release of cytokines from macrophages. Deoxycholate formulations (ABD) may also stimulate the release of histamine from mast cells and basophils. Reactions sometimes subside with later applications of the drug. This nearly universal febrile response necessitates a critical (and diagnostically difficult) professional determination as to whether the onset of high fever is a novel symptom of a fast-progressing disease, or merely the effect of the drug. To decrease the likelihood and severity of the symptoms, initial doses should be low, and increased slowly. Paracetamol, pethidine, diphenhydramine, and hydrocortisone have all been used to treat or prevent the syndrome, but the prophylactic use of these drugs is often limited by the patients condition.Intravenously administered amphotericin B in therapeutic doses has also been associated with multiple organ damage. Kidney damage is a frequently reported side effect, and can be severe and/or irreversible. Less kidney toxicity has been reported with liposomal formulations (such as AmBisome) and it has become preferred in patients with preexisting renal injury. The integrity of the liposome is disrupted when it binds to the fungal cell wall, but is not affected by the mammalian cell membrane, so the association with liposomes decreases the exposure of the kidneys to amphotericin B, which explains its less nephrotoxic effects.In addition, electrolyte imbalances such as hypokalemia and hypomagnesemia are also common. In the liver, increased liver enzymes and hepatotoxicity (up to and including fulminant liver failure) are common. In the circulatory system, several forms of anemia and other blood dyscrasias (leukopenia, thrombopenia), serious cardiac arrhythmias (including ventricular fibrillation), and even frank cardiac failure have been reported. Skin reactions, including serious forms, are also possible.
Interactions
Drug-drug interactions may occur when Amphorectin B is coadministered with the following agents:
Flucytosine: Toxicity of flucytosine is increased and allows a lower dose of amphotericin B. Amphotericin B may also facilitate entry of flucystosine into the fungal cell by interfering with the permeability of the fungal cell membrane.
Diuretics or cisplatin: Increased renal toxicity and increased risk of hypokalemia
Corticosteroids: Increased risk of hypokalemia
Imidazole Antifungals: Amphorectin B may antagonize the activity of ketoconazole and miconazole. The clinical significance of this interaction is unknown.
Neuromuscular-blocking agents: Amphorectin B-induced hypokalemia may potentiate the effects of certain paralytic agents.
Foscarnet, ganciclovir, tenofovir, adefovir: Risk of hematological and renal side effects of amphotericin B are increased
Zidovudine: Increased risk of renal and hematological toxicity .
Other nephrotoxic drugs (such as aminoglycosides): Increased risk of serious renal damage
Cytostatic drugs: Increased risk of kidney damage, hypotension, and bronchospasms
Transfusion of leukocytes: Risk of pulmonal (lung) damage occurs, space the intervals between the application of amphotericin B and the transfusion, and monitor pulmonary function
Mechanism of action
Amphotericin B binds with ergosterol, a component of fungal cell membranes, forming pores that cause rapid leakage of monovalent ions (K+, Na+, H+ and Cl−) and subsequent fungal cell death. This is amphotericin Bs primary effect as an antifungal agent. It has been found that the amphotericin B/ergosterol bimolecular complex that maintains these pores is stabilized by Van der Waals interactions. Researchers have found evidence that amphotericin B also causes oxidative stress within the fungal cell, but it remains unclear to what extent this oxidative damage contributes to the drugs effectiveness. The addition of free radical scavengers or antioxidants can lead to amphotericin resistance in some species, such as Scedosporium prolificans, without affecting the cell wall.Two amphotericins, amphotericin A and amphotericin B, are known, but only B is used clinically, because it is significantly more active in vivo. Amphotericin A is almost identical to amphotericin B (having a C=C double bond between the 27th and 28th carbons), but has little antifungal activity.
Mechanism of toxicity
Mammalian and fungal membranes both contain sterols, a primary membrane target for amphotericin B. Because mammalian and fungal membranes are similar in structure and composition, this is one mechanism by which amphotericin B causes cellular toxicity. Amphotericin B molecules can form pores in the host membrane as well as the fungal membrane. This impairment in membrane barrier function can have lethal effects. Ergosterol, the fungal sterol, is more sensitive to amphotericin B than cholesterol, the common mammalian sterol. Reactivity with the membrane is also sterol concentration dependent. Bacteria are not affected as their cell membranes do not usually contain sterols.
