page_title
stringlengths 1
91
| page_text
stringlengths 0
34.2k
|
|---|---|
Amethyst | Amethyst is a violet variety of quartz. The name comes from the Koine Greek αμέθυστος amethystos from α- a-, "not" and μεθύσκω (Ancient Greek) methysko / μεθώ metho (Modern Greek), "intoxicate", a reference to the belief that the stone protected its owner from drunkenness. Ancient Greeks wore amethyst and carved drinking vessels from it in the belief that it would prevent intoxication.
Amethyst, a semiprecious stone, is often used in jewelry and is the traditional birthstone for February.
Structure
Amethyst is a purple variety of quartz (SiO2) and owes its violet color to irradiation, impurities of iron and in some cases other transition metals, and the presence of other trace elements, which result in complex crystal lattice substitutions. The hardness of the mineral is the same as quartz, thus making it suitable for use in jewelry.
Hue and tone
Amethyst occurs in primary hues from a light lavender or pale violet, to a deep purple. Amethyst may exhibit one or both secondary hues, red and blue. High quality amethyst can be found in Siberia, Sri Lanka, Brazil, Uruguay, and the Far East. The ideal grade is called "Deep Siberian" and has a primary purple hue of around 75–80%, with 15–20% blue and (depending on the light source) red secondary hues. ‘Rose de France’ is defined by its markedly light shade of the purple, reminiscent of a lavender/lilac shade. These pale colors were once considered undesirable, but have recently become popular due to intensive marketing.Green quartz is sometimes incorrectly called green amethyst, which is a misnomer and not an appropriate name for the material, as the proper terminology is prasiolite. Other names for green quartz are vermarine or lime citrine.
Amethyst frequently shows color zoning, with the most intense color typically found at the crystal terminations. It is the most prized variety of quartz. One of a gem cutter’s tasks is to make a finished product with even color. Sometimes, only a thin layer of a natural, uncut amethyst is violet colored, or the color is very uneven. The uncut gem may have only a small portion that is suitable for faceting.The color of amethyst has been demonstrated to result from substitution by irradiation of trivalent iron (Fe3+) for silicon in the structure, in the presence of trace elements of large ionic radius, and to a certain extent, the amethyst color can naturally result from displacement of transition elements even if the iron concentration is low. Natural amethyst is dichroic in reddish violet and bluish violet, but when heated, turns yellow-orange, yellow-brown, or dark brownish and may resemble citrine, but loses its dichroism, unlike genuine citrine. When partially heated, amethyst can result in ametrine.
Amethyst can fade in tone if overexposed to light sources and can be artificially darkened with adequate irradiation. It does not fluoresce under either short-wave or long-wave UV light.
Geographic distribution
Amethyst is found in many locations around the world. Between 2000 and 2010, the greatest production was from Marabá and Pau dArco, Pará, and the Paraná Basin, Rio Grande do Sul, Brazil; Sandoval, Santa Cruz, Bolivia; Artigas, Uruguay; Kalomo, Zambia; and Thunder Bay, Ontario. Lesser amounts are found in many other locations in Africa, Brazil, Spain, Argentina, Russia, Afghanistan, South Korea, Mexico, and the United States.
Amethyst is produced in abundance in the state of Rio Grande do Sul in Brazil where it occurs in large geodes within volcanic rocks. Many of the hollow agates of southwestern Brazil and Uruguay contain a crop of amethyst crystals in the interior. Artigas, Uruguay and neighboring Brazilian state Rio Grande do Sul are large world producers, with lesser quantities mined in Minas Gerais and Bahia states.
Amethyst is also found and mined in South Korea. The large opencast amethyst vein at Maissau, Lower Austria, was historically important, but is no longer included among significant producers. Much fine amethyst comes from Russia, especially near Mursinka in the Ekaterinburg district, where it occurs in drusy cavities in granitic rocks. Amethyst was historically mined in many localities in south India, though these are no longer significant producers. One of the largest global amethyst producers is Zambia in southern Africa with an annual production of about 1000 tons.Amethyst occurs at many localities in the United States. The most important production is at Four Peaks, Gila and Maricopa Counties, Arizona, and Jacksons Crossroads, Wilkes County, Georgia.Smaller occurrences have been reported in the Red Feather Lakes, near Fort Collins, Colorado; Amethyst Mountain, Texas; Yellowstone National Park; Delaware County, Pennsylvania; Haywood County, North Carolina; Deer Hill and Stow, Maine and in the Lake Superior region of Minnesota, Wisconsin , and Michigan.Amethyst is relatively common in the Canadian provinces of Ontario and Nova Scotia. The largest amethyst mine in North America is located in Thunder Bay, Ontario.Amethyst is the official state gemstone of South Carolina. Several South Carolina amethysts are on display at the Smithsonian Museum of Natural History.
History
Amethyst was used as a gemstone by the ancient Egyptians and was largely employed in antiquity for intaglio engraved gems.The Greeks believed amethyst gems could prevent intoxication, while medieval European soldiers wore amethyst amulets as protection in battle in the belief that amethysts heal people and keep them cool-headed. Beads of amethyst were found in Anglo-Saxon graves in England. Anglican bishops wear an episcopal ring often set with an amethyst, an allusion to the description of the Apostles as "not drunk" at Pentecost in Acts 2:15.A large geode, or "amethyst-grotto", from near Santa Cruz in southern Brazil was presented at a 1902 exhibition in Düsseldorf, Germany.The meaning of amethyst varies from time to time and culture, which is why amethyst has different meanings in Feng Shui and focuses on increasing wealth. In ancient China, it was also used as a powerful tool to remove negative energies and drive away the hazards of daily life.
Synthetic amethyst
Synthetic (laboratory-grown) amethyst is produced by a synthesis method called hydrothermal growth, which grows the crystals inside a high-pressure autoclave.
Synthetic amethyst is made to imitate the best quality amethyst. Its chemical and physical properties are the same as that of natural amethyst and it can not be differentiated with absolute certainty without advanced gemmological testing (which is often cost-prohibitive). One test based on "Brazil law twinning" (a form of quartz twinning where right and left hand quartz structures are combined in a single crystal) can be used to identify most synthetic amethyst rather easily. Synthesizing twinned amethyst is possible, but this type is not available in large quantities in the market.Treated amethyst is produced by gamma ray, X-ray, or electron-beam irradiation of clear quartz (rock crystal), which has been first doped with ferric impurities. Exposure to heat partially cancels the irradiation effects and amethyst generally becomes yellow or even green. Much of the citrine, cairngorm, or yellow quartz of jewelry is said to be merely "burnt amethyst".
Cultural history
Ancient Greece
The Greek word "amethystos" may be translated as "not drunken", from Greek a-, "not" + methustos, "intoxicated". Amethyst was considered to be a strong antidote against drunkenness, which is why wine goblets were often carved from it. In his poem "LAmethyste, ou les Amours de Bacchus et dAmethyste" (Amethyst or the loves of Bacchus and Amethyste), the French poet Remy Belleau (1528–1577) invented a myth in which Bacchus, the god of intoxication, of wine, and grapes was pursuing a maiden named Amethyste, who refused his affections. Amethyste prayed to the gods to remain chaste, a prayer which the chaste goddess Diana answered, transforming her into a white stone. Humbled by Amethystes desire to remain chaste, Bacchus poured wine over the stone as an offering, dyeing the crystals purple.Variations of the story include that Dionysus had been insulted by a mortal and swore to slay the next mortal who crossed his path, creating fierce tigers to carry out his wrath. The mortal turned out to be a beautiful young woman, Amethystos, who was on her way to pay tribute to Artemis. Her life was spared by Artemis, who transformed the maiden into a statue of pure crystalline quartz to protect her from the brutal claws. Dionysus wept tears of wine in remorse for his action at the sight of the beautiful statue. The gods tears then stained the quartz purple.This myth and its variations are not found in classical sources. However, the goddess Rhea does present Dionysus with an amethyst stone to preserve the wine-drinkers sanity in historical text.
Other cultural associations
Tibetans consider amethyst sacred to the Buddha and make prayer beads from it. Amethyst is considered the birthstone of February. In the Middle Ages, it was considered a symbol of royalty and used to decorate English regalia. In the Old World, amethyst was considered one of the Cardinal gems, in that it was one of the five gemstones considered precious above all others, until large deposits were found in Brazil.
Value
Until the 18th century, amethyst was included in the cardinal, or most valuable, gemstones (along with diamond, sapphire, ruby, and emerald), but since the discovery of extensive deposits in locations such as Brazil, it has lost most of its value. It is now considered a semiprecious stone.Collectors look for depth of color; possibly with red flashes if cut conventionally. As amethyst is readily available in large structures, the value of the gem is not primarily defined by carat weight. This is different from most gemstones, since the carat weight typically exponentially increases the value of the stone. The biggest factor in the value of amethyst is the color displayed.The highest-grade amethyst (called "Deep Russian") is exceptionally rare. When one is found, its value is dependent on the demand of collectors. The highest-grade sapphires or rubies are still orders of magnitude more expensive than amethyst.
Handling and care
The most suitable setting for gem amethyst is a prong or a bezel setting. The channel method must be used with caution.Amethyst has a good hardness, and handling it with proper care will prevent any damage to the stone. Amethyst is sensitive to strong heat and may lose or change its colour when exposed to prolonged heat or light. Polishing the stone or cleaning it by ultrasonic or steamer must be done with caution.
See also
Ametrine
List of minerals
Specimen Ridge Minerals portal
References
Kostov, R. I. 1992. Amethyst. A Geological-Mineralogical and Gemmological Essay. Union of Scientists in Bulgaria, Sofia, 249 p. (in Bulgarian with English abstract)
Lieber, W. 1994. Amethyst. Geschichte, Eigenschaften, Fundorte. Christian Weise Verlag, München, 188 S. |
Collagenase | Collagenases are enzymes that break the peptide bonds in collagen. They assist in destroying extracellular structures in the pathogenesis of bacteria such as Clostridium. They are considered a virulence factor, facilitating the spread of gas gangrene. They normally target the connective tissue in muscle cells and other body organs.Collagen, a key component of the animal extracellular matrix, is made through cleavage of pro-collagen by collagenase once it has been secreted from the cell. This stops large structures from forming inside the cell itself.
In addition to being produced by some bacteria, collagenase can be made by the body as part of its normal immune response. This production is induced by cytokines, which stimulate cells such as fibroblasts and osteoblasts, and can cause indirect tissue damage.
Therapeutic uses
Collagenases have been approved for medical uses for:
treatment of Dupuytrens contracture and Peyronies disease (Xiaflex).
wound healing (Santyl)
cellulite (Qwo)
The MEROPS M9 family
This group of metallopeptidases constitutes the MEROPS peptidase family M9, subfamilies M9A and M9B (microbial collagenase, clan MA(E)). The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA and the predicted active site residues for members of this family and thermolysin occur in the motif HEXXH.Microbial collagenases have been identified from bacteria of both the Vibrio and Clostridium genera. Collagenase is used during bacterial attack to degrade the collagen barrier of the host during invasion. Vibrio bacteria are sometimes used in hospitals to remove dead tissue from burns and ulcers. Clostridium histolyticum is a pathogen that causes gas gangrene; nevertheless, the isolated collagenase has been used to treat bed sores. Collagen cleavage occurs at an Xaa+Got in Vibrio bacteria and at Yaa+Gly bonds in Clostridium collagenases.Analysis of the primary structure of the gene product from Clostridium perfringens has revealed that the enzyme is produced with a stretch of 86 residues that contain a putative signal sequence. Within this stretch is found PLGP, an amino acid sequence typical of collagenase substrates. This sequence may thus be implicated in self-processing of the collagenase.Metalloproteases are the most diverse of the seven main types of protease, with more than 50 families identified to date. In these enzymes, a divalent cation, usually zinc, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. The known metal ligands are His, Glu, Asp, or Lys and at least one other residue is required for catalysis, which may play an electrophillic role. Of the known metalloproteases, around half contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as abXHEbbHbc, where a is most often valine or threonine and forms part of the S1 subsite in thermolysin and neprilysin, b is an uncharged residue, and c a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases.
Other uses
Collagenases may be used for tenderizing meat in a manner similar to widely used tenderizers papain, bromelain and ficain.
See also
Matrix metalloproteinase
Gas gangrene
References
External links
Collagenases at the US National Library of Medicine Medical Subject Headings (MeSH) |
Cefoxitin | Cefoxitin is a second-generation cephamycin antibiotic developed by Merck & Co., Inc. from Cephamycin C in the year following its discovery, 1972. It was synthesized in order to create an antibiotic with a broader spectrum. It is often grouped with the second-generation cephalosporins. Cefoxitin requires a prescription and as of 2010 is sold under the brand name Mefoxin by Bioniche Pharma, LLC. The generic version of cefoxitin is known as cefoxitin sodium.
History and discovery
Groups of researchers at Merck and Lilly discovered Cephamycin C while looking at penicillin-producing bacteria. This followed their discovery of erythromycin, another antibiotic. Cephamycin C was the first cephem discovered but while it was highly resistant to several beta-lactamases, as is its derivative cefoxitin, it was almost only effective against Gram negative bacteria. The scientists used chemically modified the compound to give cefoxitin, so titled due to its semi-synthetic nature. This new modification broadened its spectrum to include Gram positive bacteria. More than 300 modifications were made to it and tested on the cephalosporin base with methoxy groups at the 7-alpha position. Yet only cefoxitin retained its previous effectiveness against Gram negative bacteria, developed effectiveness against Gram positive bacteria, and resisted breakdown by beta-lactamase.Cefoxitin, and the cephamycin family as a whole, served as a branching point and impulsed the discovery of more classes of beta-lactams. This is in part due to their primary and early discovery in the broths studied.
Mechanism
Cefoxitin is a beta-lactam antibiotic which binds to penicillin binding proteins, or transpeptidases. By binding to PBPs, cefoxitin prevents the PBPs from forming the cross-linkages between the peptidoglycan layers that make up the bacterial cell wall, thereby interfering with cell wall synthesis. It is a strong beta-lactamase inducer, as are certain other antibiotics (such as imipenem). However, cefoxitin is a better substrate than imipenem for beta-lactamases.
Microbiological resistance
In the presence of cefoxitin, bacteria that make beta-lactamases will increase their production and secretion to cleave the beta lactam ring. As a cephamycin, cefoxitin is highly resistant to hydrolysis by some beta-lactamases, in part due to the presence of the 7-alpha-methoxy functional group (see skeletal formula above).Another more efficient form of resistance to cefoxitin is provided by the mecA gene in bacteria. This gene codes for an alternative penicillin binding protein, PBP2a. This PBP has a lower binding affinity for penicillin-based antibiotics such as cefoxitin and will continue to cross-link the peptidoglycan layers of the cell wall even in the presence of the beta-lactam antibiotics. MRSA, or methicillin-resistant Staphylococcus aureus is a strain that has acquired resistance to cefoxitin via this gene. For the purposes of detecting bacterial strains with the mecC gene, which like mecA codes for a different PBP, cefoxitin is more reliable than oxacillin because mecC does not correlate as strongly with oxacillin resistance.
Spectrum of bacterial susceptibility
Cefoxitins spectrum of in vitro antimicrobial activity includes a broad range of gram-negative and gram-positive bacteria, including anaerobes. It is inactive against most strains of Pseudomonas aeruginosa and many strains of Enterobacter cloacae. Staphylococci that are resistant to methicillin and oxacillin should also be considered clinically resistant to cefoxitin even if they test susceptible by in vitro methods.Major bacterial strains susceptible to cefoxitin include:
methicillin-susceptible Staphylococcus aureus
Streptococcus sp.
E. coli
Salmonella sp.
Proteus vulgaris
Flavobacterium sp.
Klebsiella sp.Major bacteria resistant to cefoxitin include:
methicillin-resistant Staphylococcus aureus
Enterococci
Listeria monocytogenes
Enterobacter sp.
Bacteroides sp.
Replacement and substitution
In a 2005 study, Fernandes et al. determined that cefoxitin serves as an appropriate replacement for methicillin in determining if some bacteria display methicillin resistance. Likewise, Funsun et al. found in a 2009 study that cefoxitin disk assays correctly identified all 60 mecA-positive Staphylococcus aureus, or MRSA isolates, to be resistant to cefoxitin.Due, in part, to the unavailability of methicillin in the United States, cefoxitin has replaced methicillin for disk diffusion tests, which determine the sensitivity of a bacterial specimen to a given antibiotic. Cefoxitin also yields more accurate results for disk diffusion tests. Interpretive criteria for determining susceptibility to cefoxitin via disk diffusion are greater than or equal to 22mm resulting in a "susceptible" result for Staphylococcus aureus and greater than or equal to 25mm for coagulase-negative staphylococci to be considered susceptible.The following are susceptibility data for several medically significant microorganisms, measured by minimum inhibitory concentration, which is an alternative, liquid medium test for susceptibility.
Escherichia coli: 0.2 μg/ml – 64 μg/ml
Haemophilus influenzae: 0.5 μg/ml – 12.5 μg/ml
Streptococcus pneumoniae: 0.2 μg/ml – 1 μg/ml
Uses in medicine
Cefoxitin is sold in three major IV doses, 1g, 2g, and 10g. It is usually given to adults every six to eight hours in 1g or 2g doses. Cefoxitin may interfere with tests detecting urine glucose and result in a false positive. As with any antibiotic, it should not be given to patients who are allergic to it.Cefoxitin is used to treat:
Skin infections, primarily due to Staphylococcus
Urinary tract infections
Bronchitis
Tonsillitis
Ear infections
Bacterial pneumonia
Sepsis
Bone and joint infections
Abdominal infections and abscesses
Perineum injuries
Pelvic inflammatory disease
Gonorrhea
Infections caused by susceptible bacteria mentioned earlierCefoxitin has many other uses; it may be given prior to surgery to prevent the development of surgical wound infections, and when used in third and fourth degree perineal injuries in women after giving vaginal birth, cefoxitin decreases infection rate at two and six weeks. However, the earlier and more times a child is exposed to cefoxitin, as with early and multiple exposure to many antibiotics, the greater the likelihood of developing inflammatory bowel disease later in life. This may be due in part to a decreased variety of microorganisms in the digestive system.It is also used to treat pelvic inflammatory disease, because it is a broad spectrum antibiotic. For outpatient treatment, oral antibiotics or those with less frequent dosing may be prescribed. As an effective alternative to penicilin and spectinomycin, and replacement for methicillin, cefoxitin is used to treat gonorrhea in both men and women with few side effects.
Side effects
Side effects for cefoxitin are regarded as mild. Common side effects include:
local tenderness or pain at the site of injection
skin color change, mild diarrhea
mild nausea
headache
loss of appetite
vaginal discharge and itching
swelling of feet or legs.While cefoxitin has not been associated with alcohol incompatibility like other members of the second generation cephalosporins class, it has been with a higher risk of coagulopathy, a bleeding disorder.This is not a comprehensive list and not intended to provide medical advice. If any of the previous side effects are severe, or if an allergic reaction takes place immediately contact your doctor.
Notable drug interactions
Contraindications
A contraindication means that the drug in question should not be used under particular circumstances. For cefoxitin, this includes patients who are hypersensitive to cephalosporin antibiotics.Patients with colitis, kidney disease, or liver disease are also advised not to take cefoxitin. However, some drug databases will considers the diseases means for caution rather than contraindications.
Major or Severe
Aside from the above-mentioned contraindications and diseases which require monitoring by a doctor, the live cholera and live typhoid vaccines are known to have a severe interaction with cefoxitin.Individuals on a low sodium diet, undergoing dialysis, or who have experienced seizures, particularly following antibiotic therapy, should also consult their physician prior to taking cefoxitin.
Moderate
Only take additional antibiotics, anticoagulants and blood thinners under doctor supervision. Cefoxitin may decrease the effectiveness of hormonal birth control. This increases the risk for pregnancy and a medical consult will help determine whether backup birth control methods should be used.
Minor
Minor drug interactions do not usually require a change in treatment. Your doctor may monitor specific events, such as bleeding, while taking cefoxitin. Two such minor interactions occur between cefoxitin and heparin as well as genistein.
Pharmacodynamic and pharmacokinetic data
Pharmocokinetic and pharmacodynamic data for cefoxitin are, as of 2013, considered limited and outdated. A few relatively recent studies have attempted to remedy that.
One such study was by the Hôpitaux de Paris in collaboration with the French Ministry of Health. However, while the clinical trials were completed in 2015, no study data have been published. The expected results from using cefoxitin over carbapenems, another type of antibiotic with a wider bacterial spectrum, included effective treatment of E. coli produce extended spectrum beta-lactamase, less selective pressure on the GI tract which better maintains balanced flora, and a lower treatment cost.This followed a 2012 French study on the same E. coli strain with CTX-M-15 extended release beta-lactamase. Lepeule et al. determined that in mice, the ideal pharmacodynamic target of fT>MIC=33%, where MIC is the minimum inhibitory concentration, was obtained with 200 mg/kg every four hours. The fT>MIC (%) was increased by 11% when the administration frequency was increased from every four hours to every three hours. This implied that increasing the frequency might yield similar results in humans. The study also found no significant difference between the effectiveness of carbapenems and cefoxitin and suggested that cefoxitin can be used as an alternative treatment for CTX-M producing E. coli to carbapenems such as imipenem and ertapenem.
References
External links
"Cefoxitin". Drug Information Portal. U.S. National Library of Medicine.
"Cefoxitin sodium". Drug Information Portal. U.S. National Library of Medicine. |
Ravulizumab | Ravulizumab, sold under the brand name Ultomiris, is a humanized monoclonal antibody complement inhibitor medication designed for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. It is designed to bind to and prevent the activation of Complement component 5 (C5).Paroxysmal nocturnal hemoglobinuria is characterized by red blood cell destruction, anemia (red blood cells unable to carry enough oxygen to tissues), blood clots, and impaired bone marrow function (not making enough blood cells). In paroxysmal nocturnal hemoglobinuria, proteins known as the complement system, which is part of the immune system, become overactive because of a genetic mutation and start to attack the patients own red blood cells. Ravulizumab, is a monoclonal antibody (a type of protein) designed to attach to the C5 protein, which is part of the complement system. By attaching to the C5 protein, the medicine blocks its effect and thereby reduces the destruction of red blood cells.The most common side effects are upper respiratory tract infection (nose and throat infection), nasopharyngitis (inflammation of the nose and throat) and headache. The most serious side effect is meningococcal infection, a bacterial infection caused by Neisseria meningitidis that can cause meningitis and sepsis.
Medical uses
In the United States, ravulizumab is indicated for the treatment of adults and children one month of age and older with paroxysmal nocturnal hemoglobinuria and for the treatment of adults and children one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).In the European Union, ravulizumab is indicated in the treatment of adults with paroxysmal nocturnal haemoglobinuria:
in people with haemolysis with clinical symptom(s) indicative of high disease activity
in people who are clinically stable after having been treated with eculizumab for at least the past six months.
Names
Ravulizumab is the International Nonproprietary Name (INN).
History
Ravulizumab was developed by Alexion Pharmaceuticals, Inc. It was engineered from eculizumab to have a longer-lasting effect.Ravulizumab was approved by the US Food and Drug Administration (FDA) in December 2018. In April 2019, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the granting of a conditional marketing authorization for ravulizumab. Ravulizumab was approved for medical use in the EU in July 2019.
References
Further reading
Stern RM, Connell NT (2019). "Ravulizumab: a novel C5 inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria". Ther Adv Hematol. 10: 2040620719874728. doi:10.1177/2040620719874728. PMC 6737867. PMID 31534662.
External links
"Ravulizumab". Drug Information Portal. U.S. National Library of Medicine. |
Elagolix/estradiol/norethindrone acetate | Elagolix/estradiol/norethindrone acetate, sold under the brand name Oriahnn, is a fixed-dose combination medication used to treat heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. It contains elagolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist, estradiol, an estrogen, and norethindrone acetate, a progestin. It is taken by mouth. Oriahnn is co-packaged as a combination of elagolix/estradiol/norethindrone acetate capsules with elagolix capsules.The most common side effects include hot flushes (sudden feelings of warmth), headache, fatigue and irregular vaginal bleeding.
Medical uses
Fibroids are benign (non-cancerous) muscle tumors of the uterus that can cause heavy menstrual bleeding, pain, bowel or bladder problems and infertility. Some women may not experience any symptoms, but many do, including heavy bleeding with periods. Fibroids can occur at any age but are most common in women 35 to 49 years of age. They typically resolve after menopause but are a leading reason for hysterectomy (surgical removal of the uterus) in the United States when they cause severe symptoms.Elagolix/estradiol/norethindrone acetate is indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.
Adverse effects
Elagolix/estradiol/norethindrone acetate may cause bone loss over time, and the loss in some women may not be completely recovered after stopping treatment. Because bone loss may increase the risk for fractures, women should not take elagolix/estradiol/norethindrone acetate for more than 24 months.The drug label for the combination includes a boxed warning about the risk of vascular events (strokes) and thrombotic or thromboembolic disorders (blood clots), especially in women at increased risk for these events.
History
Elagolix/estradiol/norethindrone acetate was approved for medical use in the United States in May 2020.The efficacy of elagolix/estradiol/norethindrone acetate was established in two clinical trials in which a total of 591 premenopausal women with heavy menstrual bleeding received the drug or placebo for six months. Heavy menstrual bleeding at baseline was defined as having at least two menstrual cycles with greater than 80 mL (about a third of a cup) of menstrual blood loss (MBL). The primary endpoint was the proportion of women who achieved MBL volume less than 80 mL at the final month and 50% or greater reduction in MBL volume from the start of the study (baseline) to the final month. In the first study, 68.5% of participants who received elagolix/estradiol/norethindrone acetate achieved this endpoint (compared to 8.7% of participants who received placebo). In the second study, 76.5% of participants who received elagolix/estradiol/norethindrone acetate achieved this endpoint (compared to 10.5% of participants who received placebo).The approval of Oriahnn was granted to AbbVie Inc.
References
External links
"Elagolix". Drug Information Portal. U.S. National Library of Medicine.
"Estradiol". Drug Information Portal. U.S. National Library of Medicine.
"Norethindrone acetate". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02654054 for "Efficacy and Safety of Elagolix in Combination With Estradiol/Norethindrone Acetate for the Management of Heavy Menstrual Bleeding Associated With Uterine Fibroids in Premenopausal Women" at ClinicalTrials.gov
Clinical trial number NCT02691494 for "Efficacy and Safety of Elagolix in Combination With Estradiol/Norethindrone Acetate for the Management of Heavy Menstrual Bleeding Associated With Uterine Fibroids in Premenopausal Women (Replicate Study)" at ClinicalTrials.gov |
Benznidazole | Benznidazole is an antiparasitic medication used in the treatment of Chagas disease. While it is highly effective in early disease this decreases in those who have long-term infection. It is the first-line treatment given its moderate side effects compared to nifurtimox. It is taken by mouth.Side effects are fairly common. They include rash, numbness, fever, muscle pain, loss of appetite, and trouble sleeping. Rare side effects include bone marrow suppression which can lead to low blood cell levels. It is not recommended during pregnancy or in people with severe liver or kidney disease. Benznidazole is in the nitroimidazole family of medication and works by the production of free radicals.Benznidazole came into medical use in 1971. It is on the World Health Organizations List of Essential Medicines. As of 2012, Laboratório Farmacêutico do Estado de Pernambuco, a government run pharmaceutical company in Brazil was the only producer.
Medical uses
Benznidazole has a significant activity during the acute phase of Chagas disease, with a success rate of up to 80%. Its curative capabilities during the chronic phase are, however, limited. Some studies have found parasitologic cure (a complete elimination of T. cruzi from the body) in children during the early stage of the chronic phase, but overall failure rate in chronically infected individuals is typically above 80%.Some studies indicate treatment with benznidazole during the chronic phase, even if incapable of producing parasitologic cure because it reduces electrocardiographic changes and delays worsening of the clinical condition of the patient.Benznidazole has proven to be effective in the treatment of reactivated T. cruzi infections caused by immunosuppression, such as in people with AIDS or in those under immunosuppressive therapy related to organ transplants.
Children
Benznidazole can be used in children, with the same 5–7 mg/kg per day weight-based dosing regimen that is used to treat adult infections. A formulation for children up to two years of age is available. It was added to the WHO Essential Medicines List for Children in 2013. Children are found to be at a lower risk of adverse events compared to adults, possibly due to increased hepatic clearance of the drug. The most prevalent adverse effects in children were found to be gastrointestinal, dermatologic, and neurologic in nature. However, the incidence of severe dermatologic and neurologic adverse events is lower in the pediatric population compared to adults. It use for Chagas in children was approved by the FDA in the US in 2017.
Pregnant women
Studies in animals have shown that benznidazole can cross the placenta. Due to its potential for teratogenicity, use of benznidazole in pregnancy is not recommended.
Side effects
Side effects tend to be common and occur more frequently with increased age. The most common adverse reactions associated with benznidazole are allergic dermatitis and peripheral neuropathy. It is reported that up to 30% of people will experience dermatitis when starting treatment. Benznidazole may cause photosensitization of the skin, resulting in rashes. Rashes usually appear within the first 2 weeks of treatment and resolve over time. In rare instances, skin hypersensitivity can result in exfoliative skin eruptions, edema, and fever. Peripheral neuropathy may occur later on in the treatment course and is dose dependent. It is not permanent, but takes time to resolve.Other adverse reactions include anorexia, weight loss, nausea, vomiting, insomnia, and dysguesia, and bone marrow suppression. Gastrointestinal symptoms usually occur during the initial stages of treatment and resolves over time. Bone marrow suppression has been linked to the cumulative dose exposure.
Contraindications
Benznidazole should not be used in people with severe liver and/or kidney disease. Pregnant women should not use benznidazole because it can cross the placenta and cause teratogenicity.
Pharmacology
Mechanism of action
Benznidazole is a nitroimidazole antiparasitic with good activity against acute infection with Trypanosoma cruzi, commonly referred to as Chagas disease. Like other nitroimidazoles, benznidazoles main mechanism of action is to generate radical species which can damage the parasites DNA or cellular machinery. The mechanism by which nitroimidazoles do this seems to depend on whether or not oxygen is present. This is particularly relevant in the case of Trypanosoma species, which are considered facultative anaerobes.Under anaerobic conditions, the nitro group of nitroimidazoles is believed to be reduced by the pyruvate:ferredoxin oxidoreductase complex to create a reactive nitro radical species. The nitro radical can then either engage in other redox reactions directly or spontaneously give rise to a nitrite ion and imidazole radical instead. The initial reduction takes place because nitroimidazoles are better electron acceptors for ferredoxin than the natural substrates. In mammals, the principal mediators of electron transport are NAD+/NADH and NADP+/NADPH, which have a more positive reduction potential and so will not reduce nitroimidazoles to the radical form. This limits the spectrum of activity of nitroimidazoles so that host cells and DNA are not also damaged. This mechanism has been well-established for 5-nitroimidazoles such as metronidazole, but it is unclear if the same mechanism can be expanded to 2-nitroimidazoles (including benznidazole).In the presence of oxygen, by contrast, any radical nitro compounds produced will be rapidly oxidized by molecular oxygen, yielding the original nitroimidazole compound and a superoxide anion in a process known as "futile cycling". In these cases, the generation of superoxide is believed to give rise to other reactive oxygen species. The degree of toxicity or mutagenicity produced by these oxygen radicals depends on cells ability to detoxify superoxide radicals and other reactive oxygen species. In mammals, these radicals can be converted safely to hydrogen peroxide, meaning benznidazole has very limited direct toxicity to human cells. In Trypanosoma species, however, there is a reduced capacity to detoxify these radicals, which results in damage to the parasites cellular machinery.
Pharmacokinetics
Oral benznidazole has a bioavailability of 92%, with a peak concentration time of 3–4 hours after administration. 5% of the parent drug is excreted unchanged in the urine, which implies that clearance of benznidazole is mainly through metabolism by the liver. Its elimination half-life is 10.5-13.6 hours.
Interactions
Benznidazole and other nitroimidazoles have been shown to decrease the rate of clearance of 5-fluorouracil (including 5-fluorouracil produced from its prodrugs capecitabine, doxifluridine, and tegafur). While co-administration of any of these drugs with benznidazole is not contraindicated, monitoring for 5-fluorouracil toxicity is recommended in the event they are used together.The GLP-1 receptor agonist lixisenatide may slow down the absorption and activity of benznidazole, presumably due to delayed gastric emptying.Because nitroimidazoles can kill Vibrio cholerae cells, use is not recommended within 14 days of receiving a live cholera vaccine.Alcohol consumption can cause a disulfiram like reaction with benznidazole.
References
External links
"Benznidazole". Drug Information Portal. U.S. National Library of Medicine. |
TENEX | TENEX may refer to:
TENEX (operating system)
Techsnabexport, a Russian company specializing in export of nuclear materials
Tenex, a brand name for the medication guanfacine, a sympatholytic used to treat hypertension, ADHD and Anxiety
Tenex, a brand name for .22 LR ammunition manufactured by Eley Limited and widely used in high level competition such as the ISSF World Cup and Olympic Games
10X, an alternative name for superfine powdered sugar or confectioners sugar
10x, internet slang for "thanks"; see wikt:10x
See also
TENEX C shell |
Nateglinide | Nateglinide (INN, trade name Starlix) is a drug for the treatment of type 2 diabetes. Nateglinide was developed by Ajinomoto, a Japanese company and sold by the Swiss pharmaceutical company Novartis.
Nateglinide belongs to the meglitinide class of blood glucose-lowering drugs.
Pharmacology
Nateglinide lowers blood glucose by stimulating the release of insulin from the pancreas. It achieves this by closing ATP-dependent potassium channels in the membrane of the β cells. This depolarizes the β cells and causes voltage-gated calcium channels to open. The resulting calcium influx induces fusion of insulin-containing vesicles with the cell membrane, and insulin secretion occurs.
Contraindications
Nateglinide is contraindicated in patients who:
have known hypersensitivity to the compound or any ingredient in the formulation.
are affected with type 1 (namely insulin-dependent) diabetes mellitus.
are in diabetic ketoacidosis.
Comparisons with other drugs for type 2 diabetes
A study funded by Novo Nordisk, the U.S. distributor for Repaglinide, compared their product with Nateglinide in "A randomized, parallel-group, open-label, multicenter 16-week clinical trial". They concluded that the two were similar, but "repaglinide monotherapy was significantly more effective than nateglinide monotherapy in reducing HbA1c and FPG values after 16 weeks of therapy."
Dosage
Nateglinide is delivered in 60 mg & 120 mg tablet form.
See also
Repaglinide
References
External links
Starlix - website of the manufacturer.
How Nateglinide Works - website of the manufacturer. |
Esketamine | Esketamine, also known as (S)-ketamine or S(+)-ketamine, is the S(+) enantiomer of ketamine, is a dissociative hallucinogen drug used as a general anesthetic and as an antidepressant for treatment of depression. It is sold under the brand names Spravato (for depression), Ketanest (for anesthesia), among others. Esketamine is the active enantiomer of ketamine in terms of NMDA receptor antagonism and is more potent than racemic ketamine.It is specifically used as a therapy for treatment-resistant depression (TRD) and for major depressive disorder (MDD) with co-occurring suicidal ideation or behavior. Its effectiveness for depression is modest and similar to that of other antidepressants. Esketamine is used by infusion into a vein for anesthesia and under direct medical supervision as a nasal spray once or twice weekly for depression.Adverse effects of esketamine include dissociation, dizziness, sedation, nausea, vomiting, vertigo, numbness, anxiety, lethargy, increased blood pressure, and feelings of drunkenness. Less often, esketamine can cause bladder problems. Esketamine acts primarily as a N-methyl-D-aspartate (NMDA) receptor antagonist but also has other actions.In the form of racemic ketamine, esketamine was first synthesized in 1962 and introduced for medical use as an anesthetic in 1970. Enantiopure esketamine was introduced for medical use as an anesthetic in 1997 and as an antidepressant in 2019. It is used as an anesthetic in the European Union and as an antidepressant in the United States and Canada. Due to misuse liability as a dissociative hallucinogen, esketamine is a controlled substance.
Medical uses
Anesthesia
Esketamine is a general anesthetic and is used for similar indications as ketamine. Such uses include induction of anesthesia in high-risk patients such as those with hemorrhagic shock, anaphylactic shock, septic shock, severe bronchospasm, severe hepatic insufficiency, cardiac tamponade, and constrictive pericarditis; anesthesia in caesarian section; use of multiple anesthetics in burns; and as a supplement to regional anesthesia with incomplete nerve blocks.
Depression
Esketamine is approved under the brand name Spravato in the form of a nasal spray added to a conventional antidepressant as a therapy for treatment-resistant depression (TRD) as well as major depressive disorder (MDD) associated with suicidal ideation or behavior in adults in the United States. In the clinical trials that led to approval of esketamine, TRD was defined as MDD with inadequate response to at least two different conventional antidepressants. The nasal spray formulation of esketamine used for depression delivers two sprays containing a total of 28 mg esketamine and doses of 56 mg (2 devices) to 84 mg (3 devices) are used. The recommended dosage of Spravato is 56 mg on day 1, 56 or 84 mg twice per week during weeks 1 to 4, 56 or 84 mg once per week during weeks 5 to 8, and 56 or 84 mg every 2 weeks or once weekly during week 9 and thereafter. Dosing is individualized to the least frequent dosing necessary to maintain response or remission. Spravato is administered under the supervision of a healthcare provider and patients are monitored for at least 2 hours during each treatment session. Due to concerns about sedation, dissociation, and misuse, esketamine is available for treatment of depression only from certified providers through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Spravato REMS.Five clinical studies of esketamine for TRD (TRANSFORM-1, -2, and -3, and SUSTAIN-1 and -2) were submitted to and evaluated by the FDA when approval of esketamine for treatment of TRD was sought by Janssen Pharmaceuticals. Of these five studies, three were short-term (4-week) efficacy studies (the TRANSFORM studies). Two of these three studies (TRANSFORM-1 and -3) did not find a statistically significant antidepressant effect of esketamine relative to placebo. In the one positive short-term efficacy study (TRANSFORM-2), there was a 4.0-point difference between esketamine and placebo on the Montgomery–Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment (P = 0.020). This scale ranges from 0 to 60 and the average score of the participants at the start of the study was about 37.0 in both the esketamine and placebo groups. The total change in score after 4 weeks was –19.8 points in the esketamine group and –15.8 points in the placebo group. This corresponded to a percentage change in MADRS score from baseline of –53.5% with esketamine and –42.4% with placebo (a difference and reduction of depression score of –11.1% potentially attributable to the pharmacological action of esketamine) in these patient samples. Placebo showed 80.0% of the antidepressant effect of esketamine for TRD in this study and hence approximately 20.0% of the antidepressant response was attributable to esketamine. In the two negative short-term efficacy trials that did not reach statistical significance (TRANSFORM-1 and -3), the differences in MADRS reductions between esketamine and placebo were –3.2 (P = 0.088) and –3.6 (P = 0.059) after 4 weeks of treatment.
The 4.0-point additional reduction in MADRS score with esketamine over placebo in the single positive efficacy trial corresponds to less than "minimal improvement" and has been criticized as being below the threshold for clinically meaningful change. A difference of at least 6.5 points was originally suggested by the trial investigators to be a reasonable threshold for clinical significance. In other literature, MADRS reductions have been interpreted as "very much improved" corresponding to 27–28 points, "much improved" to 16–17 points, and "minimally improved" to 7–9 points. It has additionally been argued that the small advantage in scores with esketamine may have been related to an enhanced placebo response in the esketamine group due to functional unblinding caused by the psychoactive effects of esketamine. In other words, it is argued that the study was not truly a double-blind controlled trial. Dissociation was experienced as a side effect by a majority of participants who received esketamine (61–75% with esketamine and 5–12% with placebo; ~7-fold difference) and "severe" dissociation was experienced by 25%. Deblinding and expectancy confounds are problems with studies of hallucinogens for psychiatric indications in general. The FDA normally requires at least two positive short-term efficacy studies for approval of antidepressants, but this requirement was loosened for esketamine and a relapse-prevention trial was allowed to fill the place of the second efficacy trial instead. This is the first time that the FDA is known to have made such an exception and the decision has been criticized as lowering regulatory standards. In the relapse-prevention trial (SUSTAIN-2), the rate of depression relapse was significantly lower with esketamine continued than with it discontinued and replaced with placebo in esketamine-treated stable responders and remitters (51% rate reduction in remitters and 70% reduction in responders).
Esketamine was approved for the treatment of MDD with co-occurring suicidal ideation or behavior on the basis of two short-term (4-week) phase 3 trials (ASPIRE-1 and -2) of esketamine nasal spray added to a conventional antidepressant. The primary efficacy measure was reduction in MADRS total score after 24 hours following the first dose of esketamine. In both trials, MADRS scores were significantly reduced with esketamine relative to placebo at 24 hours. The mean MADRS scores at baseline were 39.4 to 41.3 in all groups and the MADRS reductions at 24 hours were –15.9 and –16.0 with esketamine and –12.0 and –12.2 with placebo, resulting in mean differences between esketamine and placebo of –3.8 and –3.9. The secondary efficacy measure in the trials was change in Clinical Global Impression of Suicidal Severity - Revised (CGI-SS-r) 24 hours after the first dose of esketamine. The CGI-SS-r is a single-item scale with scores ranging from 0 to 6. Esketamine was not significantly effective in reducing suicidality relative to placebo on this measure either at 24 hours or after 25 days. At 24 hours, CGI-SS-r scores were changed by –1.5 with esketamine and –1.3 with placebo, giving a non-significant mean difference between esketamine and placebo of –0.20. Hence, while efficacious in reducing depressive symptoms in people with depression and suicidality, antisuicidal effects of esketamine in such individuals have not been demonstrated.Expectations were initially very high for ketamine and esketamine for treatment of depression based on early small-scale clinical studies, with discovery of the rapid and ostensibly robust antidepressant effects of ketamine described by some authors as "the most important advance in the field of psychiatry in the past half century". According to a 2018 review, ketamine showed more than double the antidepressant effect size over placebo of conventional antidepressants in the treatment of depression based on the preliminary evidence available at the time (Cohens d = 1.3–1.7 for ketamine, Cohens d = 0.8 for midazolam (active placebo), and Cohens d = 0.53–0.81 for conventional antidepressants). However, the efficacy of ketamine/esketamine for depression declined dramatically as studies became larger and more methodologically rigorous. The effectiveness of esketamine for the indication of TRD is described as "modest" and is similar in magnitude to that of other antidepressants for treatment of MDD. The comparative effectiveness of ketamine and esketamine in the treatment of depression has not been adequately characterized. A January 2021 meta-analysis reported that ketamine was similarly effective to esketamine in terms of antidepressant effect size (SMD for depression score of –1.1 vs. –1.2) but more effective than esketamine in terms of response and remission rates (RR = 3.01 vs. RR = 1.38 for response and RR = 3.70 vs. RR = 1.47 for remission). A September 2021 Cochrane review found that ketamine had an effect size (SMD) for depression at 24 hours of –0.87, with very low certainty, and that esketamine had an effect size (SMD) at 24 hours of –0.31, based on moderate-certainty evidence. However, these meta-analyses have involved largely non-directly-comparative studies with dissimilar research designs and patient populations. Only a single clinical trial has directly compared ketamine and esketamine for depression as of May 2021. This study reported similar antidepressant efficacy as well as tolerability and psychotomimetic effects between the two agents. However, the study was small and underpowered, and more research is still needed to better-characterize the comparative antidepressant effects of ketamine and esketamine. Preliminary research suggests that arketamine, the R(−) enantiomer of ketamine, may also have its own independent antidepressant effects and may contribute to the antidepressant efficacy of racemic ketamine, but more research likewise is needed to evaluate this possibility.In February 2019, an outside panel of experts recommended in a 14–2 vote that the FDA approve the nasal spray version of esketamine for TRD, provided that it be given in a clinical setting, with people remaining on site for at least two hours after. The reasoning for this requirement is that trial participants temporarily experienced sedation, visual disturbances, trouble speaking, confusion, numbness, and feelings of dizziness during immediately after. The approval of esketamine for TRD by the FDA was controversial due to limited and mixed evidence of efficacy and safety. In January 2020, esketamine was rejected by the National Health Service (NHS) of Great Britain. The NHS questioned the benefits of the medication for depression and claimed that it was too expensive. People who have been already using esketamine were allowed to complete treatment if their doctors considered this necessary.Spravato debuted to a cost of treatment of US$32,400 per year when it launched in the United States in March 2019. The Institute for Clinical and Economic Review (ICER), which evaluates cost effectiveness of drugs analogously to the National Institute for Health and Care Excellence (NICE) in the United Kingdom, declined to recommend esketamine for depression due to its steep cost and modest efficacy, deeming it not sufficiently cost-effective.Esketamine is the second drug to be approved for TRD by the FDA, following olanzapine/fluoxetine (Symbyax) in 2009. Other agents, like the atypical antipsychotics aripiprazole (Abilify) and quetiapine (Seroquel), have been approved for use in the adjunctive therapy of MDD in people with a partial response to treatment. In a meta-analysis conducted internally by the FDA during its evaluation of esketamine for TRD, the FDA reported a standardized mean difference (SMD) of esketamine for TRD of 0.28 using the three phase 3 short-term efficacy trials conducted by Janssen. This was similar to an SMD of 0.26 for olanzapine/fluoxetine for TRD and lower than SMDs of 0.35 for aripiprazole and 0.40 for quetiapine as adjuncts for MDD. These drugs are less expensive than esketamine and may serve as more affordable alternatives to it for depression with similar effectiveness.