Amphotericin administration is limited by infusion-related toxicity. This is thought to result from innate immune production of proinflammatory cytokines.
Biosynthesis
The natural route to synthesis includes polyketide synthase components.
The carbon chains of Amphotericin B are assembled from sixteen C2 acetate and three C3propionate units by polyketide syntheses (PKSs). Polyketide biosynthesis begins with the decarboxylative condensation of a dicarboxylic acid extender unit with a starter acyl unit to form a β-ketoacyl intermediate. The growing chain is constructed by a series of Claisen reactions. Within each module, the extender units are loaded onto the current ACP domain by acetyl transferase (AT). The ACP-bound elongation group reacts in a Claisen condensation with the KS-bound polyketide chain. Ketoreductase (KR), dehydratase (DH) and enoyl reductase (ER) enzymes may also be present to form alcohol, double bonds or single bonds. After cyclisation, the macrolactone core undergoes further modification by hydroxylation, methylation and glycosylation. The order of these processes is unknown.
History
It was originally extracted from Streptomyces nodosus, a filamentous bacterium, in 1955, at the Squibb Institute for Medical Research from cultures of an undescribed streptomycete isolated from the soil collected in the Orinoco River region of Venezuela. Two antifungal substances were isolated from the soil culture, Amphotericin A and Amphotericin B, but B had better antifungal activity. For decades it remained the only effective therapy for invasive fungal disease until the development of the azole antifungals in the early 1980s.Its complete stereo structure was determined in 1970 by an X-ray structure of the N-iodoacetyl derivative. The first synthesis of the compounds naturally occurring enantiomeric form was achieved in 1987 by K. C. Nicolaou.
Formulations
It is a subgroup of the macrolide antibiotics, and exhibits similar structural elements. Currently, the drug is available in many forms. Either "conventionally" complexed with sodium deoxycholate (ABD), as a cholesteryl sulfate complex (ABCD), as a lipid complex (ABLC), and as a liposomal formulation (LAMB). The latter formulations have been developed to improve tolerability and decrease toxicity, but may show considerably different pharmacokinetic characteristics compared to conventional amphotericin B.
Names
Amphotericin name originates from the chemicals amphoteric properties.It is commercially known as: Fungilin, Fungizone, Abelcet, AmBisome, Fungisome, Amphocil, Amphotec, Halizon
References
External links
"Amphotericin B". Drug Information Portal. U.S. National Library of Medicine.
AmBisome Summaries of Product Characteristics (United Kingdom)
Amphotericin B
"Amphotericin B Liposomal Injection". MedlinePlus.
"Amphotericin B Lipid Complex Injection". MedlinePlus. |
Growth hormone therapy | Growth hormone therapy refers to the use of growth hormone (GH) as a prescription medication—it is one form of hormone therapy. Growth hormone is a peptide hormone secreted by the pituitary gland that stimulates growth and cell reproduction. In the past, growth hormone was extracted from human pituitary glands. Growth hormone is now produced by recombinant DNA technology and is prescribed for a variety of reasons. GH therapy has been a focus of social and ethical controversies for 50 years.
This article describes the history of GH treatment and the current uses and risks arising from GH use. Other articles describe GH physiology, diseases of GH excess (acromegaly and pituitary gigantism), deficiency, the recent phenomenon of HGH controversies, growth hormone in sports, and growth hormone for cows.
Medical uses
HGH deficiency in children
Growth hormone deficiency is treated by replacing growth hormone.Lonapegsomatropin was approved for medical use in the United States in August 2021.
HGH deficiency in adults
The Endocrine Society has recommended that adult patients diagnosed with growth hormone deficiency (GHd) be administered an individualized GH treatment regimen. With respect to diagnosis, their guidelines state that "adults patients with structural hypothalamic/pituitary disease, surgery or irradiation in these areas, head trauma, or evidence of other pituitary hormone deficiencies be considered for evaluation for acquired GHd" and that "idiopathic GHd in adults is very rare, and stringent criteria are necessary to make this diagnosis. Because in the absence of suggestive clinical circumstances there is a significant false-positive error rate in the response to a single GH stimulation test, we suggest the use of two tests before making this diagnosis."GH replacement therapy can provide a number of measurable benefits to GH-deficient adults. These include improved bone density, increased muscle mass, decrease of adipose tissue, faster hair and nail growth, strengthened immune system, increased circulatory system, and improved blood lipid levels, but long term mortality benefit has not yet been demonstrated.A peer-reviewed article published in 2010 indicates that "Growth hormone (GH) replacement unequivocally benefits growth, body composition, cardiovascular risk factors and quality of life. Less is known about the effects of GH on learning and memory."
Other
As of 2004, GH has been approved by the U.S. Food and Drug Administration for treatment of other conditions such as:
In adults, wasting (or cachexia) caused by AIDS.
Turner syndrome epitomizes the response of non-deficient shortness. At doses 20% higher than those used in GH deficiency, growth accelerates. With several years of treatment the median gain in adult height is about 2–3 in (5.1–7.6 cm) on this dose. The gains appear to be dose-dependent. It has been used successfully in toddlers with Turner syndrome, as well as in older girls.
Short-stature homeobox gene deficiency
Chronic kidney failure results in many problems, including growth failure. GH treatment for several years both before and after transplantation may prevent further deceleration of growth and may narrow the height deficit, though even with treatment net adult height loss may be about 4 in (10 cm)
Prader–Willi syndrome, a generally non-hereditary genetic condition, is a case where GH is prescribed for benefits in addition to height. GH is one of the treatment options an experienced endocrinologist may use when treating a child with PWS. GH can help children with PWS in height, weight, body mass, strength, and agility.. Reports have indicated increase of growth rate (especially in the first year of treatment) and a variety of other positive effects, including improved body composition (higher muscle mass, lower fat mass); improved weight management; increased energy and physical activity; improved strength, agility, and endurance; and improved respiratory function. The Prader-Willi Syndrome Association (USA) recommends that a sleep study be conducted before initiating GH treatment in a child with PWS. At this time there is no direct evidence of a causative link between growth hormone and the respiratory problems seen in PWS (among both those receiving and those not receiving GH treatment), including sudden death. A follow-up sleep study after one year of GH treatment may also be indicated. GH (specifically Pfizers version, Genotropin) is the only treatment that has received an FDA indication for children with PWS. The FDA indication only applies to children.
Children short because of intrauterine growth retardation are small for gestational age at birth for a variety of reasons. If early catch-up growth does not occur and their heights remain below the third percentile by 2 or 3 years of age, adult height is likely to be similarly low. High-dose GH treatment has been shown to accelerate growth, but data on long term benefits and risks are limited.
Idiopathic short stature (ISS) is one of the most controversial indications for GH as pediatric endocrinologists do not agree on its definition, diagnostic criteria, or limits. The term has been applied to children with severe unexplained shortness that will result in an adult height below the 3rd percentile. In the late 1990s, the pharmaceutical manufacturer Eli Lilly and Company sponsored trials of their brand of rHGH (Humatrope) in children with extreme ISS, those at least 2.25 standard deviations below mean (in the lowest 1.2 percent of the population). These boys and girls appeared to be headed toward heights of less than 63" (160 cm) and 59" (150 cm) respectively. They were treated for about 4 years and gained 1.5–3 in (3.8–7.6 cm) in adult height. Controversy has arisen as to whether all of these children were truly "short normal" children, since the average IGF1 was low. Approval of HGH for the treatment of this extreme degree of shortness led to an increase in the number of parents seeking its use to make otherwise normal children a little taller.
Adverse effects
The New England Journal of Medicine published two editorials in 2003 expressing concern about off-label uses of HGH and the proliferation of advertisements for "HGH-Releasing" dietary supplements, and emphasized that there is no evidence that use of HGH in healthy adults or in geriatric patients is safe and effective – and especially emphasized that risks of long-term HGH treatment are unknown. One editorial was by Jeffrey M. Drazen, M.D., the editor-in-chief of the journal; the other one was by Dr. Mary Lee Vance, who provided the NEJMs editorial original, cautious comment on a much cited 1990 study on the use of HGH in geriatric patients with low growth hormone levels.A small but controlled study of GH given to severely ill adults in an intensive care unit setting for the purpose of increasing strength and reducing the muscle wasting of critical illness showed a higher mortality rate for the patients having received GH. The reason is unknown, but GH is now rarely used in ICU patients unless they have severe growth hormone deficiency.GH treatment usually decreases insulin sensitivity, but some studies showed no evidence for increased diabetes incidence in GH-treated adult hypopituitary patients.In past it was believed that GH treatment could increase the cancer risk; a large study recently concluded that "With relatively short follow-up, the overall primary cancer risk in 6840 patients receiving GH as adults was not increased. Elevated SIRs (which is risk of getting cancer) were found for subgroups in the USA cohort defined by age <35 years or childhood onset GH deficiency."The FDA issued a Safety Communication in August 2011, stating that the evidence regarding recombinant human growth hormone and increased risk of death is inconclusive after reviewing sources including a French study which compared persons with certain kinds of short stature (idiopathic growth hormone deficiency and idiopathic or gestational short stature) treated with recombinant human growth hormone during childhood and who were followed over a long period of time, with individuals in the general population of France.