Adverse effects
The most common adverse effects of esketamine for depression (≥5% incidence) include dissociation, dizziness, sedation, nausea, vomiting, vertigo, numbness, anxiety, lethargy, increased blood pressure, and feelings of drunkenness. Long-term use of esketamine has been associated with bladder disease.
Pharmacology
Pharmacodynamics
Esketamine is approximately twice as potent an anesthetic as racemic ketamine.In mice, the rapid antidepressant effect of arketamine was greater and lasted longer than that of esketamine. The usefulness of arketamine over esketamine has been supported by other researchers.Esketamine inhibits dopamine transporters eight times more than arketamine. This increases dopamine activity in the brain. At doses causing the same intensity of effects, esketamine is generally considered to be more pleasant by patients. Patients also generally recover mental function more quickly after being treated with pure esketamine, which may be a result of the fact that it is cleared from their system more quickly. This is however in contradiction with arketamine being devoid of psychotomimetic side effects.Unlike arketamine, esketamine does not bind significantly to sigma receptors. Esketamine increases glucose metabolism in the frontal cortex, while arketamine decreases glucose metabolism in the brain. This difference may be responsible for the fact that esketamine generally has a more dissociative or hallucinogenic effect while arketamine is reportedly more relaxing. However, another study found no difference between racemic ketamine and esketamine on the patients level of vigilance. Interpretation of this finding is complicated by the fact that racemic ketamine is 50% esketamine.
Pharmacokinetics
Esketamine is eliminated from the human body more quickly than arketamine (R(–)-ketamine) or racemic ketamine, although arketamine slows the elimination of esketamine.
History
Esketamine was introduced for medical use as an anesthetic in Germany in 1997, and was subsequently marketed in other countries. In addition to its anesthetic effects, the medication showed properties of being a rapid-acting antidepressant, and was subsequently investigated for use as such. Esketamine received a breakthrough designation from the FDA for treatment-resistant depression (TRD) in 2013 and major depressive disorder (MDD) with accompanying suicidal ideation in 2016. In November 2017, it completed phase III clinical trials for treatment-resistant depression in the United States. Johnson & Johnson filed a Food and Drug Administration (FDA) New Drug Application (NDA) for approval on 4 September 2018; the application was endorsed by an FDA advisory panel on 12 February 2019, and on 5 March 2019, the FDA approved esketamine, in conjunction with an oral antidepressant, for the treatment of depression in adults. In August 2020, it was approved by the U.S. Food and Drug Administration (FDA) with the added indication for the short-term treatment of suicidal thoughts.Since the 1980s, closely associated ketamine has been used as a club drug also known as "Special K" for its trip-inducing side effects.
Society and culture
Names
Esketamine is the generic name of the drug and its INN and BAN, while esketamine hydrochloride is its BANM. It is also known as S(+)-ketamine, (S)-ketamine, or (–)-ketamine ((-)[+] ketamine) as well as by its developmental code name JNJ-54135419.Esketamine is sold under the brand name Spravato for use as an antidepressant and the brand names Eskesia, Ketanest, Ketanest S, Ketanest-S, Keta-S for use as an anesthetic (veterinary), among others.
Availability
Esketamine is marketed as an antidepressant in the United States; and as an anesthetic in the European Union.
Legal status
Esketamine is a Schedule III controlled substance in the United States.
References
External links
"Esketamine". Drug Information Portal. U.S. National Library of Medicine.
"Esketamine hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Factor VIII | Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the F8 gene. Defects in this gene result in hemophilia A, a recessive X-linked coagulation disorder. Factor VIII is produced in liver sinusoidal cells and endothelial cells outside the liver throughout the body. This protein circulates in the bloodstream in an inactive form, bound to another molecule called von Willebrand factor, until an injury that damages blood vessels occurs. In response to injury, coagulation factor VIII is activated and separates from von Willebrand factor. The active protein (sometimes written as coagulation factor VIIIa) interacts with another coagulation factor called factor IX. This interaction sets off a chain of additional chemical reactions that form a blood clot.Factor VIII participates in blood coagulation; it is a cofactor for factor IXa, which, in the presence of Ca2+ and phospholipids, forms a complex that converts factor X to the activated form Xa. The factor VIII gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity.People with high levels of factor VIII are at increased risk for deep vein thrombosis and pulmonary embolism. Copper is a required cofactor for factor VIII and copper deficiency is known to increase the activity of factor VIII.There is a formulation as a medication that is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.
Genetics
Factor VIII was first characterized in 1984 by scientists at Genentech. The gene for factor VIII is located on the X chromosome (Xq28). The gene for factor VIII presents an interesting primary structure, as another gene (F8A1) is embedded in one of its introns.
Structure
Factor VIII protein consists of six domains: A1-A2-B-A3-C1-C2, and is homologous to factor V.
The A domains are homologous to the A domains of the copper-binding protein ceruloplasmin. The C domains belong to the phospholipid-binding discoidin domain family, and the C2 domain mediate membrane binding.Activation of factor VIII to factor VIIIa is done by cleavage and release of the B domain. The protein is now divided to a heavy chain, consisting of the A1-A2 domains, and a light chain, consisting of the A3-C1-C2 domains. Both form non-covalently a complex in a calcium-dependent manner. This complex is the pro-coagulant factor VIIIa.
Physiology
FVIII is a glycoprotein procofactor. Although the primary site of release in humans is ambiguous, it is synthesized and released into the bloodstream by the vascular, glomerular, and tubular endothelium, and the sinusoidal cells of the liver. Hemophilia A has been corrected by liver transplantation. Transplanting hepatocytes was ineffective, but liver endothelial cells were effective.In the blood, it mainly circulates in a stable
noncovalent complex with von Willebrand factor. Upon activation by thrombin (factor IIa), it dissociates from the complex to interact with factor IXa in the coagulation cascade. It is a cofactor to factor IXa in the activation of factor X, which, in turn, with its cofactor factor Va, activates more thrombin. Thrombin cleaves fibrinogen into fibrin which polymerizes and crosslinks (using factor XIII) into a blood clot.
The factor VIII protein has a half-life of 12 hours in the blood stream when stabilized by the von Willebrand factor. No longer protected by vWF, activated FVIII is proteolytically inactivated in the process (most prominently by activated protein C and factor IXa) and quickly cleared from the blood stream.
Factor VIII is not affected by liver disease. In fact, levels usually are elevated in such instances.
Medical use
FVIII concentrated from donated blood plasma, or alternatively recombinant FVIIa can be given to hemophiliacs to restore hemostasis.
Antibody formation to factor VIII can also be a major concern for patients receiving therapy against bleeding; the incidence of these inhibitors is dependent of various factors, including the factor VIII product itself.
Immunostain target
Factor VIII related antigen is used as a target for immunohistochemistry, where endothelial cells, megakaryocytes, platelets and mast cells normally stain positive.
Contamination scandal
In the 1980s, some pharmaceutical companies such as Baxter International and Bayer sparked controversy by continuing to sell contaminated factor VIII after new heat-treated versions were available. Under FDA pressure, unheated product was pulled from US markets, but was sold to Asian, Latin American, and some European countries. The product was tainted with HIV, a concern that had been discussed by Bayer and the U.S. Food and Drug Administration (FDA).In the early 1990s, pharmaceutical companies began to produce recombinant synthesized factor products, which now prevent nearly all forms of disease transmission during replacement therapy.
History
Factor VIII was first discovered in 1937, but it was not until 1979 that its purification by Edward Tuddenham, Frances Rotblat and coworkers led to the molecular identification of the protein.
See also
Ralph Kekwick
Frances Rotblat
Edward Shanbrom
Edward Tuddenham
Ryan White
References
Further reading
External links
GeneReviews/NCBI/NIH/UW entry on Hemophilia A
The Coagulation Factor VIII Protein
Factor+VIII at the US National Library of Medicine Medical Subject Headings (MeSH)
Overview of all the structural information available in the PDB for UniProt: P00451 (Human Factor VIII) at the PDBe-KB. |
Voxelotor | Voxelotor, sold under the brand name Oxbryta, is a medication used for the treatment of sickle cell disease. Developed by Global Blood Therapeutics, voxelotor is the first hemoglobin oxygen-affinity modulator. Voxelotor has been shown to have disease-modifying potential by increasing hemoglobin levels and decreasing hemolysis indicators in sickle cell patients. It has a safe profile in sickle cell patients and healthy volunteers, without any dose-limiting toxicity.In November 2019, voxelotor received accelerated approval in the United States for the treatment of sickle cell disease (SCD) for those twelve years of age and older. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. In December 2021, voxelotor received accelerated approval in the United States for the treatment of sickle cell disease (SCD) for those aged four to eleven years.
Side effects
Common side effects include headache, diarrhea, abdominal pain, nausea, fatigue, rash and pyrexia (fever).
History
Voxelotor was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in November 2019. The FDA granted the application for voxelotor fast track designation and orphan drug designation.The approval of voxelotor was based on the results of a clinical trial with 274 participants with sickle cell disease.The FDA granted the approval of Oxbryta to Global Blood Therapeutics.
Society and culture
Legal status
On 16 December 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 Oxbryta, intended for the treatment of hemolytic anemia due to sickle cell disease. The applicant for this medicinal product is Global Blood Therapeutics Netherlands B.V. Voxelotor (Oxbryta) was approved for medical use in the European Union in February 2022.
References
External links
"Voxelotor". Drug Information Portal. U.S. National Library of Medicine. |
Sodium fluoride | Sodium fluoride (NaF) is an inorganic compound with the formula NaF. It is used in trace amounts in the fluoridation of drinking water, in toothpaste, in metallurgy, and as a flux. It is a colorless or white solid that is readily soluble in water. It is a common source of fluoride in the production of pharmaceuticals and is used to prevent dental cavities.
In 2017, it was the 247th most commonly prescribed medication in the United States, with more than one million prescriptions.
Uses
Dental caries
Fluoride salts are often added to municipal drinking water (as well as to certain food products in some countries) for the purpose of maintaining dental health. The fluoride enhances the strength of teeth by the formation of fluorapatite, a naturally occurring component of tooth enamel. Although sodium fluoride is used to fluoridate water and is the standard by which other water-fluoridation compounds are gauged, hexafluorosilicic acid (H2SiF6) and its salt sodium hexafluorosilicate (Na2SiF6) are more commonly used additives in the United States.
Osteoporosis
Fluoride supplementation has been extensively studied for the treatment of postmenopausal osteoporosis. This supplementation does not appear to be effective; even though sodium fluoride increases bone density, it does not decrease the risk of fractures.
Medical imaging
In medical imaging, fluorine-18-labelled sodium fluoride (USP, sodium fluoride F18) is one of the oldest tracers used in positron emission tomography (PET), having been in use since the 1960s. Relative to conventional bone scintigraphy carried out with gamma cameras or SPECT systems, PET offers more sensitivity and spatial resolution. Fluorine-18 has a half-life of 110 min, which requires it to be used promptly once produced; this logistical limitation hampered its adoption in the face of the more convenient technetium-99m-labelled radiopharmaceuticals. However fluorine-18 is generally considered to be a superior radiopharmaceutical for skeletal imaging. In particular it has a high and rapid bone uptake accompanied by very rapid blood clearance, which results in a high bone-to-background ratio in a short time. Additionally the annihilation photons produced by decay of 18F have a high energy of 511 keV compared to the 140 keV photons of 99mTc.
Chemistry
Sodium fluoride has a variety of specialty chemical applications in synthesis and extractive metallurgy. It reacts with electrophilic chlorides including acyl chlorides, sulfur chlorides, and phosphorus chloride. Like other fluorides, sodium fluoride finds use in desilylation in organic synthesis. Sodium fluoride can be used to produce fluorocarbons via the Finkelstein reaction; this process has the advantage of being simple to perform on a small scale but is rarely used on an industrial scale due to the existence of more effective techniques (e.g. Electrofluorination, Fowler process).
Other uses
Sodium fluoride is used as a cleaning agent (e.g., as a "laundry sour").Sodium fluoride can be used in a nuclear molten salt reactor.
Over a century ago, sodium fluoride was used as a stomach poison for plant-feeding insects. Inorganic fluorides such as fluorosilicates and sodium fluoride complex magnesium ions as magnesium fluorophosphate. They inhibit enzymes such as enolase that require Mg2+ as a prosthetic group. Thus, fluoride poisoning prevents phosphate transfer in oxidative metabolism.
Safety
The lethal dose for a 70 kg (154 lb) human is estimated at 5–10 g.Fluorides, particularly aqueous solutions of sodium fluoride, are rapidly and quite extensively absorbed by the human body.Fluorides interfere with electron transport and calcium metabolism. Calcium is essential for maintaining cardiac membrane potentials and in regulating coagulation. High ingestion of fluoride salts or hydrofluoric acid may result in fatal arrhythmias due to profound hypocalcemia. Chronic over-absorption can cause hardening of bones, calcification of ligaments, and buildup on teeth. Fluoride can cause irritation or corrosion to eyes, skin, and nasal membranes.Sodium fluoride is classed as toxic by both inhalation (of dusts or aerosols) and ingestion. In high enough doses, it has been shown to affect the heart and circulatory system. For occupational exposures, the Occupational Safety and Health Administration and the National Institute for Occupational Safety and Health have established occupational exposure limits at 2.5 mg/m3 over an eight-hour time-weighted average.In the higher doses used to treat osteoporosis, plain sodium fluoride can cause pain in the legs and incomplete stress fractures when the doses are too high; it also irritates the stomach, sometimes so severely as to cause peptic ulcer disease. Slow-release and enteric-coated versions of sodium fluoride do not have significant gastric side effects, and have milder and less frequent complications in the bones. In the lower doses used for water fluoridation, the only clear adverse effect is dental fluorosis, which can alter the appearance of childrens teeth during tooth development; this is mostly mild and is unlikely to represent any real effect on aesthetic appearance or on public health. A chronic fluoride ingestion of 1 ppm of fluoride in drinking water can cause mottling of the teeth (fluorosis) and an exposure of 1.7 ppm will produce mottling in 30%–50% of patients.
Chemical structure
Sodium fluoride is an inorganic ionic compound, dissolving in water to give separated Na+ and F− ions. Like sodium chloride, it crystallizes in a cubic motif where both Na+ and F− occupy octahedral coordination sites; its lattice spacing, approximately 462 pm, is somewhat smaller than that of sodium chloride.
Occurrence
The mineral form of NaF, villiaumite, is moderately rare. It is known from plutonic nepheline syenite rocks.
Production
NaF is prepared by neutralizing hydrofluoric acid or hexafluorosilicic acid (H2SiF6), both byproducts of the reaction of fluorapatite (Ca5(PO4)3F) from phosphate rock during the production of superphosphate fertilizer. Neutralizing agents include sodium hydroxide and sodium carbonate. Alcohols are sometimes used to precipitate the NaF:
HF + NaOH → NaF + H2OFrom solutions containing HF, sodium fluoride precipitates as the bifluoride salt sodium bifluoride (NaHF2). Heating the latter releases HF and gives NaF.
HF + NaF ⇌ NaHF2In a 1986 report, the annual worldwide consumption of NaF was estimated to be several million tonnes.
See also
Cryolite
Fluoride therapy
References
External links
"Sodium fluoride". Drug Information Portal. U.S. National Library of Medicine. |
Kinneret | Kinneret is the Hebrew name of the Sea of Galilee, the largest freshwater lake in Israel.
Other meanings of Kinneret and Kineret include:
Places
Camp Kinneret, a summer camp of Canadian Young Judaea
Kinneret (archaeological site), biblical city which gave the Sea of Galilee its Hebrew name; now Tell el-Oreimeh or Tel Kinrot on the northwestern coast of the lake
Kinneret College, college south of the Sea of Galilee
Kinneret Farm, experimental training farm (1908-1949), now museum
Kinneret Subdistrict, Israel
Kvutzat Kinneret, kibbutz southwest of the Sea of Galilee
Moshavat Kinneret, village (moshava) southwest of the Sea of Galilee
People
Kineret (singer), an Orthodox Jewish recording artist
Kinneret Shiryon (born 1955), Reform rabbi, the first female rabbi in Israel
Other
Kineret (medication), brand name of anakinra; no direct relation to the lake
Kinneret, Israeli song based on Rachel Bluwsteins poem "Perhaps" ("VeUlai")
Kinneret bream or Kinneret bleak, Acanthobrama terraesanctae, fish endemic to the Sea of Galilee and a second lake in Syria
Kinneret Zmora-Bitan Dvir, publishing company, Israel
Operation Kinneret, another name of the Israeli military Operation Olive Leaves
See also
All pages with titles containing Kinneret
All pages with titles containing Kineret |
Trifarotene | Trifarotene, sold under the brand name Aklief, is a medication for the topical treatment of acne vulgaris. It is a retinoid; more specifically, it is a fourth generation selective retinoic acid receptor (RAR)-γ agonist.Trifarotene was granted orphan drug designation for the treatment of congenital ichthyosis by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). It was approved for medical use in the United States in October 2019. In December 2019, its labelling and package leaflet text received a decentralised approval for 16 European countries.
Medical uses
In the United States, trifarotene is indicated for the topical treatment of acne vulgaris in people nine years of age and older.In both Canada and Australia, it is indicated for the topical treatment of acne vulgaris of the face and/or the trunk in people twelve years of age and older.
Society and culture
Legal status
Trifarotene was approved for medical use in the United States in October 2019, in Canada in November 2019, and in Australia in January 2021.
References
External links
"Trifarotene". Drug Information Portal. U.S. National Library of Medicine (NLM). |
Docetaxel | Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-cell lung cancer. It may be used by itself or along with other chemotherapy medication. It is given by slow injection into a vein.Common side effects include hair loss, cytopenia (low blood cell counts), numbness, shortness of breath, nausea, vomiting, and muscle pains. Other severe side effects include allergic reactions and future cancers. Docetaxel induced pneumotoxicity is also a well recognized adverse effect which has to be identified timely and treated after withholding the drug Side effects are more common in people with liver problems. Use during pregnancy may harm the baby. Docetaxel is in the taxane family of medications. It works by disrupting the normal function of microtubules and thereby stopping cell division.Docetaxel was patented in 1986 and approved for medical use in 1995. It is on the World Health Organizations List of Essential Medicines. Docetaxel is available as a generic medication.
Medical uses
Docetaxel is used in the treatment of various cancers, including breast, lung, prostate, gastric, head and neck, and ovarian cancer. Clinical data have shown docetaxel to have cytotoxic activity against breast, colorectal, lung, ovarian, prostate, liver, renal, gastric, and head and neck cancers and melanoma. In hormone-refractory prostate cancer docetaxel improves life expectancy and overall life quality.The optimal dose scheduling of taxanes remains unconfirmed, but most studies find significant mortality benefit following either a three-week or a one-week administration schedule. While a 2010 article in Current Clinical Pharmacology states, "weekly administration has emerged as the optimal schedule," the official docetaxel package insert recommends administration every three weeks.
Outcomes
Treatment with docetaxel increases survival time in people with certain types of cancer. While some clinical trials show median survival times to be increased by approximately only three months, the range of survival time is large. Many people survive beyond five years with treatment from docetaxel, however it is difficult to attribute these findings directly to treatment with docetaxel. Improved median survival time and response indicates that docetaxel slows metastatic cancer progression and can lead to disease-free survival. Conjunctive treatment of prednisone with docetaxel has been shown to lead to improved survival rate as well as improved quality of life and reduction of pain compared with treatments with mitoxantrone.As well as inhibiting mitosis, the presence of docetaxel has been found to lead to the phosphorylation of the oncoprotein bcl-2, which leads to apoptosis of cancer cells that had previously blocked the apoptotic inducing mechanism, leading to tumour regression. Enhanced effects of radiation therapy when combined with docetaxel has been observed in mice. Docetaxel has also been found to have greater cellular uptake and is retained longer intracellularly than paclitaxel allowing docetaxel treatment to be effective with a smaller dose, leading to fewer and less severe adverse effects.
Breast cancer
Docetaxel and paclitaxel have comparable efficacy metastatic breast cancer but paclitaxel has less severe side effects. Additionally, it has been noted that docetaxel is prone to cellular drug resistance via a variety of different mechanisms.
Monitoring and combination use
Docetaxel is administered via a one-hour infusion every three weeks over ten or more cycles. Treatment is given under the supervision of an oncologist. Strict monitoring of blood cell counts, liver function, serum electrolytes, serum creatinine, heart function, oxygen saturation and fluid retention is required detect adverse reactions and toxicity so that treatment can be modified or terminated if necessary.Premedication with corticosteroids is recommended before each administration of docetaxel to reduce fluid retention and hypersensitive reactions. Other medications will often be given to aid pain management and other symptoms. The treatment of breast cancer with doxorubicin and cyclophosphamide is enhanced by adjuvant treatment with docetaxel. Docetaxel is also used in combination with capecitabine, a DNA synthesis inhibitor.
Side effects
Docetaxel is a cytotoxic chemotherapeutic agent. As with all chemotherapy, adverse effects are common, and many side effects have been documented. Because docetaxel is a cell-cycle-specific agent, it is cytotoxic to all dividing cells in the body. This includes tumour cells as well as hair follicles, bone marrow and other germ cells. For this reason, common chemotherapy side effects such as hair loss occur; sometimes this can be permanent. North west France are conducting a survey to establish exactly how many people are affected in this way. Independent studies show it could be as high as 6.3%, which puts it in the common and frequent classification.Haematological adverse effects include neutropenia (95.5%), anaemia (90.4%), febrile neutropenia (11.0%) and thrombocytopenia (8.0%). Deaths due to toxicity accounted for 1.7% of the 2045 patients, and incidence was increased (9.8%) in patients with elevated baseline liver function tests (liver dysfunction).Taxane-induced pneumotoxicity is rare. However, 1–5% of patients taking docetaxel may develop severe pneumotoxicity. Patients may develop exertional breathlessness and desaturation which needs to be detected early. Chest X-Ray may show bilateral opacities and High Resolution CT chest may reveal Organizing Pneumonia (OP) pattern or Non-Specific Organizing Pneumonia (NSIP) pattern or a combination. Docetaxel-induced DPLD is a fatal adverse effect, which can be managed by the cessation of the drug and starting on steroids in adequate doses.Observations of severe side effects in the above 40 phase II and phase III studies were also recorded.
Many more side effects have been reported for conjunctive and adjuvant treatment with docetaxel as well as rare post-marketing events.
Contraindications and patient factors
Docetaxel is contraindicated for use with patients with a baseline neutrophil count less than 1500 cells/µL, a history of severe hypersensitivity reactions to docetaxel or polysorbate 80, severe liver impairment and pregnant or breast-feeding women.Side effects are experienced more frequently by patients of 65 years or older, but dosage is usually not decreased. Kidney failure is thought not to be a significant factor for docetaxel dosage adjustment. Patients with hepatic insufficiency resulting in serum bilirubin greater than the upper limit of normal (ULN) should not be administered docetaxel, though this is not a stated contraindication. Dosage should be reduced by 20% in people who develop grade 3 or 4 diarrhea following exposure to docetaxel, hepatotoxicity defined by liver enzymes at levels greater than five times the ULN, and grade 2 palmer-planter toxicity.Paediatric trials of docetaxel have been limited, and so safety of use in patients under 16 years has not been established.
Pregnancy
Based on the limited data available, docetaxel appears to be safe in pregnancy if administered during the second and third trimesters; however, maternal and fetal risks should be weighed against benefits to determine the appropriate course of action.
As with all chemotherapeutic agents, docetaxel administered to pregnant animals causes a variety of embryofetal toxicities, including death, when given during the period of organogenesis. Yet adequate studies investigating maternal and fetal effects in humans are lacking. One small systematic review that examined the use of taxanes to treat breast cancer in pregnancy showed that, out of 19 patients, only three congenital malformations occurred. Two cases of cerebral ventriculomegaly observed in the study were documented prior to the administration of chemotherapy, suggesting an alternate cause of congenital malformation. The third case involved pyloric stenosis in an infant whose mother received a combination regimen of docetaxel, doxorubicin, cyclophosphamide and paclitaxel; because the fetus was exposed to multiple drugs in utero, it remains difficult to identify docetaxel as the causative teratogenic agent. Further studies are needed to better assess the safety of docetaxel in pregnancy and determine appropriate dosing in pregnant women.
Drug interactions
Drug interactions may be the result of altered pharmacokinetics or pharmacodynamics due to one of the drugs involved. Cisplatin, dexamethasone, doxorubicin, etoposide, and vinblastine are all potentially co-administered with docetaxel and did not modify docetaxel plasma binding in phase II studies. Cisplatin is known to have a complex interaction with some CYPs and has in some events been shown to reduce docetaxel clearance by up to 25%. Anticonvulsants induce some metabolic pathways relevant to docetaxel. CYP450 and CYP3A show increased expression in response to the use of anticonvulsants and the metabolism of docetaxel metabolite M4 is processed by these CYPs. A corresponding increase in clearance of M4 by 25% is observed in patients taking phenytoin and phenobarbital, common anticonvulsants.
Erythromycin, ketoconazole and cyclosporine are CYP3A4 inhibitors and therefore inhibit the metabolic pathway of docetaxel. When used with anticonvulsants, which induce CYP3A4, an increased dose of docetaxel may be required.Pre-treatment with corticosteroids has been used to decrease hypersensitivity reactions and oedema in response to docetaxel and has shown no effect on the pharmacokinetics of docetaxel. The efficacy of docetaxel was improved by treatment with oral capecitabine, and after more than 27 months follow-up the survival benefit has been confirmed. Doxorubicin was combined with docetaxel in one study of 24 patients and resulted in an increased AUC of docetaxel by 50 to 70%, indicating doxorubicin may affect the disposition of docetaxel. Etoposide has also been shown to decrease docetaxel clearance, though patient numbers for this observation have been low.Prednisone given with docetaxel led to improved survival, quality of life and pain management in patients with hormone-refractory prostate cancer.
Chemistry
Docetaxel is of the chemotherapy drug class; taxane, and is a semi-synthetic analogue of paclitaxel (Taxol), an extract from the bark of the rare Pacific yew tree, Taxus brevifolia. Due to scarcity of paclitaxel, extensive research was carried out leading to the formulation of docetaxel – an esterified product of 10-deacetyl baccatin III, which is extracted from the renewable and more readily available leaves of the European yew tree.
Docetaxel differs from paclitaxel at two positions in its chemical structure. It has a hydroxyl functional group on carbon 10, whereas paclitaxel has an acetate ester, and a tert-butyl carbamate ester exists on the phenylpropionate side chain instead of the benzamide in paclitaxel. The carbon 10 functional group change causes docetaxel to be more water-soluble than paclitaxel.
Formulations and compositions
Docetaxel is a white powder and is the active ingredient available in 20 mg and 80 mg Taxotere single-dose vials of concentrated anhydrous docetaxel in polysorbate 80. The solution is a clear brown-yellow containing 40 mg docetaxel and 1040 mg polysorbate 80 per mL. 20 mg Taxotere is distributed in a blister carton containing one single-dose vial of Taxotere (docetaxel) preparation in 0.5 mL sterile pyrogen-free anhydrous polysorbate 80, and a single dose Taxotere solvent vial containing 1.5 mL 13% ethanol in saline to be combined and diluted in a 250 mL infusion bag containing 0.9% sodium chloride or 5% glucose for administration. 80 mg Taxotere is supplied identically but with 2.0 mL polysorbate 80 and 6.0 mL 13% ethanol in saline. The docetaxel and solvent vials are combined to give a solution of 10 mg/mL and the required dose is drawn from this solution. Vials have an overfill to compensate for liquid loss during preparation, foaming, adhesion to vial walls and the dead volume. 20 mg vials may be stored for 24 months below 25 °C away from light and 80 mg vials for 26 months in the same conditions.Recently Sanofi has got approval for one-vial formulation. With this one-vial formulation, the preparation of the infusion solution is simplified by eliminating the first dilution step.
The two-vial and one-vial formulations contain the same drug substance, docetaxel trihydrate, and the same excipients (ethanol, polysorbate 80 and citric acid).
The one-vial formulation is administered as an aqueous intravenous solution that contains the same drug substance in the same concentration as the already approved two-vial formulation. The same grade, quality, and quantity of polysorbate 80 are present in the infusion solution of both formulations. The only difference between these two formulations is the quantity of ethanol.
Active regions
A model based on electron crystallographic density and nuclear magnetic resonance deconvolution has been proposed to explain the binding of docetaxel to β-tubulin. In this T-shaped/butterfly model, a deep hydrophobic cleft exists near the surface of the β-tubulin where three potential hydrogen bonds and multiple hydrophobic contacts bind to docetaxel. The hydrophobic pocket walls contain helices H1, H6, H7 and a loop between H6 and H7 that form hydrophobic interactions with the 3’-benzamido phenyl, 3’-phenyl, and the 2-benzoyl phenyl of docetaxel. 3’-phenyl also has contact with β-sheets B8 and B10. The C-8 methyl of docetaxel has Van der Waals interactions with two residues, Thr-276 and Gln-281 near the C-terminal end of β-tubulin. Docetaxels O-21 experiences electrostatic attraction to Thr-276 and the C-12 methyl has proximity with Leu-371 on the loop between B9 and B10.
Pharmacokinetics
Absorption and distribution
Oral bioavailability has been found to be 8% ±6% on its own and, when co-administered with cyclosporine, bioavailability increased to 90% ± 44%. In practice, docetaxel is administered intravenously only to increase dose precision. Evaluation of docetaxel pharmacokinetics in phase II and III clinical studies were with 100 mg/m2 dosages given over one-hour infusions every three weeks.Docetaxel was shown to be greater than 98% plasma protein bound independent of concentration at 37 °C and pH 7.4 Docetaxels plasma protein binding includes lipoproteins, alpha1 acid glycoprotein and albumin. Alpha1 acid glycoprotein is the most variable of these proteins inter-individually, especially in cancer patients and is therefore the main determinant of docetaxels plasma binding variability. Docetaxel interacted little with erythrocytes and was unaffected by the polysorbate 80 in its storage medium. Polysorbate 80 may be the cause of hypersensitivity reasons in taxanes as recent studies indicated.The concentration-time profile of docetaxel was consistent with a three-compartment pharmacokinetic model. An initial, relatively rapid decline, with an α half-life of mean 4.5 minutes is representative of distribution to peripheral compartments from the systemic circulation. A β half-life of mean 38.3 minutes and a relatively slow γ half-life of mean 12.2 hours represent the slow efflux of docetaxel from the peripheral compartment.Administration a 100 mg/m2 dose over a one-hour infusion gave a mean total body clearance of 21 L/h/m2 and a mean steady state volume of distribution of 73.8 L/m2 or 123 L based on the mean BSA (body surface area) of 1.68 m2. Area under the plasma concentration-time curve had a mean value of 2.8 mg.h/L. The Cmax of docetaxel was found to be 4.15 ± 1.35 mg/L. Increased dose resulted in a linear increase of the area under the concentration-time curve and so it is concluded that dose is directly proportional to plasma concentration.
Metabolism and excretion
Docetaxel is mainly metabolised in the liver by the cytochrome P450 CYP3A4 and CYP3A5 subfamilies of isoenzymes. Metabolism is principally oxidative and at the tert-butylpropionate side chain, resulting first in an alcohol docetaxel (M2), which is then cyclised to three further metabolites (M1, M3 and M4). M1 and M3 are two diastereomeric hydroxyoxazolidinones and M4 is an oxazolidinedione. Phase II trials of 577 patients showed docetaxel clearance is related to body surface area and to hepatic enzyme and alpha1 acid glycoprotein plasma levels. The following model represents docetaxel clearance in humans:
where CL is total body clearance (L/h), BSA is total body surface area (m2), AAG and ALB represent alpha1 acid glycoprotein and albumin plasma concentrations (g/L) respectively, and AGE is the patients age (years). HEP12 represents a measure of hepatic dysfunction, affecting clearance of docetaxel. This final model accounted for a modest proportion of patients and identified most of the patients varying from the model (population median of CL = 35.6 L/h) as having hepatic dysfunction, indicating hepatic function as the most unpredictable factor with regards to clearance variability.Patients with significant hepatic dysfunction had an approximately 30% decrease in clearance of docetaxel and were also at a higher risk of toxicity poisoning from docetaxel treatment. Clearance has been shown from population pharmacokinetic studies to decrease significantly with age, increased alpha1 acid glycoprotein and albumin concentrations and decreased body surface area.Renal impairment is unlikely to affect metabolism or excretion of docetaxel as renal excretion contributes less than 5% of elimination. Limited data is available for docetaxel use in children with dosage between 55 and 75 mg/m2. Two paediatric studies have taken place that show a mean clearance of 33 L/h/m2 and concentration-time profiles best fitted by a two-compartmental model of distribution and elimination. Mean distribution half-life was 0.09 hours and mean elimination half-life was 1.4 hours in paediatric studies.Biodistribution of 14C-labelled docetaxel in three patients showed the bulk of the drug to be metabolised and excreted in bile to the faeces. Of the radioactively labelled docetaxel administered, 80% was eliminated to the faeces with 5% in the urine over seven days, an indication that urinary excretion of docetaxel is minimal. Saliva contributed minimal excretion and no excretion was detected through pulmonary means. The terminal half-life of docetaxel was determined as approximately 86 hours, through prolonged plasma sampling, contrary to the clinically stated terminal half-life of 10–18 hours.
Mechanism of action
Molecular target
Docetaxel binds to microtubules reversibly with high affinity and has a maximum stoichiometry of 1 mole docetaxel per mole tubulin in microtubules. This binding stabilizes microtubules and prevents depolymerisation from calcium ions, decreased temperature and dilution, preferentially at the plus end of the microtubule. Docetaxel has been found to accumulate to higher concentration in ovarian adenocarcinoma cells than kidney carcinoma cells, which may contribute to the more effective treatment of ovarian cancer by docetaxel. It has also been found to lead to the phosphorylation of oncoprotein bcl-2, which is apoptosis-blocking in its oncoprotein form.
Modes of action
The cytotoxic activity of docetaxel is exerted by promoting and stabilising microtubule assembly, while preventing physiological microtubule depolymerisation/disassembly in the absence of GTP. This leads to a significant decrease in free tubulin, needed for microtubule formation and results in inhibition of mitotic cell division between metaphase and anaphase, preventing further cancer cell progeny.Because microtubules do not disassemble in the presence of docetaxel, they accumulate inside the cell and cause initiation of apoptosis. Apoptosis is also encouraged by the blocking of apoptosis-blocking bcl-2 oncoprotein. Both in vitro and in vivo analysis show the anti-neoplastic activity of docetaxel to be effective against a wide range of known cancer cells, cooperate with other anti-neoplastic agents activity, and have greater cytotoxicity than paclitaxel, possibly due to its more rapid intracellular uptake.The main mode of therapeutic action of docetaxel is the suppression of microtubule dynamic assembly and disassembly, rather than microtubule bundling leading to apoptosis, or the blocking of bcl-2.
Cellular responses
Docetaxel exhibits cytotoxic activity on breast, colorectal, lung, ovarian, gastric, renal and prostate cancer cells. Docetaxel does not block disassembly of interphase microtubules and so does not prevent entry into the mitotic cycle, but does block mitosis by inhibiting mitotic spindle assembly. Resistance to paclitaxel or anthracycline doxorubicin does not necessarily indicate resistance to docetaxel. Microtubules formed in the presence of docetaxel are of a larger size than those formed in the presence of paclitaxel, which may result in improved cytotoxic efficacy. Abundant formation of microtubules and the prevention of replication caused by docetaxel leads to apoptosis of tumour cells and is the basis of docetaxel use as a cancer treatment. Docetaxel activity is significantly greater in ovarian and breast tumours than for lung tumours.
Society and culture
Discovery, regulation and marketing
Docetaxel is marketed worldwide under the name Taxotere by Sanofi-Aventis as well as Docefrez by Sun Pharma Global and Zytax by Zydus. Annual sales of Taxotere in 2010 were €2.122 billion (US$3.1 billion). The patent expired in 2010.Taxotere was developed by Rhône-Poulenc Rorer (now Sanofi-Aventis) following from the discoveries of Pierre Potier at CNRS at Gif-sur-Yvette during his work on improvements to the production of Taxol.
Costs
In the UK (in 2009) The cost of six cycles (18 weeks) of docetaxel at a dose of 75 mg/m2 IV every 21 days is £5,262 (based on an average body surface area 1.75 m2).
See also
Exudative hyponychial dermatitis
Scleroderma-like reaction to taxane
Taxane
Treatment of Lung Cancer
References
External links
"Docetaxel". Drug Information Portal. U.S. National Library of Medicine. |
Fondaparinux | Fondaparinux (trade name Arixtra) is an anticoagulant medication chemically related to low molecular weight heparins. It is marketed by GlaxoSmithKline. A generic version developed by Alchemia is marketed within the US by Dr. Reddys Laboratories.
Medical uses
Clinically, it is used for the prevention of deep vein thrombosis in patients who have had orthopedic surgery as well as for the treatment of deep vein thrombosis and pulmonary embolism.Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine days, but it substantially reduces major bleeding and improves long-term mortality and morbidity.It has been investigated for use in conjunction with streptokinase.
Comparison to other agents
One potential advantage of fondaparinux over LMWH or unfractionated heparin is that the risk for heparin-induced thrombocytopenia (HIT) is substantially lower. Furthermore, there have been case reports of fondaparinux being used to anti-coagulate patients with established HIT as it has no affinity for PF4. However, its renal excretion precludes its use in patients with renal dysfunction.
Unlike direct factor Xa inhibitors, it mediates its effects indirectly through antithrombin III, but unlike heparin, it is selective for factor Xa.
Pharmacology
Mechanism of action
Fondaparinux is a synthetic pentasaccharide factor Xa inhibitor. Fondaparinux binds antithrombin and accelerates its inhibition of factor Xa.
Apart from the O-methyl group at the reducing end of the molecule, the identity and sequence of the five monomeric sugar units contained in fondaparinux is identical to a sequence of five monomeric sugar units that can be isolated after either chemical or enzymatic cleavage of the polymeric glycosaminoglycans heparin and heparan sulfate (HS). Within heparin and heparan sulfate this monomeric sequence is thought to form the high-affinity binding site for the anti-coagulant factor antithrombin (AT). Binding of heparin or HS to AT has been shown to increase the anti-coagulant activity of antithrombin 1000 fold. In contrast to heparin, fondaparinux does not inhibit thrombin.
Chemistry
Abbreviations
GlcNS6S = 2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside
GlcA = β-D-glucopyranuronoside
GlcNS3,6S = 2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl
IdoA2S = 2-O-sulfo-α-L-idopyranuronoside
GlcNS6SOMe = methyl-O-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranosideFondaparinux is only accessible by chemical synthesis. Recently, Supriya Dey et al. reported an effective and scalable one-pot synthesis of Fondaparinux.The sequence of monosaccharides is D-GlcNS6S-α-(1,4)-D-GlcA-β-(1,4)-D-GlcNS3,6S-α-(1,4)-L-IdoA2S-α-(1,4)-D-GlcNS6S-OMe, as shown in the following structure:
References
External links
"Fondaparinux". Drug Information Portal. U.S. National Library of Medicine. |
Zafirlukast | Zafirlukast is an orally administered leukotriene receptor antagonist (LTRA) used for the chronic treatment of asthma. While zafirlukast is generally well tolerated, headache and stomach upset often occur. Some rare side effects can occur, which can be life-threatening, such as liver failure. Churg-Strauss syndrome has been associated with zafirlukast, but the relationship isnt thought to be causative in nature. Overdoses of zafirlukast tend to be self-limiting.
Zafirlukast, like other LTRAs, works by inhibiting the immune system. Through its action on inflammatory cells in the lungs, zafirlukast reduces the production of inflammatory mediators that are implicated in the pathogenesis of asthma. Zafirlukast is extensively hepatically metabolized by an enzyme called CYP2C9. Zafirlukast inhibits the action of CYP3A4, leading to drug-drug interactions with other drugs that are metabolized by CYP3A4. Genetic differences in LTC4 synthase and CYP2C9 may predict how a person reacts to zafirlukast treatment.
Zafirlukast (brand name Accolate) was the first cysteinyl leukotriene receptor antagonist approved in the United States. It is now approved in many other countries under other brand names.
Medical uses
Zafirlukast is FDA-approved for the prevention and treatment of asthma in adults and children older than 5 years old. Like other leukotriene receptor antagonists, zafirlukast is thought to be useful for the long-term treatment of asthma, but it is generally less effective than inhaled glucocorticoids as monotherapy (which are the standard of care) or long-acting beta-2 agonists in combination therapy. Notably, zafirlukast is ineffective in the event of an acute asthma attack.
Available forms
There are two dosage forms for zafirlukast, notable for their age-adjustments. The 20 mg tablet is for adults and children older than age 12, whereas the 10 mg tablet is for children between the ages of 5 and 12. Tablets should be stored at room temperature, out of direct sunlight, and away from sources of moisture.Tablets are for oral administration only.
Specific populations
Pediatrics
As a general rule, leukotriene receptor antagonists like zafirlukast are more effective in children that are younger and whose asthma is less atopic. Atopy refers to a predisposition towards developing allergic conditions, including asthma, hay fever, and eczema.
Geriatrics
The hepatic clearance of zafirlukast is impaired in adults 65 years of age and older, resulting in a 2–3 fold increase in the maximum plasma concentration and the total area under the curve. Zafirlukast may increase the risk for infections (7.0% vs 2.9%, zafirlukast vs. placebo incidence respectively), especially lower respiratory tract infections, in older adults, though the infections noted were not severe.
Pregnancy
Zafirlukast is considered to be "pregnancy category B." This is due, in part, to the wide safety margin of zafirlukast in animal studies investigating teratogenicity. No teratogenicity has been observed in doses up to 2000 mg/kg/day in cynomolgus monkeys, representing an equivalent 20x exposure of the maximum recommended daily oral dose in human adults. However, spontaneous abortions occurred in cynomolgus monkeys at 2000 mg/kg/day, though the dose itself was maternally toxic.
Lactation
There is limited research on the use of zafirlukast in women whom are breastfeeding. Based on data from the manufacturer, it is expected that 0.6% of the maternal weight-adjusted dose would reach a breastfed infant, though the effects in the infant are unknown.
Renal impairment
Renal impairment does not appear to affect the pharmacokinetic profile of zafirlukast.
Hepatic impairment
The hepatic clearance of zafirlukast is impaired by significant hepatic impairment. Cirrhosis of the liver can result in an increase in the maximum plasma concentration and the total area under the curve (a measure of drug exposure) by 50–60%.
Contraindications
Zafirlukast is contraindicated in people that are hypersensitive or allergic to it.
Adverse effects
Zafirlukast is generally well tolerated, though headache and gastrointestinal (GI) upset can occur. The incidence of headache is between 12 and 20%, which is similar to the incidence of headache found in patients taking placebos in the studies that lead to zafirlukasts approval. GI upset may include nausea, stomach discomfort/pain, and diarrhea. GI complaints can be lessened by taking zafirlukast with food, though this can dramatically impair the amount of drug that gets absorbed into the body (see the section on drug-food interactions below).Other common side effects include flu-like symptoms, sleep disturbances (abnormal dreams, insomnia), hallucinations, and daytime drowsiness.
Neuropsychiatric effects
Neuropsychiatric side effects have been reported with the use of zafirlukast and other LTRAs. While some side effects are less severe (e.g. abnormal dreams), others are more serious (e.g. hallucinations, tremor, suicidality). These effects were discovered through post-marketing reports, as the initial trials were not designed to monitor for neuropsychiatric side effects.
Hepatotoxicity
Zafirlukast can also cause rare but serious side effects like acute liver injury. Zafirlukast-induced hepatotoxicity generally occurs within the first 2–6 months of initiating therapy, though cases have been reported up to 13 months after starting zafirlukast. Zafirlukast-induced hepatotoxicity is characterized by a spectrum of liver damage symptoms, including fatigue, nausea, and right upper quadrant pain followed by dark urine, jaundice and pruritus. Liver enzyme elevations are common, and the pattern usually reflects hepatocellular damage, resembling acute viral hepatitis. It is unclear how the hepatotoxicity occurs, but it may be due to a metabolic intermediate of zafirlukast, since it is metabolized in the liver through the enzyme CYP2C9. When it does occur it can be fatal, and reexposure with zafirlukast may result in a worse injury. Switching zafirlukast to another medication in the same class (e.g. montelukast) or in the related class of 5-lipoxygenase inhibitors can be attempted, but caution should be employed.According to the "Dear Health Care Provider" letter from AstraZeneca, zafirlukast-induced hepatotoxicity has occurred predominantly in females.