History
Perhaps the most famous person who exemplified the appearance of untreated congenital growth hormone deficiency was Charles Sherwood Stratton (1838–1883), who was exhibited by P. T. Barnum as General Tom Thumb, and married Lavinia Warren. Pictures of the couple show the typical adult features of untreated severe growth hormone deficiency. Despite the severe shortness, limbs and trunks are proportional.By the middle of the twentieth century, endocrinologists understood the clinical features of growth hormone deficiency. GH is a protein hormone, like insulin, which had been purified from pig and cow pancreases for treatment of type 1 diabetes since the 1920s. However, pig and cow GH did not work at all in humans, due to greater species-to-species variation of molecular structure (i.e., insulin is considered more "evolutionarily conserved" than GH).
Extraction for treatment
Extracted growth hormone was used since the late 1950s until the late 1980s when its use was replaced by recombinant GH.In the late 1950s, Maurice Raben purified enough GH from human pituitary glands to successfully treat a GH-deficient boy. A few endocrinologists began to help parents of severely GH-deficient children to make arrangements with local pathologists to collect human pituitary glands after removal at autopsy. Parents would then contract with a biochemist to purify enough growth hormone to treat their child. Few families could manage such a complicated undertaking.In 1960, the National Pituitary Agency was formed as a branch of the U.S. National Institutes of Health. The purpose of this agency was to supervise the collection of human pituitary glands when autopsies were performed, arrange for large-scale extraction and purification of GH, and distribute it to a limited number of pediatric endocrinologists for treating GH-deficient children under research protocols. Canada, UK, Australia, New Zealand, France, Israel, and other countries establish similar government-sponsored agencies to collect pituitaries, purify GH, and distribute it for treatment of severely GH-deficient children.Supplies of this “cadaver growth hormone” were limited, and only the most severely deficient children were treated. From 1963 to 1985 about 7700 children in the U.S. and 27,000 children worldwide were given GH extracted from human pituitary glands to treat severe GH deficiency. Physicians trained in the relatively new specialty of pediatric endocrinology provided most of this care, but in the late 1960s there were only a hundred of these physicians in a few dozen of the largest university medical centers around the world.In 1977, the NPA GH extraction and purification procedure was refined and improved.A shortage of available cadaver GH worsened in the late 1970s as the autopsy rate in the U.S. declined, while the number of pediatric endocrinologists able to diagnose and treat GH deficiency increased. GH was "rationed." Often, treatment would be stopped when a child reached an arbitrary minimal height, such as 5 ft 0 in (1.52 m). Children who were short for reasons other than severe GH deficiency were lied to and told that they would not benefit from treatment. Only those pediatric endocrinologists that remained at university medical centers with departments able to support a research program had access to NPA growth hormone.
In the late 1970s, a Swedish pharmaceutical company, Kabi, contracted with a number of hospitals in Europe to buy pituitary glands for the first commercial GH product, Crescormon. Although an additional source of GH was welcomed, Crescormon was greeted with ambivalence by pediatric endocrinologists in the United States. The first concern was that Kabi would begin to purchase pituitaries in the U.S., which would quickly undermine the NPA, which relied on a donation system like blood transfusion. As the number of autopsies continued to shrink, would pathologists sell pituitaries to a higher bidder? The second offense was Kabi-Pharmacias marketing campaign, which was directed at primary care physicians under the slogan, “Now, you determine the need,” implying that the services of a specialist were not needed for growth hormone treatment anymore and that any short child might be a candidate for treatment. Although the Crescormon controversy in the U.S. is long forgotten, Kabis pituitary purchase program continued to generate scandal in Europe as recently as 2000.