Churg-Strauss syndrome
Several cases of Churg-Strauss syndrome, also known as allergic angiitis and granulomatosis, have been reported with the use of zafirlukast, montelukast, pranlukast, and other asthma medications. When Churg-Strauss syndrome occurs, it tends to occur in people with long-standing asthma and sinus inflammation, chronic oral corticosteroid use, and the recent initiation of a new anti-asthma therapy (like zafirlukast) in conjunction with tapering the corticosteroids. While the exact etiology of the development of Churg-Strauss symptoms in proximity to initiating zafirlukast is unknown, it is thought that withdrawal of chronic corticosteroids "unmasks" the previously undetected disease. Because corticosteroid withdrawal often happens while starting a new anti-asthma medication (like zafirlukast), this explains the rare but notable association. These cases may represent misdiagnosed asthma, as Churg-Strauss syndrome can induce symptoms of airway obstruction that are akin to an acute asthma exacerbation. As these asthma-like symptoms are reduced by zafirlukast, the symptoms of Churg-Strauss (e.g. neuropathy) increase due to the lack of the broader, anti-inflammatory coverage that the steroid was providing.
Overdose
The highest overdose reported with zafirlukast is 200 mg. All overdose patients have survived. Symptoms reported included rash and upset stomach.
Interactions
Drug-drug interactions
Zafirlukast is an inhibitor of the hepatic drug-metabolizing enzyme cytochrome P450 family 3 subfamily A member 4 (CYP3A4). Zafirlukast may increase the concentration of drugs that are metabolized through CYP3A4, such as the anticoagulant medication warfarin and the antiepileptic drugs phenytoin and carbamazepine.
Drug-food interactions
The oral absorption (bioavailability) of zafirlukast is decreased by 40% when it is taken with high fat or high protein meals. To avoid this interaction, zafirlukast should be taken on an empty stomach. An empty stomach is classified as an hour before, or two hours after, consuming a meal.
Pharmacology
Pharmacodynamics
Zafirlukast is an antagonist of cysteinyl leukotriene receptor 1 (CysLT1), a receptor found throughout the smooth muscle of the lungs, within interstitial lung macrophages (white blood cells that operate in the interstitial space of the lungs), and rarely in epithelial cells. CystLT1 is a receptor for a specific class of leukotrienes that contain the amino acid cysteine. These cysteinyl leukotrienes include leukotriene C4, leukotriene D4, and leukotriene E4, all of which are produced by inflammatory cells like eosinophils, basophils, and macrophages in the lungs. Through their action on CysLT1 these leukotrienes can trigger bronchoconstriction, a state in which the bronchial passages of the lungs constrict, leading to the characteristic, reactive airway symptoms associated with bronchial asthma. The other pro-inflammatory effects of leukotrienes, such as their inhibition of mucus clearance and their stimulation of mucus secretion and edema, are thought to play a role in the characteristic symptoms of allergic rhinitis (also called hay fever). By inhibiting the action of these specific leukotrienes, zafirlukast is thought to exert an anti-inflammatory effect against leukotriene-mediated inflammatory conditions.
Pharmacokinetics
Absorption
Zafirlukast is rapidly absorbed into the bloodstream following oral administration, reaching peak plasma levels within 3 hours of taking the dose. The peak plasma level is the maximum concentration of zafirlukast in the blood.
Distribution
Zafirlukast is moderately distributed into the bodys tissues, with an apparent steady state volume of distribution of 70 liters. Zafirlukast is highly plasma protein bound, 99% bound to albumin. Albumin is the most abundant protein found in human plasma and is capable of carrying and transporting drugs (like zafirlukast) throughout the body. In vivo research indicates that zafirlukast has low blood-brain barrier penetration. The blood-brain barrier is a protective system that prevents many chemicals from entering the brain.
Metabolism
Zafirlukast undergoes extensive hepatic metabolism into inactive metabolites. Zafirlukast is primarily metabolized by the enzyme CYP2C9 to a hydroxylated metabolite.
Elimination
Zafirlukast is primarily cleared through biliary excretion at a rate of 20 liters/hour. Zafirlukast is undetectable in urine. The mean terminal half-life ranges 8–16 hours, following linear kinetics up to doses of 80 mg.
Pharmacogenomics
LTC4 synthase
Genetic polymorphisms in the LTC4 synthase promoter may predict response to zafirlukast. The single-nucleotide polymorphism (SNP) A444C (the wild-type DNA base adenine, at the 444th position on the gene, is mutated; cytosine is there instead), which is associated with a severe asthma phenotype, has been shown to decrease the clinical response to zafirlukast (both when the genetic alteration was heterozygous or homozygous).
CYP2C9
Zafirlukast is metabolized through the hepatic enzyme CYP2C9. SNPs that decrease the function of CYP2C9 (such as CYP2C9*3 and CYP2C9*13) may decrease the hepatic clearance of zafirlukast, leading to increased exposure of zafirlukast. Notably, the CYP2C9*3 polymorphism is more commonly encountered in people of south/central Asian ancestry (10.165%) compared to people of Caucasian (7.083%), African American (1.170%), African (1.033%), middle eastern (9.312%), and east Asian (3.365%) ancestry.
Chemistry
Synthesis
Zafirlukast can be synthesized by the following method:
Physiochemical properties
Pure zafirlukast is described as a fine, white to pale yellow, amorphous powder. It is practically insoluble in water, slightly soluble in methanol, and freely soluble in tetrahydrofuran, dimethylsulfoxide, and acetone.
History
Zafirlukast was the first cysteinyl leukotriene receptor antagonist approved in the United States. Zafirlukast was approved in 1996.
Society and culture
Economics
While preliminary evidence suggests that zafirlukast may reduce healthcare costs, the cost-effectiveness of using zafirlukast has not been established.
Brand names
Research
Mechanism of action
There is some research to suggest that zafirlukast actually acts as a partial inverse agonist at the CysLT1 receptor, though zafirlukast is still classified as an antagonist at this receptor. The possible clinical significance of this effect, if true, is unknown.
Other indications
There is some evidence that suggests that zafirlukast may be beneficial in the treatment of chronic urticaria (hives), whether due to a known cause such as cold-exposure or due to an unknown cause (idiopathic). A pilot study indicated that zafirlukast may be of some benefit in cystic fibrosis. In the setting of chronic obstructive pulmonary disorder (COPD), a disease characterized by chronic inflammation of the lungs, zafirlukast has been shown to improve lung function.
Veterinary use
Zafirlukast is sometimes used for the treatment of bronchial asthma in cats.
References
External links
"Zafirlukast". Drug Information Portal. U.S. National Library of Medicine. |
Omacetaxine mepesuccinate | Omacetaxine mepesuccinate (INN, trade names Synribo ), formerly named as homoharringtonine or HHT, is a pharmaceutical drug substance that is indicated for treatment of chronic myeloid leukemia (CML).
HHT is a natural plant alkaloid derived from Cephalotaxus fortunei. HHT and related compound esters of cephalotaxine were described first in 1970, and were the subject of intensive research efforts by Chinese investigators to clarify their role as anticancer and antileukemic agents from the 1970s until the present. It was approved by the US FDA in October 2012 for the treatment of adult patients with CML with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs).
Medical uses
Omacetaxine/homoharringtonine is indicated for use as a treatment for patients with chronic myeloid leukaemia who are resistant or intolerant of tyrosine kinase inhibitors.In June 2009, results of a long-term open label Phase II study were published, which investigated the use of omacetaxine infusions in CML patients. After twelve months of treatment, about one third of patients showed a cytogenetic response. A study in patients who had failed imatinib and who had the drug resistant T315I mutation achieved cytogenetic response in 28% of patients and hematologic response in 80% of patients, according to preliminary data.Phase I studies including a small number of patients have shown benefit in treating myelodysplastic syndrome (MDS, 25 patients) and acute myelogenous leukaemia (AML, 76 patients). Patients with solid tumors did not benefit from omacetaxine.
Adverse effects
By frequency:
Very common (>10% frequency):
Common (1–10% frequency):
Seizures
Haemorrhage† Myelosuppression, including: thrombocytopenia, anaemia, neutropenia and lymphopenia, in descending order of frequency.
Omacetaxine mepesuccinate can cause fetal harm when administered to a pregnant woman. Women using HHT should avoid becoming pregnant and also avoid nursing while receiving HHT.
Mechanism of action
Omacetaxine is a protein translation inhibitor. It inhibits protein translation by preventing the initial elongation step of protein synthesis. It interacts with the ribosomal A-site and prevents the correct positioning of amino acid side chains of incoming aminoacyl-tRNAs. Omacetaxine acts only on the initial step of protein translation and does not inhibit protein synthesis from mRNAs that have already commenced translation.
== References == |
Tolcapone | Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinsons disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-O-methyltransferase (COMT). It has demonstrated significant liver toxicity, which has led to suspension of marketing authorisations in a number of countries.
In comparison with entacapone, another nitrocatechol COMT inhibitor, tolcapone has a longer half life (2.9 hours vs. 0.8 hours) and can better penetrate the blood–brain barrier, acting both in the central nervous system and in the periphery. However, entacapone is less toxic for the liver.
Medical uses
Tolcapone is used in the treatment of Parkinsons disease as an adjunct to levodopa/carbidopa or levodopa/benserazide medications. Levodopa is a prodrug for dopamine, which reduces Parkinson symptoms; carbidopa and benserazide are aromatic L-amino acid decarboxylase (AADC) inhibitors.Without administration of tolcapone, the beneficial effects of levodopa tend to wear off more quickly, resulting in motor fluctuations.
Contraindications
Combining tolcapone with non-selective monoamine oxidase inhibitors such as phenelzine or tranylcypromine is contraindicated. Tolcapone is also contraindicated for people with liver diseases or increased liver enzymes.
Side effects
Tolcapone has demonstrated significant liver toxicity (hepatotoxicity) that limits the drugs utility. Entacapone is an alternative, largely since it has a more favorable toxicity profile.
The hepatotoxicity can be related to elevated levels of transaminases, but studies have shown that minimal risk exists for those without preexisting liver conditions when their enzyme levels were being monitored. No clear mechanism is implicated, but it has been hypothesized that it has something to do with abnormal mitochondrial respiration due to the uncoupling of oxidative phosphorylation.Other side effects regard the increase in dopaminergic activity, including digestive symptoms. Treatment with tolcapone runs the risk of eliciting or prolonging dyskinesia; this can be counteracted by decreasing the dose of levodopa. This occurs because the administration of tolcapone results in the accumulation of the biological methyl donor S-adenosyl-L-methionine (SAM) in the striatum that induces Parkinson symptoms.Digestive symptoms include nausea and diarrhea; further dopaminergic side effects include orthostatic hypotension, dry mouth, sweating and dizziness. Tolcapone causes more severe diarrhea than entacapone; this was the most common reason for therapy termination in studies. Urine discoloration comes from yellow tolcapone metabolites being excreted in the urine and is harmless.
Interactions
While increase of dopamine levels is a desired interaction, tolcapone can theoretically also increase the levels of other drugs metabolised by COMT, such as the AADC inhibitors carbidopa and benzerazide, as well as methyldopa, dobutamine, apomorphine, adrenaline, and isoprenaline. In studies, a slight interaction with benzerazide was seen, but not with carbidopa. Other interactions with this group of drugs have not been studied. A related type of theoretical interactions is with drugs that increase catecholamine concentrations, such as monoamine oxidase (MAO) inhibitors and noradrenaline reuptake inhibitors; these also showed only slight effects in practice. Combination with non-selective MAO inhibitors might be dangerous.Due to its affinity to the liver enzyme CYP2C9, interactions with drugs being metabolised by this enzyme are also possible, but unlikely. No interaction with tolbutamide, a 2C9 substrate, was observed in studies.
Pharmacology
Mechanism of action
Tolcapone selectively and reversibly binds to the catalytic site of COMT in both the periphery and the central nervous system (CNS) with greater affinity than any of the three catecholamines, including levodopa. It thereby prevents the 3-O-methylation of levodopa by COMT in the periphery, which produces 3-O-methyldopa, a major metabolite that competes with levodopa to cross the blood–brain barrier. More of the levodopa that is administered reaches the CNS. Additionally, levodopa that has already reached the CNS, after being converted to dopamine, will not be degraded as quickly when tolcapone inhibits COMT activity. Thus, tolcapone improves the bioavailability and reduces the clearance of levodopa and subsequently dopamine from the CNS.
The strength of the binding affinity of tolcapone, represented by the inhibition constant Ki (2.5 nM), can be thought of as the dissociation constant for enzyme and inhibitor complex kinetics. Maximum catalytic activity denotes the efficacy of tolcapone (Vmax = 58.4 pmol/min·mg).
Pharmacokinetics
Tolcapone is quickly absorbed from the gut to about 85%. It has an absolute bioavailability of 65%, which is only slightly decreased when taken with food. The substance reaches highest blood plasma concentrations after about two hours. When in the bloodstream, it is almost completely (>99.9%) bound to plasma proteins, primarily albumin. The main inactivation step is glucuronidation; other processes are methylation by COMT, hydroxylation by CYP3A4 and CYP2A6 with subsequent oxidation to a carboxylic acid, and possibly a minor path with reduction to an amine with subsequent acetylation.The half-life of tolcapone is two to three hours, the volume of distribution (Vd) being 0.3 L/kg (21 L in an average 70 kg person). 60% of the metabolites are excreted via the urine and 40% via the feces. Only 0.5% of the drug are excreted in unchanged form via the urine.
99% of tolcapone is in monoanionic form in the body because the physiological pH is 7.4. Tolcapone penetrates the blood–brain barrier much better than two other nitrocatechols, nitecapone and entacapone, because it has higher lipophilicity due to its R-substituent. Partition coefficients quantify the ability of the molecule to cross the blood–brain barrier. LogPIdce= 0.2, –1.4, –0.4 for tolcapone, nitecapone and entacopone respectively. Partition coefficients in this case were measured in 1,2-dichloroethane/H2O solution which caused molecules to be in ionized form. There is no current explanation for how these charged molecules permeate the blood–brain barrier.
Chemistry
Tolcapone is an intensely yellow, odorless, bitter tasting, non-hygroscopic, crystalline compound with a relative molecular mass of 273.25 g/mol. It melts at 143 to 146 °C (289 to 295 °F), is practically insoluble in water and acids but soluble in 0.1 M aqueous sodium hydroxide solution. The pKa values are 4.5 and 10.6 for the two phenyl groups; and the maximum absorption is at 268 nm (in 0.1 M hydrochloric acid / ethanol). Its chemical name is 3,4-dihydroxy-4-methyl-5-nitrobenzophenone.
Synthesis
A synthesis of tolcapone proposed in 2008, begins with a Grignard reaction between a benzaldehyde derivative and p-tolyl magnesium bromide. The alcohol thus produced is then converted to a ketone using sodium t-butoxide. The benzyl protecting group is removed by palladium-catalyzed hydrogenation in the presence of ammonium formate. A nitro group is introduced at the 5-position adjacent to the hydroxyl group unmasked in the cleavage of the benzyl ether. The synthesis ends with cleavage of the methoxy group using aluminum chloride to yield the product alcohol.
History
Tolcapone was introduced into the European market in August 1997, and subsequently into the United States market in March 1998. Liver toxicity was reported in four people who were administered tolcapone, three people died due to complications. Consequentially, the marketing authorization of tolcapone was suspended from December, 1998 until August, 2004 when it was lifted. In November 1998, the company that manufactured tolcapone voluntarily removed the drug from the market. The authorization was then renewed in August 2009.As a result of reported complications, the U.S. Food and Drug Administration (FDA) issued a black box warning for tolcapone and label revisions that aimed to regulate the monitoring of those prescribed tolcapone for Parkinsons disease in November 1998. A number of other countries withdrew tolcapone from the market; Australia in February 1999, Bulgaria in April 1999, Iceland in November 1998, Lithuania in December 1998.
Research
Because of preliminary data suggesting the drug may have activity, the U.S. FDA has granted tolcapone "orphan drug status" in studies aiming at the treatment of familial transthyretin amyloidosis (ATTR). However, tolcapone is not FDA approved for the treatment of this disease.
References
External links
"Tolcapone". Drug Information Portal. U.S. National Library of Medicine. |
Delsym | Delsym is an American brand of cough medicine owned by Reckitt, and manufactured at Unither Manufacturing in Rochester, NY. It is different from most brands of cough medicine in that the active ingredient is "time released". The time release feature allows the drug to suppress the cough reflex for a longer period of time. The active ingredient per teaspoon (5 mL) is dextromethorphan polistirex, equivalent to dextromethorphan HBr 30 mg.
Method of action
The active ingredient, dextromethorphan (metabolized to dextrorphan), is surrounded by an edible plastic called polistirex. When the Delsym arrives in the stomach, an initial amount of dextromethorphan is immediately released into the bloodstream while the rest is surrounded by a plastic that is slowly dissolved by stomach acid. After the polistirex is dissolved sufficiently, more dextromethorphan is released.
Recreational use
Intentionally consuming more than the recommended dosage of Delsym may result in euphoria, lack of coordination, hallucinations, apathy, feelings of dissociation, and disorientation. This is due to dextromethorphan as well as its pharmacologically-active metabolite dextrorphan, both dissociative drugs that work as NMDA receptor antagonists the same way nitrous oxide (N2O), ketamine, and phencyclidine (PCP) do. Because of the abuse potential, many pharmacies and large retail chains have begun taking precautions such as restricting sales to those under age 18 and limiting the number of sales of dextromethorphan-containing products per customer.
References
External links
Official website |
Cabotegravir | Cabotegravir, sold under the brand name Vocabria among others, is a antiretroviral medication used for the treatment of HIV/AIDS. It is available in the form of tablets and as an intramuscular injection, as well as in an injectable combination with rilpivirine under the brand name Cabenuva.It is an integrase inhibitor with a carbamoyl pyridone structure similar to that of dolutegravir.In December 2021, the U.S. Food and Drug Administration approved cabotegravir for pre-exposure prophylaxis (PrEP) in at-risk people under the brand name Apretude.
Medical uses
Cabotegravir in combination with rilpivirine is indicated for the treatment of human immunodeficiency virus type-1 (HIV-1) in adults. The combination injection is intended for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/mL) with their current antiretroviral treatment, and when the virus has not developed resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors. The tablets are used to check whether a person tolerates the treatment before the injection therapy is started.The two medicines are the first antiretroviral drugs that come in a long-acting injectable formulation.Cabotegravir (Apretude) is indicated for use in at-risk people weighing at least 35 kilograms (77 lb) for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV.
Contraindications and interactions
Cabotegravir must not be combined with the drugs rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenytoin or phenobarbital, which induce the enzyme UGT1A1. These drugs significantly decrease cabotegravir concentrations in the body and thus may reduce its effectiveness. Additionally, they induce the enzyme CYP3A4, which leads to reduced rilpivirine concentrations in the body. Additionally, patients who are breastfeeding or plan to breastfeed should not take Cabotegravir because it is not known if it will pass within the breast milk.
Adverse effects
The most common side effects of the injectable combination therapy with rilpivirine are reactions at the injection site (in up to 84% of patients) such as pain and swelling, as well as headache (up to 12%) and fever or feeling hot (in 10%). For the tablets, headache and a hot feeling were slightly less frequent. Less common side effects (under 10%) for both formulations are depressive disorders, insomnia, and rashes.
Pharmacology
Mechanism of action
Cabotegravir is an integrase strand transfer inhibitor. This means it blocks the HIVs enzyme integrase, thereby preventing its genome from being integrated into the human cells DNA. As this is a necessary step for the virus to replicate, its further spread is hampered.
Pharmacokinetics
When taken by mouth, cabotegravir reaches highest blood plasma levels after three hours. Taking the drug together with food slightly increases its concentrations in the blood, but this is not clinically relevant. After injection into the muscle, cabotegravir is slowly absorbed into the bloodstream, reaching its highest blood plasma levels after about seven days.Over 99% of the substance are bound to plasma proteins. The drug is inactivated in the body by glucuronidation, mainly by the enzyme UGT1A1, and to a much lesser extent by UGT1A9. More than 90% of the circulating substance are the unchanged cabotegravir, however. The biological half-life is 41 hours for the tablets and 5.6 to 11.5 weeks for the injection.Elimination has only been studied for oral administration: Most of the drug is eliminated via the faeces in unchanged form (47%). It is not known how much of this amount comes from the bile, and how much was not absorbed in the first place. (The bile actually contains the glucuronide, but this could be broken up again in the gut lumen to give the parent substance that is observed in the faeces.) To a lesser extent it is excreted via the urine (27%), almost exclusively as the glucuronide.
Pharmacogenomics
UGT1A1 poor metabolizers have 1.3- to 1.5-fold increased cabotegravir concentrations in the body. This is not considered clinically significant.
Chemistry
Cabotegravir is a white to off-white, crystalline powder that is practically insoluble in aqueous solutions under pH 9, and slightly soluble above pH 10. It is slightly acidic with a pKa of 7.7 for the enolic acid and 1.1 (calculated) for the carboxamide. The molecule has two asymmetric carbon atoms; only one of the four possible configurations is present in the medication.
Formulation
In studies, the agent was packaged into nanoparticles (GSK744LAP) conferring a biological half-life of 21 to 50 days following a single dose. The marketed injection achieves its long half-life not via nanoparticles but with a suspension of the free cabotegravir acid. The tablets contain cabotegravir sodium salt.
History
Cabotegravir was examined in the clinical trials HPTN 083 and HPTN 084. In 2020, 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 Vocabria intended for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with rilpivirine injection. The EMA also recommended marketing authorization be given for rilpivirine and cabotegravir injections to be used together for the treatment of people with HIV-1 infection. Cabotegravir was approved for medical use in the European Union in December 2020.
Society and culture
Names
Cabotegravir is the United States Adopted Name (USAN) and the international nonproprietary name (INN).
Research
Pre-exposure prophylaxis
In 2020, results for some studies were released showing success in using injectable cabotegravir for long-acting pre-exposure prophylaxis (PrEP) with greater efficacy than the emtricitabine/tenofovir combination being widely used for PrEP at the time.The safety and efficacy of cabotegravir to reduce the risk of acquiring HIV were evaluated in two randomized, double-blind trials that compared cabotegravir to emtricitabine/tenofovir, a once daily oral medication for HIV PrEP. Trial 1 included HIV-uninfected men and transgender women who have sex with men and have high-risk behavior for HIV infection. Trial 2 included uninfected cisgender women at risk of acquiring HIV.In Trial 1, 4,566 cisgender men and transgender women who have sex with men received either cabotegravir or emtricitabine/tenofovir. The trial measured the rate of HIV infections among trial participants taking daily cabotegravir followed by cabotegravir injections every two months compared to daily oral emtricitabine/tenofovir. The trial showed participants who took cabotegravir had 69% less risk of getting infected with HIV when compared to participants who took emtricitabine/tenofovir.In Trial 2, 3,224 cisgender women received either cabotegravir or emtricitabine/tenofovir. The trial measured the rate of HIV infections in participants who took oral cabotegravir and injections of cabotegravir compared to those who took emtricitabine/tenofovir orally. The trial showed participants who took cabotegravir had 90% less risk of getting infected with HIV when compared to participants who took emtricitabine/tenofovir.In December 2021, the U.S. Food and Drug Administration (FDA) approved cabotegravir for pre-exposure prophylaxis. The FDA granted the approval of Apretude to Viiv.
References
External links
"Cabotegravir". Drug Information Portal. U.S. National Library of Medicine. |
Ferric derisomaltose | Ferric derisomaltose, sold under the brand name Monoferric, is a medication for the treatment of iron deficiency anemia (IDA) in adults who have intolerance to oral iron or have had unsatisfactory response to oral iron or who have non-hemodialysis dependent chronic kidney disease (NDD-CKD). It was approved for use in the United States in January 2020. It is given intravenously.
References
External links
"Ferric derisomaltose". Drug Information Portal. U.S. National Library of Medicine. |
Tizanidine | Tizanidine, sold under the brand name Zanaflex among others, is a medication that is used to treat muscle spasticity due to spinal cord injury or multiple sclerosis. Effectiveness appears similar to baclofen or diazepam. It is taken by mouth.Common side effects of Tizanidine include dry mouth, sleepiness, weakness, and dizziness. Serious side effects may include low blood pressure, liver problems, psychosis, and QT prolongation. It is unclear if use in pregnancy and breastfeeding is safe. It is an α2-adrenergic agonist and how it works is not entirely clear.Tizanidine was approved for medical use in the United States in 1996. It is available as a generic medication. In 2019, it was the 92nd most commonly prescribed medication in the United States, with more than 8 million prescriptions.
Medical uses
Tizanidine has been found to be as effective as other antispasmodic drugs and is more tolerable than baclofen and diazepam.
Side effects
Side effects include dizziness, drowsiness, weakness, nervousness, confusion, hallucinations, strange dreams, depression, vomiting, dry mouth, constipation, diarrhea, stomach pain, heartburn, increased muscle spasms, back pain, rash, sweating, and a tingling sensation in the arms, legs, hands, and feet.
Interactions
Concomitant use of tizanidine and moderate or potent CYP1A2 inhibitors (such as zileuton, certain antiarrhythmics (amiodarone, mexiletine, propafenone, verapamil), cimetidine, famotidine, aciclovir, ticlopidine and oral contraceptives) is contraindicated. Concomitant use of tizanidine with fluvoxamine, a potent CYP1A2 inhibitor in humans, resulted in a 33-fold increase in the tizanidine AUC (plasma drug concentration-time curve). For this reason both fluvoxamine and tizanidine should not be taken at the same time. Fluoroquinolone antibiotics such as moxifloxacin, levofloxacin, and ciprofloxacin should also be avoided due to an increased serum concentration of tizanidine when administered concomitantly. Tizanidine has the potential to interact with other central nervous system depressants. Alcohol should be avoided, particularly as it can upset the stomach. The CNS-depressant effects of tizanidine and alcohol are additive. Caution with the following interactions:
antibiotics such as enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, ofloxacin, sparfloxacin, trovafloxacin, or norfloxacin;
blood pressure medications such as clonidine, guanabenz, guanfacine (Tenex), or methyldopa;
heart rhythm medications such as amiodarone (Cordarone, Pacerone), mexiletine (Mexitil), propafenone (Rhythmol), and verapamil (Calan, Covera, Isoptin).
Pharmacology
Tizanidine is an α2 receptor agonist closely related to clonidine. It has approximately one tenth to one fifteenth of the pressure lowering effect of clonidine. The relation between the α2 receptor agonism and the spasmolytic action is still not fully understood.
Route of administration
Tizanidine is available as a tablet or capsule. Capsules may be opened and sprinkled on food. However, this may change the absorption of the medication compared to taking the capsule whole.
Chemistry
It has a volume of distribution of 2.4 L/kg following intravenous administration.
References
External links
"Tizanidine". Drug Information Portal. U.S. National Library of Medicine.
"Tizanidine hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
"Tizanidine side effects". Drug Information Portal. tizanidine-side-effects.us. |
Zinc gluconate | Zinc gluconate is the zinc salt of gluconic acid. It is an ionic compound consisting of two anions of gluconate for each zinc(II) cation. Zinc gluconate is a popular form for the delivery of zinc as a dietary supplement providing 14.35% elemental zinc by weight.
Gluconic acid is found naturally, and is industrially made by the fermentation of glucose, typically by Aspergillus niger, but also by other fungi, e.g. Penicillium, or by bacteria, e.g. Acetobacter, Pseudomonas and Gluconobacter. In its pure form, it is a white to off-white powder. It can also be made by electrolytic oxidation, although this is a more expensive process. The advantages are a lower microbiological profile, and a more complete reaction, yielding a product with a longer shelf life.
Zinc gluconate and the common cold
Zinc gluconate has been used in lozenges for treating the common cold. However, controlled trials with lozenges which include zinc acetate have found it has the greatest effect on the duration of colds. Zinc has also been administered nasally for treating the common cold, but has been reported to cause anosmia in some cases.
Safety concerns
Instances of anosmia (loss of smell) have been reported with intranasal use of some products containing zinc gluconate. In September 2003, Zicam faced lawsuits from users who claimed that the product, a nasal gel containing zinc gluconate and several inactive ingredients, negatively affected their sense of smell and sometimes taste. Some plaintiffs alleged experiencing a strong and very painful burning sensation when they used the product. Matrixx Initiatives, Inc., the maker of Zicam, responded that only a small number of people had experienced problems and that anosmia can be caused by the common cold itself. In January 2006, 340 lawsuits were settled for $12 million.The U.S. Food and Drug Administration (FDA) considers zinc gluconate to be generally recognized as safe (GRAS) when used in accordance with good manufacturing practice, although this does not constitute a finding by the FDA that the substance is a useful dietary supplement. On 16 June 2009 the FDA "warned consumers to stop using and discard three zinc-containing Zicam intranasal products. The products may cause a loss of sense of smell. ... FDA is concerned that the loss of sense of smell may be permanent." Matrixx responded that the FDAs allegations were "unfounded and misleading", citing a lack of evidence from controlled tests that Zicam causes anosmia. In its warning, the FDA stated, "This warning does not involve oral zinc tablets and lozenges taken by mouth. Dietary zinc is also not subject to this warning."
Veterinary use
A zinc gluconate-based product, also containing arginine, is used as a veterinary chemical castration drug. For dogs, the product is injected directly into the testicles. It has been sold under various brand names, including Neutersol and Esterilsol.
References
External links
A12CB02 (WHO) |
Alogliptin | Alogliptin, sold under the brand names Nesina and Vipidia,) is an oral anti-diabetic drug in the DPP-4 inhibitor (gliptin) class. Alogliptin does not decrease the risk of heart attack and stroke. Like other members of the gliptin class, it causes little or no weight gain, exhibits relatively little risk of hypoglycemia, and has relatively modest glucose-lowering activity. Alogliptin and other gliptins are commonly used in combination with metformin in people whose diabetes cannot adequately be controlled with metformin alone.In April 2016, the U.S. Food and Drug Administration (FDA) added a warning about increased risk of heart failure. It was developed by Syrrx, a company which was acquired by Takeda Pharmaceutical Company in 2005.
Medical uses
Alogliptin is a dipeptidyl peptidase-4 inhibitor that decreases blood sugar similar to the other.
Side effects
Adverse events include mild hypoglycemia based on clinical studies. Alogliptin is not associated with increased weight, increased risk of cardiovascular events. It may also cause joint pain that can be severe and disabling. In April 2016, the U.S. Food and Drug Administration (FDA) added a warning about increased risk of heart failure.
Market access
In December 2007, Takeda submitted a New Drug Application (NDA) for alogliptin to the United States Food and Drug Administration (USFDA), after positive results from Phase III clinical trials. In September 2008, the company also filed for approval in Japan, winning approval in April 2010. The company also filed a Marketing Authorization Application (MAA) elsewhere outside the United States, which was withdrawn in June 2009 needing more data. The first USFDA NDA failed to gain approval and was followed by a pair of NDAs (one for alogliptin and a second for a combination of alogliptin and pioglitazone) in July 2011. In 2012, Takeda received a negative response from the USFDA on both of these NDAs, citing a need for additional data.In 2013, the FDA approved the drug in three formulations: as a stand-alone with the brand-name Nesina, combined with metformin using the name Kazano, and when combined with pioglitazone as Oseni.
References
External links
"Alogliptin". Drug Information Portal. U.S. National Library of Medicine.
Media related to Alogliptin at Wikimedia Commons |
Dasiglucagon | Dasiglucagon, sold under the brand name Zegalogue, is a medication used to treat severe hypoglycemia in people with diabetes.The most common side effects include nausea, vomiting, headache, diarrhea, and injection site pain.Dasiglucagon was approved for medical use in the United States in March 2021. It was designated an orphan drug in August 2017.
Medical uses
Dasiglucagon is indicated for the treatment of severe hypoglycemia in people aged six years of age and older with diabetes.
Contraindications
Dasiglucagon is contraindicated in people with pheochromocytoma or insulinoma.
References
External links
"Dasiglucagon". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03378635 for "A Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Type 1 Diabetes Subjects" at ClinicalTrials.gov
Clinical trial number NCT03688711 for "Trial to Confirm the Clinical Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Subjects With T1DM" at ClinicalTrials.gov
Clinical trial number NCT03667053 for "Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in T1DM Children" at ClinicalTrials.gov |
Promethazine | Promethazine is a first-generation antihistamine and antiemetic used to treat allergies, insomnia, and nausea. It may also help with some symptoms associated with the common cold and may also be used for sedating people who are agitated or anxious. Promethazine is available by mouth in syrup or tablet dosage forms, as a rectal suppository, or by injection into a muscle.Common side effects of promethazine include confusion and sleepiness; consumption of alcohol or other sedatives can make these symptoms worse. It is unclear if use of promethazine during pregnancy or breastfeeding is safe for the baby. Use of promethazine is not recommended in those less than two years old, due to potentially negative effects on breathing. Use of promethazine by injection into a vein is not recommended, due to potential skin damage. Promethazine is in the phenothiazine family of medications.Promethazine was made in the 1940s by a team of scientists from Rhône-Poulenc laboratories. It was approved for medical use in the United States in 1951. It is a generic medication and is available under many brand names globally. In 2019, it was the 174th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Medical uses
Promethazine has a variety of medical uses, including:
Sedation
For nausea and vomiting associated with anesthesia or chemotherapy. It is commonly used postoperatively as an antiemetic. The antiemetic activity increases with increased dosing; however, side effects also increase, which often limits maximal dosing.
For moderate to severe morning sickness and hyperemesis gravidarum: In the UK, promethazine is drug of first choice, being preferred as an older drug with which there is a greater experience of use in pregnancy (second in line being metoclopramide or prochlorperazine).
For allergies such as hay fever and together with other medications in anaphylaxis
To aid with symptoms of the common cold
Motion sickness, including space sickness
Hemolytic disease of the newborn
Anxiety before surgery
Side effects
Some documented side effects include:
Tardive dyskinesia, pseudoparkinsonism, acute dystonia (effects due to dopamine D2 receptor antagonism)
Confusion in the elderly
Drowsiness, dizziness, fatigue, more rarely vertigo
Known to have effects on serotonin and dopamine receptors.
Dry mouth
Nausea
Respiratory depression in patients under age of two and in those with severely compromised pulmonary function
Blurred vision, xerostomia, dry nasal passages, dilated pupils, constipation, and urinary retention. (due to cholinergic effects)
Chest discomfort/pressure (In children less than 2 years old)
AkathisiaLess frequent:
Cardiovascular side effects to include arrhythmias and hypotension
Neuroleptic malignant syndrome
Liver damage and cholestatic jaundice
Bone marrow suppression, potentially resulting in agranulocytosis, thrombocytopenia, and leukopenia
Depression of the thermoregulatory mechanism resulting in hypothermia/hyperthermiaRare side effects include:
SeizuresBecause of potential for more severe side effects, this drug is on the list to avoid in the elderly. In many countries (including the US and UK), promethazine is contraindicated in children less than two years of age, and strongly cautioned against in children between two and six, due to problems with respiratory depression and sleep apnea.Promethazine is listed as one of the drugs of highest anticholinergic activity in a study of anticholinergenic burden, including long-term cognitive impairment.
Pharmacology
Promethazine, a phenothiazine derivative, is structurally different from the neuroleptic phenothiazines, with similar but different effects. It acts primarily as a strong antagonist of the H1 receptor (antihistamine) and a moderate mACh receptor antagonist (anticholinergic), and also has weak to moderate affinity for the 5-HT2A, 5-HT2C, D2, and α1-adrenergic receptors, where it acts as an antagonist at all sites, as well. New studies have shown that promethazine acts as a strong non-competitive selective NMDA receptor antagonist; which might promote sedation in addition with the strong antihistaminergic effects of the H1 receptor, but also as a weaker analgesic. It does not however affect the AMPA receptors.Another notable use of promethazine is as a local anesthetic, by blockage of sodium channels.
Chemistry
Solid promethazine hydrochloride is a white to faint-yellow, practically odorless, crystalline powder. Slow oxidation may occur upon prolonged exposure to air, usually causing blue discoloration. Its hydrochloride salt is freely soluble in water and somewhat soluble in alcohol. Promethazine is a chiral compound, occurring as a mixture of enantiomers.
History
Promethazine was first synthesized by a group at Rhone-Poulenc (which later became part of Sanofi) led by Paul Charpentier in the early 1940s. The team was seeking to improve on diphenhydramine; the same line on medical chemistry led to the creation of chlorpromazine.
Society and culture
As of July 2017 it was marketed under many brand names worldwide: Allersoothe, Antiallersin, Anvomin, Atosil, Avomine, Closin N, Codopalm, Diphergan, Farganesse, Fenazil, Fenergan, Fenezal, Frinova, Hiberna, Histabil, Histaloc, Histantil, Histazin, Histazine, Histerzin, Lenazine, Lergigan, Nufapreg, Otosil, Pamergan, Pharmaniaga, Phenadoz, Phenerex, Phenergan, Phénergan, Pipolphen, Polfergan, Proazamine, Progene, Prohist, Promet, Prometal, Prometazin, Prometazina, Promethazin, Prométhazine, Promethazinum, Promethegan, Promezin, Proneurin, Prothazin, Prothiazine, Prozin, Pyrethia, Quitazine, Reactifargan, Receptozine, Romergan, Sominex, Sylomet, Xepagan, Zinmet, and Zoralix.
It is also marketed in many combination drug formulations:
with carbocisteine as Actithiol Antihistaminico, Mucoease, Mucoprom, Mucotal Prometazine, and Rhinathiol;
with paracetamol (acetaminophen) as Algotropyl, Calmkid, Fevril, Phen Plus, and Velpro-P;
with paracetamol and dextromethorphan as Choligrip na noc, Coldrex Nočná Liečba, Fedril Night Cold and Flu, Night Nurse, and Tachinotte;
with paracetamol, phenylephrine, and salicylamide as Flukit;
with dextromethorphan as Axcel Dextrozine and Hosedyl DM;
with dextromethorphan and ephedrine as Methorsedyl;
with dextromethorphan and pseudoephedrine as Sedilix-DM;
with dextromethorphan and phenylephedrine as Sedilix-RX;
with pholcodine as Codo-Q Junior and Tixylix;
with pholcodine and ephedrine as Phensedyl Dry Cough Linctus;
with pholcodine and phenylephedrine as Russedyl Compound Linctus;
with pholcodine and phenylpropanolamine as Triple P;
with codeine as Kefei and Procodin;
with codeine and ephedrine as Dhasedyl, Fendyl, and P.E.C.;
with ephedrine and dextromethorphan as Dhasedyl DM;
with glutamic acid as Psico-Soma, and Psicosoma;
with noscapine as Tussisedal; and
with chlorpromazine and phenobarbital as Vegetamin.
Recreational use
The recreational drug lean, also known as purple drank among other names, often contains a combination of promethazine with codeine-containing cold medication.
Product liability lawsuit
In 2009, the US Supreme Court ruled on a product liability case involving promethazine. Diana Levine, a woman with a migraine, was administered Wyeths Phenergan via IV push. The drug was injected improperly, resulting in gangrene and subsequent amputation of her right forearm below the elbow. A state jury awarded her $6 million in punitive damages.
The case was appealed to the Supreme Court on grounds of federal preemption and substantive due process. The Supreme Court upheld the lower courts rulings, stating that "Wyeth could have unilaterally added a stronger warning about IV-push administration" without acting in opposition to federal law. In effect, this means drug manufacturers can be held liable for injuries if warnings of potential adverse effects, approved by the US Food and Drug Administration (FDA), are deemed insufficient by state courts.
On September 9, 2009, the FDA required a boxed warning be put on promethazine for injection, stating the contraindication for subcutaneous administration. The preferred administrative route is intramuscular, which reduces risk of surrounding muscle and tissue damage.
References
External links
"Promethazine". U.S. National Library of Medicine and National Institutes of Health. |
Ciprofloxacin | Ciprofloxacin is a fluoroquinolone antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra abdominal infections, certain types of infectious diarrhea, respiratory tract infections, skin infections, typhoid fever, and urinary tract infections, among others. For some infections it is used in addition to other antibiotics. It can be taken by mouth, as eye drops, as ear drops, or intravenously.Common side effects include nausea, vomiting, and diarrhea. Severe side effects include an increased risk of tendon rupture, hallucinations, and nerve damage. In people with myasthenia gravis, there is worsening muscle weakness. Rates of side effects appear to be higher than some groups of antibiotics such as cephalosporins but lower than others such as clindamycin. Studies in other animals raise concerns regarding use in pregnancy. No problems were identified, however, in the children of a small number of women who took the medication. It appears to be safe during breastfeeding. It is a second-generation fluoroquinolone with a broad spectrum of activity that usually results in the death of the bacteria.Ciprofloxacin was patented in 1980 and introduced in 1987. It is on the World Health Organizations List of Essential Medicines. The World Health Organization classifies ciprofloxacin as critically important for human medicine. It is available as a generic medication. In 2019, it was the 113th most commonly prescribed medication in the United States, with more than 5 million prescriptions.
Medical uses
Ciprofloxacin is used to treat a wide variety of infections, including infections of bones and joints, endocarditis, gastroenteritis, malignant otitis externa, respiratory tract infections, cellulitis, urinary tract infections, prostatitis, anthrax, and chancroid.Ciprofloxacin only treats bacterial infections; it does not treat viral infections such as the common cold. For certain uses including acute sinusitis, lower respiratory tract infections and uncomplicated gonorrhea, ciprofloxacin is not considered a first-line agent.
Ciprofloxacin occupies an important role in treatment guidelines issued by major medical societies for the treatment of serious infections, especially those likely to be caused by Gram-negative bacteria, including Pseudomonas aeruginosa. For example, ciprofloxacin in combination with metronidazole is one of several first-line antibiotic regimens recommended by the Infectious Diseases Society of America for the treatment of community-acquired abdominal infections in adults. It also features prominently in treatment guidelines for acute pyelonephritis, complicated or hospital-acquired urinary tract infection, acute or chronic prostatitis, certain types of endocarditis, certain skin infections, and prosthetic joint infections.In other cases, treatment guidelines are more restrictive, recommending in most cases that older, narrower-spectrum drugs be used as first-line therapy for less severe infections to minimize fluoroquinolone-resistance development. For example, the Infectious Diseases Society of America recommends the use of ciprofloxacin and other fluoroquinolones in urinary tract infections be reserved to cases of proven or expected resistance to narrower-spectrum drugs such as nitrofurantoin or trimethoprim/sulfamethoxazole. The European Association of Urology recommends ciprofloxacin as an alternative regimen for the treatment of uncomplicated urinary tract infections, but cautions that the potential for "adverse events have to be considered".Although approved by regulatory authorities for the treatment of respiratory infections, ciprofloxacin is not recommended for respiratory infections by most treatment guidelines due in part to its modest activity against the common respiratory pathogen Streptococcus pneumoniae. "Respiratory quinolones" such as levofloxacin, having greater activity against this pathogen, are recommended as first line agents for the treatment of community-acquired pneumonia in patients with important co-morbidities and in patients requiring hospitalization (Infectious Diseases Society of America 2007). Similarly, ciprofloxacin is not recommended as a first-line treatment for acute sinusitis.Ciprofloxacin is approved for the treatment of gonorrhea in many countries, but this recommendation is widely regarded as obsolete due to resistance development.
Pregnancy
In the United States ciprofloxacin is pregnancy category C. This category includes drugs for which no adequate and well-controlled studies in human pregnancy exist, and for which animal studies have suggested the potential for harm to the fetus, but potential benefits may warrant use of the drug in pregnant women
despite potential risks. An expert review of published data on experiences with ciprofloxacin use during pregnancy by the Teratogen Information System concluded therapeutic doses during
pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state no risk exists. Exposure to quinolones, including levofloxacin, during the first-trimester is not associated with an increased risk of stillbirths, premature births, birth defects, or low birth weight.Two small post-marketing epidemiology studies of mostly short-term, first-trimester exposure found that fluoroquinolones did not increase risk of major malformations, spontaneous abortions, premature birth, or low birth weight. The label notes, however, that these studies are insufficient to reliably evaluate the definitive safety or risk of less common defects by ciprofloxacin in pregnant women and their developing fetuses.
Breastfeeding
Fluoroquinolones have been reported as present in a mothers milk and thus passed on to the nursing child. The U.S. Food and Drug Administration (FDA) recommends that because of the risk of serious adverse reactions (including articular damage) in infants nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Children
Oral and intravenous ciprofloxacin are approved by the FDA for use in children for only two indications due to the risk of permanent injury to the musculoskeletal system:
Inhalational anthrax (postexposure)
Complicated urinary tract infections and pyelonephritis due to Escherichia coli, but never as first-line agents.Current recommendations by the American Academy of Pediatrics note the systemic use of ciprofloxacin in children should be restricted to infections caused by multidrug-resistant pathogens or when no safe or effective alternatives are available.
Spectrum of activity
Its spectrum of activity includes most strains of bacterial pathogens responsible for community-acquired pneumonias, bronchitis, urinary tract infections, and gastroenteritis. Ciprofloxacin is particularly effective against Gram-negative bacteria (such as Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Proteus mirabilis, and Pseudomonas aeruginosa), but is less effective against Gram-positive bacteria (such as methicillin-sensitive Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecalis) than newer fluoroquinolones.
Bacterial resistance
As a result of its widespread use to treat minor infections readily treatable with older, narrower spectrum antibiotics, many bacteria have developed resistance to this drug in recent years, leaving it significantly less effective than it would have been otherwise.Resistance to ciprofloxacin and other fluoroquinolones may evolve rapidly, even during a course of treatment. Numerous pathogens, including enterococci, Streptococcus pyogenes and Klebsiella pneumoniae (quinolone-resistant) now exhibit resistance. Widespread veterinary usage of the fluoroquinolones, particularly in Europe, has been implicated. Meanwhile, some Burkholderia cepacia, Clostridium innocuum and Enterococcus faecium strains have developed resistance to ciprofloxacin to varying degrees.Fluoroquinolones had become the class of antibiotics most commonly prescribed to adults in 2002. Nearly half (42%) of those prescriptions in the U.S. were for conditions not approved by the FDA, such as acute bronchitis, otitis media, and acute upper respiratory tract infection, according to a study supported in part by the Agency for Healthcare Research and Quality. Additionally, they were commonly prescribed for medical conditions that were not even bacterial to begin with, such as viral infections, or those to which no proven benefit existed.
Contraindications
Contraindications include:
Taking tizanidine at the same time
Use by those who are hypersensitive to any member of the quinolone class of antimicrobial agents
Use by those who are diagnosed with myasthenia graves, as muscle weakness may be exacerbatedCiprofloxacin is also considered to be contraindicated in children (except for the indications outlined above), in pregnancy, to nursing mothers, and in people with epilepsy or other seizure disorders.
Caution may be required in people with Marfan syndrome or Ehlers-Danlos syndrome.
Adverse effects
Adverse effects can involve the tendons, muscles, joints, nerves, and the central nervous system.Rates of adverse effects appear to be higher than with some groups of antibiotics such as cephalosporins but lower than with others such as clindamycin. Compared to other antibiotics some studies find a higher rate of adverse effects while others find no difference.In clinical trials most of the adverse events were described as mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment. Some adverse effects may be permanent. Ciprofloxacin was stopped because of an adverse event in 1% of people treated with the medication by mouth. The most frequently reported drug-related events, from trials of all formulations, all dosages, all drug-therapy durations, and for all indications, were nausea (2.5%), diarrhea (1.6%), abnormal liver function tests (1.3%), vomiting (1%), and rash (1%). Other adverse events occurred at rates of <1%.
Tendon problems
Ciprofloxacin includes a boxed warning in the United States due to an increased risk of tendinitis and tendon rupture, especially in people who are older than 60 years, people who also use corticosteroids, and people with kidney, lung, or heart transplants. Tendon rupture can occur during therapy or even months after discontinuation of the medication. One study found that fluoroquinolone use was associated with a 1.9-fold increase in tendon problems. The risk increased to 3.2 in those over 60 years of age and to 6.2 in those over the age of 60 who were also taking corticosteroids. Among the 46,766 quinolone users in the study, 38 (0.08%) cases of Achilles tendon rupture were identified.
Cardiac arrhythmia
The fluoroquinolones, including ciprofloxacin, are associated with an increased risk of cardiac toxicity, including QT interval prolongation, torsades de pointes, ventricular arrhythmia, and sudden death.
Nervous system
Because Ciprofloxacin is lipophilic, it has the ability to cross the blood-brain barrier. The 2013 FDA label warns of nervous system effects. Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold, and may cause other central nervous system adverse effects. Headache, dizziness, and insomnia have been reported as occurring fairly commonly in postapproval review articles, along with a much lower incidence of serious CNS adverse effects such as tremors, psychosis, anxiety, hallucinations, paranoia, and suicide attempts, especially at higher doses. Like other fluoroquinolones, it is also known to cause peripheral neuropathy that may be irreversible, such as weakness, burning pain, tingling or numbness.
Cancer
Ciprofloxacin is active in six of eight in vitro assays used as rapid screens for the detection of genotoxic effects, but is not active in in vivo assays of genotoxicity. Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively (about 1.7 and 2.5 times the highest recommended therapeutic dose based upon mg/m2). Results from photo co-carcinogenicity testing indicate ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control.
Other
The other black box warning is that ciprofloxacin should not be used in people with myasthenia gravis due to possible exacerbation of muscle weakness which may lead to breathing problems resulting in death or ventilator support. Fluoroquinolones are known to block neuromuscular transmission. There are concerns that fluoroquinolones including ciprofloxacin can affect cartilage in young children.Clostridium difficile-associated diarrhea is a serious adverse effect of ciprofloxacin and other fluoroquinolones; it is unclear whether the risk is higher than with other broad-spectrum antibiotics.A wide range of rare but potentially fatal adverse effects reported to the U.S. FDA or the subject of case reports includes aortic dissection, toxic epidermal necrolysis, Stevens–Johnson syndrome, low blood pressure, allergic pneumonitis, bone marrow suppression, hepatitis or liver failure, and sensitivity to light. The medication should be discontinued if a rash, jaundice, or other sign of hypersensitivity occurs.Children and the elderly are at a much greater risk of experiencing adverse reactions.
Overdose
Overdose of ciprofloxacin may result in reversible renal toxicity. Treatment of overdose includes emptying of the stomach by induced vomiting or gastric lavage, as well as administration of antacids containing magnesium, aluminium, or calcium to reduce drug absorption. Renal function and urinary pH should be monitored. Important support includes adequate hydration and urine acidification if necessary to prevent crystalluria. Hemodialysis or peritoneal dialysis can only remove less than 10% of ciprofloxacin. Ciprofloxacin may be quantified in plasma or serum to monitor for drug accumulation in patients with hepatic dysfunction or to confirm a diagnosis of poisoning in acute overdose victims.
Interactions
Ciprofloxacin interacts with certain foods and several other drugs leading to undesirable increases or decreases in the serum levels or distribution of one or both drugs.
Ciprofloxacin should not be taken with antacids containing magnesium or aluminum, highly buffered drugs (sevelamer, lanthanum carbonate, sucralfate, didanosine), or with supplements containing calcium, iron, or zinc. It should be taken two hours before or six hours after these products. Magnesium or aluminum antacids turn ciprofloxacin into insoluble salts that are not readily absorbed by the intestinal tract, reducing peak serum concentrations by 90% or more, leading to therapeutic failure. Additionally, it should not be taken with dairy products or calcium-fortified juices alone, as peak serum concentration and the area under the serum concentration-time curve can be reduced up to 40%. However, ciprofloxacin may be taken with dairy products or calcium-fortified juices as part of a meal.Ciprofloxacin inhibits the drug-metabolizing enzyme CYP1A2 and thereby can reduce the clearance of drugs metabolized by that enzyme. CYP1A2 substrates that exhibit increased serum levels in ciprofloxacin-treated patients include tizanidine, theophylline, caffeine, methylxanthines, clozapine, olanzapine, and ropinirole. Co-administration of ciprofloxacin with the CYP1A2 substrate tizanidine (Zanaflex) is contraindicated due to a 583% increase in the peak serum concentrations of tizanidine when administered with ciprofloxacin as compared to administration of tizanidine alone. Use of ciprofloxacin is cautioned in patients on theophylline due to its narrow therapeutic index. The authors of one review recommended that patients being treated with ciprofloxacin reduce their caffeine intake. Evidence for significant interactions with several other CYP1A2 substrates such as cyclosporine is equivocal or conflicting.The Committee on Safety of Medicines and the FDA warn that central nervous system adverse effects, including seizure risk, may be increased when NSAIDs are combined with quinolones. The mechanism for this interaction may involve a synergistic increased antagonism of GABA neurotransmission.Altered serum levels of the antiepileptic drugs phenytoin and carbamazepine (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.Ciprofloxacin is a potent inhibitor of CYP1A2, CYP2D6, and CYP3A4.
Mechanism of action
Ciprofloxacin is a broad-spectrum antibiotic of the fluoroquinolone class. It is active against some Gram-positive and many Gram-negative bacteria. It functions by inhibiting a type II topoisomerase (DNA gyrase) and topoisomerase IV, necessary to separate bacterial DNA, thereby inhibiting cell division. Bacterial DNA fragmentation will occur as a result of inhibition of the enzymes.
Pharmacokinetics
Ciprofloxacin for systemic administration is available as immediate-release tablets, extended-release tablets, an oral suspension, and as a solution for intravenous administration. When administered over one hour as an intravenous infusion, ciprofloxacin rapidly distributes into the tissues, with levels in some tissues exceeding those in the serum. Penetration into the central nervous system is relatively modest, with cerebrospinal fluid levels normally less than 10% of peak serum concentrations. The serum half-life of ciprofloxacin is about 4–6 hours, with 50–70% of an administered dose being excreted in the urine as unmetabolized drug. An additional 10% is excreted in urine as metabolites. Urinary excretion is virtually complete 24 hours after administration. Dose adjustment is required in the elderly and in those with renal impairment.Ciprofloxacin is weakly bound to serum proteins (20–40%). It is an inhibitor of the drug-metabolizing enzyme cytochrome P450 1A2, which leads to the potential for clinically important drug interactions with drugs metabolized by that enzyme.Ciprofloxacin is about 70% orally available when administered orally, so a slightly higher dose is needed to achieve the same exposure when switching from IV to oral administrationThe extended release oral tablets allow once-daily administration by releasing the drug more slowly in the gastrointestinal tract. These tablets contain 35% of the administered dose in an immediate-release form and 65% in a slow-release matrix. Maximum serum concentrations are achieved between 1 and 4 hours after administration. Compared to the 250- and 500-mg immediate-release tablets, the 500-mg and 1000-mg XR tablets provide higher Cmax, but the 24‑hour AUCs are equivalent.
Ciprofloxacin immediate-release tablets contain ciprofloxacin as the hydrochloride salt, and the XR tablets contain a mixture of the hydrochloride salt as the free base.
Chemical properties
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4 g/mol. It is a faintly yellowish to light yellow crystalline substance.Ciprofloxacin hydrochloride (USP) is the monohydrochloride monohydrate salt of ciprofloxacin. It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8 g/mol. Its empirical formula is C17H18FN3O3HCl•H2O.
Usage
Ciprofloxacin is the most widely used of the second-generation quinolones. In 2010, over 20 million prescriptions were written, making it the 35th-most commonly prescribed generic drug and the 5th-most commonly prescribed antibacterial in the U.S.
History
The first members of the quinolone antibacterial class were relatively low-potency drugs such as nalidixic acid, used mainly in the treatment of urinary tract infections owing to their renal excretion and propensity to be concentrated in urine. In 1979, the publication of a patent filed by the pharmaceutical arm of Kyorin Seiyaku Kabushiki Kaisha disclosed the discovery of norfloxacin, and the demonstration that certain structural modifications including the attachment of a fluorine atom to the quinolone ring leads to dramatically enhanced antibacterial potency. In the aftermath of this disclosure, several other pharmaceutical companies initiated research and development programs with the goal of discovering additional antibacterial agents of the fluoroquinolone class.
The fluoroquinolone program at Bayer focused on examining the effects of very minor changes to the norfloxacin structure. In 1983, the company published in vitro potency data for ciprofloxacin, a fluoroquinolone antibacterial having a chemical structure differing from that of norfloxacin by the presence of a single carbon atom. This small change led to a two- to 10-fold increase in potency against most strains of Gram-negative bacteria. Importantly, this structural change led to a four-fold improvement in activity against the important Gram-negative pathogen Pseudomonas aeruginosa, making ciprofloxacin one of the most potent known drugs for the treatment of this intrinsically antibiotic-resistant pathogen.The oral tablet form of ciprofloxacin was approved in October 1987, just one year after the approval of norfloxacin. In 1991, the intravenous formulation was introduced. Ciprofloxacin sales reached a peak of about 2 billion euros in 2001, before Bayers patent expired in 2004, after which annual sales have averaged around €200 million.The name probably originates from the International Scientific Nomenclature: ci- (alteration of cycl-) + propyl + fluor- + ox- + az- + -mycin.
Society and culture
Cost
It is available as a generic medication and not very expensive. At least one company, Turtle Pharma Private Limited provides industrial-size amounts
Generic equivalents
On 24 October 2001, the Prescription Access Litigation (PAL) project filed suit to dissolve an agreement between Bayer and three of its competitors which produced generic versions of drugs (Barr Laboratories, Rugby Laboratories, and Hoechst-Marion-Roussel) that PAL claimed was blocking access to adequate supplies and cheaper, generic versions of ciprofloxacin. The plaintiffs charged that Bayer Corporation, a unit of Bayer AG, had unlawfully paid the three competing companies a total of $200 million to prevent cheaper, generic versions of ciprofloxacin from being brought to the market, as well as manipulating its price and supply. Numerous other consumer advocacy groups joined the lawsuit. On 15 October 2008, five years after Bayers patent had expired, the United States District Court for the Eastern District of New York granted Bayers and the other defendants motion for summary judgment, holding that any anticompetitive effects caused by the settlement agreements between Bayer and its codefendants were within the exclusionary zone of the patent and thus could not be redressed by federal antitrust law, in effect upholding Bayers agreement with its competitors.
Available forms
Ciprofloxacin for systemic administration is available as immediate-release tablets, as extended-release tablets, as an oral suspension, and as a solution for intravenous infusion. It is also available for local administration as eye drops and ear drops.
Litigation
A class action was filed against Bayer AG on behalf of employees of the Brentwood Post Office in Washington, D.C., and workers at the U.S. Capitol, along with employees of American Media, Inc. in Florida and postal workers in general who alleged they developed serious adverse effects from taking ciprofloxacin in the aftermath of the anthrax attacks in 2001. The action alleged Bayer failed to warn class members of the potential side effects of the drug, thereby violating the Pennsylvania Unfair Trade Practices and Consumer Protection Laws. The class action was defeated and the litigation abandoned by the plaintiffs. A similar action was filed in 2003 in New Jersey by four New Jersey postal workers but was withdrawn for lack of grounds, as workers had been informed of the risks of ciprofloxacin when they were given the option of taking the drug.
Research
As resistance to ciprofloxacin has grown since its introduction, research has been conducted to discover and develop analogs that can be effective against resistant bacteria; some have been looked at in antiviral models as well.
References
External links
"Ciprofloxacin". Drug Information Portal. U.S. National Library of Medicine.
"Ciprofloxacin hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
"Ciprofloxacin Ophthalmic". MedlinePlus. |
Midazolam | Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia and procedural sedation, and to treat severe agitation. It works by inducing sleepiness, decreasing anxiety, and causing a loss of ability to create new memories. The drug does not cause an individual to become unconscious, merely to be sedated. It is also useful for the treatment of prolonged (lasting over 5 minutes) seizures. Midazolam can be given by mouth, intravenously, by injection into a muscle, by spraying into the nose, or through the cheek. When given intravenously, it typically begins working within five minutes; when injected into a muscle, it can take fifteen minutes to begin working. Effects last between one and six hours.
Side effects can include a decrease in efforts to breathe, low blood pressure, and sleepiness. Tolerance to its effects and withdrawal syndrome may occur following long-term use. Paradoxical effects, such as increased activity, can occur especially in children and older people. There is evidence of risk when used during pregnancy but no evidence of harm with a single dose during breastfeeding. It belongs to the benzodiazepine class of drugs and works by increasing the activity of the GABA neurotransmitter in the brain.Midazolam was patented in 1974 and came into medical use in 1982. It is on the World Health Organizations List of Essential Medicines. Midazolam is available as a generic medication. In many countries, it is a controlled substance.
Medical uses
Seizures
Midazolam is sometimes used for the acute management of prolonged seizures. Long-term use for the management of epilepsy is not recommended due to the significant risk of tolerance (which renders midazolam and other benzodiazepines ineffective) and the significant side effect of sedation. A benefit of midazolam is that in children it can be given in the cheek or in the nose for acute seizures, including status epilepticus. Midazolam is effective for status epilepticus or when intravenous access cannot be obtained, and has advantages of being water-soluble, having a rapid onset of action and not causing metabolic acidosis from the propylene glycol vehicle (which is not required due to its solubility in water), which occurs with other benzodiazepines.Drawbacks include a high degree of breakthrough seizures—due to the short half-life of midazolam—in over 50% of people treated, as well as treatment failure in 14–18% of people with refractory status epilepticus. Tolerance develops rapidly to the anticonvulsant effect, and the dose may need to be increased by several times to maintain anticonvulsant therapeutic effects. With prolonged use, tolerance and tachyphylaxis can occur and the elimination half-life may increase, up to days. Buccal and intranasal midazolam may be both easier to administer and more effective than rectally administered diazepam in the emergency control of seizures.
Procedural sedation
Intravenous midazolam is indicated for procedural sedation (often in combination with an opioid, such as fentanyl), preoperative sedation, for the induction of general anesthesia, and for sedation of people who are ventilated in critical care units. Midazolam is superior to diazepam in impairing memory of endoscopy procedures, but propofol has a quicker recovery time and a better memory-impairing effect. It is the most popular benzodiazepine in the intensive care unit (ICU) because of its short elimination half-life, combined with its water solubility and its suitability for continuous infusion. However, for long-term sedation, lorazepam is preferred due to its long duration of action, and propofol has advantages over midazolam when used in the ICU for sedation, such as shorter weaning time and earlier tracheal extubation.Midazolam is sometimes used in neonatal intensive care units. When used, additional caution is required in newborns; midazolam should not be used for longer than 72 hours due to risks of tachyphylaxis, and the possibility of development of a benzodiazepine withdrawal syndrome, as well as neurological complications. Bolus injections should be avoided due to the increased risk of cardiovascular depression, as well as neurological complications.
Midazolam is also sometimes used in newborns who are receiving mechanical ventilation, although morphine is preferred, owing to its better safety profile for this indication.Sedation using midazolam can be used to relieve anxiety and manage behaviour in children undergoing dental treatment.
Agitation
Midazolam, in combination with an antipsychotic drug, is indicated for the acute management of schizophrenia when it is associated with aggressive or out-of-control behaviour.
End of life care
In the final stages of end-of-life care, midazolam is routinely used at low doses via subcutaneous injection to help with agitation, restlessness or anxiety in the last hours or days of life. At higher doses during the last weeks of life, midazolam is considered a first line agent in palliative continuous deep sedation therapy when it is necessary to alleviate intolerable suffering not responsive to other treatments, but the need for this is rare.
Administration
Routes of administration of midazolam can be oral, intranasal, buccal, intravenous, and intramuscular.
Contraindications
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, in alcohol- or other drug-dependent individuals or those with comorbid psychiatric disorders. Additional caution is required in critically ill patients, as accumulation of midazolam and its active metabolites may occur. Kidney or liver impairments may slow down the elimination of midazolam leading to prolonged and enhanced effects. Contraindications include hypersensitivity, acute narrow-angle glaucoma, shock, hypotension, or head injury. Most are relative contraindications.
Side effects
Side effects of midazolam in the elderly are listed above. People experiencing amnesia as a side effect of midazolam are generally unaware their memory is impaired, unless they had previously known it as a side effect.Long-term use of benzodiazepines has been associated with long-lasting deficits in memory, and show only partial recovery six months after stopping benzodiazepines. It is unclear whether full recovery occurs after longer periods of abstinence. Benzodiazepines can cause or worsen depression. Paradoxical excitement occasionally occurs with benzodiazepines, including a worsening of seizures. Children and elderly individuals or those with a history of excessive alcohol use and individuals with a history of aggressive behavior or anger are at increased risk of paradoxical effects. Paradoxical reactions are particularly associated with intravenous administration. After nighttime administration of midazolam, residual hangover effects, such as sleepiness and impaired psychomotor and cognitive functions, may persist into the next day. This may impair the ability of users to drive safely and may increase the risk of falls and hip fractures. Sedation, respiratory depression and hypotension due to a reduction in systematic vascular resistance, and an increase in heart rate can occur. If intravenous midazolam is given too quickly, hypotension may occur. A "midazolam infusion syndrome" may result from high doses, is characterised by delayed arousal hours to days after discontinuation of midazolam, and may lead to an increase in the length of ventilatory support needed.In rare susceptible individuals, midazolam has been known to cause a paradoxical reaction, a well-documented complication with benzodiazepines. When this occurs, the individual may experience anxiety, involuntary movements, aggressive or violent behavior, uncontrollable crying or verbalization, and other similar effects. This seems to be related to the altered state of consciousness or disinhibition produced by the drug. Paradoxical behavior is often not recalled by the patient due to the amnesia-producing properties of the drug. In extreme situations, flumazenil can be administered to inhibit or reverse the effects of midazolam. Antipsychotic medications, such as haloperidol, have also been used for this purpose.Midazolam is known to cause respiratory depression. In healthy humans, 0.15 mg/kg of midazolam may cause respiratory depression, which is postulated to be a central nervous system (CNS) effect. When midazolam is administered in combination with fentanyl, the incidence of hypoxemia or apnea becomes more likely.Although the incidence of respiratory depression/arrest is low (0.1–0.5%) when midazolam is administered alone at normal doses, the concomitant use with CNS acting drugs, mainly analgesic opiates, may increase the possibility of hypotension, respiratory depression, respiratory arrest, and death, even at therapeutic doses. Potential drug interactions involving at least one CNS depressant were observed for 84% of midazolam users who were subsequently required to receive the benzodiazepine antagonist flumazenil. Therefore, efforts directed toward monitoring drug interactions and preventing injuries from midazolam administration are expected to have a substantial impact on the safe use of this drug.
Pregnancy and breastfeeding
Midazolam, when taken during the third trimester of pregnancy, may cause risk to the neonate, including benzodiazepine withdrawal syndrome, with possible symptoms including hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of hypotonia and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Other neonatal withdrawal symptoms include hyperexcitability, tremor, and gastrointestinal upset (diarrhea or vomiting). Breastfeeding by mothers using midazolam is not recommended.
Elderly
Additional caution is required in the elderly, as they are more sensitive to the pharmacological effects of benzodiazepines, metabolise them more slowly, and are more prone to adverse effects, including drowsiness, amnesia (especially anterograde amnesia), ataxia, hangover effects, confusion, and falls.
Tolerance, dependence, and withdrawal
A benzodiazepine dependence occurs in about one-third of individuals who are treated with benzodiazepines for longer than 4 weeks, which typically results in tolerance and benzodiazepine withdrawal syndrome when the dose is reduced too rapidly. Midazolam infusions may induce tolerance and a withdrawal syndrome in a matter of days. The risk factors for dependence include dependent personality, use of a benzodiazepine that is short-acting, high potency and long-term use of benzodiazepines. Withdrawal symptoms from midazolam can range from insomnia and anxiety to seizures and psychosis. Withdrawal symptoms can sometimes resemble a persons underlying condition. Gradual reduction of midazolam after regular use can minimise withdrawal and rebound effects. Tolerance and the resultant withdrawal syndrome may be due to receptor down-regulation and GABAA receptor alterations in gene expression, which causes long-term changes in the function of the GABAergic neuronal system.Chronic users of benzodiazepine medication who are given midazolam experience reduced therapeutic effects of midazolam, due to tolerance to benzodiazepines. Prolonged infusions with midazolam results in the development of tolerance; if midazolam is given for a few days or more a withdrawal syndrome can occur. Therefore, preventing a withdrawal syndrome requires that a prolonged infusion be gradually withdrawn, and sometimes, continued tapering of dose with an oral long-acting benzodiazepine such as clorazepate dipotassium. When signs of tolerance to midazolam occur during intensive care unit sedation the addition of an opioid or propofol is recommended. Withdrawal symptoms can include irritability, abnormal reflexes, tremors, clonus, hypertonicity, delirium and seizures, nausea, vomiting, diarrhea, tachycardia, hypertension, and tachypnea. In those with significant dependence, sudden discontinuation may result in withdrawal symptoms such as status epilepticus.
Overdose
A midazolam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. Benzodiazepine overdose in healthy individuals is rarely life-threatening with proper medical support; however, the toxicity of benzodiazepines increases when they are combined with other CNS depressants such as alcohol, opioids, or tricyclic antidepressants. The toxicity of benzodiazepine overdose and the risk of death are also increased in the elderly and those with obstructive pulmonary disease or when used intravenously. Treatment is supportive; activated charcoal can be used within an hour of the overdose. The antidote for an overdose of midazolam (or any other benzodiazepine) is flumazenil. While effective in reversing the effects of benzodiazepines it is not used in most cases as it may trigger seizures in mixed overdoses and benzodiazepine dependent individuals.Symptoms of midazolam overdose can include:
Detection in body fluids
Concentrations of midazolam or its major metabolite, 1-hydroxymidazolam glucuronide, may be measured in plasma, serum, or whole blood to monitor for safety in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalized patients, or to assist in a forensic investigation of a case of fatal overdosage. Patients with renal dysfunction may exhibit prolongation of elimination half-life for both the parent drug and its active metabolite, with accumulation of these two substances in the bloodstream and the appearance of adverse depressant effects.
Interactions
Protease inhibitors, nefazodone, sertraline, grapefruit, fluoxetine, erythromycin, diltiazem, clarithromycin inhibit the metabolism of midazolam, leading to a prolonged action. St Johns wort, rifapentine, rifampin, rifabutin, phenytoin enhance the metabolism of midazolam leading to a reduced action. Sedating antidepressants, antiepileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opioids, antipsychotics and alcohol enhance the sedative effects of midazolam. Midazolam is metabolized almost completely by cytochrome P450-3A4. Atorvastatin administration along with midazolam results in a reduced elimination rate of midazolam. St Johns wort decreases the blood levels of midazolam. Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations.
Pharmacology
Midazolam is a short-acting benzodiazepine in adults with an elimination half-life of 1.5–2.5 hours. In the elderly, as well as young children and adolescents, the elimination half-life is longer. Midazolam is metabolised into an active metabolite alpha1-hydroxymidazolam. Age-related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite. However, the active metabolite of midazolam is minor and contributes to only 10 percent of biological activity of midazolam. Midazolam is poorly absorbed orally, with only 50 percent of the drug reaching the bloodstream. Midazolam is metabolised by cytochrome P450 (CYP) enzymes and by glucuronide conjugation. The therapeutic as well as adverse effects of midazolam are due to its effects on the GABAA receptors; midazolam does not activate GABAA receptors directly but, as with other benzodiazepines, it enhances the effect of the neurotransmitter GABA on the GABAA receptors (↑ frequency of Cl− channel opening) resulting in neural inhibition. Almost all of the properties can be explained by the actions of benzodiazepines on GABAA receptors. This results in the following pharmacological properties being produced: sedation, induction of sleep, reduction in anxiety, anterograde amnesia, muscle relaxation and anticonvulsant effects.
History
Midazolam is among about 35 benzodiazepines currently used medically, and was synthesized in 1975 by Walser and Fryer at Hoffmann-LaRoche, Inc in the United States. Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs. The anticonvulsant properties of midazolam were studied in the late 1970s, but not until the 1990s did it emerge as an effective treatment for convulsive status epilepticus. As of 2010, it is the most commonly used benzodiazepine in anesthetic medicine. In acute medicine, midazolam has become more popular than other benzodiazepines, such as lorazepam and diazepam, because it is shorter lasting, is more potent, and causes less pain at the injection site. Midazolam is also becoming increasingly popular in veterinary medicine due to its water solubility. In 2018 it was revealed the CIA considered using Midazolam as a "truth serum" on terrorist suspects in project "Medication".
Society and culture
Cost
Midazolam is available as a generic medication.
Availability
Midazolam is available in the United States as a syrup or as an injectable solution.Dormicum brand midazolam is marketed by Roche as white, oval, 7.5-mg tablets in boxes of two or three blister strips of 10 tablets, and as blue, oval, 15-mg tablets in boxes of two (Dormonid 3x) blister strips of 10 tablets. The tablets are imprinted with "Roche" on one side and the dose of the tablet on the other side. Dormicum is also available as 1-, 3-, and 10-ml ampoules at a concentration of 5 mg/ml. Another manufacturer, Novell Pharmaceutical Laboratories, makes it available as Miloz in 3- and 5-ml ampoules. Midazolam is the only water-soluble benzodiazepine available. Another maker is Roxane Laboratories; the product in an oral solution, Midazolam HCl Syrup, 2 mg/ml clear, in a red to purplish-red syrup, cherry in flavor. It becomes soluble when the injectable solution is buffered to a pH of 2.9–3.7. Midazolam is also available in liquid form. It can be administered intramuscularly, intravenously, intrathecally, intranasally, buccally, or orally.
Legal status
In the Netherlands, midazolam is a List II drug of the Opium Law.
Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances. In the United Kingdom, midazolam is a Schedule 3/Class C controlled drug. In the United States, midazolam (DEA number 2884) is on the Schedule IV list of the Controlled Substances Act as a non-narcotic agent with low potential for abuse.
Marketing authorization
In 2011, the European Medicines Agency (EMA) granted a marketing authorisation for a buccal application form of midazolam, sold under the brand name Buccolam. Buccolam was initially approved for the treatment of prolonged, acute, convulsive seizures in people from three months to less than 18 years of age. This was the first application of a paediatric-use marketing authorisation.
Use in executions
The drug has been introduced for use in executions by lethal injection in certain jurisdictions in the United States in combination with other drugs. It was introduced to replace pentobarbital after the latters manufacturer disallowed that drugs use for executions. Midazolam acts as a sedative but will fail to render the condemned prisoner unconscious, at which time vecuronium bromide and potassium chloride are administered, stopping the prisoners breathing and heart, respectively. Since the condemned prisoner is not unconscious but merely sedated, two very different things, those following two drugs can cause extreme pain and panic in the soon to die prisoner.Midazolam has been used as part of a three-drug cocktail, with vecuronium bromide and potassium chloride in Florida and Oklahoma prisons. Midazolam has also been used along with hydromorphone in a two-drug protocol in Ohio and Arizona.The usage of midazolam in executions became controversial after condemned inmate Clayton Lockett apparently regained consciousness and started speaking midway through his 2014 execution when the state of Oklahoma attempted to execute him with an untested three-drug lethal injection combination using 100 mg of midazolam. Prison officials reportedly discussed taking him to a hospital before he was pronounced dead of a heart attack 40 minutes after the execution began. An observing doctor stated that Locketts vein had ruptured. It is not clear whether his death was caused by one or more of the drugs or by a problem in the administration procedure, nor is it clear what quantities of vecuronium bromide and potassium chloride were released to his system before the execution was cancelled.
Notable incidents
The state of Florida used midazolam to execute William Frederick Happ in October 2013.The state of Ohio used midazolam in the execution of Dennis McGuire in January 2014; it took McGuire 24 minutes to die after the procedure started, and he gasped and appeared to be choking during that time, leading to questions about the dosing and timing of the drug administration, as well as the choice of drugs.The execution of Ronald Bert Smith in the state of Alabama on 8 December 2016, "went awry soon after (midazolam) was administered"
again putting the effectiveness of the drug in question.In October 2016, the state of Ohio announced that it would resume executions in January 2017, using a formulation of midazolam, vecuronium bromide, and potassium chloride, but this was blocked by a Federal judge. On 26 July 2017, Ronald Phillips was executed with a three-drug cocktail including midazolam after the Supreme Court refused to grant a stay. Prior to this, the last execution in Ohio had been that of Dennis McGuire. Murderer Gary Ottes lawyers unsuccessfully challenged his Ohio execution, arguing that midazolam might not protect him from serious pain when the other drugs are administered. He died without incident in about 14 minutes on 13 September 2017.On 24 April 2017, the state of Arkansas carried out a double-execution of Jack Harold Jones, 52, and Marcel Williams, 46. The state of Arkansas attempted to execute eight people before its supply of midazolam expired on 30 April 2017. Two of them were granted a stay of execution, and another, Ledell T. Lee, 51, was executed on 20 April 2017.On 28 October 2021, the state of Oklahoma executed inmate John Marion Grant, 60, using midazolam as part of its three-drug cocktail hours after the U.S. Supreme Court ruled to lift a stay of execution for Oklahoma death row inmates. The execution was the states first since 2015. Witnesses to the execution said that when the first drug, midazolam, began to flow at 4:09 p.m., Grant started convulsing about two dozen times and vomited. Grant continued breathing, and a member of the execution team wiped the vomit off his face. At 4:15 p.m., officials said Grant was unconscious, and he was pronounced dead at 4:21 p.m.
Legal challenges
In Glossip v. Gross, attorneys for three Oklahoma inmates argued that midazolam could not achieve the level of unconsciousness required for surgery, meaning severe pain and suffering was likely. They argued that midazolam was cruel and unusual punishment and thus contrary to the Eighth Amendment to the United States Constitution. In June 2015, the U.S. Supreme Court ruled that they had failed to prove that midazolam was cruel and unusual when compared to known, available alternatives.The state of Nevada is also known to use midazolam in execution procedures. In July 2018, one of the manufacturers accused state officials of obtaining the medication under pretences. This incident was the first time a drug company successfully, though temporarily, halted an execution. A previous attempt in 2017, to halt an execution in the state of Arizona by another drug manufacturer was not successful.
References
External links
"Midazolam". Drug Information Portal. U.S. National Library of Medicine.
"Midazolam hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Inchem - Midazolam |
Verteporfin | Verteporfin (trade name Visudyne), a benzoporphyrin derivative, is a medication used as a photosensitizer for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular degeneration. Verteporfin accumulates in these abnormal blood vessels and, when stimulated by nonthermal red light with a wavelength of 689 nm in the presence of oxygen, produces highly reactive short-lived singlet oxygen and other reactive oxygen radicals, resulting in local damage to the endothelium and blockage of the vessels.Verteporfin is also used off-label for the treatment of central serous retinopathy.
Administration
Verteporfin is usually injected intravenously into the largest arm vein. It is injected at a dose of 6 mg/m2 and light-activated. It is usually is given 15 minutes before laser treatment. This dose can be repeated 4 times per year.
Contraindications
Porphyria.
Side effects
Most common side effects are blurred vision, headache, and local effects at the injection site. Also, photosensitivity; it is strictly advised to avoid exposure to sunlight and unscreened lighting until 48 hours after verteporfin administration.Dogs and rats have been treated with inactivated daily doses 32–70 times higher than the dose advised for humans. The 4 weeks of treatment resulted in mild extravascular hemolysis and hematopoiesis in the animals.
Interactions
Verteporfin is known to interact with the herbal remedy feverfew (Tanacetum parthenium), the latter of which seems to act as an antagonist to verteporfin for unknown reasons. Taking the two substances simultaneously is inadvisable.Verteporfin does not appear to be metabolized by Cytochrome P450 enzymes, therefore not affecting Cytochrome P450 metabolism of other drugs.
Shortages
In May 2020, a low manufacturing capacity caused disruption. This effected the usage of verteporfin among providers and patients in Europe. The EMA expected normal manufacturing to return by the first quarter 2022.
Potential against scarring
Verteporfin is FDA approved. Verteporfin is a YAP pathway inhibitor. Verteporfin displays a wide spectrum of anti-fibrotic properties. Verteporfin prevents fibrosis in several human organs. Verteporfin was first noted as a drug that blocked cell proliferation in the liver. It is an inhibitor of fibrosis in patients with persistent cholestasis. Research has highlighted that verteporfin decreased expression of fibrotic genes in fibroblasts collected from nodules of patients suffering from Dupuytrens contracture. In 2018 information revealed verteporfin stopped fibrosis in the lung.
Verteporfin is a marketed drug with a good safety profile. Physicians use verteporfin off-label. In 2018, physicians described the off-label usage for Peyronies disease as an interesting step.In 2021, scientists tested verteporfin to reveal if the drug would prevent scar tissue in skin. The testing of verteporfin on humans cleft lips was due to occur in late 2021.
References
External links
"Visudyne". Novartis. |
Naltrexone/bupropion | Naltrexone/bupropion, sold under the brand name Contrave among others, is a fixed-dose combination medication for the management of chronic obesity in adults in combination with a reduced-calorie diet and increased physical activity. It contains naltrexone, an opioid antagonist, and bupropion, an aminoketone antidepressant. It is taken by mouth. Both medications have individually shown some evidence of effectiveness in weight loss, and the combination has been shown to have some synergistic effects on weight.In September 2014, a sustained release formulation of the drug was approved for marketing in the United States under the brand name Contrave. The combination was subsequently approved in the European Union in the spring of 2015, where it is sold under the name Mysimba. It was approved in Canada under the Contrave brand name in 2018.
Medical uses
Naltrexone/bupropion is indicated, as an adjunct to a reduced-calorie diet and increased physical activity, for the management of weight in adults with an initial body mass index (BMI) of:
30 kg/m2 (obese), or
27 kg/m2 to < 30 kg/m2, (overweight) in the presence of one or more weight-related comorbidities, like type 2 diabetes, dyslipidaemia, or controlled high blood pressure
Available forms
Each Contrave tablet contains 8 mg naltrexone and 90 mg bupropion. Once full dosing is reached (after 4 weeks of administration), the total dosage of Contrave for overweightness or obesity is two tablets twice daily or 32 mg naltrexone and 360 mg bupropion per day.
Contraindications
The manufacturer recommends against its use in people that have/are:
History of seizures
History of an eating disorder such as bulimia nervosa or anorexia nervosa
Taking opioid pain medicines, taking medicines to stop opioid addiction, or are in opiate withdrawal
Taking an MAOI or have taken an MAOI in the last 14 days
Pregnant
Abruptly stopped using: alcohol, benzodiazepines, barbiturates, or antiepileptic drugs
Adverse effects
The U.S. Food and Drug Administration (FDA) has put a boxed warning onto this medicine because it may affect mood and increase the likelihood of suicidal thoughts in people under 25 years old. This is attributed to the bupropion component, as antidepressants have been associated with increased risk of suicidal thoughts, but not suicide, and only in people younger than 25.The safety and effectiveness in children under the age of 18 has not been studied.
Mechanism of action
Individually, naltrexone and bupropion each target pathways in the central nervous system that influence appetite and energy use.
Bupropion is a reuptake inhibitor and releasing agent of both norepinephrine and dopamine, and a nicotinic acetylcholine receptor antagonist, and it activates proopiomelanocortin (POMC) neurons in the hypothalamus which give an effect downstream, resulting in loss of appetite and increased energy output. The POMC is regulated by endogenous opioids via opioid-mediated negative feedback.
Naltrexone is a pure opioid antagonist, which further augments bupropions activation of the POMC.Combined, naltrexone/bupropion has an effect on the reward pathway that results in reduced food craving. In 2009, Monash University physiologist Michael Cowley was awarded one of Australias top research honors, the Commonwealth Science Ministers Prize for Life Scientist of the Year, in recognition of his elucidation of these pathways, which led to the development of the combination medication.
History
Orexigen submitted a New Drug Application (NDA) for this drug combination to the U.S. Food and Drug Administration (FDA) on 31 March 2010. Having paid a fee under the Prescription Drug User Fee Act, Orexigen was given a deadline for the FDA to approve or reject the drug of 31 January 2011. On 7 December 2010, an FDA Advisory Committee voted 13-7 for the approval of Contrave, and voted 11-8 for the conduct of a post-marketing cardiovascular outcomes study. Subsequently, on 2 February 2011, the FDA rejected the drug and it was decided that an extremely large-scale study of the long-term cardiovascular effects of Contrave would be needed, before approval could be considered. It was ultimately approved in the United States in the fall of 2014.In December 2014, the EUs Committee for Medicinal Products for Human Use (CHMP) endorsed the combination for licensure as an obesity medication when used alongside diet and exercise. Approval was granted in late March 2015.In May 2015, Orexigen ended a safety study of its diet drug earlier than planned, because an independent panel of experts says the drug maker “inappropriately” compromised the trial by prematurely releasing interim data. The early data release reported a reduction in heart attacks that was no longer observed when a more complete view of the data was analyzed.In 2018, Orexigen sold its assets, including Contrave, to Nalpropion Pharmaceuticals.
Marketing and sales
The sustained-release formulation, Contrave, is marketed by Takeda under license from the combination medications developer, Orexigen Therapeutics. As of 2015, Orexigen received 20% of net sales from Takeda.At the time of its approval by the FDA, Wells Fargo analyst Matthew Andrews estimated that Contraves U.S. sales would reach approximately US$200,000,000 in 2016, exceeding that of the dominant alternative obesity medications lorcaserin and phentermine/topiramate. Despite being initially impeded by technical issues, the growth in filled prescriptions in the first months after approval was very rapid — substantially exceeding the equivalent early uptake of either of the two alternative medications just cited. The first quarter of sales for Contrave (Q1 2015) showed net sales of US$11,500,000.Despite having been approved for use in Europe in March 2015, sales of Contrave have not begun as Orexigen has not yet found a marketing partner.
See also
Bupropion/zonisamide
Bupropion/dextromethorphan
References
External links
"Bupropion mixture with naltrexone". Drug Information Portal. U.S. National Library of Medicine. |
Pemigatinib | Pemigatinib, sold under the brand name Pemazyre, is an anti-cancer medication used for the treatment of bile duct cancer (cholangiocarcinoma). Pemigatinib works by blocking FGFR2 in tumor cells to prevent them from growing and spreading.Pemigatinib belongs to a group of medicines called protein kinase inhibitors. It works by blocking enzymes known as protein kinases, particularly those that are part of receptors (targets) called fibroblast growth factor receptors (FGFRs). FGFRs are found on the surface of cancer cells and are involved in the growth and spread of the cancer cells. By blocking the tyrosine kinases in FGFRs, pemigatinib is expected to reduce the growth and spread of the cancer.The most common adverse reactions are hyperphosphatemia and hypophosphatemia (electrolyte disorders), alopecia (spot baldness), diarrhea, nail toxicity, fatigue, dysgeusia (taste distortion), nausea, constipation, stomatitis (sore or inflammation inside the mouth), dry eye, dry mouth, decreased appetite, vomiting, joint pain, abdominal pain, back pain and dry skin. Ocular (eye) toxicity is also a risk of pemigatinib. Additional common adverse reactions include rash, anemia, epistaxis, serous retinal detachment, extremity pain, dyspepsia, blurred vision, peripheral edema, and dizziness.
Medical uses
Pemigatinib is indicated for the treatment of adults with locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that have progressed after at least one prior line of systemic therapy. In the United States it is also indicated for the treatment of relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement.Cholangiocarcinoma is a rare form of cancer that forms in bile ducts, which are slender tubes that carry the digestive fluid bile from the liver to gallbladder and small intestine. Pemigatinib is indicated for the treatment of adults with bile duct cancer (cholangiocarcinoma) that is locally advanced (when cancer has grown outside the organ it started in, but has not yet spread to distant parts of the body) or metastatic (when cancer cells spread to other parts of the body) and who have tumors that have a fusion or other rearrangement of a gene called fibroblast growth factor receptor 2 (FGFR2).
History
Pemigatinib was approved for use in the United States in April 2020 along with the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.The approval of pemigatinib in the United States was based on the results the FIGHT-202 (NCT02924376) multicenter open-label single-arm trial that enrolled 107 participants with locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement who had received prior treatment. The trial was conducted at 67 sites in the United States, Europe, and Asia. During the clinical trial, participants received pemigatinib once a day for 14 consecutive days, followed by 7 days off, in 21-day cycles until the disease progressed or the patient experienced an unreasonable level of side effects. To assess how well pemigatinib was working during the trial, participants were scanned every eight weeks. The trial used established criteria to measure how many participants experienced a complete or partial shrinkage of their tumors during treatment (overall response rate). The overall response rate was 36% (95% CI: 27%, 45%), with 2.8% of participants having a complete response and 33% having a partial response. Among the 38 participants who had a response, 24 participants (63%) had a response lasting six months or longer and seven participants (18%) had a response lasting 12 months or longer.The U.S. Food and Drug Administration (FDA) granted the application for pemigatinib priority review, breakthrough therapy and orphan drug designations. The FDA granted approval of Pemazyre to Incyte Corporation.On 24 August 2018, orphan designation (EU/3/18/2066) was granted by the European Commission to Incyte Biosciences Distribution B.V., the Netherlands, for pemigatinib for the treatment of biliary tract cancer. On 17 October 2019, orphan designation EU/3/19/2216 was granted by the European Commission to Incyte Biosciences Distribution B.V., the Netherlands, for pemigatinib for the treatment of myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2. On 28 January 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 Pemazyre, intended for the second-line treatment of advanced or metastatic cholangiocarcinoma characterized by fusion or rearrangements of fibroblast growth factor receptor 2. The applicant for this medicinal product is Incyte Biosciences Distribution B.V. Pemigatinib was approved for medical use in the European Union in March 2021.Efficacy was evaluated in FIGHT-203 (NCT03011372), a multicenter open-label, single-arm trial that included 28 participants with relapsed or refractory MLNs with FGFR1 rearrangement. Eligible participants were either not candidates for or have relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or after a disease modifying therapy (e.g., chemotherapy). Pemigatinib was administered until disease progression, unacceptable toxicity, or until participants were able to receive allo-HSCT.
Society and culture
Names
Pemigatinib is the international nonproprietary name (INN).
References
Further reading
Roskoski R (January 2020). "The role of fibroblast growth factor receptor (FGFR) protein-tyrosine kinase inhibitors in the treatment of cancers including those of the urinary bladder". Pharmacol. Res. 151: 104567. doi:10.1016/j.phrs.2019.104567. PMID 31770593.
External links
"Pemigatinib". Drug Information Portal. U.S. National Library of Medicine.
"Pemigatinib". National Cancer Institute.
Clinical trial number NCT02924376 for "Efficacy and Safety of Pemigatinib in Subjects With Advanced/Metastatic or Surgically Unresectable Cholangiocarcinoma Who Failed Previous Therapy - (FIGHT-202)" at ClinicalTrials.gov
Clinical trial number NCT03011372 for "A Study to Evaluate the Efficacy and Safety of Pemigatinib (INCB054828) in Subjects With Myeloid/Lymphoid Neoplasms With FGFR1 Rearrangement - (FIGHT-203)" at ClinicalTrials.gov |
Cetacaine | Cetacaine is a topical anesthetic that contains the active ingredients benzocaine (14%), butamben (2%), and tetracaine hydrochloride (2%). Cetacaine also contains small amounts of benzalkonium chloride at 0.5% and 0.005% of cetyl dimethyl ethyl ammonium bromide all in a bland water-soluble base. Although Cetacaine has been widely used in the medical and dental fields, it has yet to be officially approved by the FDA. Cetacaine is produced by the company Cetylite Industries, Inc. and they provide Cetacaine in three forms: liquid, gel, and spray.