Recombinant human growth hormone (rHGH)
In 1981, the new American corporation Genentech, after collaboration with Kabi, developed and started trials of recombinant human growth hormone (rHGH) made by a new technology (recombinant DNA) in which human genes were inserted into bacteria so that they could produce unlimited amounts of the protein. Because this was new technology, approval was deferred as lengthy safety trials continued over the next four years.In 1985, four young adults in the U.S. having received NPA growth hormone in the 1960s developed CJD (Creutzfeldt–Jakob disease). The connection was recognized within a few months, and use of human pituitary GH rapidly ceased. Between 1985 and 2003, a total of 26 cases of CJD occurred in adults having received NPA GH before 1977 (out of 7700), comparable numbers of cases occurred around the world. By 2003 there had been no cases in people who received only GH purified by the improved 1977 methods.Discontinuation of human cadaver growth hormone led to rapid Food and Drug Administration approval of Genentechs recombinant human growth hormone, which was introduced in 1985 as Protropin in the United States. Although this previously scarce commodity was suddenly available in "bucketfuls", the price of treatment (US$10,000–30,000 per year) was the highest at the time. Genentech justified it by the prolonged research and development investment, orphan drug status, and a pioneering post-marketing surveillance registry for tracking safety and effectiveness (National Cooperative Growth Study).Within a few years, GH treatment had become more common and competitors entered the market. Eli Lilly launched a competing natural sequence growth hormone (Humatrope). Pharmacia (formerly Kabi, now Pfizer) introduced Genotropin. Novo Nordisk introduced Norditropin. Serono (now EMD Serono) introduced Saizen and Serostim. Ferring has introduced Zomacton. Genentech eventually introduced another HGH product, Nutropin, and stopped making Protropin in 2004. Price competition had begun. Teva, which is primarily a generics company, has introduced Tev-tropin. Chinese companies have entered the market as well and have introduced more pricing competition: NeoGenica BioScience Ltd. introduced Hypertropin, GeneScience introduced Jintropin, Anhui Anke Biotechnology introduced Ansomone, Shanghai United Kefei Biotechnology introduced Kefei HGH, and Hygene BioPharm introduced Hygetropin. These are all recombinant human growth hormone products and they have competed with various marketing strategies. Most children with severe deficiency in the developed world are now likely to have access to a pediatric endocrinologist and be diagnosed and offered treatment.Pediatric endocrinology became a recognizable specialty in the 1950s, but did not reach board status in the U.S. until the late 1970s. Even 10 years later, as a cognitive, procedureless specialty dealing with mostly rare diseases, it was one of the smallest, lowest-paid, and more obscure of the medical specialities. Pediatric endocrinologists were the only physicians interested in the arcana of GH metabolism and childrens growth, but their previously academic arguments took on new practical significance with major financial implications.
The major scientific arguments dated back to the days of GH scarcity:
Everyone agrees on the nature and diagnosis of severe GH deficiency, but what are the edges and variations?
How should marked constitutional delay be distinguished from partial GH deficiency?
To what extent is "normal shortness" a matter of short children naturally making less growth hormone?
Can a child make GH in response to a stimulation test but fail to make enough in "daily life" to grow normally?
If a stimulation test is used to define deficiency, what GH cutoff should be used to define normal?It was the ethical questions that were new. Is GH not a wise use of finite healthcare resources, or is the physicians primary responsibility to the patient? If GH is given to most extremely short children to make them taller, will the definition of “extremely short” simply rise, negating the expected social benefit? If GH is given to short children whose parents can afford it, will shortness become a permanent mark of lower social origins? More of these issues are outlined in the ethics section. Whole meetings were devoted to these questions; pediatric endocrinology had become a specialty with its own bioethics issues.
Despite the price, the 1990s became an era of experimentation to see what else growth hormone could help. The medical literature of the decade contains hundreds of reports of small trials of GH use in nearly every type of growth failure and shortness imaginable. In most cases, the growth responses were modest. For conditions with a large enough potential market, more rigorous trials were sponsored by pharmaceutical companies that were making growth hormone to achieve approval to market for those specific indications. Turner syndrome and chronic kidney failure were the first of these “nonGH-deficient causes of shortness” to receive FDA approval for GH treatment, and Prader-Willi syndrome and intrauterine growth retardation followed. Similar expansion of use occurred in Europe.One obvious potential market was adult GH deficiency. By the mid-1990s, several GH companies had sponsored or publicized research into the quality of life of adults with severe GH deficiency. Most were people having been treated with GH in childhood for severe deficiency. Although the injections are painless, many of them had been happy to leave injections behind as they reached final heights in the low-normal range. However, as adults in their 30s and 40s, these people, who had been children with growth hormone deficiency, were now adults with growth hormone deficiency and had more than their share of common adult problems: reduced physical, mental, and social energy, excess adipose and diminished muscle, diminished libido, poor bone density, higher cholesterol levels, and higher rates of cardiovascular disease. Research trials soon confirmed that a few months of GH could improve nearly all of these parameters. However, despite marketing efforts, most GH-deficient adults remain untreated.
Though GH use was slow to be accepted among adults with GH deficiency, similar research to see if GH treatment could slow or reverse some of the similar effects of aging attracted much public interest. The most publicized trial was reported by Daniel Rudman in 1990. As with other types of hormone supplementation for aging (testosterone, estrogen, DHEA), confirmation of benefit and accurate understanding of risks has been only slowly evolving.
In 1997, Ronald Klatz of the American Academy of Anti-Aging Medicine published Grow Young With HGH: The Amazing Medically Proven Plan To Reverse the Effects Of Aging, an uncritical touting of GH as the answer to aging. This time, the internet amplified the proposition and spawned a hundred frauds and scams. However, their adoption of the "HGH" term has provided an easy way to distinguish the hype from the evidence. In 2003, growth hormone hit the news again, when the US FDA granted Eli Lilly approval to market Humatrope for the treatment of idiopathic short stature. The indication was controversial for several reasons, the primary one being the difficulty in defining extreme shortness with normal test results as a disease rather than the extreme end of the normal height rangeRecombinant growth hormone available in the U.S. (and their manufacturers) include Nutropin (Genentech), Humatrope (Eli Lilly and Company), Genotropin (Pfizer), Norditropin (Novo Nordisk), Tev-Tropin (Teva) and Saizen (Merck Serono). The products are nearly identical in composition, efficacy, and cost, varying primarily in the formulations and delivery devices.Somapacitan-beco (Sogroya) is first once-per week subcutaneous human growth hormone (hGH) therapy that was approved in the United States. It was approved for medical use in the United States in August 2020.
Terminology
Growth hormone (GH l) is also called somatotropin (British: somatotrophin). The human form of growth hormone is known as human growth hormone, or hGH (ovine growth hormone, or sheep growth hormone, is abbreviated oGH). GH can refer either to the natural hormone produced by the pituitary (somatotropin), or biosynthetic GH for therapy.Cadaver growth hormone is the term for GH extracted from the pituitary glands of human cadavers between 1960 and 1985 for therapy of deficient children. In the U.S., cadaver GH, also referred to as NPA growth hormone, was provided by the National Pituitary Agency, and by other national programs and commercial firms as well. In 1985 it was associated with the development of Creutzfeldt–Jakob disease, and was withdrawn from use.RHGH (rHGH, rhGH) refers to recombinant human growth hormone, that is, somatropin (INN). Its amino acid sequence is identical with that of endogenous human GH.It is coincidental that RHGH also refers to rhesus monkey GH (RhGH), using the accepted naming convention of Rh for rhesus. Rhesus growth hormone was never used by physicians to treat human patients, but rhesus GH was part of the lore of the underground anabolic steroid community in those years, and fraudulent versions may have been bought and sold in gyms.met-GH refers to methionyl–growth hormone, that is, somatrem (INN). This was the first recombinant GH product marketed (trade name Protropin by Genentech). It had the same amino acid sequence as human GH with an extra methionine at the end of the chain to facilitate the manufacturing process. It was discontinued in 2004.rBST refers to recombinant bovine somatotropin (cow growth hormone), or recombinant bovine GH (rbGH, RBGH).
References
== Further reading == |
Ezetimibe/rosuvastatin | Ezetimibe/rosuvastatin, sold under the brand name Ridutrin among others, is a combination medication used to treat high cholesterol. In some countries it is sold as a kit or a pack containing two distinct pills. It is also available in the form of a composite package containing the two separate pills.The combination was approved for medical use in the United States in March 2021.