Medical uses
Cetacaine is a benzocaine-based anesthetic that also contains other active ingredients that include butamben and tetracaine hydrochloride. The main use for this drug is to produce anesthesia to mucous membranes to numb and help control the pain in that area. The spray form of Cetacaine is also used to help prevent gagging in the patient. The anesthetic effect of Cetacaine can be expected to take effect in about 30 seconds and last between 30–60 minutes depending on location and application amount. Cetacaine can and has been used for surgeries that include bronchi, ear, esophagus, larynx, mouth, nose, pharynx, rectal, and vaginal procedures. These procedures can include periodontal treatment, pre-probing, pre-scaling/root planning procedures, pre-injection, and laser dentistry.
Available forms
The dosage should be applied directly to the site where anesthesia is required. The dosage should be modified according to the patient and there has not been a dosage specified for children.Spray: Cetacaine spray should be applied for only one second and dosage should not exceed an application spray longer than 2 seconds.
Gel: Use a cotton swab to apply 200 mg to the needed area and the dosage should not exceed 400 mg.
Liquid: Apply 200 mg either directly or by using cotton applicator to the location and the dosage should not exceed 400 mg.
Adverse effects
Cetacaine has been known to cause adverse effects in the patients it has been administered to. These include hypersensitivity in the form of anaphylaxis, dermatitis, erythema, pruritus which can lead to oozing and vesiculation. There have also been accounts of rashes, edema, urticarial and other allergic symptoms as well as methemoglobinemia. Other adverse effects can include: tremors, twitching, dizziness, confusion, hypo-tension, vomiting, euphoria, and blurred or double vision.
Pregnancy and breastfeeding
It has not been determined of Cetacaine has any adverse defects on the formation of the fetus or if it is transferred through breastfeeding. It is recommended that professional advise should be taken in these regards.
Pharmacology
Mechanism of action
Cetacaine acts quickly in about 30 seconds and can last between 30–60 minutes. This is due to benzocaine causing the immediate anesthetic effect, while butamben and tetracaine hydrochloride causes the extended effect of Cetacaine.The actual mechanism for the onset of anesthesia is unknown, but it is believed that the active ingredients reversibly block nerve conduction therefore causing the numbing sensation. This stabilizes the neuron and prevents signals from being transferred.
Pharmacokinetics
The rate of absorption through the skin and after diffusing in and back out of the nerve membrane it is metabolized by plasma cholinesterase and then excreted in urine.
Contraindications
This product should not be used to cover a large area for anesthetic affect causing an adverse reaction. The liquid and other forms of Cetacaine should not be administered via injection or used under dentures, on eyes or with patients with a cholinesterase deficiency.
Interactions
Cetacaine can have interaction with other drugs being taken by patients one of the interactions that can lead to methemoglobinemia is the interaction with sodium nitrate as well as prilocaine, which can lead to severe illness or death. As well as others listed on the referenced site.
History
The marketing start date for Cetacaine was January 1, 1960, but benzocaine was first produced in 1890 by German scientist 1890 by Eduard Ritsert. Cetacaine is mainly used in the dental field but has seen use as well in the medical field when dealing with small surgeries on or around mucus membranes. Benzocaine-based anesthetics (which includes Cetacaine) have started to come scrutiny by the FDA. In 2006 the FDA has announced that benzocaine-based anesthetics can cause methemoglobinemia and with that listed warnings and precautions to take when dealing with benzocaine based drugs. The FDA also during this time started to take many Benzocaine based drugs that were not approved off the market and fining those companies they were under.
Research
From looking at the patent bank the only research that has occurred around Cetacaine has been with certain medical procedures that use Cetacaine as an anesthetic or new dispensing containers or methods.
One of the only studies that are current with Cetacaine is the one that the FDA is conducting surrounding the issue of patients contracting methemoglobinemia from the use of Cetacaine. In these studies it was recorded that 319 cases were reported and out of the 319, 32 were considered life-threatening and 3 cases resulted in death.
Economics
Cost effectivenss
Cetacaine has been used in the medical and dental field for a long time now. Its main competitors have been benzocaine and other benzocaine-based drugs. The use of Cetacaine has allowed for faster in and out times for patients, cheaper costs, easier use for the doctors or dentists needing to apply an anesthetic and better patient compliance (less anxiety).Cetacaine compared to some of the leading competitors is considered by most a cheaper option. For the spray option the bottle containing 56g can dispense 100 doses and only cost the dentist $0.79 per dose. The liquid Cetacaine that comes in the 30 g bottle can dose 73 full mouths at a cost of about $0.75 per dose.
Manufacturer
The company the makes Cetacaine is called Cetylite Industries, Inc. This company is based out of Pennsauken, NJ and has a total of 75 employees. Cetylite brings in total revenue of around $7,500,000 with their main product being the topical anesthetics, and infection prevention products.
== References == |
Methyldopa | Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure. It is one of the preferred treatments for high blood pressure in pregnancy. For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred. It can be given by mouth or injection into a vein. Onset of effects is around 5 hours and they last about a day.Common side effects include sleepiness. More severe side effects include red blood cell breakdown, liver problems, and allergic reactions. Methyldopa is in the alpha-2 adrenergic receptor agonist family of medication. It works by stimulating the brain to decrease the activity of the sympathetic nervous system.Methyldopa was discovered in 1960. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Methyldopa is used in the clinical treatment of the following disorders:
Hypertension (or high blood pressure)
Gestational hypertension (or pregnancy-induced hypertension) and pre-eclampsia.
Side effects
Methyldopa is capable of inducing a number of adverse side effects, which range from mild to severe. Nevertheless, they are generally mild when the dose is less than 1 gram per day. Side effects may include:
Psychological
Depression or even suicidal ideation, as well as nightmares
Apathy or anhedonia, as well as dysphoria
Anxiety, especially of the social anxiety variant
Decreased alertness, awareness, and wakefulness
Impaired attention, focus, and concentration
Decreased desire, drive, and motivation
Fatigue or lethargy or malaise or lassitude
Sedation or drowsiness or somnolence or sleepiness
Agitation or restlessness
Cognitive and memory impairment
Derealization or depersonalization, as well as mild psychosis
Sexual dysfunction including impaired libido, desire, and drive
Physiological
Dizziness, lightheadedness, or vertigo
Miosis or pupil constriction
Xerostomia or dry mouth
Gastrointestinal disturbances such as diarrhea or constipation
Headache or migraine
Myalgia or muscle aches, arthralgia or joint pain, or paresthesia ("pins and needles")
Restless legs syndrome (RLS)
Parkinsonian symptoms such as muscle tremors, rigidity, hypokinesia, or balance or postural instability
Akathisia, ataxia, dyskinesia as well as even tardive dyskinesia, or dystonia
Bells palsy or facial paralysis
Sexual dysfunction consisting of impaired erectile dysfunction or anorgasmia
Hyperprolactinemia or excess prolactin, gynecomastia/breast enlargement in males, or amenorrhoea or absence of menstrual cycles in females
Bradycardia or decreased heart rate
Hypotension or decreased blood pressure (though this may also be considered a therapeutic benefit)
Orthostatic hypotension (also known as postural hypotension)
Hepatitis, hepatotoxicity, or liver dysfunction or damage
Pancreatitis or inflammation of the pancreas
Warm autoimmune hemolytic anemia or deficiency in red blood cells (RBCs)
Myelotoxicity or bone marrow suppression, potentially leading to thrombocytopenia or blood platelet deficiency or leukopenia or white blood cell (WBC) deficiency
Hypersensitivity such as lupus erythematosus, myocarditis, or pericarditis
Lichenoid reactions such as skin lesions or rashes
Pallor
Rebound/withdrawal
Rebound hypertension via withdrawal on account of tolerance upon the abrupt discontinuation of methyldopa has been reported.
Mechanism of action
The mechanism of action of methyldopa is not fully clear. Although it is a centrally acting sympathomimetic, it does not block reuptake or transporters. It may reduce the dopaminergic and serotonergic transmission in the peripheral nervous system and it indirectly affects norepinephrine (noradrenaline) synthesis. Methyldopa acts on alpha-2 adrenergic receptors, which are found on the pre synaptic nerve terminal. This inhibits the synthesis of norepinephrine by inhibiting tyrosine hydroxylase.
The S-enantiomer of methyldopa is a competitive inhibitor of the enzyme aromatic L-amino acid decarboxylase (LAAD), which converts L-DOPA into dopamine. L-DOPA can cross the blood brain barrier and thus methyldopa may have similar effects. LAAD converts it into alpha-methyldopamine, a false prescursor to norepinephrine, which in turn reduces synthesis of norepinephrine in the vesicles. Dopamine beta hydroxylase (DBH) converts alpha-methyldopamine into alpha-methylnorepinephrine, which is an agonist of the presynaptic α2-adrenergic receptor causing inhibition of neurotransmitter release.
Pharmacokinetics
Maximum decrease in blood pressure occurs 4-6 hours after oral dosage. The half-life of methyldopa is 105 minutes. Methyldopa exhibits variable absorption from the gastrointestinal tract. It is metabolized in the liver and intestines and is excreted in urine.
History
When methyldopa was first introduced, it was the mainstay of antihypertensive treatment, but its use has declined on account of relatively severe adverse side effects, with increased use of other safer and more tolerable agents such as alpha blockers, beta blockers, and calcium channel blockers. Additionally, it has yet to be associated with reducing adverse cardiovascular events including myocardial infarction and stroke, or overall all-cause mortality reduction in clinical trials. Nonetheless, one of methyldopas still current indications is in the management of pregnancy-induced hypertension (PIH), as it is relatively safe in pregnancy compared to many other antihypertensives which may affect the fetus.
See also
Difluoromethyldopa
D-DOPA (dextrodopa)
L-DOPA (levodopa; trade names Sinemet, Pharmacopa, Atamet, Stalevo, Madopar, Prolopa, etc.)
L-DOPS (droxidopa)
Dopamine (Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc.)
Norepinephrine (noradrenaline; Levophed, etc.)
Epinephrine (adrenaline; Adrenalin, EpiPed, Twinject, etc.)
References
== External links == |
Estradiol/progesterone | Estradiol/progesterone (E2/P4), sold under the brand names Bijuva and Juvenum, is a combined estrogen and progestogen medication which is used in the treatment of menopausal symptoms in postmenopausal women. It contains estradiol, an estrogen, and progesterone, a progestogen, and is available in both oral and intramuscular formulations. E2/P4 differs from other estrogen–progestogen formulations in that the sex-hormonal agents used are bioidentical.
Bijuva (formerly TX-001HR/TX-12-001HR) is an oral combination of estradiol (E2), an estrogen, and progesterone (P4), a progestogen, which was developed by TherapeuticsMD and is approved in the United States for the treatment of menopausal symptoms in women. It is also under development for the treatment of endometrial hyperplasia in women. The medication contains 2 mg solubilized E2 and 200 mg P4 in each gelatin capsule. It is the first combination of E2 and P4 in oral capsule form that has been developed for clinical use. Bijuva is currently in phase III clinical trials for endometrial hyperplasia. The medication was approved by the Food and Drug Administration for the treatment of menopausal symptoms in October 2018.E2/P4 is available as an aqueous suspension of E2 and P4 encapsulated in microspheres for use by intramuscular injection once a month under the brand name Juvenum in Mexico. It was introduced for the treatment and prevention of menopausal symptoms like hot flashes, vulvovaginal symptoms, and osteoporosis in December 2014. The combination contains relatively low doses of E2 and P4 (1 mg and 20 mg, respectively) contained within microspheres that results in a slower release of the hormones. Studies of this formulation have been published.E2/P4 with 5 mg E2 and 150 to 300 mg P4 encapsulated in microspheres in an aqueous suspension has been studied as a once-a-month combined injectable contraceptive but has not been further developed or introduced for medical use. E2/P4 with 5 mg E2 and 100 mg P4 in a macrocrystalline aqueous suspension has also been studied as a once-a-month combined injectable contraceptive, but likewise was not further developed.As of April 2022, a vaginal ring containing E2/P4 (developmental code names DARE-HRT1 and JNP-0201) is under development for use in menopausal hormone therapy.
References
External links
"Estradiol mixture with progesterone". Drug Information Portal. U.S. National Library of Medicine. |
Almotriptan | Almotriptan (trade name Axert and others) is a triptan medication discovered and developed by Almirall for the treatment of heavy migraine headache.
It was patented in 1992 and approved for medical use in 2000.
Medical uses
Almotriptan is prescribed to treat the acute headache phase of migraine attacks with or without aura. Almotriptan is the only oral triptan approved in the US for the treatment of migraine in adolescent from 12 to 17 years of age.
Efficacy
The efficacy and tolerability of almotriptan has been studied in numerous randomised, controlled trials totaling more than 4800 adults with either moderate or severe attacks of migraine. Its efficacy is significantly more effective than placebo and alleviates nausea, photophobia and phonophobia linked to migraine attacks. Almotriptan has similar efficacy as a standard dose of sumatriptan, another triptan drug, and fewer adverse effects.
Contraindications
As with other triptans, almotriptan should not be used in patients with a history, symptoms or signs of ischaemic heart disease (myocardial infarction, angina pectoris, documented silent ischaemia, Prinzmetals angina) or severe hypertension and uncontrolled mild or moderate hypertension.
Other contraindications are previous cerebrovascular accident (CVA) or transient ischaemic attack (TIA), peripheral vascular disease, severe hepatic impairment, concomitant administration of ergotamine, ergotamine derivatives (including methysergide) and other 5-HT1B/D agonists.
Side effects
Almotriptan has proved to have an adverse effects profile similar to placebo when used following the Summary of Product Characteristics instructions (see references).
Pharmacology
Mechanism of action
Like all triptans, almotriptan has a high and specific affinity for serotonin 5-HT1B/1D receptors. Binding of the drug to the receptor leads to vasoconstriction of the cranial (brain) blood vessels and thus affects the redistribution of blood flow. Almotriptan significantly increases cerebral blood flow and reduces blood flow through extracerebral cranial vessels. Even though it affects cranial blood vessels a single standard dose of almotriptan has no clinically significant effect on blood pressure or heart rate in both young and elderly healthy volunteers. Larger doses seem to slightly increase blood pressure but not beyond clinical relevance.
Pharmacokinetics
Almotriptan has linear pharmacokinetics up to the 16-fold standard dose. Its biological half-life is 3 hours, and its bioavailability 70%.
Cmax is observed 1.5–4 hours after oral administration, and approximately 50% of the drug is excreted unchanged in the urine. Metabolism is mediated through the enzymes MAO-A and CYP3A4 and CYP2D6 oxidation.
Almotriptan clearance is moderately reduced in the elderly but does not require dose adjustment. Sex does not alter the pharmacokinetics of the drug. People with moderate-to-severe renal dysfunction are recommended to use only half the dose.
Interactions
Almotriptan is metabolized mainly by MAO-A and to lesser extent by CYP3A4 and CYP2D6. Studies of drugs used as preventive against migraine (propranolol and verapamil), anti-depressants (moclobemide and fluoxetine) yielded results that showed significant altering of the pharmacokinetics of almotriptan though they were deemed not clinically relevant.
Society and culture
Brand names
Brand names include Axert (US, Canada), Almogran (Belgium, Denmark, Finland, France, Germany, Italy, Ireland Portugal, Spain, the United Kingdom, the Netherlands, Sweden, Switzerland, South Korea...), Almotrex (Italy), Almozen (Bulgaria and Poland) and Amignul (Spain).
References
External links
"Almotriptan". Drug Information Portal. U.S. National Library of Medicine.
"Almotriptan malate". Drug Information Portal. U.S. National Library of Medicine. |
Procarbazine | Procarbazine is a chemotherapy medication used for the treatment of Hodgkins lymphoma and brain cancers. For Hodgkins it is often used together with chlormethine, vincristine, and prednisone while for brain cancers such as glioblastoma multiforme it is used with lomustine and vincristine. It is typically taken by mouth.Common side effect include low blood cell counts and vomiting. Other side effects include tiredness and depression. It is not recommended in people with severe liver or kidney problems. Use in pregnancy is known to harm the baby. Procarbazine is in the alkylating agents family of medication. How it works is not clearly known.Procarbazine was approved for medical use in the United States in 1969. It is on the World Health Organizations List of Essential Medicines. In the United Kingdom a month of treatment cost the National Health Service 450 to 750 pounds.
Medical uses
When used to treat Hodgkins lymphoma, it is often delivered as part of the BEACOPP regimen that includes bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine (tradename Oncovin), prednisone, and procarbazine. The first combination chemotherapy developed for Hodgkins lymphoma (HL), MOPP also included procarbazine (ABVD has supplanted MOPP as standard first line treatment for HL, with BEACOPP as an alternative for advanced/unfavorable HL). Alternatively, when used to treat certain brain tumors (malignant gliomas), it is often dosed as PCV when combined with lomustine (often called CCNU) and vincristine.
Dose should be adjusted for kidney disease or liver disease.
Side effects
Very common (greater than 10% of people experience them) adverse effects include loss of appetite, nausea and vomiting. Other side effects of unknown frequency include reduction in leukocytes, reduction in platelets, reduction in neutrophils, which can lead to increased infections including lung infections; severe allergy-like reactions that can lead to angioedema and skin reactions; lethargy; liver complications including jaundice and abnormal liver function tests; reproductive effects including reduction in sperm count and ovarian failure.When combined with ethanol, procarbazine may cause a disulfiram-like reaction in some people.It weakly inhibits MAO in the gastrointestinal system, so it can cause hypertensive crises if associated with the ingestion of tyramine-rich foods such as aged cheeses; this appears to be rare.Procarbazine rarely causes chemotherapy-induced peripheral neuropathy, a progressive, enduring, often irreversible tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs.
Pharmacology
Procarbazine works, in part, as an alkylating agent and methylates guanine at the O-6 position (much like dacarbazine also does). Guanine is one of the four nucleotides that makes up DNA. The methylated DNA is prone to breakage, and RNA and protein synthesis is inhibited. Proliferating cancer cells need to replicate their DNA and undergo programmed cell death (apoptosis) in response to DNA strand breaks. Normal or non-proliferating cells are more apt to repair the DNA damage, but still some of the healthy cells will be damaged. Procarbazine is metabolized in the liver to an azo-derivative and then further metabolized by the cytochrome P-450 system to an active azoxy-derivative.
References
External links
MOPP Treatment Regimen
PCV Information
Procarbazine Drug Information Provided by Lexi-Comp – Merck Manual
RX Listing for Matulane
"Procarbazine". Drug Information Portal. U.S. National Library of Medicine. |
Doxercalciferol | Doxercalciferol (or 1-hydroxyergocalciferol, trade name Hectorol) is drug for secondary hyperparathyroidism and metabolic bone disease. It is a synthetic analog of ergocalciferol (vitamin D2). It suppresses parathyroid synthesis and secretion.Docercalciferol is the vitamin D2 analogue of alfacalcidol. It undergoes 25-hydroxylation in the liver to become the active ercalcitriol, without the involvement of kidneys.
== References == |
Gemcitabine | Gemcitabine, with brand names including Gemzar, is a chemotherapy medication. It treats cancers including testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer. It is administered by intravenous infusion. It acts against neoplastic growth, and it inhibits the replication of Orthohepevirus A, the causative agent of Hepatitis E, through upregulation of interferon signaling.Common side effects include bone marrow suppression, liver and kidney problems, nausea, fever, rash, shortness of breath, mouth sores, diarrhea, neuropathy, and hair loss. Use during pregnancy will likely result in fetal harm. Gemcitabine is in the nucleoside analog family of medication. It works by blocking the creation of new DNA, which results in cell death.Gemcitabine was patented in 1983 and was approved for medical use in 1995. Generic versions were introduced in Europe in 2009 and in the US in 2010. It is on the WHO Model List of Essential Medicines.
Medical uses
Gemcitabine treats various carcinomas. It is used as a first-line treatment alone for pancreatic cancer, and in combination with cisplatin for advanced or metastatic bladder cancer and advanced or metastatic non-small cell lung cancer. It is used as a second-line treatment in combination with carboplatin for ovarian cancer and in combination with paclitaxel for breast cancer that is metastatic or cannot be surgically removed.It is commonly used off-label to treat cholangiocarcinoma and other biliary tract cancers.It is given by intravenous infusion at a chemotherapy clinic.
Contraindications and interactions
Taking gemcitabine can also affect fertility in men and women, sex life, and menstruation. Women taking gemcitabine should not become pregnant, and pregnant and breastfeeding women should not take it.As of 2014, drug interactions had not been studied.
Adverse effects
Gemcitabine is a chemotherapy drug that works by killing any cells that are dividing. Cancer cells divide rapidly and so are targeted at higher rates by gemcitabine, but many essential cells also divide rapidly, including cells in skin, the scalp, the stomach lining, and bone marrow, resulting in adverse effects.: 265 The gemcitabine label carries warnings that it can suppress bone marrow function and cause loss of white blood cells, loss of platelets, and loss of red blood cells, and that it should be used carefully in people with liver, kidney, or cardiovascular disorders. People taking it should not take live vaccines. The warning label also states it may cause posterior reversible encephalopathy syndrome, that it may cause capillary leak syndrome, that it may cause severe lung conditions like pulmonary edema, pneumonia, and adult respiratory distress syndrome, and that it may harm sperm.More than 10% of users develop adverse effects, including difficulty breathing, low white and red blood cells counts, low platelet counts, vomiting and nausea, elevated transaminases, rashes and itchy skin, hair loss, blood and protein in urine, flu-like symptoms, and edema.Common adverse effects (occurring in 1–10% of users) include fever, loss of appetite, headache, difficulty sleeping, tiredness, cough, runny nose, diarrhea, mouth and lip sores, sweating, back pain, and muscle pain.Thrombotic thrombocytopenic purpura (TTP) is a rare but serious side effect that been associated with particular chemotherapy medications including gemcitabine. TTP is a blood disorder and can lead to microangipathic hemolytic anemia (MAHA), neurologic abnormalities, fever, and renal disease.
Pharmacology
Gemcitabine is hydrophilic and must be transported into cells via molecular transporters for nucleosides (the most common transporters for gemcitabine are SLC29A1 SLC28A1, and SLC28A3). After entering the cell, gemcitabine is first modified by attaching a phosphate to it, and so it becomes gemcitabine monophosphate (dFdCMP). This is the rate-determining step that is catalyzed by the enzyme deoxycytidine kinase (DCK). Two more phosphates are added by other enzymes. After the attachment of the three phosphates gemcitabine is finally pharmacologically active as gemcitabine triphosphate (dFdCTP). After being thrice phosphorylated, gemcitabine can masquerade as deoxycytidine triphosphate and is incorporated into new DNA strands being synthesized as the cell replicates.When gemcitabine is incorporated into DNA it allows a native, or normal, nucleoside base to be added next to it. This leads to "masked chain termination" because gemcitabine is a "faulty" base, but due to its neighboring native nucleoside it eludes the cells normal repair system (base-excision repair). Thus, incorporation of gemcitabine into the cells DNA creates an irreparable error that leads to inhibition of further DNA synthesis, and thereby leading to cell death.The form of gemcitabine with two phosphates attached (dFdCDP) also has activity; it inhibits the enzyme ribonucleotide reductase (RNR), which is needed to create new DNA nucleotides. The lack of nucleotides drives the cell to uptake more of the components it needs to make nucleotides from outside the cell, which also increases uptake of gemcitabine.
Chemistry
Gemcitabine is a synthetic pyrimidine nucleoside prodrug—a nucleoside analog in which the hydrogen atoms on the 2 carbon of deoxycytidine are replaced by fluorine atoms.The synthesis described and pictured below is the original synthesis done in the Eli Lilly Company labs. Synthesis begins with enantiopure D-glyceraldehyde (R)-2 as the starting material which can made from D-mannitol in 2–7 steps. Then fluorine is introduced by a "building block" approach using ethyl bromodifluroacetate. Then, Reformatsky reaction under standard conditions will yield a 3:1 anti/syn diastereomeric mixture, with one major product. Separation of the diastereomers is carried out via HPLC, thus yielding the anti-3 gemcitabine in a 65% yield. At least two other full synthesis methods have also been developed by different groups.
History
Gemcitabine was first synthesized in Larry Hertels lab at Eli Lilly and Company during the early 1980s. It was intended as an antiviral drug, but preclinical testing showed that it killed leukemia cells in vitro.During the early 1990s gemcitabine was studied in clinical trials. The pancreatic cancer trials found that gemcitabine increased one-year survival time significantly, and it was approved in the UK in 1995 and approved by the FDA in 1996 for pancreatic cancers. In 1998, gemcitabine received FDA approval for treating non-small cell lung cancer and in 2004, it was approved for metastatic breast cancer.European labels were harmonized by the EMA in 2008.By 2008, Lillys worldwide sales of gemcitabine were about $1.7 billion; at that time its US patents were set to expire in 2013 and its European patents in 2009. The first generic launched in Europe in 2009, and patent challenges were mounted in the US which led to invalidation of a key Lilly patent on its method to make the drug. Generic companies started selling the drug in the US in 2010 when the patent on the chemical itself expired. Patent litigation in China made headlines there and was resolved in 2010.
Society and culture
As of 2017, gemcitabine was marketed under many brand names worldwide: Abine, Accogem, Acytabin, Antoril, axigem, Bendacitabin, Biogem, Boligem, Celzar, Citegin, Cytigem, Cytogem, Daplax, DBL, Demozar, Dercin, Emcitab, Enekamub, Eriogem, Fotinex, Gebina, Gemalata, Gembin, Gembine, Gembio, Gemcel, Gemcetin, Gemcibine, Gemcikal, Gemcipen, Gemcired, Gemcirena, Gemcit, Gemcitabin, Gemcitabina, Gemcitabine, Gemcitabinum, Gemcitan, Gemedac, Gemflor, Gemful, Gemita, Gemko, Gemliquid, Gemmis, Gemnil, Gempower, Gemsol, Gemstad, Gemstada, Gemtabine, Gemtavis, Gemtaz, Gemtero, Gemtra, Gemtro, Gemvic, Gemxit, Gemzar, Gentabim, Genuten, Genvir, Geroam, Gestredos, Getanosan, Getmisi, Gezt, Gitrabin, Gramagen, Haxanit, Jemta, Kalbezar, Medigem, Meditabine, Nabigem, Nallian, Oncogem, Oncoril, Pamigeno, Ribozar, Santabin, Sitagem, Symtabin, Yu Jie, Ze Fei, and Zefei.
Research
Because it is clinically valuable and is only useful when delivered intravenously, methods to reformulate it so that it can be given by mouth have been a subject of research.Research into pharmacogenomics and pharmacogenetics has been ongoing. As of 2014, it was not clear whether or not genetic tests could be useful in guiding dosing and which people respond best to gemcitabine. However, it appears that variation in the expression of proteins (SLC29A1, SLC29A2, SLC28A1, and SLC28A3) used for transport of gemcitabine into the cell lead to variations in its potency. Similarly, the genes that express proteins that lead to its inactivation (deoxycytidine deaminase, cytidine deaminase, and NT5C) and that express its other intracellular targets (RRM1, RRM2, and RRM2B) lead to variations in response to the drug. Research has also been ongoing to understand how mutations in pancreatic cancers themselves determine response to gemcitabine.It has been studied as a treatment for Kaposi sarcoma, a common cancer in people with AIDS which is uncommon in the developed world but not uncommon in the developing world.
See also
IMM-101
References
External links
"Gemcitabine". Drug Information Portal. U.S. National Library of Medicine. |
Tagraxofusp | Tagraxofusp, sold under the brand name Elzonris, is an anti-cancer medication for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). It was approved for use in the United States in 2018, and after a second review, in the EU in January 2021. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.Tagraxofusp is a fusion protein consisting of interleukin 3 (IL-3) fused to diphtheria toxin. The fusion protein readily kills cultured pDC by binding to their IL-3 receptors to thereby gain entrance to the cells and then blocking these cells protein synthesis (due to its diphtheria toxin portion inhibiting eukaryotic elongation factor 2).
Society and culture
Legal status
In July 2020, the European Medicines Agency (EMA) recommended the refusal of the marketing authorization for tagraxofusp. The Agency was concerned that due to the design of the study and the small number of participants, it was not possible to be sure how effective the medicine was in treating blastic plasmacytoid dendritic cell neoplasm. In addition, the medicine could cause capillary leak syndrome (an unpredictable, potentially life-threatening side effect due to increased permeability of small blood vessels), which had led to some fatal outcomes.On 12 November 2020, the Committee for Medicinal Products for Human Use (CHMP) of the EMA adopted a positive opinion following a re-examination procedure, recommending the granting of a marketing authorization for the medicinal product Elzonris, intended for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp was approved for medical use in the European Union in January 2021.
References
External links
"Tagraxofusp". Drug Information Portal. U.S. National Library of Medicine.
"Tagraxofusp-erzs". NCI Drug Dictionary. National Cancer Institute.
"Tagraxofusp-erzs". National Cancer Institute. 22 January 2019. |
Tepotinib | Tepotinib, sold under the brand name Tepmetko, is a medication used for the treatment of adults with non-small cell lung cancer (NSCLC).Tepotinib first received marketing approval in Japan, in March 2020, as a "line-agnostic" drug, meaning it is approved both for treatment-naive patients and for those in whom previous attempts at treatment have failed. U.S. approval followed in February 2021. It is the second therapy approved by the U.S. Food and Drug Administration (FDA) to treat non-small cell lung cancer with these particular mutations, after capmatinib.
Medical uses
Tepotinib is indicated for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping.
Adverse effects
The most common side effects seen in clinical trials were edema, fatigue, nausea, diarrhea, muscle aches, and shortness of breath. Like capmatinib, tepotinib can also cause interstitial lung disease and liver damage, and is toxic to a developing fetus. The most common treatment-related adverse effect in a 2021 study were peripheral edema (54.1%), nausea (20.0%), diarrhea (19.6%), blood creatinine increased (17.6%), and hypoalbuminemia (14.5%), which were mostly mild or moderate.
Society and culture
Legal status
On 16 December 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 Tepmetko, intended for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring alterations leading to mesenchymal-epithelial transition factor gene exon 14 (METex14) skipping. The applicant for this medicinal product is Merck Europe B.V. Tepotinib (Tepmetko) was approved for medical use in the European Union in February 2022.
References
Further reading
Paik PK, Felip E, Veillon R, Sakai H, Cortot AB, Garassino MC, et al. (September 2020). "Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations". N Engl J Med. 383 (10): 931–43. doi:10.1056/NEJMoa2004407. PMC 8422679. PMID 32469185.
External links
"Tepotinib". Drug Information Portal. U.S. National Library of Medicine.
"Tepotinib hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
"Tepotinib hydrochloride". NCI Drug Dictionary. National Cancer Institute.
Clinical trial number NCT02864992 for "Tepotinib Phase II in Non-small Cell Lung Cancer (NSCLC) Harboring MET Alterations (VISION)" at ClinicalTrials.gov |
Prednicarbate | Prednicarbate is a relatively new topical corticosteroid drug. It is similar in potency to hydrocortisone. Corticosteroids have always been an important part of the pharmacological arsenal of dermatology; however, their tendency to produce side-effects has caused the need to search for new preparations.It is nonhalogenated.
== References == |
Tecovirimat | Tecovirimat, sold under the brand name Tpoxx among others, is an antiviral medication with activity against orthopoxviruses such as smallpox and monkeypox. It is the first antipoxviral drug approved in the United States. It is an inhibitor of the orthopoxvirus VP37 envelope wrapping protein.The drug works by blocking cellular transmission of the virus, thus preventing the disease. Tecovirimat has been effective in laboratory testing; it has been shown to protect animals from monkeypox and rabbitpox and causes no serious side effects in humans. Tecovirimat was first used for treatment in December 2018, after a laboratory-acquired vaccinia virus infection.Two million doses of tecovirimat are stockpiled in the US Strategic National Stockpile should an orthopoxvirus-based bioterror attack occur. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
Medical uses
In the United States, tecovirimat is indicated for the treatment of human smallpox disease. In the European Union it is indicated for the treatment of smallpox, monkeypox, and cowpox.
Mechanism of action
Tecovirimat inhibits the function of a major envelope protein required for the production of extracellular virus. The drug prevents the virus from leaving an infected cell, hindering the spread of the virus within the body.
Chemistry
The first synthesis of tecovirimat was published in a patent filed by scientists at Siga Technologies in 2004. It is made in two steps from cycloheptatriene.
A Diels–Alder reaction with maleic anhydride forms the main ring system and a subsequent reaction with 4-trifluormethylbenzhydrazide gives the cyclic imide of the drug.
History
Originally researched by the National Institute of Allergy and Infectious Diseases, the drug was owned by Viropharma and discovered in collaboration with scientists at the United States Army Medical Research Institute of Infectious Diseases. It is owned and manufactured by Siga Technologies. Siga and Viropharma were issued a patent for tecovirimat in 2012.
Clinical trials
As of 2009, the results of clinical trials support its use against smallpox and other related orthopoxviruses. It shows potential for a variety of uses including preventive healthcare, as a post-exposure therapeutic, as a therapeutic, and an adjunct to vaccination.Tecovirimat can be taken by mouth and as of 2008, was permitted for phase II trials by the U.S. Food and Drug Administration (FDA). In phase I trials, tecovirimat was generally well tolerated with no serious adverse events. Due to its importance for biodefense, the FDA designated tecovirimat for fast-track status, creating a path for expedited FDA review and eventual regulatory approval. On 13 July 2018, the FDA announced approval of tecovirimat for the treatment of smallpox.On 25 August 2022, the AIDS Clinical Trials Group (ACTG) began a randomized, placebo-controlled, double-blinded trial on the safety and efficacy of tecovirimat for monkeypox, known as STOMP (Study of Tecovirimat for Human Monkeypox Virus), aiming to enroll at least 500 participants with acute monkeypox infection.
Society and culture
Legal status
In November 2021, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product tecovirimat siga, intended for the treatment of orthopoxvirus disease (smallpox, monkeypox, cowpox, and vaccinia complications) in adults and in children who weigh at least 13 kilograms (29 lb) The applicant for this medicinal product is Siga Technologies Netherlands B.V. Tecovirimat was approved for medical use in the European Union in January 2022.In December 2021, Health Canada approved oral tecovirimat for the treatment of smallpox in people weighing at least 13 kilograms (29 lb).As of August 2022, Tpoxx is available in the US only through the Strategic National Stockpile as a Centers for Disease Control and Prevention investigational new drug. Intravenous Tpoxx has no lower weight cap and can be used in infants under the investigational new drug protocol.
References
External links
"Tecovirimat". Drug Information Portal. U.S. National Library of Medicine.
"Tecovirimat monohydrate". Drug Information Portal. U.S. National Library of Medicine. |
Raloxifene | Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to reduce the risk of breast cancer in those at high risk. It is taken by mouth.Common side effects include hot flashes, leg cramps, swelling, and joint pain. Severe side effects may include blood clots and stroke. Use during pregnancy may harm the baby. The medication may worsen menstrual symptoms. Raloxifene is a selective estrogen receptor modulator (SERM) and therefore a mixed agonist–antagonist of the estrogen receptor (ER). It has estrogenic effects in bone and antiestrogenic effects in the breasts and uterus.Raloxifene was approved for medical use in the United States in 1997. It is available as a generic medication. In 2017, it was the 330th most commonly prescribed medication in the United States, with more than 900 thousand prescriptions.
Medical uses
Raloxifene is used for the treatment and prevention of osteoporosis in postmenopausal women. It is used at a dosage of 60 mg/day for both the prevention and treatment of osteoporosis. In the case of either osteoporosis prevention or treatment, supplemental calcium and vitamin D should be added to the diet if daily intake is inadequate.Raloxifene is used to reduce the risk of breast cancer in postmenopausal women. It is used at a dosage of 60 mg/day for this indication. In the Multiple Outcomes of Raloxifene (MORE) clinical trial, raloxifene decreased the risk of all types of breast cancer by 62%, of invasive breast cancer by 72%, and of invasive estrogen receptor-positive breast cancer by 84%. Conversely, it does not reduce the risk of estrogen receptor-negative breast cancer. There were no obvious differences in effectiveness of raloxifene in the MORE trial for prevention of breast cancer at a dosage of 60 mg/m2/day relative to 120 mg/m2/day. In the Study of Tamoxifen and Raloxifene (STAR) trial, 60 mg/day raloxifene was 78% as effective as 20 mg/day tamoxifen in preventing non-invasive breast cancer. Women with undetectable levels of estradiol (<2.7 pg/mL) have a naturally low risk of breast cancer and, in contrast to women with detectable levels of estradiol, do not experience significant benefit from raloxifene in terms of reduction of breast cancer risk.
Contraindications
Raloxifene is contraindicated in lactating women or women who are or who may become pregnant. It also may be of concern to women with active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.
Side effects
Common side effects of raloxifene include hot flashes (25–28% vs. 18–21% for placebo), vaginal dryness, and leg cramps (generally mild; 5.5% vs. 1.9% for placebo). Raloxifene does not cause breast tenderness, endometrial hyperplasia, menstrual bleeding, or endometrial cancer. It does not appear to affect cognition or memory. Raloxifene is a teratogen; i.e., it can cause developmental abnormalities such as birth defects.
Raloxifene may infrequently cause serious blood clots to form in the legs, lungs, or eyes. Other reactions experienced include leg swelling/pain, trouble breathing, chest pain, and vision changes. Black box warnings were added to the label of raloxifene in 2007 warning of increased risk of death due to stroke for postmenopausal women with documented coronary heart disease or at increased risk for major coronary events, as well as increased risk for deep vein thrombosis and pulmonary embolism. The risk of venous thromboembolism with raloxifene is increased by several-fold in postmenopausal women (RR = 3.1). Raloxifene has a lower risk of thromboembolism than tamoxifen. In the MORE trial, raloxifene caused a 40% decrease in risk of cardiovascular events in women who were at increased risk for coronary artery disease, although there was no decrease in cardiovascular events for the group as a whole.A report in September 2009 from Health and Human Services Agency for Healthcare Research and Quality suggests that tamoxifen and raloxifene used to treat breast cancer, significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.A recent human case report in July 2016 suggests that raloxifene may in fact, at some point, also stimulate breast cancer growth leading to a reduction of advanced breast cancer disease upon the withdrawal of the drug.Unlike other SERMs, such as tamoxifen, raloxifene has no risk of uterine hyperplasia or endometrial cancer (RR = 0.8).Raloxifene does not increase the incidence of breast pain or tenderness in postmenopausal women.
Overdose
Raloxifene has been studied in clinical trials across a dosage range of 30 to 600 mg/day, and was well-tolerated at all dosages.
Pharmacology
Pharmacodynamics
Mechanism of action
Raloxifene is a selective estrogen receptor modulator (SERM) and hence is a mixed agonist and antagonist of the estrogen receptor (ER) in different tissues. It has estrogenic activity in some tissues, such as bone and the liver, and antiestrogenic activity in other tissues, such as the breasts and uterus. Its affinity (Kd) for the ERα is approximately 50 pM, which is similar to that of estradiol. Relative to estradiol, raloxifene has been reported to possess about 8 to 34% of the affinity for the ERα and 0.5 to 76% of the affinity for the ERβ. Raloxifene acts as a partial agonist of the ERα and as a pure antagonist of the ERβ. In contrast to the classical ERs, raloxifene is an agonist of the G protein-coupled estrogen receptor (GPER) (EC50 = 10–100 nM), a membrane estrogen receptor.
Clinical effects
Raloxifene has antiestrogenic effects in the mammary glands in preclinical studies. In accordance, raloxifene reduces breast density in postmenopausal women, a known risk factor for breast cancer. It does not stimulate the uterus in postmenopausal women, and results in no increase in risk of endometrial thickening, vaginal bleeding, endometrial hyperplasia, or endometrial cancer. At the same time, raloxifene has minimal antiestrogenic effect in the uterus in premenopausal women. This may possibly be due to inadequate tissue exposure of the uterus to raloxifene in these estrogen-rich individuals.In premenopausal women, raloxifene increases levels of follicle-stimulating hormone (FSH) and estradiol. Conversely, in postmenopausal women, raloxifene has been found to reduce levels of the gonadotropins, luteinizing hormone (LH) and FSH, while not affecting levels of estradiol. Raloxifene also decreases prolactin levels in postmenopausal women. In men, raloxifene has been found to disinhibit the hypothalamic–pituitary–gonadal axis (HPG axis) and thereby increase total testosterone levels. Due to the simultaneous increase in sex hormone-binding globulin (SHBG) levels however, free testosterone levels often remain unchanged in men during therapy with raloxifene.Raloxifene has estrogenic effects on liver protein synthesis. It increases SHBG levels in both pre- and postmenopausal women as well as in men. The medication decreases levels of total and low-density lipoprotein (LDL) cholesterol, C-reactive protein, apolipoprotein B, and homocysteine. Conversely, it has little effect on levels of triglycerides and high-density lipoprotein (HDL). Raloxifene has been shown to inhibit the oxidation of LDL cholesterol in vitro. The medication has been found to decrease insulin-like growth factor 1 (IGF-1) levels in pre- and postmenopausal women as well as in men. It has also been found to increase insulin-like growth factor binding protein 3 (IGFBP-3) levels in pre- and postmenopausal women. Due to activation of estrogen receptors in the liver, raloxifene has procoagulatory effects, such as decreasing levels of fibrinogen and influencing levels of other coagulation factors. For these reasons, raloxifene increases the risk of thrombosis.Raloxifene increases bone mineral density in postmenopausal women but decreases it in premenopausal women. In the MORE trial, the risk of vertebral fractures was decreased by 30%, and bone mineral density was increased in the spine (by 2.1% at 60 mg, 2.4% at 120 mg) and femoral neck (2.6% at 60 mg, 2.7% at 120 mg). It has been found to possess estrogenic effects in adipose tissue in postmenopausal women, promoting a shift from an android fat distribution to a gynoid fat distribution. The medication has been found to increase levels of leptin, an adipokine.
Pharmacokinetics
Absorption
The absorption of raloxifene is approximately 60%. However, due to extensive first-pass metabolism, the absolute bioavailability of raloxifene is only 2.0%. Raloxifene is rapidly absorbed from the intestines upon oral administration. Peak plasma levels of raloxifene occur 0.5 to 6 hours after an oral dose. In healthy postmenopausal women treated with 60 mg/day raloxifene, peak circulating raloxifene levels normalized by dose and body weight were (i.e., divided by (mg/kg)), 0.50 ng/mL (500 pg/mL) after a single dose and 1.36 ng/mL (1,360 pg/mL after multiple doses).
Distribution
Raloxifene is widely distributed throughout the body. There is extensive distribution of raloxifene into the liver, serum, lungs, and kidneys. The volume of distribution of raloxifene with a single 30 to 150 mg oral dose is approximately 2348 L/kg, which corresponds to ~170,000 L for a 72 kg person. Both raloxifene and its glucuronide metabolites show high plasma protein binding (>95%), including to both albumin and α1 acid glycoprotein, but not to sex hormone-binding globulin. More specifically, raloxifene is 98.2 ± 0.4% bound to plasma proteins.
Metabolism
Raloxifene is metabolized in the liver and undergoes enterohepatic recycling. It is metabolized exclusively by glucuronidation and is not metabolized by the cytochrome P450 system. Less than 1% of radiolabeled material in plasma comprises unconjugated raloxifene. The metabolites of raloxifene include several glucuronides. The elimination half-life of raloxifene after a single dose is 27.7 hours (1.2 days), whereas its half-life at steady state at a dosage of 60 mg/day is 15.8 to 86.6 hours (0.7–3.6 days), with an average of 32.5 hours (1.4 days). The extended half-life of raloxifene is attributed to enterohepatic recirculation and its high plasma protein binding. Raloxifene and its glucuronide conjugates are interconverted by reversible metabolism and enterohepatic recycling, which prolongs the elimination half-life of raloxifene with oral administration. The medication is deconjugated into its active form in a variety of tissues, including liver, lungs, spleen, bone, uterus, and kidneys.
Elimination
Raloxifene is mainly excreted in bile and is eliminated in feces. Less than 0.2% of a dose is excreted unchanged in urine and less than 6% of a dose is excreted in urine as glucuronide conjugates.
Chemistry
Raloxifene hydrochloride has the empirical formula C28H27NO4S•HCl, which corresponds to a molecular weight of 510.05 g/mol. Raloxifene hydrochloride is an off-white to pale-yellow solid that is slightly soluble in water.Raloxifene is a benzothiophene derivative and is structurally distinct from the triphenylethylene SERMs like tamoxifen, clomifene, and toremifene. It is the only benzothiophene SERM to have been marketed. A benzothiophene SERM that was not marketed is arzoxifene (LY-353381). Bazedoxifene (Duavee, Viviant) and pipendoxifene (ERA-923) are structurally related to raloxifene but are technically not benzothiophenes and instead are indoles.
History
Raloxifene was approved in the United States for the prevention of postmenopausal osteoporosis in 1997, the treatment of postmenopausal osteoporosis in 1999, and to prevent or reduce the risk of breast cancer in certain postmenopausal women in 2007. It received orphan designation in 2005.