Medical uses
Ezetimibe/rosuvastatin is indicated as an adjunct to diet in people with primary non-familial hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C); and alone or as an adjunct to other LDL-C-lowering therapies in people with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C.
References
External links
"Ridutrin (rosuvastatin zinc/ezetimibe) Public Assessment Report Scientific discussion" (PDF). NL/H/3017/001-003/DC. |
Claravis | Claravis may refer to:
A brand name for the drug isotretinoin
The genus of the blue ground dove |
Avalglucosidase alfa | Avalglucosidase alfa, sold under the brand name Nexviazyme, is an enzyme replacement therapy medication used for the treatment of glycogen storage disease type II (Pompe disease).The most common side effects include headache, fatigue, diarrhea, nausea, joint pain (arthralgia), dizziness, muscle pain (myalgia), itching (pruritus), vomiting, difficulty breathing (dyspnea), skin redness (erythema), feeling of "pins and needles" (paresthesia) and skin welts (urticaria).People with Pompe disease have an enzyme deficiency that leads to the accumulation of a complex sugar, called glycogen, in skeletal and heart muscles, which causes muscle weakness and premature death from respiratory or heart failure.Avalglucosidase alfa was approved for medical use in the United States in August 2021, and in the European Union in June 2022.
Medical uses
Avalglucosidase alfa is indicated for the treatment of people aged one year and older with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency).
Mechanism of action
Avalglucosidase alfa is composed of the human GAA enzyme that is conjugated with a couple of bis-mannose-6-phosphate (bis-M6P) tetra-mannose glycans. The bis-MGP of avalglucosidase alpha binds to the cation-independent mannose-6-phosphate receptor which is located on the skeletal muscles. Once the molecule binds to the receptor, the drug enters the cell. The drug then enters the lysosomes of the cell. Within the lysosome of the cell, the drugs undergoes cleavage proteolytically and then acts as an enzyme.
Pharmacokinetics
The volume of distribution of avalglucosidase alfa was 3.4 L in patients who had Pompe disease of a late onset. The average half-life of avalglucosidase alfa was 1.6 hours, measured in patients with late stage Pompe disease. There is little information availible on the metabolism of the avalglucosidase alfa. The protein portion of the drug however does break down into small peptides via catabolic pathways. The clearance of the drug is 0.9 L/hour in patients that exhibited late-stage Pompe disease.
Blackbox warnings
Avalglucosidase alfa has a blackbox warning for hypersensitivity, infusion-related reactions, and cardiorespiratory failure.
Society and culture
Legal status
In July 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Nexviadyme, intended for the treatment of glycogen storage disease type II (Pompe disease). The applicant for this medicinal product is Genzyme Europe BV. In August 2021, Genzyme Europe BV requested a re-examination. Avalglucosidase alfa was approved for medical use in the European Union in June 2022.The U.S. Food and Drug Administration (FDA) granted the application for avalglucosidase alfa fast track, priority review, breakthrough therapy, and orphan drug designations. The FDA granted the approval of Nexviazyme to Genzyme Corporation.
Names
Avalglucosidase alfa is the international nonproprietary name (INN).
References
External links
"Avalglucosidase alfa". Drug Information Portal. U.S. National Library of Medicine. |
Desmopressin | Desmopressin, sold under the trade name DDAVP among others, is a medication used to treat diabetes insipidus, bedwetting, hemophilia A, von Willebrand disease, and high blood urea levels. In hemophilia A and von Willebrand disease, it should only be used for mild to moderate cases. It may be given in the nose, by injection into a vein, by mouth, or under the tongue.Common side effects include headaches, diarrhea, and low blood sodium. The low blood sodium that results may cause seizures. It should not be used in people with significant kidney problems or low blood sodium. It appears to be safe to use during pregnancy. It is a synthetic analogue of vasopressin, the hormone that plays roles in the control of the body’s osmotic balance, blood pressure regulation, kidney function, and reduction of urine production.Desmopressin was approved for medical use in the United States in 1978. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication.
Medical uses
Bed wetting
Desmopressin is used to treat nocturnal enuresis (bedwetting). It is usually prescribed in the form of desmopressin acetate, by mouth. Children taking DDAVP have 2.2 fewer wet nights per week and are 4.5 times more likely to sleep without disruption compared with placebo.