Society and culture
Names
Raloxifene is the generic name of the drug and its INN and BAN, while raloxifène is its DCF and raloxifene hydrochloride is its USAN, BANM, and JAN. It has also been known by the name keoxifene.Raloxifene is sold mainly under the brand name Evista and to a lesser extent the brand name Optruma. It is also sold under a variety of other brand names in various countries.
Availability
Raloxifene is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere throughout Europe, Australia, New Zealand, South Africa, Latin America, Southern, Eastern, and Southeastern Asia, and elsewhere in the world such as in Israel and Egypt.Raloxifene is provided in the form of 60 mg oral tablets.
Controversy
An editorial in Lancet Oncology criticized the way that research about the medication for breast cancer prevention was released.
Research
Clinical studies of raloxifene for metastatic breast cancer in women have been conducted but found little effectiveness at 60 mg/day in those previously treated with tamoxifen, though modest effectiveness has been observed at higher doses. In contrast to tamoxifen, raloxifene is not approved for the treatment of breast cancer.Raloxifene has been studied in men for a variety of uses, such as for treatment of schizophrenia, prostate cancer, and osteoporosis. It has been studied in combination with castration and bicalutamide, a nonsteroidal antiandrogen, for the treatment of prostate cancer.Raloxifene has been studied as an adjunct in the treatment of schizophrenia in postmenopausal women. A 2017 meta-analysis concluded that it was safe and effective for this indication, although further studies with larger sample sizes are needed for confirmation. It may be effective in women with less severe symptoms.A tissue-selective estrogen-receptor complex (TSEC) of estradiol and raloxifene has been studied in postmenopausal women.Raloxifene (60 mg/day) was reported to be effective in the treatment of pubertal gynecomastia in adolescent boys in a small retrospective chart review. Other SERMs are also known to be effective in the treatment of gynecomastia.Raloxifene has been reported to augment the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs).June 18th 2020, Exscalate4CoV, the private-public consortium supported by the EU’s Horizon 2020 programme for research and innovation, led by Dompé farmaceutici and currently representing 18 partners (including Fraunhofer Institute, CINECA, Chelonia Applied Science, Swiss Institute of Bioinformatics and others) has requested access to clinical trials for the use of Raloxifene in COVID-19 patients. Raloxifene, already proven effective against Mers and Sars in preclinical tests, has been indicated as effective against SARS-CoV-2 by the “in-silico” research conducted by the consortium which has shown efficacy in countering the replication of the virus in cells. The IP for its use against SARS-CoV-2 has already been protected on May 6 2020 in the name Dompé farmaceutici, Fraunhofer Institute and KU Leuven, to facilitate the largest possible access. Raloxifene would be used in mildly symptomatic COVID-19 patients to halt the spread of infection. This result emerged from the first virtual (in silico) screening conducted on the Consortium’s supercomputers of more than 400.000 molecules (safe-in-man drugs and natural products) made available by Dompé farmaceutici and the partner Fraunhofer (IME) to the Consortium. The molecules were prioritized if in clinical stage or already on the market. 7.000 molecules with certain promising characteristics were tested.
References
Further reading
Barrett-Connor E (2001). "Raloxifene: risks and benefits". Ann N Y Acad Sci. 949 (1): 295–303. Bibcode:2001NYASA.949..295B. doi:10.1111/j.1749-6632.2001.tb04036.x. PMID 11795366. S2CID 41412601.
Heringa M (2003). "Review on raloxifene: profile of a selective estrogen receptor modulator". Int J Clin Pharmacol Ther. 41 (8): 331–45. doi:10.5414/cpp41331. PMID 12940590.
Sporn MB, Dowsett SA, Mershon J, Bryant HU (2004). "Role of raloxifene in breast cancer prevention in postmenopausal women: clinical evidence and potential mechanisms of action". Clin Ther. 26 (6): 830–40. doi:10.1016/s0149-2918(04)90127-0. PMID 15262454.
Vogel VG (2009). "The NSABP Study of Tamoxifen and Raloxifene (STAR) trial". Expert Rev Anticancer Ther. 9 (1): 51–60. doi:10.1586/14737140.9.1.51. PMC 2785111. PMID 19105706.
Wickerham DL, Costantino JP, Vogel VG, Cronin WM, Cecchini RS, Ford LG, Wolmark N (2009). "The use of tamoxifen and raloxifene for the prevention of breast cancer". Recent Results Cancer Res. Recent Results in Cancer Research. 181: 113–9. doi:10.1007/978-3-540-69297-3_12. ISBN 978-3-540-69296-6. PMC 5110043. PMID 19213563.
Vogel VG (2011). "Update on raloxifene: role in reducing the risk of invasive breast cancer in postmenopausal women". Breast Cancer: Targets and Therapy. 3: 127–37. doi:10.2147/BCTT.S11288. PMC 3846694. PMID 24367182.
Yang ZD, Yu J, Zhang Q (2013). "Effects of raloxifene on cognition, mental health, sleep and sexual function in menopausal women: a systematic review of randomized controlled trials". Maturitas. 75 (4): 341–8. doi:10.1016/j.maturitas.2013.05.010. PMID 23764354.
External links
"Raloxifene". Drug Information Portal. U.S. National Library of Medicine.
"Raloxifene hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Adderall | Adderall and Mydayis are trade names for a combination drug called mixed amphetamine salts containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine. Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine, which are marketed as Evekeo and Dexedrine/Zenzedi, respectively. Adderall is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used illicitly as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as a euphoriant. It is a central nervous system (CNS) stimulant of the phenethylamine class.Adderall is generally well tolerated and effective in treating the symptoms of ADHD and narcolepsy. At therapeutic doses, Adderall causes emotional and cognitive effects such as euphoria, change in sex drive (loss of sex drive), increased wakefulness, and improved cognitive control. At these doses, it induces physical effects such as a faster reaction time, fatigue resistance, and increased muscle strength. In contrast, much larger doses of Adderall can impair cognitive control, cause rapid muscle breakdown, provoke panic attacks, or induce a psychosis (e.g., paranoia, delusions, hallucinations). The side effects of Adderall vary widely among individuals, but most commonly include insomnia, dry mouth, loss of appetite, and weight loss. The risk of developing an addiction or dependence is insignificant when Adderall is used as prescribed at fairly low daily doses, such as those used for treating ADHD; however, the routine use of Adderall in larger daily doses poses a significant risk of addiction or dependence due to the pronounced reinforcing effects that are present at high doses. Recreational doses of amphetamine are generally much larger than prescribed therapeutic doses, and carry a far greater risk of serious adverse effects.The two amphetamine enantiomers that compose Adderall (levoamphetamine and dextroamphetamine) alleviate the symptoms of ADHD and narcolepsy by increasing the activity of the neurotransmitters norepinephrine and dopamine in the brain, which results in part from their interactions with human trace amine-associated receptor 1 (hTAAR1) and vesicular monoamine transporter 2 (VMAT2) in neurons. Dextroamphetamine is a more potent CNS stimulant than levoamphetamine, but levoamphetamine has slightly stronger cardiovascular and peripheral effects and a longer elimination half-life than dextroamphetamine. The levoamphetamine component of Adderall has been reported to improve the treatment response in some individuals relative to dextroamphetamine alone. Adderalls active ingredient, amphetamine, shares many chemical and pharmacological properties with the human trace amines, particularly phenethylamine and N-methylphenethylamine, the latter of which is a positional isomer of amphetamine. In 2020, Adderall was the 22nd most commonly prescribed medication in the United States, with more than 26 million prescriptions.
Uses
Medical
Adderall is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy (a sleep disorder).
Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage, but in humans with ADHD, pharmaceutical amphetamines at therapeutic dosages appear to improve brain development and nerve growth. Reviews of magnetic resonance imaging (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus of the basal ganglia.Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD. Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety. Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes across 9 categories of outcomes related to academics, antisocial behavior, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use (i.e., academic, occupational, health, financial, and legal services), and social function. One review highlighted a nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity. Another review indicated that, based upon the longest follow-up studies conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a substance use disorder as an adult.Current models of ADHD suggest that it is associated with functional impairments in some of the brains neurotransmitter systems; these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to the prefrontal cortex. Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems. Approximately 80% of those who use these stimulants see improvements in ADHD symptoms. Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans. The Cochrane reviews on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse side effects. A Cochrane review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.
Available forms
Adderall is available as immediate-release (IR) tablets or two different extended-release (XR) formulations. The extended-release capsules are generally used in the morning. A shorter, 12-hour extended-release formulation is available under the brand Adderall XR and is designed to provide a therapeutic effect and plasma concentrations identical to taking two doses 4 hours apart. The longer extended-release formulation, approved for 16 hours, is available under the brand Mydayis. In the United States, the immediate and extended release formulations of Adderall are both available as generic drugs.
Enhancing performance
Cognitive performance
In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults; these cognition-enhancing effects of amphetamine are known to be partially mediated through the indirect activation of both dopamine receptor D1 and adrenoceptor α2 in the prefrontal cortex. A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information. Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals. Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior. Stimulants such as amphetamine can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid. Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for enhancement of academic performance rather than as recreational drugs. However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.
Physical performance
Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness; however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies. In healthy people at oral therapeutic doses, amphetamine has been shown to increase muscle strength, acceleration, athletic performance in anaerobic conditions, and endurance (i.e., it delays the onset of fatigue), while improving reaction time. Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system. Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a "safety switch", allowing the core temperature limit to increase in order to access a reserve capacity that is normally off-limits. At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance; however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.Adderall has been banned in the National Football League (NFL), Major League Baseball (MLB), National Basketball Association (NBA), and the National Collegiate Athletics Association (NCAA). In leagues such as the NFL, there is a very rigorous process required to obtain an exemption to this rule even when the athlete has been medically prescribed the drug by their physician.
Recreational
Adderall has high potential for misuse as a recreational drug. Adderall tablets can either be swallowed, crushed and snorted, or dissolved in water and injected. Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.Many postsecondary students have reported using Adderall for study purposes in different parts of the developed world. Among these students, some of the risk factors for misusing ADHD stimulants recreationally include: possessing deviant personality characteristics (i.e., exhibiting delinquent or deviant behavior), inadequate accommodation of disability, basing ones self-worth on external validation, low self-efficacy, earning poor grades, and having an untreated mental health disorder.
Contraindications
Adverse effects
The adverse side effects of Adderall are many and varied, but the amount of substance consumed is the primary factor in determining the likelihood and severity of side effects. Adderall is currently approved for long-term therapeutic use by the USFDA. Recreational use of Adderall generally involves far larger doses and is therefore significantly more dangerous, involving a much greater risk of serious adverse drug effects than dosages used for therapeutic purposes.
Physical
Cardiovascular side effects can include hypertension or hypotension from a vasovagal response, Raynauds phenomenon (reduced blood flow to the hands and feet), and tachycardia (increased heart rate). Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections. Gastrointestinal side effects may include abdominal pain, constipation, diarrhea, and nausea. Other potential physical side effects include appetite loss, blurred vision, dry mouth, excessive grinding of the teeth, nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold, tics (a type of movement disorder), and weight loss. Dangerous physical side effects are rare at typical pharmaceutical doses.Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths. In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident. Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating. This effect can be useful in treating bed wetting and loss of bladder control. The effects of amphetamine on the gastrointestinal tract are unpredictable. If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system); however, amphetamine may increase motility when the smooth muscle of the tract is relaxed. Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of amphetamine or other ADHD stimulants. However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease.
Psychological
At normal therapeutic doses, the most common psychological side effects of amphetamine include increased alertness, apprehension, concentration, initiative, self-confidence and sociability, mood swings (elated mood followed by mildly depressed mood), insomnia or wakefulness, and decreased sense of fatigue. Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness; these effects depend on the users personality and current mental state. Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users. Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy. According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses, meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.
Reinforcement disorders
Addiction
Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses; in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult. Pathological overactivation of the mesolimbic pathway, a dopamine pathway that connects the ventral tegmental area to the nucleus accumbens, plays a central role in amphetamine addiction. Individuals who frequently self-administer high doses of amphetamine have a high risk of developing an amphetamine addiction, since chronic use at high doses gradually increases the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction. Once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-seeking) with further increases in its expression. While there are currently no effective drugs for treating amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction. Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction; exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction.
Biomolecular mechanisms
Chronic use of amphetamine at excessive doses causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms. The most important transcription factors that produce these alterations are Delta FBJ murine osteosarcoma viral oncogene homolog B (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor-kappa B (NF-κB). ΔFosB is the most significant biomolecular mechanism in addiction because ΔFosB overexpression (i.e., an abnormally high level of gene expression which produces a pronounced gene-related phenotype) in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and regulates multiple behavioral effects (e.g., reward sensitization and escalating drug self-administration) involved in addiction. Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression. It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression. Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB). Similarly, accumbal G9a hyperexpression results in markedly increased histone 3 lysine residue 9 dimethylation (H3K9me2) and blocks the induction of ΔFosB-mediated neural and behavioral plasticity by chronic drug use, which occurs via H3K9me2-mediated repression of transcription factors for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g., CDK5). ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. Since both natural rewards and addictive drugs induce the expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction. Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sexual addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use. These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.The effects of amphetamine on gene regulation are both dose- and route-dependent. Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses. The few studies that have used equivalent (weight-adjusted) human therapeutic doses and oral administration show that these changes, if they occur, are relatively minor. This suggests that medical use of amphetamine does not significantly affect gene regulation.
Pharmacological treatments
As of December 2019, there is no effective pharmacotherapy for amphetamine addiction. Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions; however, as of February 2016, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs. Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors in the nucleus accumbens; magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel. One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain. Supplemental magnesium treatment has been shown to reduce amphetamine self-administration (i.e., doses given to oneself) in humans, but it is not an effective monotherapy for amphetamine addiction.A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in randomized controlled trials (RCTs) for amphetamine and methamphetamine addiction; it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration. There was low- to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion, mirtazapine, sertraline), antipsychotics (aripiprazole), anticonvulsants (topiramate, baclofen, gabapentin), naltrexone, varenicline, citicoline, ondansetron, prometa, riluzole, atomoxetine, dextroamphetamine, and modafinil.
Behavioral treatments
A 2018 systematic review and network meta-analysis of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate). Other treatment modalities examined in the analysis included monotherapy with contingency management or community reinforcement approach, cognitive behavioral therapy, 12-step programs, non-contingent reward-based therapies, psychodynamic therapy, and other combination therapies involving these.Additionally, research on the neurobiological effects of physical exercise suggests that daily aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of drug addiction and is an effective adjunct therapy (i.e., a supplemental treatment) for amphetamine addiction. Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions. In particular, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces increased dopamine receptor D2 (DRD2) density in the striatum. This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density. One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or c-Fos immunoreactivity in the striatum or other parts of the reward system.
Dependence and withdrawal
Drug tolerance develops rapidly in amphetamine abuse (i.e., recreational amphetamine use), so periods of extended abuse require increasingly larger doses of the drug in order to achieve the same effect.
According to a Cochrane review on withdrawal in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose." This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in roughly 88% of cases, and persist for 3–4 weeks with a marked "crash" phase occurring during the first week. Amphetamine withdrawal symptoms can include anxiety, drug craving, depressed mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams. The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence. Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose.
Overdose
Interactions
Monoamine oxidase inhibitors (MAOIs) taken with amphetamine may result in a hypertensive crisis if taken within two weeks after last use of an MAOI type drug.
Inhibitors of enzymes that directly metabolize amphetamine (particularly CYP2D6 and FMO3) will prolong the elimination of amphetamine and increase drug effects.
Serotonergic drugs (such as most antidepressants) co-administered with amphetamine increases the risk of serotonin syndrome.
Stimulants and antidepressants (sedatives and depressants) may increase (decrease) the drug effects of amphetamine, and vice versa.
Gastrointestinal and urinary pH affect the absorption and elimination of amphetamine, respectively. Gastrointestinal alkalinizing agents increase the absorption of amphetamine. Urinary alkalinizing agents increase concentration of non-ionized species, decreasing urinary excretion.
Proton-pump inhibitors (PPIs) modify the absorption of Adderall XR and Mydayis.
Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD.
Pharmacology
Mechanism of action
Amphetamine, the active ingredient of Adderall, works primarily by increasing the activity of the neurotransmitters dopamine and norepinephrine in the brain. It also triggers the release of several other hormones (e.g., epinephrine) and neurotransmitters (e.g., serotonin and histamine) as well as the synthesis of certain neuropeptides (e.g., cocaine and amphetamine regulated transcript (CART) peptides). Both active ingredients of Adderall, dextroamphetamine and levoamphetamine, bind to the same biological targets, but their binding affinities (that is, potency) differ somewhat. Dextroamphetamine and levoamphetamine are both potent full agonists (activating compounds) of trace amine-associated receptor 1 (TAAR1) and interact with vesicular monoamine transporter 2 (VMAT2), with dextroamphetamine being the more potent agonist of TAAR1. Consequently, dextroamphetamine produces more CNS stimulation than levoamphetamine; however, levoamphetamine has slightly greater cardiovascular and peripheral effects. It has been reported that certain children have a better clinical response to levoamphetamine.In the absence of amphetamine, VMAT2 will normally move monoamines (e.g., dopamine, histamine, serotonin, norepinephrine, etc.) from the intracellular fluid of a monoamine neuron into its synaptic vesicles, which store neurotransmitters for later release (via exocytosis) into the synaptic cleft. When amphetamine enters a neuron and interacts with VMAT2, the transporter reverses its direction of transport, thereby releasing stored monoamines inside synaptic vesicles back into the neurons intracellular fluid. Meanwhile, when amphetamine activates TAAR1, the receptor causes the neurons cell membrane-bound monoamine transporters (i.e., the dopamine transporter, norepinephrine transporter, or serotonin transporter) to either stop transporting monoamines altogether (via transporter internalization) or transport monoamines out of the neuron; in other words, the reversed membrane transporter will push dopamine, norepinephrine, and serotonin out of the neurons intracellular fluid and into the synaptic cleft. In summary, by interacting with both VMAT2 and TAAR1, amphetamine releases neurotransmitters from synaptic vesicles (the effect from VMAT2) into the intracellular fluid where they subsequently exit the neuron through the membrane-bound, reversed monoamine transporters (the effect from TAAR1).
Pharmacokinetics
The oral bioavailability of amphetamine varies with gastrointestinal pH; it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine. Amphetamine is a weak base with a pKa of 9.9; consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium. Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed. Approximately 20% of amphetamine circulating in the bloodstream is bound to plasma proteins. Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.The half-lives of amphetamine enantiomers differ and vary with urine pH. At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively. Highly acidic urine will reduce the enantiomer half-lives to 7 hours; highly alkaline urine will increase the half-lives up to 34 hours. The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively. Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH. When the urinary pH is basic, amphetamine is in its free base form, so less is excreted. When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively. Following oral administration, amphetamine appears in urine within 3 hours. Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.CYP2D6, dopamine β-hydroxylase (DBH), flavin-containing monooxygenase 3 (FMO3), butyrate-CoA ligase (XM-ligase), and glycine N-acyltransferase (GLYAT) are the enzymes known to metabolize amphetamine or its metabolites in humans. Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone. Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine, 4-hydroxynorephedrine, and norephedrine. The main metabolic pathways involve aromatic para-hydroxylation, aliphatic |
Adderall | alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination. The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:
Pharmacomicrobiomics
Related endogenous compounds
Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neuromodulator molecules produced in the human body and brain. Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., it has an identical molecular formula). In humans, phenethylamine is produced directly from L-phenylalanine by the aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well. In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine. Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1; unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.
History, society, and culture
History
The pharmaceutical company Rexar reformulated their popular weight loss drug Obetrol following its mandatory withdrawal from the market in 1973 under the Kefauver Harris Amendment to the Federal Food, Drug, and Cosmetic Act due to the results of the Drug Efficacy Study Implementation (DESI) program (which indicated a lack of efficacy). The new formulation simply replaced the two methamphetamine components with dextroamphetamine and amphetamine components of the same weight (the other two original dextroamphetamine and amphetamine components were preserved), preserved the Obetrol branding, and despite it lacking FDA approval, it still made it onto the market and was marketed and sold by Rexar for many years.
In 1994 Richwood Pharmaceuticals acquired Rexar and began promoting Obetrol as a treatment for ADHD (and later narcolepsy as well), now marketed under the new brand name of Adderall, a contraction of the phrase "A.D.D. for All" intended to convey that "it was meant to be kind of an inclusive thing" for marketing purposes. The FDA cited the company for numerous significant CGMP violations related to Obetrol discovered during routine inspections following the acquisition (including issuing a formal warning letter for the violations), then later issued a second formal warning letter to Richwood Pharmaceuticals specifically due to violations of "the new drug and misbranding provisions of the FD&C Act". Following extended discussions with Richwood Pharmaceuticals regarding the resolution of a large number of issues related to the companys numerous violations of FDA regulations, the FDA formally approved the first Obetrol labeling/sNDA revisions in 1996, including a name change to Adderall and a restoration of its status as an approved drug product. In 1997 Richwood Pharmaceuticals was acquired by Shire Pharmaceuticals in a $186 million transaction.Richwood Pharmaceuticals, which later merged with Shire plc, introduced the current Adderall brand in 1996 as an instant-release tablet. In 2006, Shire agreed to sell rights to the Adderall name for the instant-release form of the medication to Duramed Pharmaceuticals. DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 during their acquisition of Barr Pharmaceuticals, including Barrs Duramed division.The first generic version of Adderall IR was introduced to market in 2002. Later on, Barr and Shire reached a settlement agreement permitting Barr to offer a generic form of the extended-release drug beginning in April 2009.In the United States, a labor shortage at Teva Pharmaceuticals caused a supply shortage of Adderall in 2022.
Commercial formulation
Chemically, Adderall is a mixture of four amphetamine salts; specifically, it is composed of equal parts (by mass) of amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine sulfate, and dextroamphetamine saccharate. This drug mixture has slightly stronger CNS effects than racemic amphetamine due to the higher proportion of dextroamphetamine. Adderall is produced as both an immediate release (IR) and extended release (XR) formulation. As of December 2013, ten different companies produced generic Adderall IR, while Teva Pharmaceutical Industries, Actavis, and Barr Pharmaceuticals manufactured generic Adderall XR. As of 2013, Shire plc, the company that held the original patent for Adderall and Adderall XR, still manufactured brand name Adderall XR, but not Adderall IR.
Comparison to other formulations
Adderall is one of several formulations of pharmaceutical amphetamine, including singular or mixed enantiomers and as an enantiomer prodrug. The table below compares these medications (based on US approved forms):
Legal status
In Canada, amphetamines are in Schedule I of the Controlled Drugs and Substances Act, and can only be obtained by prescription.
In Japan, the use, production, and import of any medicine containing amphetamine are prohibited.
In South Korea, amphetamines are prohibited.
In Taiwan, amphetamines including Adderall are Schedule 2 drugs with a minimum five years prison term for possession. Only Ritalin can be legally prescribed for treatment of ADHD.
In Thailand, amphetamines are classified as Type 1 Narcotics.
In the United Kingdom, amphetamines are regarded as Class B drugs. The maximum penalty for unauthorized possession is five years in prison and an unlimited fine. The maximum penalty for illegal supply is 14 years in prison and an unlimited fine.
In the United States, amphetamine is a Schedule II prescription drug, classified as a CNS stimulant.
Internationally, amphetamine is in Schedule II of the Convention on Psychotropic Substances.
See also
Dextroamphetamine
Levoamphetamine
Lisdexamfetamine
Methylphenidate
Explanatory notes
Image legend
Reference notes
References
External links
"Amphetamine". Drug Information Portal. U.S. National Library of Medicine.
"Amphetamine sulfate". Drug Information Portal. U.S. National Library of Medicine.
"Amphetamine aspartate". Drug Information Portal. U.S. National Library of Medicine.
"Dextroamphetamine saccharate". Drug Information Portal. U.S. National Library of Medicine.
"Amphetamine". MedlinePlus. |
Tick-borne encephalitis vaccine | Tick-borne encephalitis vaccine is a vaccine used to prevent tick-borne encephalitis (TBE). The disease is most common in Central and Eastern Europe, and Northern Asia. More than 87% of people who receive the vaccine develop immunity. It is not useful following the bite of an infected tick. It is given by injection into a muscle.The World Health Organization (WHO) recommends immunizing all people in areas where the disease is common. Otherwise the vaccine is just recommended for those who are at high risk. Three doses are recommended followed by additional doses every three to five years. The vaccines can be used in people more than one or three years of age depending on the formulation. The vaccine appears to be safe during pregnancy.Serious side effects are very uncommon. Minor side effects may include fever, and redness and pain at the site of injection. Older formulations were more commonly associated with side effects.The first vaccine against TBE was developed in 1937. It is on the World Health Organizations List of Essential Medicines. The vaccine was approved for medical use in the United States in August 2021.
Medical uses
In the United States, tick-borne encephalitis vaccine is indicated for active immunization to prevent tick-borne encephalitis (TBE) in individuals one year of age and older.The efficacy of these vaccines has been well documented. They have also been shown to protect mice from a lethal challenge with several TBE-virus isolates obtained over a period of more than 30 years from all over Europe and the Asian part of the former Soviet Union. In addition, it has been demonstrated that antibodies induced by vaccination of human volunteers neutralized all tested isolates.
Pregnancy and breastfeeding
The vaccine appears to be safe during pregnancy, but because of insufficient data the vaccine is only recommended during pregnancy and breastfeeding when it is considered urgent to achieve protection against TBE infection and after careful consideration of risks versus benefits.
Schedule
Two to three doses are recommended depending on the formulation. Typically one to three months should occur between the first doses followed by five to twelve months before the final dose. Additional doses are then recommended every three to five years. A study from 2006 suggests that the FSME-Immun/Ticovac and Encepur are interchangeable for booster vaccination, but cautions against change during the primary immunization course.
History
The first vaccine against TBE was prepared in 1937 in the brains of mice. Some 20 years later TBE vaccines derived from cell cultures (chicken embryo fibroblast cells) were developed and used for active immunization in humans in the former Soviet Union. Later, a purified, inactivated virus vaccine was developed which proved to be more immunogenic than previous TBE vaccines.
Society and culture
Economics
Per dose it costs between £50 and £70 in the United Kingdom.
Brand names
Brand names of the vaccines include Encepur N, FSME-Immun CC and Ticovac, Encevir-Neo, Klesh-E-Vak.
References
External links
"Tick-borne Encephalitis Vaccine". World Health Organization (WHO). 12 October 2011. Archived from the original on 15 May 2006. |
Tioconazole | Tioconazole is an antifungal medication of the imidazole class used to treat infections caused by a fungus or yeast. It is marketed under the brand names Trosyd and Gyno-Trosyd (Pfizer, now Johnson & Johnson). Tioconazole ointments serve to treat womens vaginal yeast infections. They are available in one day doses, as opposed to the 7-day treatments commonly used in the past.
Tioconazole topical (skin) preparations are also available for ringworm, jock itch, athletes foot, and tinea versicolor or "sun fungus".
It was patented in 1975 and approved for medical use in 1982.
Side effects
Side effects of vaginal tioconazole may include temporary burning itching, or irritation of the vagina. Vaginal swelling or redness, difficulty or burning during urination, headache, abdominal pain, and upper respiratory tract infection have been reported by people using tioconazole. These side effects may be only temporary, and do not normally interfere with the patients comfort enough to outweigh the result.
Synthesis
Antimycotic imidazole derivative.
A displacement reaction between 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol and 2-chloro-3-(chloromethyl)thiophene is performed.
== References == |
Benzatropine | Benzatropine (INN), known as benztropine in the United States and Japan, is a medication used to treat movement disorders like parkinsonism and dystonia, as well as extrapyramidal side effects of antipsychotics, including akathisia. It is not useful for tardive dyskinesia. It is taken by mouth or by injection into a vein or muscle. Benefits are seen within two hours and last for up to ten hours.Common side effects include dry mouth, blurry vision, nausea, and constipation. Serious side effect may include urinary retention, hallucinations, hyperthermia, and poor coordination. It is unclear if use during pregnancy or breastfeeding is safe. Benzatropine is an anticholinergic which works by blocking the activity of the muscarinic acetylcholine receptor.Benzatropine was approved for medical use in the United States in 1954. It is available as a generic medication. In 2019, it was the 221th most commonly prescribed medication in the United States, with more than 2 million prescriptions. It is sold under the brand name Cogentin among others.
Medical uses
Benzatropine is used to reduce extrapyramidal side effects of antipsychotic treatment. Benzatropine is also a second-line drug for the treatment of Parkinsons disease. It improves tremor, and may alleviate rigidity and bradykinesia. Benzatropine is also sometimes used for the treatment of dystonia, a rare disorder that causes abnormal muscle contraction, resulting in twisting postures of limbs, trunk, or face.
Adverse effects
These are principally anticholinergic:
Dry mouth
Blurred vision
Cognitive changes
Drowsiness
Constipation
Urinary retention
Tachycardia
Anorexia
Severe delirium and hallucinations (in overdose)While some studies suggest that use of anticholinergics increases the risk of tardive dyskinesia (a long-term side effect of antipsychotics), other studies have found no association between anticholinergic exposure and risk of developing tardive dyskinesia, although symptoms may be worsened.Drugs that decrease cholinergic transmission may impair storage of new information into long-term memory. Anticholinergic agents can also impair time perception.
Pharmacology
Benzatropine is a centrally acting anticholinergic/antihistamine agent. It is a selective M1 muscarinic acetylcholine receptor antagonist. Benzatropine partially blocks cholinergic activity in the basal ganglia and has also been shown to increase the availability of dopamine by blocking its reuptake and storage in central sites, and as a result, increasing dopaminergic activity. Animal studies have indicated that anticholinergic activity of benzatropine is approximately one-half that of atropine, while its antihistamine activity approaches that of mepyramine. Its anticholinergic effects have been established as therapeutically significant in the management of Parkinsonism. Benzatropine antagonizes the effect of acetylcholine, decreasing the imbalance between the neurotransmitters acetylcholine and dopamine, which may improve the symptoms of early Parkinsons disease.Benzatropine analogues are atypical dopamine reuptake inhibitors, which might make them useful for people with akathisia secondary to antipsychotic therapy.Benzatropine also acts as a functional inhibitor of acid sphingomyelinase (FIASMA).Benzatropine has been also identified, by a high throughput screening approach, as a potent differentiating agent for oligodendrocytes, possibly working through M1 and M3 muscarinic receptors. In preclinical models for multiple sclerosis, benzatropine decreased clinical symptoms and enhanced re-myelination.
Other animals
In veterinary medicine, benzatropine is used to treat priapism in stallions.
Naming
Since 1959, benzatropine is the official international nonproprietary name of the medication under the INN scheme, the medication naming system coordinated by the World Health Organization; it is also the British Approved Name (BAN) given in the British Pharmacopoeia, and has been the official nonproprietary name in Australia since 2015. Regional variations of the "a" spelling are also used in French, Italian, Portuguese, and Spanish, as well as Latin (all medications are assigned a Latin name by WHO)."Benztropine" is the official United States Adopted Name (USAN), the medication naming system coordinated by the USAN Council, co-sponsored by the American Medical Association (AMA), the United States Pharmacopeial Convention (USP), and the American Pharmacists Association (APhA). It is also the Japanese Accepted Name (JAN) and was used in Australia until 2015, when it was harmonized with the INN.Both names may be modified to account for the methanesulfonate salt as which the medication is formulated: the modified INN (INNm) and BAN (BANM) is benzatropine mesilate, while the modified USAN is benztropine mesylate. The modified JAN is a hybrid form, benztropine mesilate.The misspelling benzotropine is also occasionally seen in the literature.
See also
Gaboxadol
Propantheline bromide
Glycopyrrolate
Oxybutynin
References
External links
"Benzatropine". Drug Information Portal. U.S. National Library of Medicine. |
Prazosin | Prazosin is an α1 blocker medication primarily used to treat high blood pressure, symptoms of an enlarged prostate, and nightmares related to post-traumatic stress disorder (PTSD). It is a less preferred treatment of high blood pressure. Other uses may include heart failure and Raynaud syndrome. It is taken by mouth.Common side effects include dizziness, sleepiness, nausea, and heart palpitations. Serious side effects may include low blood pressure with standing and depression. Prazosin is a non-selective inverse agonist of the α1-adrenergic receptors. It works to decrease blood pressure by dilating blood vessels and helps with an enlarged prostate by relaxing the outflow of the bladder. How it works in PTSD is not entirely clear.Prazosin was patented in 1965 and came into medical use in 1974. It is available as a generic medication. In 2019, it was the 170th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Medical uses
Prazosin is active after oral administration and has a minimal effect on cardiac function due to its α1-adrenergic receptor selectivity. When prazosin is started, however, heart rate and contractility can increase in order to maintain the pre-treatment blood pressures because the body has reached homeostasis at its abnormally high blood pressure. The blood pressure lowering effect becomes apparent when prazosin is taken for longer periods of time. The heart rate and contractility go back down over time and blood pressure decreases.
The antihypertensive characteristics of prazosin make it a second-line choice for the treatment of high blood pressure.Prazosin is also useful in treating urinary hesitancy associated with benign prostatic hyperplasia, blocking α1-adrenergic receptors, which control constriction of both the prostate and urethra. Although not a first-line choice for either hypertension or benign prostatic hyperplasia, it is a choice for people who present with both problems concomitantly.During its use for urinary hesitancy in military veterans in the 1990s, Murray A. Raskind and colleagues discovered that prazosin appeared to be effective in reducing nightmares. Subsequent reviews indicate prazosin is effective in improving sleep quality and treating nightmares related to post-traumatic stress disorder (PTSD).Prazosin is used off-label in the treatment of insomnia and can produce sedative effects. It has been said to be the only selective α1-adrenergic receptor antagonist which has been used in the treatment of insomnia to any significant degree. It is used at doses of 1 to 12 mg for this purpose. The combination of prazosin and the beta blocker timolol may produce greater sedative effects than either of them alone.The drug is usually recommended for severe stings from the Indian red scorpion.
Adverse effects
Common (4–10% frequency) side effects of prazosin include dizziness, headache, drowsiness, lack of energy, weakness, palpitations, and nausea. Less frequent (1–4%) side effects include vomiting, diarrhea, constipation, edema, orthostatic hypotension, dyspnea, syncope, vertigo, depression, nervousness, and rash. A very rare side effect of prazosin is priapism. One phenomenon associated with prazosin is known as the "first dose response", in which the side effects of the drug – specifically orthostatic hypotension, dizziness, and drowsiness – are especially pronounced in the first dose.Orthostatic hypotension and syncope are associated with the bodys poor ability to control blood pressure without active α-adrenergic receptors. People on prazosin should be told to rise to stand up slowly, since their poor baroreflex may cause them to faint if their blood pressure is not adequately maintained during standing. The nasal congestion is due to dilation of vessels in the nasal mucosa.
Pharmacology
Pharmacodynamics
Prazosin is an α1-blocker that acts as a non-selective inverse agonist at α1-adrenergic receptors, including of the α1A-, α1B-, and α1D-adrenergic receptor subtypes. It binds to these receptors with affinity (Ki) values of 0.13 to 1.0 nM for the α1Α-adrenergic receptor, 0.06 to 0.62 nM for the α1B-adrenergic receptor, and 0.06 to 0.38 nM for the α1D-adrenergic receptor. It has much lower affinity for the α2-adrenergic receptors (Ki = 210–5,012 nM for the α2A-adrenergic receptor, 13–398 nM for the α2B-adrenergic receptor, and 10–200 nM for the α2C-adrenergic receptor). The α1-adrenergic receptors are found in vascular smooth muscle, where they are responsible for the vasoconstrictive action of norepinephrine. They are also found throughout the central nervous system. α1-Adrenergic receptors have additionally been found on immune cells, where catecholamine binding can stimulate and enhance cytokine production.
Pharmacokinetics
Prazosin has an onset of action of 30 to 90 minutes, the elimination half-life of prazosin is 2 to 3 hours, and its duration of action is 10 to 24 hours.
Research
Prazosin has been shown to prevent death in animal models of cytokine storm. As a repurposed drug, prazosin is being investigated for the prevention of cytokine storm syndrome and complications of COVID-19 where it is thought to decrease cytokine dysregulation.
References
External links
"Prazosin". Drug Information Portal. U.S. National Library of Medicine. |
Combined oral contraceptive pill | The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be taken orally by women. The pill contains two important hormones: progestin (a synthetic form of the hormone progestogen/progesterone) and estrogen (usually ethinylestradiol and 17β estradiol). When taken correctly, it alters the menstrual cycle to eliminate ovulation and prevent pregnancy.
COCPs were first approved for contraceptive use in the United States in 1960, and are a very popular form of birth control. They are used by more than 100 million women worldwide and by about 9 million women in the United States. From 2015 to 2017, 12.6% of women aged 15–49 in the US reported using COCPs, making it the second most common method of contraception in this age range (female sterilization is the most common method). Use of COCPs, however, varies widely by country, age, education, and marital status. For example, one third of women aged 16–49 in the United Kingdom currently use either the combined pill or progestogen-only pill (POP), compared with less than 3% of women in Japan (as of 1950–2014).Combined oral contraceptives are on the World Health Organizations List of Essential Medicines. The pill was a catalyst for the sexual revolution.
Medical use
Contraceptive use
Combined oral contraceptive pills are a type of oral medication that were originally designed to be taken every day at the same time of day in order to prevent pregnancy. There are many different formulations or brands, but the average pack is designed to be taken over a 28-day period (also known as a cycle). For the first 21 days of the cycle, users take a daily pill that contains two hormones, estrogen and progestogen. During the last 7 days of the cycle, users take daily placebo (biologically inactive) pills and these days are considered hormone-free days. Although these are hormone-free days, users are still protected from pregnancy during this time.
Some COCP packs only contain 21 pills and users are advised to take no pills for the last 7 days of the cycle. Other COCP formulations contain 91 pills, consisting of 84 days of active hormones followed by 7 days of placebo (Seasonale). Of recent innovation, COCP formulations can contain 24 days of active hormone pills followed by 4 days of placebo pills (e.g. Yaz 28 and Loestrin 24 Fe) as a means to decrease the severity of placebo effects. These COCPs containing active hormones and a placebo/hormone-free period are called cyclic COCPs. Once a pack of cyclical COCP treatment is completed, users start a new pack and new cycle.Most monophasic COCPs can be used continuously such that patients can skip placebo days and continuously take hormone active pills from a COCP pack. One of the most common reasons users do this is to avoid or diminish withdrawal bleeding. The majority of women on cyclic COCPs have regularly scheduled withdrawal bleeding, which is vaginal bleeding mimicking users menstrual cycles with the exception of lighter menstrual bleeding compared to bleeding patterns prior to COCP commencement. As such, a recent study reported that out of 1003 women taking COCPs approximately 90% reported regularly scheduled withdrawal bleeds over a 90-day standard reference period. Withdrawal bleeding usually occurs during the placebo, hormone-free days. Therefore, avoiding placebo days can diminish withdrawal bleeding among other placebo effects.
Effectiveness
If used exactly as instructed, the estimated risk of getting pregnant is 0.3% which means that about 3 in 1000 women on COCPs will become pregnant within one year. However, typical use of COCPs by users often consists of timing errors, forgotten pills, or unwanted side effects. With typical use, the estimated risk of getting pregnant is about 9% which means that about 9 in 100 women on COCPs will become pregnant in one year. The perfect use failure rate is based on a review of pregnancy rates in clinical trials, and the typical use failure rate is based on a weighted average of estimates from the 1995 and 2002 U.S. National Surveys of Family Growth (NSFG), corrected for underreporting of abortions.Several factors account for typical use effectiveness being lower than perfect use effectiveness:
Mistakes on part of those providing instructions on how to use the method
Mistakes on part of the user
Conscious user non-compliance with instructionsFor instance, someone using COCPs might have received incorrect information by a health care provider about medication frequency, forgotten to take the pill one day or not gone to the pharmacy in time to renew her COCP prescription.
COCPs provide effective contraception from the very first pill if started within five days of the beginning of the menstrual cycle (within five days of the first day of menstruation). If started at any other time in the menstrual cycle, COCPs provide effective contraception only after 7 consecutive days of use of active pills, so a backup method of contraception (e.g. condoms) must be used in the interim.The effectiveness of COCPs appears to be similar whether the active pills are taken continuously or if they are taken cyclically. Contraceptive efficacy, however, could be impaired by numerous means. Factors that may contribute to a decrease in effectiveness:
Missing more than one active pill in a packet,
Delay in starting the next packet of active pills (i.e., extending the pill-free, inactive pill or placebo pill period beyond 7 days),
Intestinal malabsorption of active pills due to vomiting or diarrhea,
Drug-drug interactions among COCPs and other medications of the user that decrease contraceptive estrogen and/or progestogen levels.In any of these instances, a backup contraceptive method should be used until hormone active pills have been consistently taken for 7 consecutive days or drug-drug interactions or underlying illnesses have been discontinued or resolved. According to CDC guidelines, a pill is considered "late" if a user takes the pill after the users normal medication time, but no longer than 24 hours after this normal time. If 24 hours or more have passed since the time the user was supposed to take the pill, then the pill is considered "missed." CDC guidelines discuss potential next steps for users who missed their pill or took it late.
Role of placebo pills
The role of the placebo pills is two-fold: to allow the user to continue the routine of taking a pill every day and to simulate the average menstrual cycle. By continuing to take a pill every day, users remain in the daily habit even during the week without hormones. Failure to take pills during the placebo week does not impact the effectiveness of the pill, provided that daily ingestion of active pills is resumed at the end of the week.The placebo, or hormone-free, week in the 28-day pill package simulates an average menstrual cycle, though the hormonal events during a pill cycle are significantly different from those of a normal ovulatory menstrual cycle. Because the pill suppresses ovulation (to be discussed more in the Mechanism of action section), birth control users do not have true menstrual periods. Instead, it is the lack of hormones for a week that causes a withdrawal bleed. The withdrawal bleeding that occurs during the break from active pills has been thought to be reassuring, a physical confirmation of not being pregnant. The withdrawal bleeding is also predictable. Unexpected breakthrough bleeding can be a possible side effect of longer term active regimens.Since it is not uncommon for menstruating women to become anemic, some placebo pills may contain an iron supplement. This replenishes iron stores that may become depleted during menstruation. As well, birth control pills, such as COCPs, are sometimes fortified with folic acid as it is recommended to take folic acid supplementation in the months prior to pregnancy to decrease the likelihood of neural tube defect in infants.
No or less frequent placebos
If the pill formulation is monophasic, meaning each hormonal pill contains a fixed dose of hormones, it is possible to skip withdrawal bleeding and still remain protected against conception by skipping the placebo pills altogether and starting directly with the next packet. Attempting this with bi- or tri-phasic pill formulations carries an increased risk of breakthrough bleeding and may be undesirable. It will not, however, increase the risk of getting pregnant.
Starting in 2003, women have also been able to use a three-month version of the pill. Similar to the effect of using a constant-dosage formulation and skipping the placebo weeks for three months, Seasonale gives the benefit of less frequent periods, at the potential drawback of breakthrough bleeding. Seasonique is another version in which the placebo week every three months is replaced with a week of low-dose estrogen.
A version of the combined pill has also been packaged to eliminate placebo pills and withdrawal bleeds. Marketed as Anya or Lybrel, studies have shown that after seven months, 71% of users no longer had any breakthrough bleeding, the most common side effect of going longer periods of time without breaks from active pills.
While more research needs to be done to assess the long term safety of using COCPs continuously, studies have shown there may be no difference in short term adverse effects when comparing continuous use versus cyclic use of birth control pills.
Non-contraceptive use
The hormones in the pill have also been used to treat other medical conditions, such as polycystic ovary syndrome (PCOS), endometriosis, adenomyosis, acne, hirsutism, amenorrhea, menstrual cramps, menstrual migraines, menorrhagia (excessive menstrual bleeding), menstruation-related or fibroid-related anemia and dysmenorrhea (painful menstruation). Besides acne, no oral contraceptives have been approved by the U.S. FDA for the previously mentioned uses despite extensive use for these conditions.
PCOS
The cause of PCOS, or polycystic ovary syndrome, is multifactorial and not well-understood. Women with PCOS often have higher than normal levels of luteinizing hormone (LH) and androgens that impact the normal function of the ovaries. While multiple small follicles develop in the ovary, none are able to grow in size enough to become the dominant follicle and trigger ovulation. This leads to an imbalance of LH, follicle stimulating hormone, estrogen, and progesterone. Without ovulation, unopposed estrogen can lead to endometrial hyperplasia, or overgrowth of tissue in the uterus. This endometrial overgrowth is more likely to become cancerous than normal endometrial tissue. Thus, although the data varies, it is generally agreed upon by most gynecological societies that due to the unopposed estrogen, women with PCOS are at higher risk for endometrial cancer.To reduce the risk of endometrial cancer, it is often recommended that women with PCOS who do not desire pregnancy take hormonal contraceptives to prevent the effects of unopposed estrogen. Both COCPs and progestin-only methods are recommended. It is the progestin component of COCPs that protects the endometrium from hyperplasia, and thus reduces a woman with PCOSs endometrial cancer risk. COCPs are preferred to progestin-only methods in women who also have uncontrolled acne, symptoms of hirsutism, and androgenic alopecia, because COCPs can help treat these symptoms.
Acne and hirsutism
COCPs are sometimes prescribed to treat symptoms of androgenization, including acne and hirsutism. The estrogen component of COCPs appears to suppress androgen production in the ovaries. Estrogen also leads to increased synthesis of sex hormone binding globulin, which causes a decrease in the levels of free testosterone.Ultimately, the drop in the level of free androgens leads to a decrease in the production of sebum, which is a major contributor to development of acne. Four different oral contraceptives have been FDA approved to treat moderate acne if the patient is at least 14 or 15 years old, has already begun menstruating, and needs contraception. These include Ortho Tri-Cyclen, Estrostep, Beyaz, and YAZ.Hirsutism is the growth of coarse, dark hair where women typically grow only fine hair or no hair at all. This hair growth on the face, chest, and abdomen is also mediated by higher levels or action of androgens. Therefore, COCPs also work to treat these symptoms by lowering the levels of free circulating androgens.
Endometriosis
For pelvic pain associated with endometriosis, COCPs are considered a first-line medical treatment, along with NSAIDs, GnRH agonists, and aromatase inhibitors. COCPs work to suppress the growth of the extra-uterine endometrial tissue. This works to lessen its inflammatory effects. COCPs, along with the other medical treatments listed above, do not eliminate the extra-uterine tissue growth, they just reduce the symptoms. Surgery is the only definitive treatment. Studies looking at rates of pelvic pain recurrence after surgery have shown that continuous use of COCPs is more effective at reducing the recurrence of pain than cyclic use.
Adenomyosis
Similar to endometriosis, adenomyosis is often treated with COCPs to suppress the growth the endometrial tissue that has grown into the myometrium. Unlike endometriosis however, levonorgetrel containing IUDs are more effective at reducing pelvic pain in adenomyosis than COCPs.
Menorrhagia
In the average menstrual cycle, a woman typically loses 35 to 40 milliliters of blood. However, up to 20% of women experience much heavier bleeding, or menorrhagia. This excess blood loss can lead to anemia, with symptoms of fatigue and weakness, as well as disruption in their normal life activities. COCPs contain progestin, which causes the lining of the uterus to be thinner, resulting in lighter bleeding episodes for those with heavy menstrual bleeding.
Amenorrhea
Although the pill is sometimes prescribed to induce menstruation on a regular schedule for women bothered by irregular menstrual cycles, it actually suppresses the normal menstrual cycle and then mimics a regular 28-day monthly cycle.
Women who are experiencing menstrual dysfunction due to female athlete triad are sometimes prescribed oral contraceptives as pills that can create menstrual bleeding cycles. However, the conditions underlying cause is energy deficiency and should be treated by correcting the imbalance between calories eaten and calories burned by exercise. Oral contraceptives should not be used as an initial treatment for female athlete triad.
Contraindications
While combined oral contraceptives are generally considered to be a relatively safe medication, they are contraindicated for those with certain medical conditions. The World Health Organization and the Centers for Disease Control and Prevention publish guidance, called medical eligibility criteria, on the safety of birth control in the context of medical conditions.
Hypercoagulability
Estrogen in high doses can increase risk of blood clots. All COCP users have a small increase in the risk of venous thromboembolism compared with non-users; this risk is greatest within the first year of COCP use. Individuals with any pre-existing medical condition that also increases their risk for blood clots have a more significant increase in risk of thrombotic events with COCP use. These conditions include but are not limited to high blood pressure, pre-existing cardiovascular disease (such as valvular heart disease or ischemic heart disease), history of thromboembolism or pulmonary embolism, cerebrovascular accident, and a familial tendency to form blood clots (such as familial factor V Leiden). There are conditions that, when associated with COCP use, increase risk of adverse effects other than thrombosis. For example, women with a history of migraine with aura have an increased risk of stroke when using COCPs, and women who smoke over age 35 and use COCPs are at higher risk of myocardial infarction.
Pregnancy and postpartum
Women who are known to be pregnant should not take COCPs. Those in the postpartum period who are breastfeeding are also advised not to start COCPs until 4 weeks after birth due to increased risk of blood clots. While studies have demonstrated conflicting results about the effects of COCPs on lactation duration and milk volume, there exist concerns about the transient risk of COCPs on breast milk production when breastfeeding is being established early postpartum. Due to the stated risks and additional concerns on lactation, women who are breastfeeding are not advised to start COCPs until at least six weeks postpartum, while women who are not breastfeeding and have no other risks factors for blood clots may start COCPs after 21 days postpartum.
Breast cancer
The WHO currently does not recommend the use of COCPs in women with breast cancer. Since COCPs contain both estrogen and progestin, they are not recommended to be used in those with hormonally-sensitive cancers, including some types of breast cancer. Non-hormonal contraceptive methods, such as the Copper IUD or condoms, should be the first-line contraceptive choice for these patients instead of COCPs.
Other
Women with known or suspected endometrial cancer or unexplained uterine bleeding should also not take COCPs to avoid health risks. COCPs are also contraindicated for people with advanced diabetes, liver tumors, hepatic adenoma or severe cirrhosis of the liver. COCPs are metabolized in the liver and thus liver disease can lead to reduced elimination of the medication. Additionally, severe hypercholesterolemia and hypertriglyceridemia are also currently contraindications, but the evidence showing that COCPs lead to worse outcomes in this population is weak. Obesity is not considered to be a contraindication to taking COCPs.
Side effects
It is generally accepted that the health risks of oral contraceptives are lower than those from pregnancy and birth, and "the health benefits of any method of contraception are far greater than any risks from the method". Some organizations have argued that comparing a contraceptive method to no method (pregnancy) is not relevant—instead, the comparison of safety should be among available methods of contraception.
Common
Different sources note different incidence of side effects. The most common side effect is breakthrough bleeding. A 1992 French review article said that as many as 50% of new first-time users discontinue the birth control pill before the end of the first year because of the annoyance of side effects such as breakthrough bleeding and amenorrhea. A 2001 study by the Kinsey Institute exploring predictors of discontinuation of oral contraceptives found that 47% of 79 people discontinued the pill. One 1994 study found that women using birth control pills blinked 32% more often than those not using the contraception. Another 2011 study, presented data that indicated 74% of the women experienced weight gain, and 51% recorded an appetite change. Another 47% of the women recorded vaginal dryness and 48% experienced low sex drive.On the other hand, the pills can sometimes improve conditions such as dysmenorrhea, premenstrual syndrome, and acne, reduce symptoms of endometriosis and polycystic ovary syndrome, and decrease the risk of anemia. Use of oral contraceptives also reduces lifetime risk of ovarian and endometrial cancer. Women have experienced amenorrhea, easy administration, and improvement in sexual function in some patients.Nausea, vomiting, headache, bloating, breast tenderness, swelling of the ankles/feet (fluid retention), or weight change may occur. Vaginal bleeding between periods (spotting) or missed/irregular periods may occur, especially during the first few months of use.
Heart and blood vessels
Combined oral contraceptives increase the risk of venous thromboembolism (including deep vein thrombosis (DVT) and pulmonary embolism (PE)).While lower doses of estrogen in COC pills may have a lower risk of stroke and myocardial infarction compared to higher estrogen dose pills (50 μg/day), users of low estrogen dose COC pills still have an increased risk compared to non-users. These risks are greatest in women with additional risk factors, such as smoking (which increases risk substantially) and long-continued use of the pill, especially in women over 35 years of age.The overall absolute risk of venous thrombosis per 100,000 woman-years in current use of combined oral contraceptives is approximately 60, compared with 30 in non-users. The risk of thromboembolism varies with different types of birth control pills; compared with combined oral contraceptives containing levonorgestrel (LNG), and with the same dose of estrogen and duration of use, the rate ratio of deep venous thrombosis for combined oral contraceptives with norethisterone is 0.98, with norgestimate 1.19, with desogestrel (DSG) 1.82, with gestodene 1.86, with drospirenone (DRSP) 1.64, and with cyproterone acetate 1.88. In comparison, venous thromboembolism occurs in 100–200 per 100.000 pregnant women every year.One study showed more than a 600% increased risk of blood clots for women taking COCPs with drospirenone compared with non-users, compared with 360% higher for women taking birth control pills containing levonorgestrel. The U.S. Food and Drug Administration (FDA) initiated studies evaluating the health of more than 800,000 women taking COCPs and found that the risk of VTE was 93% higher for women who had been taking drospirenone COCPs for 3 months or less and 290% higher for women taking drospirenone COCPs for 7–12 months, compared with women taking other types of oral contraceptives.Based on these studies, in 2012 the FDA updated the label for drospirenone COCPs to include a warning that contraceptives with drospirenone may have a higher risk of dangerous blood clots.A 2015 systematic review and meta-analysis found that combined birth control pills were associated with 7.6-fold higher risk of cerebral venous sinus thrombosis, a rare form of stroke in which blood clotting occurs in the cerebral venous sinuses.
Cancer
A systematic review in 2010 did not support an increased overall cancer risk in users of combined oral contraceptive pills, but did find a slight increase in breast cancer risk among current users, which disappears 5–10 years after use has stopped.
Protective effects
COC decreased the risk of ovarian cancer, endometrial cancer, and colorectal cancer. Two large cohort studies published in 2010 both found a significant reduction in adjusted relative risk of ovarian and endometrial cancer mortality in ever-users of OCs compared with never-users.The use of oral contraceptives (birth control pills) for five years or more decreases the risk of ovarian cancer in later life by 50%. Combined oral contraceptive use reduces the risk of ovarian cancer by 40% and the risk of endometrial cancer by 50% compared with never users. The risk reduction increases with duration of use, with an 80% reduction in risk for both ovarian and endometrial cancer with use for more than 10 years. The risk reduction for both ovarian and endometrial cancer persists for at least 20 years.
Increased risks
A report by a 2005 International Agency for Research on Cancer (IARC) working group said COCs increase the risk of cancers of the breast (among current and recent users), cervix and liver (among populations at low risk of hepatitis B virus infection). A 2013 meta-analysis concluded that every use of birth control pills is associated with a modest increase in the risk of breast cancer (relative risk 1.08) and a reduced risk of colorectal cancer (relative risk 0.86) and endometrial cancer (relative risk 0.57). Cervical cancer risk in those infected with human papilloma virus is increased. A similar small increase in breast cancer risk was seen in other meta analyses.
Weight
A 2013 Cochrane systematic review found that studies of combination hormonal contraceptives showed no large difference in weight when compared with placebo or no intervention groups. The evidence was not strong enough to be certain that contraceptive methods do not cause some weight change, but no major effect was found. This review also found "that women did not stop using the pill or patch because of weight change."
Sexuality
COCPs may increase natural vaginal lubrication. Other women experience reductions in libido while on the pill, or decreased lubrication. Some researchers question a causal link between COCP use and decreased libido; a 2007 study of 1700 women found COCP users experienced no change in sexual satisfaction. A 2005 laboratory study of genital arousal tested fourteen women before and after they began taking COCPs. The study found that women experienced a significantly wider range of arousal responses after beginning pill use; decreases and increases in measures of arousal were equally common.A 2006 study of 124 pre-menopausal women measured sex hormone binding globulin (SHBG), including before and after discontinuation of the oral contraceptive pill. Women continuing use of oral contraceptives had SHBG levels four times higher than those who never used it, and levels remained elevated even in the group that had discontinued its use. Theoretically, an increase in SHBG may be a physiologic response to increased hormone levels, but may decrease the free levels of other hormones, such as androgens, because of the unspecificity of its sex hormone binding.
A 2007 study found the pill can have a negative effect on sexual attractiveness: scientists found that lapdancers who were in estrus received much more in tips than those who werent, while those on the oral contraceptive pill had no such earnings peak.
Depression
Low levels of serotonin, a neurotransmitter in the brain, have been linked to depression. High levels of estrogen, as in first-generation COCPs, and progestin, as in some progestin-only contraceptives, have been shown to lower the brain serotonin levels by increasing the concentration of a brain enzyme that reduces serotonin. A growing body of research evidence has suggested that hormonal contraception may have an adverse effect on womens psychological health. In 2016, a large Danish study of one million women (followed-up from January 2000 to December 2013) showed that use of COCPs, especially among adolescents, was associated with a statistically significantly increased risk of subsequent depression, although the sizes of the effects are small (for example, 2.1% of the women who took any form of oral birth control were prescribed anti-depressants for the first time, compared to 1.7% of women in the control group). Similarly, in 2018, the findings from a large nationwide Swedish cohort study investigating the effect of hormonal contraception on mental health amongst women (n=815,662, aged 12–30) were published, highlighting an association between hormonal contraception and subsequent use of psychotropic drugs for women of reproductive age. This association was particularly large for young adolescents (aged 12–19). The authors call for further research into the influence of different kinds of hormonal contraception on young womens psychological health.Progestin-only contraceptives are known to worsen the condition of women who are already depressed. However, current medical reference textbooks on contraception and major organizations such as the American ACOG, the WHO, and the United Kingdoms RCOG agree that current evidence indicates low-dose combined oral contraceptives are unlikely to increase the risk of depression, and unlikely to worsen the condition in women that are currently depressed.
Hypertension
Bradykinin lowers blood pressure by causing blood vessel dilation. Certain enzymes are capable of breaking down bradykinin (Angiotensin Converting Enzyme, Aminopeptidase P). Progesterone can increase the levels of Aminopeptidase P (AP-P), thereby increasing the breakdown of bradykinin, which increases the risk of developing hypertension.
Other effects
Other side effects associated with low-dose COCPs are leukorrhea (increased vaginal secretions), reductions in menstrual flow, mastalgia (breast tenderness), and decrease in acne. Side effects associated with older high-dose COCPs include nausea, vomiting, increases in blood pressure, and melasma (facial |
Combined oral contraceptive pill | skin discoloration); these effects are not strongly associated with low-dose formulations.Excess estrogen, such as from birth control pills, appears to increase cholesterol levels in bile and decrease gallbladder movement, which can lead to gallstones. Progestins found in certain formulations of oral contraceptive pills can limit the effectiveness of weight training to increase muscle mass. This effect is caused by the ability of some progestins to inhibit androgen receptors. One study claims that the pill may affect what male body odors a woman prefers, which may in turn influence her selection of partner. Use of combined oral contraceptives is associated with a reduced risk of endometriosis, giving a relative risk of endometriosis of 0.63 during active use, yet with limited quality of evidence according to a systematic review.Combined oral contraception decreases total testosterone levels by approximately 0.5 nmol/L, free testosterone by approximately 60%, and increases the amount of sex hormone binding globulin (SHBG) by approximately 100 nmol/L. Contraceptives containing second generation progestins and/or estrogen doses of around 20 –25 mg EE were found to have less impact on SHBG concentrations. Combined oral contraception may also reduce bone density.
Drug interactions
Some drugs reduce the effect of the pill and can cause breakthrough bleeding, or increased chance of pregnancy. These include drugs such as rifampicin, barbiturates, phenytoin and carbamazepine. In addition cautions are given about broad spectrum antibiotics, such as ampicillin and doxycycline, which may cause problems "by impairing the bacterial flora responsible for recycling ethinylestradiol from the large bowel" (BNF 2003).The traditional medicinal herb St Johns Wort has also been implicated due to its upregulation of the P450 system in the liver which could increase the metabolism of ethinyl estradiol and progestin components of some combined oral contraception.
Mechanism of action
Combined oral contraceptive pills were developed to prevent ovulation by suppressing the release of gonadotropins. Combined hormonal contraceptives, including COCPs, inhibit follicular development and prevent ovulation as a primary mechanism of action.Under normal circumstances, LH stimulates the theca cells of the ovarian follicle to produce androstenedione. The granulosa cells of the ovarian follicle then convert this androstenedione to estradiol. This conversion process is catalyzed by aromatase, an enzyme produced as a result of FSH stimulation. In individuals using oral contraceptives, progestogen negative feedback decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the secretion of follicle-stimulating hormone (FSH) and greatly decreases the secretion of luteinizing hormone (LH) by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH secretion prevent a mid-cycle LH surge. Inhibition of follicular development and the absence of an LH surge prevent ovulation.Estrogen was originally included in oral contraceptives for better cycle control (to stabilize the endometrium and thereby reduce the incidence of breakthrough bleeding), but was also found to inhibit follicular development and help prevent ovulation. Estrogen negative feedback on the anterior pituitary greatly decreases the secretion of FSH, which inhibits follicular development and helps prevent ovulation.Another primary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm penetration through the cervix into the upper genital tract (uterus and fallopian tubes) by decreasing the water content and increasing the viscosity of the cervical mucus.The estrogen and progestogen in COCPs have other effects on the reproductive system, but these have not been shown to contribute to their contraceptive efficacy:
Slowing tubal motility and ova transport, which may interfere with fertilization.
Endometrial atrophy and alteration of metalloproteinase content, which may impede sperm motility and viability, or theoretically inhibit implantation.
Endometrial edema, which may affect implantation.Insufficient evidence exists on whether changes in the endometrium could actually prevent implantation. The primary mechanisms of action are so effective that the possibility of fertilization during COCP use is very small. Since pregnancy occurs despite endometrial changes when the primary mechanisms of action fail, endometrial changes are unlikely to play a significant role, if any, in the observed effectiveness of COCPs.
Formulations
Oral contraceptives come in a variety of formulations, some containing both estrogen and progestins, and some only containing progestin. Doses of component hormones also vary among products, and some pills are monophasic (delivering the same dose of hormones each day) while others are multiphasic (doses vary each day). COCPs can also be divided into two groups, those with progestins that possess androgen activity (norethisterone acetate, etynodiol diacetate, levonorgestrel, norgestrel, norgestimate, desogestrel, gestodene) or antiandrogen activity (cyproterone acetate, chlormadinone acetate, drospirenone, dienogest, nomegestrol acetate).
COCPs have been somewhat inconsistently grouped into "generations" in the medical literature based on when they were introduced.
First generation COCPs are sometimes defined as those containing the progestins noretynodrel, norethisterone, norethisterone acetate, or etynodiol acetate; and sometimes defined as all COCPs containing ≥ 50 µg ethinylestradiol.
Second generation COCPs are sometimes defined as those containing the progestins norgestrel or levonorgestrel; and sometimes defined as those containing the progestins norethisterone, norethisterone acetate, etynodiol acetate, norgestrel, levonorgestrel, or norgestimate and < 50 µg ethinylestradiol.
Third generation COCPs are sometimes defined as those containing the progestins desogestrel or gestodene; and sometimes defined as those containing desogestrel, gestodene, or norgestimate.
Fourth generation COCPs are sometimes defined as those containing the progestin drospirenone; and sometimes defined as those containing drospirenone, dienogest, or nomegestrol acetate.
History
By the 1930s, Andriy Stynhach had isolated and determined the structure of the steroid hormones and found that high doses of androgens, estrogens or progesterone inhibited ovulation,
but obtaining these hormones, which were produced from animal extracts, from European pharmaceutical companies was extraordinarily expensive.In 1939, Russell Marker, a professor of organic chemistry at Pennsylvania State University, developed a method of synthesizing progesterone from plant steroid sapogenins, initially using sarsapogenin from sarsaparilla, which proved too expensive. After three years of extensive botanical research, he discovered a much better starting material, the saponin from inedible Mexican yams (Dioscorea mexicana and Dioscorea composita) found in the rain forests of Veracruz near Orizaba. The saponin could be converted in the lab to its aglycone moiety diosgenin. Unable to interest his research sponsor Parke-Davis in the commercial potential of synthesizing progesterone from Mexican yams, Marker left Penn State and in 1944 co-founded Syntex with two partners in Mexico City. When he left Syntex a year later the trade of the barbasco yam had started and the period of the heyday of the Mexican steroid industry had been started. Syntex broke the monopoly of European pharmaceutical companies on steroid hormones, reducing the price of progesterone almost 200-fold over the next eight years.Midway through the 20th century, the stage was set for the development of a hormonal contraceptive, but pharmaceutical companies, universities and governments showed no interest in pursuing research.
Progesterone to prevent ovulation
Progesterone, given by injections, was first shown to inhibit ovulation in animals in 1937 by Makepeace and colleagues.In early 1951, reproductive physiologist Gregory Pincus, a leader in hormone research and co-founder of the Worcester Foundation for Experimental Biology (WFEB) in Shrewsbury, Massachusetts, first met American birth control movement founder Margaret Sanger at a Manhattan dinner hosted by Abraham Stone, medical director and vice president of Planned Parenthood (PPFA), who helped Pincus obtain a small grant from PPFA to begin hormonal contraceptive research. Research started on April 25, 1951, with reproductive physiologist Min Chueh Chang repeating and extending the 1937 experiments of Makepeace et al. that was published in 1953 and showed that injections of progesterone suppressed ovulation in rabbits. In October 1951, G. D. Searle & Company refused Pincus request to fund his hormonal contraceptive research, but retained him as a consultant and continued to provide chemical compounds to evaluate.In March 1952, Sanger wrote a brief note mentioning Pincus research to her longtime friend and supporter, suffragist and philanthropist Katharine Dexter McCormick, who visited the WFEB and its co-founder and old friend Hudson Hoagland in June 1952 to learn about contraceptive research there. Frustrated when research stalled from PPFAs lack of interest and meager funding, McCormick arranged a meeting at the WFEB on June 6, 1953, with Sanger and Hoagland, where she first met Pincus who committed to dramatically expand and accelerate research with McCormick providing fifty times PPFAs previous funding.Pincus and McCormick enlisted Harvard clinical professor of gynecology John Rock, chief of gynecology at the Free Hospital for Women and an expert in the treatment of infertility, to lead clinical research with women. At a scientific conference in 1952, Pincus and Rock, who had known each other for many years, discovered they were using similar approaches to achieve opposite goals. In 1952, Rock induced a three-month anovulatory "pseudopregnancy" state in eighty of his infertility patients with continuous gradually increasing oral doses of an estrogen (5 to 30 mg/day diethylstilbestrol) and progesterone (50 to 300 mg/day), and within the following four months 15% of the women became pregnant.In 1953, at Pincus suggestion, Rock induced a three-month anovulatory "pseudopregnancy" state in twenty-seven of his infertility patients with an oral 300 mg/day progesterone-only regimen for 20 days from cycle days 5–24 followed by pill-free days to produce withdrawal bleeding. This produced the same 15% pregnancy rate during the following four months without the amenorrhea of the previous continuous estrogen and progesterone regimen. But 20% of the women experienced breakthrough bleeding and in the first cycle ovulation was suppressed in only 85% of the women, indicating that even higher and more expensive oral doses of progesterone would be needed to initially consistently suppress ovulation. Similarly, Ishikawa and colleagues found that ovulation inhibition occurred in only a "proportion" of cases with 300 mg/day oral progesterone. Despite the incomplete inhibition of ovulation by oral progesterone, no pregnancies occurred in the two studies, although this could have simply been due to chance. However, Ishikawa et al. reported that the cervical mucus in women taking oral progesterone became impenetrable to sperm, and this may have accounted for the absence of pregnancies.Progesterone was abandoned as an oral ovulation inhibitor following these clinical studies due to the high and expensive doses required, incomplete inhibition of ovulation, and the frequent incidence of breakthrough bleeding. Instead, researchers would turn to much more potent synthetic progestogens for use in oral contraception in the future.
Progestins to prevent ovulation
Pincus asked his contacts at pharmaceutical companies to send him chemical compounds with progestogenic activity. Chang screened nearly 200 chemical compounds in animals and found the three most promising were Syntexs norethisterone and Searles noretynodrel and norethandrolone.Chemists Carl Djerassi, Luis Miramontes, and George Rosenkranz at Syntex in Mexico City had synthesized the first orally highly active progestin norethisterone in 1951. Frank B. Colton at Searle in Skokie, Illinois had synthesized the orally highly active progestins noretynodrel (an isomer of norethisterone) in 1952 and norethandrolone in 1953.In December 1954, Rock began the first studies of the ovulation-suppressing potential of 5–50 mg doses of the three oral progestins for three months (for 21 days per cycle—days 5–25 followed by pill-free days to produce withdrawal bleeding) in fifty of his patients with infertility in Brookline, Massachusetts. Norethisterone or noretynodrel 5 mg doses and all doses of norethandrolone suppressed ovulation but caused breakthrough bleeding, but 10 mg and higher doses of norethisterone or noretynodrel suppressed ovulation without breakthrough bleeding and led to a 14% pregnancy rate in the following five months. Pincus and Rock selected Searles noretynodrel for the first contraceptive trials in women, citing its total lack of androgenicity versus Syntexs norethisterone very slight androgenicity in animal tests.
Combined oral contraceptive
Noretynodrel (and norethisterone) were subsequently discovered to be contaminated with a small percentage of the estrogen mestranol (an intermediate in their synthesis), with the noretynodrel in Rocks 1954–5 study containing 4–7% mestranol. When further purifying noretynodrel to contain less than 1% mestranol led to breakthrough bleeding, it was decided to intentionally incorporate 2.2% mestranol, a percentage that was not associated with breakthrough bleeding, in the first contraceptive trials in women in 1956. The noretynodrel and mestranol combination was given the proprietary name Enovid.The first contraceptive trial of Enovid led by Celso-Ramón García and Edris Rice-Wray began in April 1956 in Río Piedras, Puerto Rico. A second contraceptive trial of Enovid (and norethisterone) led by Edward T. Tyler began in June 1956 in Los Angeles. On January 23, 1957, Searle held a symposium reviewing gynecologic and contraceptive research on Enovid through 1956 and concluded Enovids estrogen content could be reduced by 33% to lower the incidence of estrogenic gastrointestinal side effects without significantly increasing the incidence of breakthrough bleeding.While these large-scale trials contributed to the initial understanding of the pill formulations clinical effects, the ethical implications of the trials generated significant controversy. Of note is the apparent lack of both autonomy and informed consent among participants in the Puerto Rican cohort prior to the trials. Many of these participants hailed from impoverished, working-class backgrounds.
Public availability
United States
On June 10, 1957, the Food and Drug Administration (FDA) approved Enovid 10 mg (9.85 mg noretynodrel and 150 µg mestranol) for menstrual disorders, based on data from its use by more than 600 women. Numerous additional contraceptive trials showed Enovid at 10, 5, and 2.5 mg doses to be highly effective. On July 23, 1959, Searle filed a supplemental application to add contraception as an approved indication for 10, 5, and 2.5 mg doses of Enovid. The FDA refused to consider the application until Searle agreed to withdraw the lower dosage forms from the application. On May 9, 1960, the FDA announced it would approve Enovid 10 mg for contraceptive use, and did so on June 23, 1960. At that point, Enovid 10 mg had been in general use for three years and, by conservative estimate, at least half a million women had used it.Although FDA-approved for contraceptive use, Searle never marketed Enovid 10 mg as a contraceptive. Eight months later, on February 15, 1961, the FDA approved Enovid 5 mg for contraceptive use. In July 1961, Searle finally began marketing Enovid 5 mg (5 mg noretynodrel and 75 µg mestranol) to physicians as a contraceptive.Although the FDA approved the first oral contraceptive in 1960, contraceptives were not available to married women in all states until Griswold v. Connecticut in 1965 and were not available to unmarried women in all states until Eisenstadt v. Baird in 1972.The first published case report of a blood clot and pulmonary embolism in a woman using Enavid (Enovid 10 mg in the U.S.) at a dose of 20 mg/day did not appear until November 1961, four years after its approval, by which time it had been used by over one million women. It would take almost a decade of epidemiological studies to conclusively establish an increased risk of venous thrombosis in oral contraceptive users and an increased risk of stroke and myocardial infarction in oral contraceptive users who smoke or have high blood pressure or other cardiovascular or cerebrovascular risk factors. These risks of oral contraceptives were dramatized in the 1969 book The Doctors Case Against the Pill by feminist journalist Barbara Seaman who helped arrange the 1970 Nelson Pill Hearings called by Senator Gaylord Nelson. The hearings were conducted by senators who were all men and the witnesses in the first round of hearings were all men, leading Alice Wolfson and other feminists to protest the hearings and generate media attention. Their work led to mandating the inclusion of patient package inserts with oral contraceptives to explain their possible side effects and risks to help facilitate informed consent. Todays standard dose oral contraceptives contain an estrogen dose that is one third lower than the first marketed oral contraceptive and contain lower doses of different, more potent progestins in a variety of formulations.Beginning in 2015, certain states passed legislation allowing pharmacists to prescribe oral contraceptives. Such legislation was considered to address physician shortages and decrease barriers to birth control for women. Currently, pharmacists in Oregon, California, Colorado, Hawaii, Maryland, and New Mexico have authority to prescribe birth control after receiving specialized training and certification from their respective state Board of Pharmacy. Other states are considering this legislation, including Illinois, Minnesota, Missouri, and New Hampshire.
Australia
The first oral contraceptive introduced outside the United States was Scherings Anovlar (norethisterone acetate 4 mg + ethinylestradiol 50 µg) on January 1, 1961, in Australia.
Germany
The first oral contraceptive introduced in Europe was Scherings Anovlar on June 1, 1961, in West Germany. The lower hormonal dose, still in use, was studied by the Belgian Gynaecologist Ferdinand Peeters.
United Kingdom
Before the mid-1960s, the United Kingdom did not require pre-marketing approval of drugs. The British Family Planning Association (FPA) through its clinics was then the primary provider of family planning services in the UK and provided only contraceptives that were on its Approved List of Contraceptives (established in 1934). In 1957, Searle began marketing Enavid (Enovid 10 mg in the U.S.) for menstrual disorders. Also in 1957, the FPA established a Council for the Investigation of Fertility Control (CIFC) to test and monitor oral contraceptives which began animal testing of oral contraceptives and in 1960 and 1961 began three large clinical trials in Birmingham, Slough, and London.In March 1960, the Birmingham FPA began trials of noretynodrel 2.5 mg + mestranol 50 µg, but a high pregnancy rate initially occurred when the pills accidentally contained only 36 µg of mestranol—the trials were continued with noretynodrel 5 mg + mestranol 75 µg (Conovid in the UK, Enovid 5 mg in the U.S.).
In August 1960, the Slough FPA began trials of noretynodrel 2.5 mg + mestranol 100 µg (Conovid-E in the UK, Enovid-E in the U.S.).
In May 1961, the London FPA began trials of Scherings Anovlar.In October 1961, at the recommendation of the Medical Advisory Council of its CIFC, the FPA added Searles Conovid to its Approved List of Contraceptives.
On December 4, 1961, Enoch Powell, then Minister of Health, announced that the oral contraceptive pill Conovid could be prescribed through the NHS at a subsidized price of 2s per month.
In 1962, Scherings Anovlar and Searles Conovid-E were added to the FPAs Approved List of Contraceptives.
France
On December 28, 1967, the Neuwirth Law legalized contraception in France, including the pill. The pill is the most popular form of contraception in France, especially among young women. It accounts for 60% of the birth control used in France. The abortion rate has remained stable since the introduction of the pill.
Japan
In Japan, lobbying from the Japan Medical Association prevented the pill from being approved for general use for nearly 40 years. The higher dose "second generation" pill was approved for use in cases of gynecological problems, but not for birth control. Two main objections raised by the association were safety concerns over long-term use of the pill, and concerns that pill use would lead to decreased use of condoms and thereby potentially increase sexually transmitted infection (STI) rates.However, when the Ministry of Health and Welfare approved Viagras use in Japan after only six months of the applications submission, while still claiming that the pill required more data before approval, womens groups cried foul. The pill was subsequently approved for use in June 1999, when Japan became the last UN member country to do so. However, the pill has not become popular in Japan. According to estimates, only 1.3 percent of 28 million Japanese females of childbearing age use the pill, compared with 15.6 percent in the United States. The pill prescription guidelines the government has endorsed require pill users to visit a doctor every three months for pelvic examinations and undergo tests for sexually transmitted diseases and uterine cancer. In the United States and Europe, in contrast, an annual or bi-annual clinic visit is standard for pill users. However, beginning as far back as 2007, many Japanese OBGYNs have required only a yearly visit for pill users, with multiple checks a year recommended only for those who are older or at increased risk of side effects. As of 2004, condoms accounted for 80% of birth control use in Japan, and this may explain Japans comparatively low rates of AIDS.
Society and culture
The pill was approved by the FDA in the early 1960s; its use spread rapidly in the late part of that decade, generating an enormous social impact. Time magazine placed the pill on its cover in April, 1967. In the first place, it was more effective than most previous reversible methods of birth control, giving women unprecedented control over their fertility. Its use was separate from intercourse, requiring no special preparations at the time of sexual activity that might interfere with spontaneity or sensation, and the choice to take the pill was a private one. This combination of factors served to make the pill immensely popular within a few years of its introduction.Claudia Goldin, among others, argue that this new contraceptive technology was a key player in forming womens modern economic role, in that it prolonged the age at which women first married allowing them to invest in education and other forms of human capital as well as generally become more career-oriented. Soon after the birth control pill was legalized, there was a sharp increase in college attendance and graduation rates for women. From an economic point of view, the birth control pill reduced the cost of staying in school. The ability to control fertility without sacrificing sexual relationships allowed women to make long term educational and career plans.Because the pill was so effective, and soon so widespread, it also heightened the debate about the moral and health consequences of pre-marital sex and promiscuity. Never before had sexual activity been so divorced from reproduction. For a couple using the pill, intercourse became purely an expression of love, or a means of physical pleasure, or both; but it was no longer a means of reproduction. While this was true of previous contraceptives, their relatively high failure rates and their less widespread use failed to emphasize this distinction as clearly as did the pill. The spread of oral contraceptive use thus led many religious figures and institutions to debate the proper role of sexuality and its relationship to procreation. The Roman Catholic Church in particular, after studying the phenomenon of oral contraceptives, re-emphasized the stated teaching on birth control in the 1968 papal encyclical Humanae vitae. The encyclical reiterated the established Catholic teaching that artificial contraception distorts the nature and purpose of sex. On the other side Anglican and other Protestant churches, such as the Evangelical Church in Germany (EKD), accepted the combined oral contraceptive pill.The United States Senate began hearings on the pill in 1970 and where different viewpoints were heard from medical professionals. Dr. Michael Newton, President of the College of Obstetricians and Gynecologists said:
The evidence is not yet clear that these still do in fact cause cancer or related to it. The FDA Advisory Committee made comments about this, that if there wasnt enough evidence to indicate whether or not these pills were related to the development of cancer, and I think thats still thin; you have to be cautious about them, but I dont think there is clear evidence, either one way or the other, that they do or dont cause cancer.
Another physician, Dr. Roy Hertz of the Population Council, said that anyone who takes this should know of "our knowledge and ignorance in these matters" and that all women should be made aware of this so they can decide to take the pill or not.The Secretary of Health, Education, and Welfare at the time, Robert Finch, announced the federal government had accepted a compromise warning statement which would accompany all sales of birth control pills.
Result on popular culture
The introduction of the birth control pill in 1960 allowed more women to find employment opportunities and further their education. As a result of women getting more jobs and an education, their husbands had to start taking over household tasks like cooking. Wanting to stop the change that was occurring in terms of gender norms in an American household, many films, television shows, and other popular culture items portrayed what an ideal American family should be. Below are listed some examples:
Poem
The Pill Versus the Springhill Mine Disaster was the title poem of a 1968 collection by Richard Brautigan.
Music
Singer Loretta Lynn commented on how women no longer had to choose between a relationship and a career in her 1974 album with a song entitled "The Pill", which told the story of a married womans use of the drug to liberate herself from her traditional role as wife and mother.
Environmental impact
A woman using COCPs excretes from her urine and feces natural estrogens, estrone (E1) and estradiol (E2), and synthetic estrogen ethinylestradiol (EE2).
These hormones can pass through water treatment plants and into rivers. Other forms of contraception, such as the contraceptive patch, use the same synthetic estrogen (EE2) that is found in COCPs, and can add to the hormonal concentration in the water when flushed down the toilet. This excretion is shown to play a role in causing endocrine disruption, which affects the sexual development and reproduction of wild fish populations in segments of streams contaminated by treated sewage effluents.
A study done in British rivers supported the hypothesis |
Combined oral contraceptive pill | that the incidence and the severity of intersex wild fish populations were significantly correlated with the concentrations of the E1, E2, and EE2 in the rivers.A review of activated sludge plant performance found estrogen removal rates varied considerably but averaged 78% for estrone, 91% for estradiol, and 76% for ethinylestradiol (estriol effluent concentrations are between those of estrone and estradiol, but estriol is a much less potent endocrine disruptor to fish).Several studies have suggested that reducing human population growth through increased access to contraception, including birth control pills, can be an effective strategy for climate change mitigation as well as adaptation. According to Thomas Wire, contraception is the greenest technology because of its cost-effectiveness in combating global warming — each $7 spent on contraceptives would reduce global carbon emissions by 1 tonne over four decades, while achieving the same result with low-carbon technologies would require $32.
See also
Estradiol-containing oral contraceptive
Hormone replacement therapy (HRT)
List of estrogens available in the United States
List of progestogens available in the United States
Progestogen-only injectable contraceptive
References
Further reading
Black A, Guilbert E, Costescu D, Dunn S, Fisher W, Kives S, et al. (April 2017). "No. 329-Canadian Contraception Consensus Part 4 of 4 Chapter 9: Combined Hormonal Contraception". Journal of Obstetrics and Gynaecology Canada. 39 (4): 229–268.e5. doi:10.1016/j.jogc.2016.10.005. PMID 28413042.
External links
The Birth Control Pill—CBC Digital Archives
The Birth of the Pill—slide show by Life magazine |
Iobenguane | Iobenguane, or MIBG, is an aralkylguanidine analog of the adrenergic neurotransmitter norepinephrine (noradrenaline), typically used as a radiopharmaceutical. It acts as a blocking agent for adrenergic neurons. When radiolabeled, it can be used in nuclear medicinal diagnostic and therapy techniques as well as in neuroendocrine chemotherapy treatments.
It localizes to adrenergic tissue and thus can be used to identify the location of tumors such as pheochromocytomas and neuroblastomas. With iodine-131 it can also be used to treat tumor cells that take up and metabolize norepinephrine.
Usage and mechanism
MIBG is absorbed by and accumulated in granules of adrenal medullary chromaffin cells, as well as in pre-synaptic adrenergic neuron granules. The process in which this occurs is closely related to the mechanism employed by norepinephrine and its transporter in vivo. The norepinephrine transporter (NET) functions to provide norepinephrine uptake at the synaptic terminals and adrenal chromaffin cells. MIBG, by bonding to NET, finds its roles in imaging and therapy.
Metabolites and excretion
Less than 10% of the administered MIBG gets metabolized into m-iodohippuric acid (MIHA), and the mechanism for how this metabolite is produced is unknown.
Diagnostic imaging
MIBG concentrates in endocrine tumors, most commonly neuroblastoma, paraganglioma, and pheochromocytoma. It also accumulates in norepinephrine transporters in adrenergic nerves in the heart, lungs, adrenal medulla, salivary glands, liver, and spleen, as well as in tumors that originate in the neural crest. When labelled with iodine-123 it serves as a whole-body, non-invasive scintigraphic screening for germ-line, somatic, benign, and malignant neoplasms originating in the adrenal glands. It can detect both intra and extra-adrenal disease. The imaging is highly sensitive and specific.Iobenguane concentrates in presynaptic terminals of the heart and other autonomically innervated organs. This enables the possible non-invasive use as an in vivo probe to study these systems.Alternatives to imaging with 123I-MIBG, for certain indications and under clinical and research use, include the positron-emitting isotope iodine-124, and other radiopharmaceuticals such as 68Ga-DOTA and 18F-FDOPA for positron emission tomography (PET). 123I-MIBG imaging on a gamma camera can offer significantly higher cost-effectiveness and availability compared to PET imaging, and is particularly effective where 131I-MIBG therapy is subsequently planned, due to their directly comparable uptake.
Side effects
Side effects post imaging are rare but can include tachycardia, pallor, vomiting, and abdominal pain.
Radionuclide therapy
MIBG can be radiolabelled with the beta emitting radionuclide 131I for the treatment of certain pheochromocytomas, paragangliomas, carcinoid tumors, neuroblastomas, and medullary thyroid cancer.
Thyroid precautions
Thyroid blockade with (nonradioactive) potassium iodide is indicated for nuclear medicine scintigraphy with iobenguane/mIBG. This competitively inhibits radioiodine uptake, preventing excessive radioiodine levels in the thyroid and minimizing risk of thyroid ablation (in treatment with 131I). The minimal risk of thyroid cancer is also reduced as a result.The dosing regime for the FDA-approved commercial 123I-MIBG product Adreview is potassium iodide or Lugols solution containing 100mg iodide, weight adjusted for children and given an hour before injection. EANM guidelines, endorsed by the SNMMI, suggest a variety of regimes in clinical use, for both children and adults.Product labeling for diagnostic 131I iobenguane recommends giving potassium iodide one day before injection and continuing 5 to 7 days following. 131I iobenguane used for therapeutic purposes requires a different pre-medication duration, beginning 24–48 hours before iobenguane injection and continuing 10–15 days after injection.
Clinical trials
Iobenguane I 131 for cancers
Iobenguane I 131, marketed under the trade name Azedra, has had a clinical trial as a treatment for malignant, recurrent or unresectable pheochromocytoma and paraganglioma, and the FDA approved it on July 30, 2018. The drug is developed by Progenics Pharmaceuticals.
References
External links
"Iobenguane". Drug Information Portal. U.S. National Library of Medicine.
"Iobenguane I 131". Drug Information Portal. U.S. National Library of Medicine.
"Iobenguane I 123". Drug Information Portal. U.S. National Library of Medicine.
"iobenguane I 131". NCI Drug Dictionary.
"Iobenguane I 131". National Cancer Institute. 15 August 2018. |
Glycation | Glycation (sometimes called non-enzymatic glycosylation) is the covalent attachment of a sugar to a protein or lipid. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is the non-enzymatic process responsible for many (e.g. micro and macrovascular) complications in diabetes mellitus and is implicated in some diseases and in aging. Glycation end products are believed to play a causative role in the vascular complications of diabetes mellitus.In contrast with glycation, glycosylation is the enzyme-mediated ATP-dependent attachment of sugars to protein or lipid. Glycosylation occurs at defined sites on the target molecule. It is a common form of post-translational modification of proteins and is required for the functioning of the mature protein.
Biochemistry
Glycations occur mainly in the bloodstream to a small proportion of the absorbed simple sugars: glucose, fructose, and galactose. It appears that fructose has approximately ten times the glycation activity of glucose, the primary body fuel. Glycation can occur through Amadori reactions, Schiff base reactions, and Maillard reactions; which lead to advanced glycation end products (AGEs).
Biomedical implications
Red blood cells have a consistent lifespan of 120 days and are accessible for measurement of glycated hemoglobin. Measurement of HbA1c—the predominant form of glycated hemoglobin—enables medium-term blood sugar control to be monitored in diabetes.
Some glycation product are implicated in many age-related chronic diseases, including cardiovascular diseases (the endothelium, fibrinogen, and collagen are damaged) and Alzheimers disease (amyloid proteins are side-products of the reactions progressing to AGEs).Long-lived cells (such as nerves and different types of brain cell), long-lasting proteins (such as crystallins of the lens and cornea), and DNA can sustain substantial glycation over time. Damage by glycation results in stiffening of the collagen in the blood vessel walls, leading to high blood pressure, especially in diabetes. Glycations also cause weakening of the collagen in the blood vessel walls, which may lead to micro- or macro-aneurysm; this may cause strokes if in the brain.
See also
Advanced glycation end-product
Alagebrium
Fructose
Galactose
Glucose
Glycosylation
Glycated hemoglobin
List of aging processes
Additional reading
Ahmed N, Furth AJ (July 1992). "Failure of common glycation assays to detect glycation by fructose". Clin. Chem. 38 (7): 1301–3. doi:10.1093/clinchem/38.7.1301. PMID 1623595.
Vlassara H (June 2005). "Advanced glycation in health and disease: role of the modern environment". Annals of the New York Academy of Sciences. 1043 (1): 452–60. Bibcode:2005NYASA1043..452V. doi:10.1196/annals.1333.051. PMID 16037266. S2CID 20952378.
== References == |
Cycloserine | Cycloserine, sold under the brand name Seromycin, is a GABA transaminase inhibitor and an antibiotic, used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active drug resistant tuberculosis. It is given by mouth.Common side effects include allergic reactions, seizures, sleepiness, unsteadiness, and numbness. It is not recommended in people who have kidney failure, epilepsy, depression, or are alcoholics. It is unclear if use during pregnancy is safe for the baby. Cycloserine is similar in structure to the amino acid D-alanine and works by interfering with the formation of the bacterias cell wall.Cycloserine was discovered in 1954 from a type of Streptomyces. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Tuberculosis
For the treatment of tuberculosis, cycloserine is classified as a second-line drug, i.e. its use is only considered if one or more first-line drugs cannot be used. Hence, cycloserine is restricted for use only against multiple drug-resistant and extensively drug-resistant strains of M. tuberculosis. Another reason for limited use of this drug is the neurological side effects it causes, since it is able to penetrate into the central nervous system (CNS) and cause headaches, drowsiness, depression, dizziness, vertigo, confusion, paresthesias, dysarthria, hyperirritability, psychosis, convulsions, and shaking (tremors). Overdose of cycloserine may result in paresis, seizures, and coma, while alcohol consumption may increase the risk of seizures. Coadministration of pyridoxine can reduce the incidence of some of these CNS side effects (e.g. convulsions) caused by cycloserine.