Nighttime urination
In 2017, the FDA approved Desmopressin has some benefit for adults who have problems with night time urination (known as nocturia).
Bleeding disorders
Desmopressin (DDAVP) is usually the first line treatment for mild to moderate type 1 von Willebrand disease. It is not recommended in severe disease or in those with abnormal factor VIII. Usefulness in type 2A, 2M, or 2N von Willebrand disease is variable. Generally not recommended in 2B and type 3 von Willebrand disease.Desmopressin is only recommended in mild hemophilia A. It may be used both for bleeding due to trauma or to try to prevent bleeding due to surgery. It is not effective in the treatment of hemophilia B (factor IX deficiency) or severe hemophilia A. May also be used in uremia induced bleeding.
Diabetes insipidus
Desmopressin is used in the treatment of central diabetes insipidus (DI) as a replacement for endogenous antidiuretic hormone (ADH) that is in insufficient quantity due to decreased or non-existent secretion or production of ADH by the posterior pituitary or hypothalamus, respectively. It is also used in the diagnostic workup for diabetes insipidus, in order to distinguish central from DI due to the kidneys. Desmopressin is not effective at treating nephrogenic DI, thus a positive response is generally indicative of central DI.
Side effects
headaches
facial flushing
nausea
hyponatremia
seizuresUS drug regulators added warning to the nasal sprays after two people died and fifty-nine other people had seizures. This occurred due to hyponatremia, a deficit of the bodys sodium levels, and the nasal spray is no longer approved for use in children in the United States. However, US drug regulators have said that desmopressin tablets can still be considered safe for treatment of nocturnal enuresis in children as long as the person is otherwise healthy.
Patients must stop taking desmopressin if they develop severe vomiting and diarrhea, fever, the flu, or severe cold. Patients should also be very cautious about taking desmopressin during hot weather conditions or following strenuous exercise, as these conditions can place stress on the bodys electrolyte and water balance.
A body needs to maintain a balance of water and (sodium). If sodium levels become too low (hyponatremia) – either as a result of increased water take-up or reduced salt levels – a person may have seizures and, in extreme cases, may die.
Mechanism of action
Desmopressin works by limiting the amount of water that is eliminated in the urine; that is, it is an antidiuretic. It works at the level of the renal collecting duct by binding to V2 receptors, which signal for the translocation of aquaporin channels via cytosolic vesicles to the apical membrane of the collecting duct. The presence of these aquaporin channels in the distal nephron causes increasing water reabsorption from the urine, which becomes passively re-distributed from the nephron to systemic circulation by way of basolateral membrane channels. Desmopressin also stimulates release of von Willebrand factor from endothelial cells by acting on the V2 receptor. It also increases endogenous levels of factor VIII, making it useful in the treatment of hemophilia A.Desmopressin is degraded more slowly than recombinant vasopressin, and requires less frequent administration. In addition, it has little effect on blood pressure, while vasopressin may cause arterial hypertension. Vasopressin stimulates the release of ACTH, which indirectly increases responsiveness of alpha-1 receptor in blood vessel smooth muscle, increasing vessel tone and blood pressure. Several studies have shown that Desmopressin does not stimulate ACTH release (except in Cushings Disease), and therefore does not directly raise blood pressure, however, one study showed that it stimulates ACTH release in over 50% of healthy subjects. Additionally, desmopressin is able to enhance ACTH and cortisol release in normal subjects following oCRH administration, but not in patients with anorexia nervosa.
Chemistry
Desmopressin (1-deamino-8-D-arginine vasopressin) is a synthetic form of the normal human hormone arginine vasopressin (the antidiuretic hormone, or ADH), a peptide containing nine amino acids.
Compared to vasopressin, desmopressins first amino acid has been deaminated, and the arginine at the eighth position is in the dextro rather than the levo form (see stereochemistry).
References
Further reading
Leissinger, C; Becton, D; Cornell, C Jr; Cox Gill, J (2001). "High-dose DDAVP intranasal spray (Stimate) for the prevention and treatment of bleeding in patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease and symptomatic carriers of haemophilia A.". Haemophilia. 7 (3): 258–66. doi:10.1046/j.1365-2516.2001.00500.x. PMID 11380629. S2CID 20472310.
External links
"Desmopressin". Drug Information Portal. U.S. National Library of Medicine. |
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