Psychiatry
A 2015 Cochrane review found no evidence of benefit in anxiety disorders as of 2015. Another review found preliminary evidence of benefit. Evidence for use in addiction is tentative but also unclear.
Mechanism of action
Cycloserine works as an antibiotic by inhibiting cell-wall biosynthesis in bacteria. As a cyclic analogue of D-alanine, cycloserine acts against two crucial enzymes important in the cytosolic stages of peptidoglycan synthesis: alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl). The first enzyme is a pyridoxal 5-phosphate-dependent enzyme which converts the L-alanine to the D-alanine form. The second enzyme is involved in joining two of these D-alanine residues together by catalyzing the formation of the ATP-dependent D-alanine-D-alanine dipeptide bond between the resulting D-alanine molecules. If both of these enzymes are inhibited, then D-alanine residues cannot form and previously formed D-alanine molecules cannot be joined together. This effectively leads to inhibition of peptidoglycan synthesis.
Chemical properties
Under mildly acidic conditions, cycloserine hydrolyzes to give hydroxylamine and D-serine. Cycloserine can be conceptualized as a cyclized version of serine, with an oxidative loss of dihydrogen to form the nitrogen-oxygen bond.Cycloserine is stable under basic conditions, with the greatest stability at pH = 11.5.
History
The compound was first isolated nearly simultaneously by two teams. Workers at Merck isolated the compound, which they called oxamycin, from a species of Streptomyces. The same team prepared the molecule synthetically. Workers at Eli Lilly isolated the compound from strains of Streptomyces orchidaceus. It was shown to hydrolyze to serine and hydroxylamine.
Economics
In the U.S., the price of cycloserine increased from $500 for 30 pills to $10,800 in 2015 after the Chao Center for Industrial Pharmacy and Contract Manufacturing changed ownership to Rodelis Therapeutics in August 2015.The price increase was rescinded after the previous owner, the Purdue University Research Foundation, which retained "oversight of the manufacturing operation" intervened and Rodelis returned the drug to an NGO of Purdue University. The foundation now will charge $1,050 for 30 capsules, twice what it charged before". Eli Lilly has been criticised for not ensuring that the philanthropic initiative continued. Due to US antitrust laws, however, no company may control the price of a product after it is outlicensed.In 2015, the cost in the United States was increased to US$3,150 a month and then decreased to US$1,050 per month.
Research
There is some experimental evidence to suggest that D-cycloserine aids in learning by helping form stronger neural connections. It has been investigated as an aid to facilitate exposure therapy in people with PTSD and anxiety disorders as well as treatment with schizophrenia. In a clinical trial, a course of D-cycloserine combined with a single dose of ketamine was investigated for treatment resistant bipolar depression. When administered for 8 weeks after a ketamine infusion, cycloserine appeared to potentiate the antidepressant effects in all trial participants.
References
External links
"Cycloserine". Drug Information Portal. U.S. National Library of Medicine. |
FLAC | FLAC (; Free Lossless Audio Codec) is an audio coding format for lossless compression of digital audio, developed by the Xiph.Org Foundation, and is also the name of the free software project producing the FLAC tools, the reference software package that includes a codec implementation. Digital audio compressed by FLACs algorithm can typically be reduced to between 50 and 70 percent of its original size and decompresses to an identical copy of the original audio data.
FLAC is an open format with royalty-free licensing and a reference implementation which is free software. FLAC has support for metadata tagging, album cover art, and fast seeking.
History
Development was started in 2000 by Josh Coalson. The bit-stream format was frozen when FLAC entered beta stage with the release of version 0.5 of the reference implementation on 15 January 2001. Version 1.0 was released on 20 July 2001.On 29 January 2003, the Xiph.Org Foundation and the FLAC project announced the incorporation of FLAC under the Xiph.org banner. Xiph.org is home to other free compression formats such as Vorbis, Theora, Speex and Opus.Version 1.3.0 was released on 26 May 2013, at which point development was moved to the Xiph.org git repository.
Composition
The FLAC project consists of:
The stream formats
A simple container format for the stream, also called FLAC (or Native FLAC)
libFLAC, a library of reference encoders and decoders, and a metadata interface
libFLAC++, an object-oriented wrapper around libFLAC
flac, a command-line program based on libFLAC to encode and decode FLAC streams
metaflac, a command-line metadata editor for .flac files and for applying ReplayGain
Input plugins for various music players (Winamp, XMMS, foobar2000, musikCube, and many more)
With Xiph.org incorporation, the Ogg container format, suitable for streaming (also called Ogg FLAC)The specification of the stream format can be implemented by anyone without prior permission (Xiph.org reserves the right to set the FLAC specification and certify compliance), and neither the FLAC format nor any of the implemented encoding or decoding methods are covered by any patent. The reference implementation is free software. The source code for libFLAC and libFLAC++ is available under the BSD license, and the sources for flac, metaflac, and the plugins are available under the GNU General Public License.
In its stated goals, the FLAC project encourages its developers not to implement copy prevention features (DRM) or lossy compression of any kind.
Design
File structure
A FLAC file consists of the magic number fLaC, metadata, and encoded audio.The encoded audio is divided into frames, which consists of a header, a data block, and a CRC16 checksum. Each frame is encoded independent of each other. A frame header begins with a sync word, used to identify the beginning of a valid frame. The rest of the header contains the number of samples, position of the frame, channel assignment, and optionally the sample rate and bit depth. The data block contains the audio information.Metadata in FLAC precedes the audio. Properties like the sample rate and the number of channels are always contained in the metadata. It may also contain other information, the album cover for example. FLAC uses Vorbis comments for some types of metadata, like the title and artist name.
Encoding and decoding
The FLAC encoding algorithm consists of multiple stages. In the first stage, the input audio is split into blocks. If the audio contains multiple channels, each channel is encoded separately as a subblock. The encoder then tries to find a good mathematical approximation of the block, either by fitting a simple polynomial, or through general linear predictive coding. A description of the approximation, which is only a few bytes in length, is then written. Finally, the difference between the approximation and the input, called residual, is encoded using Rice coding. In many cases, a description of the approximation and the encoded residual takes up less space than using pulse code modulation.The decoding process is the reverse of encoding. The compressed residual is first decoded. The description of the mathematical approximation is then used to calculate a waveform. The result is formed by adding the residual and the calculated waveform. As FLAC compresses losslessly, the decoded waveform is identical to the waveform before encoding.
For two-channel stereo, the encoder may choose to joint encode the audio. The channels are transformed into a side channel, which is the difference between the two input channels, and a mid channel, the sum of the two input channels. In place of a mid channel, the left channel or the right channel may be encoded instead, which is sometimes more space efficient.Even though the reference encoder uses a single block size for the whole stream, FLAC allows the block size in samples to vary per block.
Compression
The amount of compression is determined by various parameters, including the order of the linear prediction model and the block size. Regardless of the amount of compression, the original data can always be reconstructed perfectly.
For users convenience, the reference implementation defines 9 compression levels, which are presets of the more technical parameters to the encoding algorithm. The levels are labeled from 0 to 8, with higher numbers resulting in a higher compression ratio, at the cost of compression speed. The meaning of each compression level varies by implementation.FLAC is optimized for decoding speed at the expense of encoding speed. A benchmark has shown that, while there is little variation in decoding speed as compression level increases, beyond the default compression level 5, the encoding process takes up considerably more time with little space saved compared to level 5.
Comparison to other formats
FLAC is specifically designed for efficient packing of audio data, unlike general-purpose lossless algorithms such as DEFLATE, which are used in ZIP and gzip. While ZIP may reduce the size of a CD-quality audio file by 10–20%, FLAC is able to reduce the size of audio data by 40–50% by taking advantage of the characteristics of audio.
The technical strengths of FLAC compared to other lossless formats lie in its ability to be streamed and decoded quickly, independent of compression level.
Since FLAC is a lossless scheme, it is suitable as an archive format for owners of CDs and other media who wish to preserve their audio collections. If the original media are lost, damaged, or worn out, a FLAC copy of the audio tracks ensures that an exact duplicate of the original data can be recovered at any time. An exact restoration from a lossy copy (e.g., MP3) of the same data is impossible. FLAC being lossless means it is highly suitable for transcoding e.g. to MP3, without the normally associated transcoding quality loss between one lossy format and another. A CUE file can optionally be created when ripping a CD. If a CD is read and ripped perfectly to FLAC files, the CUE file allows later burning of an audio CD that is identical in audio data to the original CD, including track order and pregap, but excluding CD-Text and other additional data such as lyrics and CD+G graphics.
Adoption and implementations
The reference implementation of FLAC is implemented as the libFLAC core encoder & decoder library, with the main distributable program flac being the reference implementation of the libFLAC API. This codec API is also available in C++ as libFLAC++. The reference implementation of FLAC compiles on many platforms, including most Unix (such as Solaris, BSD) and Unix-like (including Linux), Microsoft Windows, BeOS, and OS/2 operating systems. There are build-systems for autoconf/automake, MSVC, Watcom C, and Xcode. There is currently no multicore support in libFLAC, but utilities such as GNU parallel and various graphical frontends can be used to spin up multiple instances of the encoder.
FLAC playback support in portable audio devices and dedicated audio systems is limited compared to formats such as MP3 or uncompressed PCM. FLAC support is included by default in Windows 10, Android, BlackBerry 10 and Jolla devices.
In 2014, several aftermarket mobile electronics companies introduced multimedia solutions that include support for FLAC. These include the NEX series from Pioneer Electronics and the VX404 and NX404 from Clarion.
The European Broadcasting Union (EBU) has adopted the FLAC format for the distribution of high quality audio over its Euroradio network. The Windows operating system has supported native FLAC integration since the introduction of Windows 10. The Android operating system has supported native FLAC playback since version 3.1. macOS High Sierra and iOS 11 add native FLAC playback support.Among others the Pono music player and streaming service used the FLAC format. Bandcamp insists on a lossless format for uploading, and has FLAC as a download option. The Wikimedia Foundation sponsored a free and open-source online ECMAScript FLAC tool for browsers supporting the required HTML5 features.
Various other containers are supported, independently from used operating system, depending on used playback software.
See also
Comparison of audio coding formats
References
External links
Official website
Lossless audio formats comparison: measuring FLAC against five other lossless audio formats
Lossless comparison: FLAC against seven other lossless audio formats on Hydrogenaudio
GSMArena Phone Finder: all phones & tablets with FLAC support |
Levonorgestrel | Levonorgestrel is a hormonal medication which is used in a number of birth control methods. It is combined with an estrogen to make combination birth control pills. As an emergency birth control, sold under the brand name Plan B among others, it is useful within 72 hours of unprotected sex. The more time that has passed since sex, the less effective the medication becomes, and it does not work after pregnancy (implantation) has occurred. Levonorgestrel works by preventing ovulation or fertilization from occurring. It decreases the chances of pregnancy by 57 to 93%. In an intrauterine device (IUD), such as Mirena among others, it is effective for the long-term prevention of pregnancy. A levonorgestrel-releasing implant is also available in some countries.Common side effects include nausea, breast tenderness, headaches, and increased, decreased, or irregular menstrual bleeding. When used as an emergency contraceptive, if pregnancy occurs, there is no evidence that its use harms the fetus. It is safe to use during breastfeeding. Birth control that contains levonorgestrel will not change the risk of sexually transmitted infections. It is a progestin and has effects similar to those of the hormone progesterone. It works primarily by preventing ovulation and closing off the cervix to prevent the passage of sperm.Levonorgestrel was patented in 1960 and introduced for medical use together with ethinylestradiol in 1970. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In the United States, levonorgestrel-containing emergency contraceptives are available over the counter (OTC) for all ages. In 2016, it was the 223rd most commonly prescribed medication in the United States, with more than two million prescriptions.
Medical uses
Birth control
At low doses, levonorgestrel is used in monophasic and triphasic formulations of combined oral contraceptive pills, with available monophasic doses ranging from 100 to 250 µg, and triphasic doses of 50 µg/75 µg/125 µg. It is combined with the estrogen ethinylestradiol in these formulations.At very low daily dose of 30 µg, levonorgestrel is used in some progestogen-only pill formulations.Levonorgestrel is the active ingredient in a number of intrauterine devices including Mirena and Skyla. It is also the active ingredient in the birth control implants Norplant and Jadelle.One of the more common forms of contraception that contains only levonorgestrel is an IUD. One IUD, the Mirena, is a small hollow cylinder containing levonorgestrel and polydimethylsiloxane and covered with a release rate controlling membrane.
Emergency birth control
Levonorgestrel is used in emergency contraceptive pills (ECPs), both in a combined Yuzpe regimen which includes estrogen, and as a levonorgestrel-only method. The levonorgestrel-only method uses levonorgestrel 1.5 mg (as a single dose or as two 0.75 mg doses 12 hours apart) taken within three days of unprotected sex. With one study indicating that beginning as late as 120 hours (5 days) after intercourse could be effective. However, taking more than one dose of emergency contraception does not increase the chance of pregnancy not happening. Planned Parenthood asserts "Taking the morning-after pill (also known as emergency contraception) multiple times doesnt change its effectiveness, and wont cause any long-term side effects." There is no age, I.D, or prescription required to purchase emergency contraception. Plan B hit the market in 1999 where it could be bought by anyone older than 18. However, in 2013, the rules were changed so that Plan B could be purchased at any age without ID or prescription.
The primary mechanism of action of levonorgestrel as a progestogen-only emergency contraceptive pill is, according to International Federation of Gynecology and Obstetrics (FIGO), to prevent fertilization by inhibition of ovulation and thickening of cervical mucus. FIGO has stated that: "review of the evidence suggests that LNG [levonorgestreol] ECPs cannot prevent implantation of a fertilized egg. Language on implantation should not be included in LNG ECP product labeling." In November 2013, the European Medicines Agency (EMA) approved a change to the label saying it cannot prevent implantation of a fertilized egg.Other studies still find the evidence to be unclear. While it is unlikely that emergency contraception affects implantation it is impossible to completely exclude the possibility of post-fertilization effect.In November 2013, the EMA also approved a change to the label for HRA Pharmas NorLevo saying: "In clinical trials, contraceptive efficacy was reduced in women weighing 75 kg [165 pounds] or more, and levonorgestrel was not effective in women who weighed more than 80 kg [176 pounds]." In November 2013 and January 2014, the FDA and the EMA said they were reviewing whether increased weight and body mass index (BMI) reduce the efficacy of emergency contraceptives.An analysis of four WHO randomised clinical trials, published in January 2017, showed pregnancy rates of 1.25% (68/5428) in women with BMI under 25, 0.61% (7/1140) in women with BMI between 25 and 30, and 2.03% (6/295) in women with BMI over 30. These values yield an eight-fold reduction in efficacy for women with BMI over 30 compared to women with BMI under 25. However, emergency contraceptives remain effective regardless of BMI.
Hormone therapy
Levonorgestrel is used in combination with an estrogen in menopausal hormone therapy. It is used under the brand name Klimonorm as a combined oral tablet with estradiol valerate and under the brand name Climara Pro as a combined transdermal patch with estradiol.
Available forms
As a type of emergency contraception, levonorgestrel is used after unprotected intercourse to reduce the risk of pregnancy. However, it can serve different hormonal purposes in its different methods of delivery. It is available for use in a variety of forms:
By mouth
Levonorgestrel can be taken by mouth as a form of emergency birth control. The typical dosage is either 1.5 mg taken once or 0.75 mg taken 12–24 hours apart. The effectiveness in both methods is similar. The most widely used form of oral emergency contraception is the progestin-only pill, which contains a 1.5 mg dosage of levonorgestrel. Levonorgestrel-only emergency contraceptive pills are reported to have an 89% effectiveness rate if taken within the recommended 72 hours after sex. The efficacy of the drug decreases by 50% for each 12 hour delay in taking the dose after the emergency contraceptive regimen has been started.
Skin patch
Estradiol with levonorgestrel in the form of a skin patch is used under the brand name Climara Pro for hormone replacement therapy in postmenstrual women, treating symptoms such as hot flashes or osteoporosis. The simultaneous delivery of a progestogen such as levonorgestrel is necessary for the protection of the endometrium.
Intrauterine device
The levonorgestrel intrauterine system (LNG-IUS) is a type of long-term birth control that releases the progestin into the uterine cavity. Levonorgestrel is released at a constant, gradual rate of 0.02 mg per day by the polydimethylsiloxane membrane of the device, which renders it effective for up to five years. Because it is inserted directly into the uterus, levonorgestrel is present in the endometrium in much higher concentrations that would result from a LNG-containing oral pill; the LNG-IUS delivers 391 ng of levonorgestrel to the inner uterine region while a comparable oral contraceptive delivers only 1.35 ng. This high level of levonorgestrel impedes the function of the endometrium, making it hostile for sperm transport, fertilization, and implantation of an ovum.
Implant
Subcutaneous implants of levonorgestrel have been marketed as birth control implants under the brand names Norplant and Jadelle and are available for use in some countries.
Contraindications
Known or suspected pregnancy is a contraindication of levonorgestrel as an emergency contraceptive.
Side effects
After an intake of 1.5 mg levonorgestrel in clinical trials, very common side effects (reported by 10% or more) included: hives, dizziness, hair loss, headache, nausea, abdominal pain, uterine pain, delayed menstruation, heavy menstruation, uterine bleeding, and fatigue; common side effects (reported by 1% to 10%) included diarrhea, vomiting, and painful menstruation; these side effects usually disappeared within 48 hours. However, the long term side effects common with oral contraceptives such as arterial disease are lower with levonorgestrel than in combination pills.Levonorgestrel as a contraceptive intrauterine device is associated with a higher risk of breast cancer than with non-use.
Overdose
Overdose of levonorgestrel as an emergency contraceptive has not been described. Nausea and vomiting might be expected.
Interactions
If taken together with drugs that induce the CYP3A4 cytochrome P450 liver enzyme, levonorgestrel may be metabolized faster and may have lower effectiveness.
These include, but are not limited to barbiturates, bosentan, carbamazepine, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, St. Johns wort and topiramate.
Pharmacology
Pharmacodynamics
Levonorgestrel is a progestogen with weak androgenic activity. It has no other important hormonal activity, including no estrogenic, glucocorticoid, or antimineralocorticoid activity. The lack of significant mineralocorticoid or antimineralocorticoid activity with levonorgestrel is in spite of it having relatively high affinity for the mineralocorticoid receptor, which is as much as 75% of that of aldosterone.
Progestogenic activity
Levonorgestrel is a progestogen; that is, an agonist of the progesterone receptor (PR), the main biological target of the progestogen sex hormone progesterone. It has effects similar to those of the hormone progesterone. As a contraceptive, it works primarily by preventing ovulation and closing off the cervix to prevent the passage of sperm. The endometrial transformation dose of levonorgestrel is 150 to 250 μg/day or 2.5 to 6 mg per cycle.Due to its progestogenic activity, levonorgestrel has antigonadotropic effects and is able to suppress the secretion of the gonadotropins, luteinizing hormone and follicle-stimulating hormone, from the pituitary gland. This in turn, results in suppression of gonadal activity, including reduction of fertility and gonadal sex hormone production in both women and men. The ovulation-inhibiting dose of levonorgestrel in premenopausal women is 50 to 60 μg/day.In men, levonorgestrel causes marked suppression of circulating testosterone levels secondary to its antigonadotropic effects. In healthy young men, levonorgestrel alone at a dose of 120 to 240 μg/day orally for 2 weeks suppressed testosterone levels from ~450 ng/dL to ~248 ng/dL (–45%). Because of its effects on testosterone levels, and due to its androgenic activity being only weak and hence insufficient for purposes of androgen replacement in males, levonorgestrel has potent functional antiandrogenic effects in men. Consequently, it is able to produce adverse effects like decreased libido and erectile dysfunction, among others. In relation to this, levonorgestrel has been combined with an androgen like testosterone or dihydrotestosterone when it has been studied as a hormonal contraceptive in men.
Androgenic activity
Levonorgestrel is a weak agonist of the androgen receptor (AR), the main biological target of the androgen sex hormone testosterone. It is a weakly androgenic progestin and in women may cause androgenic biochemical changes and side effects such as decreased sex hormone-binding globulin (SHBG) levels, decreased HDL cholesterol levels, weight gain, and acne.In combination with a potent estrogen like ethinylestradiol however, all contraceptives containing androgenic progestins are negligibly androgenic in practice and in fact can be used to treat androgen-dependent conditions like acne and hirsutism in women. This is because ethinylestradiol causes a marked increase in SHBG levels and thereby decreases levels of free and hence bioactive testosterone, acting as a functional antiandrogen. Nonetheless, contraceptives containing progestins that are less androgenic increase SHBG levels to a greater extent and may be more effective for such indications. Levonorgestrel is currently the most androgenic progestin that is used in contraceptives, and contraceptives containing levonorgestrel may be less effective for androgen-dependent conditions relative to those containing other progestins that are less androgenic.
Other activity
Levonorgestrel 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 levonorgestrel is approximately 95% (range 85 to 100%). The plasma protein binding of levonorgestrel is about 98%. It is bound 50% to albumin and 48% to SHBG. Levonorgestrel is metabolized in the liver, via reduction, hydroxylation, and conjugation (specifically glucuronidation and sulfation). Oxidation occurs primarily at the C2α and C16β positions, while reduction occurs in the A ring. 5α-Dihydrolevonorgestrel is produced as an active metabolite of levonorgestrel by 5α-reductase. The elimination half-life of levonorgestrel is 24 to 32 hours, although values as short as 8 hours and as great as 45 hours have been reported. About 20 to 67% of a single oral dose of levonorgestrel is eliminated in urine and 21 to 34% in feces.
Chemistry
Levonorgestrel, also known as 17α-ethynyl-18-methyl-19-nortestosterone or as 17α-ethynyl-18-methylestr-4-en-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone. It is the C13β or levorotatory stereoisomer and enantiopure form of norgestrel, the C13α or dextrorotatory isomer being inactive. Levonorgestrel is more specifically a derivative of norethisterone (17α-ethynyl-19-nortestosterone) and is the parent compound of the gonane (18-methylestrane or 13β-ethylgonane) subgroup of the 19-nortestosterone family of progestins. Besides levonorgestrel itself, this group includes desogestrel, dienogest, etonogestrel, gestodene, norelgestromin, norgestimate, and norgestrel. Levonorgestrel acetate and levonorgestrel butanoate are C17β esters of levonorgestrel. Levonorgestrel has a molecular weight of 312.45 g/mol and a partition coefficient (log P) of 3.8.
History
Norgestrel (rac-13-ethyl-17α-ethynyl-19-nortestosterone), the racemic mixture containing levonorgestrel and dextronorgestrel, was discovered by Hughes and colleagues at Wyeth in 1963 via structural modification of norethisterone (17α-ethynyl-19-nortestosterone). It was the first progestogen to be manufactured via total chemical synthesis. Norgestrel was introduced for medical use as a combined birth control pill with ethinylestradiol under the brand name Eugynon in Germany in 1966 and under the brand name Ovral in the United States 1968, and as a progestogen-only pill under the brand name Ovrette in the United States in 1973. Following its discovery, norgestrel had been licensed by Wyeth to Schering AG, which separated the racemic mixture into its two optical isomers and identified levonorgestrel (13β-ethyl-17α-ethynyl-19-nortestosterone) as the active component of the mixture. Levonorgestrel was first studied in humans by 1970, and was introduced for medical use in Germany as a combined birth control pill with ethinylestradiol under the brand name Neogynon in August 1970. A more widely used formulation, containing lower doses of ethinylestradiol and levonorgestrel, was introduced under the brand name Microgynon by 1973. In addition to combined formulations, levonorgestrel was introduced as a progestogen-only pill under the brand names Microlut by 1972 and Microval by 1974. Many other formulations and brand names of levonorgestrel-containing birth control pills have also been marketed.Levonorgestrel, taken alone in a single high dose, was first evaluated as a form of emergency contraception in 1973. It was the second progestin to be evaluated for such purposes, following a study of quingestanol acetate in 1970. In 1974, the Yuzpe regimen, which consisted of high doses of a combined birth control pill containing ethinylestradiol and norgestrel, was described as a method of emergency contraception by A. Albert Yuzpe and colleagues, and saw widespread interest. Levonorgestrel-only emergency contraception was introduced under the brand name Postinor by 1978. Ho and Kwan published the first study comparing levonorgestrel only and the Yuzpe regimen as methods of emergency contraception in 1993 and found that they had similar effectiveness but that levonorgestrel alone was better-tolerated. In relation to this, the Yuzpe regimen has largely been replaced as a method of emergency contraception by levonorgrestrel-only preparations. Levonorgestrel-only emergency contraception was approved in the United States under the brand name Plan B in 1999, and has also been marketed widely elsewhere throughout the world under other brand names such as Levonelle and NorLevo in addition to Postinor. In 2013, the Food and Drug Administration approved Plan B One-Step for sale over-the-counter in the United States without a prescription or age restriction.Levonorgestrel has also been introduced for use as a progestogen-only intrauterine device under the brand names Mirena and Skyla among others, as a progestogen-only birth control implant under the brand names Norplant and Jadelle, as a combined oral tablet with estradiol valerate for menopausal hormone therapy under the brand name Klimonorm, and as a combined transdermal patch with estradiol for menopausal hormone therapy under the brand name Climara Pro. Ester prodrugs of levonorgestrel such as levonorgestrel acetate and levonorgestrel butanoate have been developed and studied as other forms of birth control such as long-acting progestogen-only injectable contraceptives and contraceptive vaginal rings, but have not been marketed for medical use.
Society and culture
Generic names
Levonorgestrel is the generic name of the drug and its INN, USAN, USP, BAN, DCIT, and JAN, while lévonorgestrel is its DCF. It is also known as d-norgestrel, d(–)-norgestrel, or D-norgestrel, as well as by its developmental code names WY-5104 (Wyeth) and SH-90999 (Schering AG).
Brand names
Levonorgestrel is marketed alone or in combination with an estrogen (specifically ethinylestradiol, estradiol, or estradiol valerate) under a multitude of brand names throughout the world, including Alesse, Altavera, Alysena, Amethia, Amethyst, Ashlyna, Aviane, Camrese, Chateal, Climara Pro, Cycle 21, Daysee, Emerres, Enpresse, Erlibelle, Escapelle, Falmina, Introvale, Isteranda, Jadelle, Jaydess, Jolessa, Klimonorm, Kurvelo, Kyleena, Lessina, Levlen, Levodonna, Levonelle, Levonest, Levosert, Levora, Liletta, Loette, Logynon, LoSeasonique, Lutera, Lybrel, Marlissa, Microgynon, Microlut, Microvlar, Min-Ovral, Miranova, Mirena, My Way, Myzilra, Next Choice, Nordette, Norgeston, NorLevo, Norplant, One Pill, Option 2, Orsythia, Ovima, Ovranette, Plan B, Plan B One-Step, Portia, Postinor, Postinor-2, Preventeza, Ramonna, Rigevidon, Quartette, Quasense, Seasonale, Seasonique, Skyla, Sronyx, Tri-Levlen, Trinordiol, Triphasil, Triquilar, Tri-Regol, Trivora, and Upostelle, among many others. These formulations are used as emergency contraceptives, normal contraceptives, or in menopausal hormone therapy for the treatment of menopausal symptoms.As an emergency contraceptive, levonorgestrel is often referred to colloquially as the "morning-after pill".
Availability
Levonorgestrel is very widely marketed throughout the world and is available in almost every country.
Accessibility
Levonorgestrel-containing emergency contraception is available over-the-counter in some countries, such as the United States. On some college campuses, Plan B is available from vending machines.A policy update in 2015, required all pharmacies, clinics, and emergency departments run by Indian Health Services (for Native Americans) to have Plan B One-Step in stock, to distribute it to any woman (or her representative) who asked for it without a prescription, age verification, registration or any other requirement, to provide orientation training to all staff regarding the medication, to provide unbiased and medically accurate information about emergency contraception, and to make someone available at all times to distribute the pill in case the primary staffer objected to providing it on religious or moral grounds.
Research
Levonorgestrel has been studied in combination with androgens such as testosterone and dihydrotestosterone as a hormonal contraceptive for men.
References
External links
Monograph for levonorgestrel - Uk Medicines Information
"Levonorgestrel". Drug Information Portal. U.S. National Library of Medicine. |
Potassium citrate | Potassium citrate (also known as tripotassium citrate) is a potassium salt of citric acid with the molecular formula K3C6H5O7. It is a white, hygroscopic crystalline powder. It is odorless with a saline taste. It contains 38.28% potassium by mass. In the monohydrate form, it is highly hygroscopic and deliquescent.
As a food additive, potassium citrate is used to regulate acidity, and is known as E number E332. Medicinally, it may be used to control kidney stones derived from uric acid or cystine.
Synthesis
Potassium citrate can be synthesized by the neutralization of citric acid which is achieved by the addition of potassium bicarbonate, potassium carbonate or potassium hydroxide to it. The solution can then be filtered and the solvent can be evaporated till granulation.
Uses
Potassium citrate is rapidly absorbed when given by mouth, and is excreted in the urine. Since it is an alkaline salt, it is effective in reducing the pain and frequency of urination when these are caused by highly acidic urine. It is used for this purpose in dogs and cats, but is chiefly employed as a non-irritating diuretic.
Potassium citrate is an effective way to treat/manage gout and arrhythmia, if the patient is hypokalemic.
It is widely used to treat urinary calculi (kidney stones), and is often used by patients with cystinuria. A systematic review showed a significant reduction in the incidence of stone formation RR 0.26, 95% CI 0.10 to 0.68.It is also used as an alkalizing agent in the treatment of mild urinary tract infections, such as cystitis.It is also used in many soft drinks as a buffering agent.Frequently used in an aqueous solution with other potassium salts, it is a wet chemical fire suppressant that is particularly useful against kitchen fires. Its alkaline pH encourages saponification to insulate the fuel from oxidizing air, and the endothermic dehydration reaction absorbs heat energy to reduce temperatures.
Administration
Potassium citrate is usually administered by mouth in dilute aqueous solution, because of its somewhat caustic effect on the stomach lining, and the potential for other mild health hazards.
References
External links
Tanner, G.A. "Potassium citrate improves renal function in rats with polycystic kidney disease". Journal of the American Society of Nephrology. Retrieved December 17, 2016. |
Hydroxypropyl cellulose | Hydroxypropyl cellulose (HPC) is a derivative of cellulose with both water solubility and organic solubility. It is used as an excipient, and topical ophthalmic protectant and lubricant.
Chemistry
HPC is an ether of cellulose in which some of the hydroxyl groups in the repeating glucose units have been hydroxypropylated forming -OCH2CH(OH)CH3 groups using propylene oxide. The average number of substituted hydroxyl groups per glucose unit is referred to as the degree of substitution (DS). Complete substitution would provide a DS of 3. Because the hydroxypropyl group added contains a hydroxyl group, this can also be etherified during preparation of HPC. When this occurs, the number of moles of hydroxypropyl groups per glucose ring, moles of substitution (MS), can be higher than 3.
Because cellulose is very crystalline, HPC must have an MS about 4 in order to reach a good solubility in water. HPC has a combination of hydrophobic and hydrophilic groups, so it has a lower critical solution temperature (LCST) at 45 °C. At temperatures below the LCST, HPC is readily soluble in water; above the LCST, HPC is not soluble.
HPC forms liquid crystals and many mesophases according to its concentration in water. Such mesophases include isotropic, anisotropic, nematic and cholesteric. The last one gives many colors such as violet, green and red.
Uses
Lacrisert, manufactured by Aton Pharma, is a formulation of HPC used for artificial tears. It is used to treat medical conditions characterized by insufficient tear production such as keratoconjunctivitis sicca), recurrent corneal erosions, decreased corneal sensitivity, exposure and neuroparalytic keratitis. HPC is also used as a lubricant for artificial eyes.
HPC is used as a thickener, a low level binder and as an emulsion stabiliser with E number E463. In pharmaceuticals it is used as a binder in tablets.
HPC is used as a sieving matrix for DNA separations by capillary and microchip electrophoresis.HPC is the main ingredient in Cellugel, which is used in book conservation. Cellugel is described as "A safe, penetrating consolidant for leather book covers affected by red rot" and is produced by Preservation Solutions.
See also
Carboxymethyl cellulose
Methyl cellulose
Hypromellose
== Notes and references == |
Elosulfase alfa | Elosulfase alfa (trade name Vimizim) is a drug for the treatment of Morquio syndrome which is caused by a deficiency in the enzyme N-acetylgalactosamine-6-sulfatase. Elosulfase alfa is a synthetic version of this enzyme.
Elosulfase alfa was developed by BioMarin Pharmaceutical Inc. and approved for use in the US by the Food and Drug Administration in 2014.The drug is used in enzyme replacement therapy; a 2014 study confirmed it was effective on young patients with Morquio syndrome type A. Treatment with this medication was most effective upon respiratory symptoms, activities of daily living and growth, as confirmed in a 2015 paper.The cost of elosulfase alfa in some countries is $2,080,000-$6,240,000 a year, which has made it difficult for some health systems to afford it.In June 2019, a Belgian court issued a preliminary injunction forcing BioMarin to continue supplying Vimizim to a young girl suffering from Morquio syndrome free of charge. BioMarin stopped providing the drug for free at the beginning of the year after negotiations with Belgian health authorities regarding reimbursement of the product repeatedly failed. This caused the parents to start legal proceedings to force the company to keep providing the medicine free of charge. BioMarin was ordered to keep doing so until a definitive judgment would be rendered, or until the medicine would be available on the Belgian market at a reasonable price.
== References == |
Mecasermin | Mecasermin, sold under the brand name Increlex, also known as recombinant human insulin-like growth factor-1 (rhIGF-1), is a recombinant form of human insulin-like growth factor 1 (IGF-I) which is used in the long-term treatment of growth failure and short stature in children with severe primary IGF-I deficiency, for instance due to growth hormone deficiency or Laron syndrome (growth hormone insensitivity).Mecasermin has a biological half-life of about 5.8 hours in children with severe primary IGF-1 deficiency.A related medication is mecasermin rinfabate (brand name Iplex), which is a combination of mecasermin (rhIGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), and insulin-like growth factor binding protein acid labile subunit (IGFALS) as a ternary complex. The complex serves to prolong the action of mecasermin in the human body; the half-life of mecasermin when provided as this complex is 13.4 hours in individuals with severe primary IGF-1 deficiency.
References
External links
"Mecasermin". Drug Information Portal. U.S. National Library of Medicine. |
Decitabine/cedazuridine | Decitabine/cedazuridine, sold under the brand name Inqovi, is a fixed-dose combination medication for the treatment of adults with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). It is a combination of decitabine, a nucleoside metabolic inhibitor, and cedazuridine, a cytidine deaminase inhibitor.The most common side effects of decitabine/cedazuridine include fatigue, constipation, hemorrhage, muscle pain (myalgia), mucositis (mouth sores), arthralgia (joint pain), nausea, dyspnea, diarrhea, rash, dizziness, fever with low white blood cell count (febrile neutropenia), edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and transaminase increased. The combination can cause fetal harm.Decitabine/cedazuridine was approved for medical use in the United States and in Canada in July 2020.
Medical uses
Decitabine/cedazuridine is indicated for treatment of adults with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.MDS is a type of blood cancer in which blood cells in the bone marrow are defective leading to a low number of one or more types of blood cells.
History
Decitabine/cedazuridine was approved for medical use in the United States and in Canada in July 2020.The U.S. Food and Drug Administration (FDA) granted the application of decitabine combined with cedazuridine priority review and orphan drug designation. The orphan drug designation was granted in August 2019 for the treatment of myelodysplastic syndromes (including chronic myelomonocytic leukemia).Decitabine combined with cedazuridine was investigated in two open-label, randomized, crossover trials. Trial ASTX727-01-B (NCT02103478) included 80 adult participants with MDS (International Prognostic Scoring System [IPSS] Intermediate-1, Intermediate-2, or high-risk) or CMML and trial ASTX727-02 (NCT03306264) included 133 adult participants with MDS or CMML, including all French-American-British classification criteria and IPSS Intermediate-1, Intermediate-2, or high-risk prognostic scores. The trials were conducted at 51 sites in the United States and Canada.In both trials, participants were randomized 1:1 to receive decitabine combined with cedazuridine (35 mg decitabine and 100 mg cedazuridine) orally in cycle 1 and decitabine 20 mg/m2 intravenously in cycle 2 or the reverse sequence. Both decitabine combined with cedazuridine and intravenous decitabine were administered once daily on days 1 through 5 of a 28-day cycle. Starting with cycle 3, all participants received decitabine combined with cedazuridine orally once daily on days 1 through 5 of each 28-day cycle until disease progression or unacceptable toxicity. Both trials provided comparison of exposure and safety in the first two cycles between oral decitabine combined with cedazuridine and intravenous decitabine and description of disease response with decitabine combined with cedazuridine. Comparison of disease response between the decitabine combined with cedazuridine and intravenous decitabine was not possible because all participants received decitabine combined with cedazuridine starting from Cycle 3.The FDA approval of decitabine combined with cedazuridine was based on clinical trial results which showed similar drug concentrations between intravenous decitabine and decitabine combined with cedazuridine. Additionally, about half of the participants who were formerly dependent on transfusions were able to no longer require transfusions during an 8-week period. The safety profile of decitabine combined with cedazuridine was also similar to intravenous decitabine. The FDA granted the approval of Inqovi to Astex Pharmaceuticals, Inc., a subsidiary of Otsuka Pharmaceutical Co. Ltd.
References
External links
"Decitabine". Drug Information Portal. U.S. National Library of Medicine.
"Cedazuridine". Drug Information Portal. U.S. National Library of Medicine.
"Decitabine". National Cancer Institute.
"Cedazuridine". National Cancer Institute.
Clinical trial number NCT02103478 for "Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral CDAi in Patients With MDS" at ClinicalTrials.gov
Clinical trial number NCT03306264 for "Study of ASTX727 vs IV Decitabine in MDS, CMML, and AML" at ClinicalTrials.gov
"ASTX727 – Hematologic Malignancies". Astex. |
Norethisterone acetate | Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.Side effects of NETA include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and others. NETA 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 weak androgenic and estrogenic activity and no other important hormonal activity. The medication is a prodrug of norethisterone in the body.NETA was patented in 1957 and was introduced for medical use in 1964. It is sometimes referred to as a "first-generation" progestin. NETA is marketed widely throughout the world. It is available as a generic medication.
Medical uses
NETA is used as a hormonal contraceptive in combination with estrogen, in the treatment of gynecological disorders such as abnormal uterine bleeding, and as a component of menopausal hormone therapy for the treatment of menopausal symptoms.
Available forms
NETA is available in the form of tablets for use by mouth both alone and in combination with estrogens including estradiol, estradiol valerate, and ethinylestradiol. Transdermal patches providing a combination of 50 μg/day estradiol and 0.14 or 0.25 mg/day NETA are available under the brand names CombiPatch and Estalis.NETA was previously available for use by intramuscular injection in the form of ampoules containing 20 mg NETA, 5 mg estradiol benzoate, 8 mg estradiol valerate, and 180 mg testosterone enanthate in oil solution under the brand name Ablacton to suppress lactation in postpartum women.
Contraindications
Side effects
Side effects of NETA include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and others.
Overdose
Interactions
Pharmacology
NETA is a prodrug of norethisterone in the body. Upon oral ingestion, it is rapidly converted into norethisterone by esterases during intestinal and first-pass hepatic metabolism. Hence, as a prodrug of norethisterone, NETA has essentially the same effects, acting as a potent progestogen with additional weak androgenic and estrogenic activity (the latter via its metabolite ethinylestradiol).In terms of dosage equivalence, norethisterone and NETA are typically used at respective dosages of 0.35 mg/day and 0.6 mg/day as progestogen-only contraceptives, and at respective dosages of 0.5–1 mg/day and 1–1.5 mg/day in combination with ethinylestradiol in combined oral contraceptives. Conversely, the two drugs have been used at about the same dosages in menopausal hormone therapy for the treatment of menopausal symptoms. NETA is of about 12% higher molecular weight than norethisterone due to the presence of its C17β acetate ester.Micronization of NETA has been found to increase its potency by several-fold in animals and women. The endometrial transformation dosage of micronized NETA per cycle is 12 to 14 mg, whereas that for non-micronized NETA is 30 to 60 mg.NETA metabolizes into ethinylestradiol at a rate of 0.20 to 0.33% across a dose range of 10 to 40 mg. Peak levels of ethinylestradiol with a 10, 20, or 40 mg dose of NETA were 58, 178, and 231 pg/mL, respectively. For comparison, a 30 to 40 μg dose of oral ethinylestradiol typically results in a peak ethinylestradiol level of 100 to 135 pg/mL. As such, in terms of ethinylestradiol exposure, 10 to 20 mg NETA may be equivalent to 20 to 30 μg ethinylestradiol and 40 mg NETA may be similar to 50 μg ethinylestradiol. In another study however, 5 mg NETA produced an equivalent of 28 μg ethinylestradiol (0.7% conversion rate) and 10 mg NETA produced an equivalent of 62 μg ethinylestradiol (1.0% conversion rate). Due to its estrogenic activity via ethinylestradiol, high doses of NETA have been proposed for add-back in the treatment of endometriosis without estrogen supplementation. Generation of ethinylestradiol with high doses of NETA may increase the risk of venous thromboembolism but may also decrease menstrual bleeding relative to progestogen exposure alone.NETA has antigonadotropic effects via its progestogenic activity and can dose-dependently suppress gonadotropin and sex hormone levels in women and men. The ovulation-inhibiting dose of NETA is about 0.5 mg/day in women. In healthy young men, NETA alone at a dose of 5 to 10 mg/day orally for 2 weeks suppressed testosterone levels from ~527 ng/dL to ~231 ng/dL (–56%).
Chemistry
NETA, also known as norethinyltestosterone acetate, as well as 17α-ethynyl-19-nortestosterone 17β-acetate or 17α-ethynylestra-4-en-17β-ol-3-one 17β-acetate, is a progestin, or synthetic progestogen, of the 19-nortestosterone group, and a synthetic estrane steroid. It is the C17β acetate ester of norethisterone. NETA is a derivative of testosterone with an ethynyl group at the C17α position, the methyl group at the C19 position removed, and an acetate ester attached at the C17β position. In addition to testosterone, it is a combined derivative of nandrolone (19-nortestosterone) and ethisterone (17α-ethynyltestosterone).
Synthesis
Chemical syntheses of NETA have been published.
History
Schering AG filed for a patent for NETA in June 1957, and the patent was issued in December 1960. The drug was first marketed, by Parke-Davis as Norlestrin in the United States, in March 1964. This was a combination formulation of 2.5 mg NETA and 50 μg ethinylestradiol and was indicated as an oral contraceptive. Other early brand names of NETA used in oral contraceptives included Minovlar and Anovlar.
Society and culture
Generic names
Norethisterone acetate is the INN, BANM, and JAN of NETA while norethindrone acetate is its USAN and USP.
Brand names
NETA is marketed under a variety of brand names throughout the world including Primolut-Nor (major), Aygestin (US), Gestakadin, Milligynon, Monogest, Norlutate (US, CA), Primolut N, SH-420 (UK), Sovel, and Styptin among others.
Availability
United States
NETA is marketed in high-dose 5 mg oral tablets in the United States under the brand names Aygestin and Norlutate for the treatment of gynecological disorders. In addition, it is available under a large number of brand names at much lower dosages (0.1 to 1 mg) in combination with estrogens such as ethinylestradiol and estradiol as a combined oral contraceptive and for use in menopausal hormone therapy for the treatment of menopausal symptoms.
Research
NETA has been studied for use as a potential male hormonal contraceptive in combination with testosterone in men.
See also
Ethinylestradiol/norethisterone acetate
Norethisterone enanthate
== References == |
Interleukin 2 | Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15.5–16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for immunity. IL-2 is part of the bodys natural response to microbial infection, and in discriminating between foreign ("non-self") and "self". IL-2 mediates its effects by binding to IL-2 receptors, which are expressed by lymphocytes. The major sources of IL-2 are activated CD4+ T cells and activated CD8+ T cells.
IL-2 receptor
IL-2 is a member of a cytokine family, each member of which has a four alpha helix bundle; the family also includes IL-4, IL-7, IL-9, IL-15 and IL-21. IL-2 signals through the IL-2 receptor, a complex consisting of three chains, termed alpha (CD25), beta (CD122) and gamma (CD132). The gamma chain is shared by all family members.The IL-2 receptor (IL-2R) α subunit binds IL-2 with low affinity (Kd~ 10−8 M). Interaction of IL-2 and CD25 alone does not lead to signal transduction due to its short intracellular chain but has the ability (when bound to the β and γ subunit) to increase the IL-2R affinity 100-fold. Heterodimerization of the β and γ subunits of IL-2R is essential for signalling in T cells. IL-2 can signalize either via intermediate-affinity dimeric CD122/CD132 IL-2R (Kd~ 10−9 M) or high-affinity trimeric CD25/CD122/CD132 IL-2R (Kd~ 10−11 M). Dimeric IL-2R is expressed by memory CD8+ T cells and NK cells, whereas regulatory T cells and activated T cells express high levels of trimeric IL-2R.
IL-2 signaling pathways and regulation
The pleiotropic effects of IL-2 are enabled due to the fact that IL-2 signal can be transduced via 3 different signaling pathways; JAK-STAT, PI3K/Akt/mTOR and MAPK/ERK pathway. After IL-2 binding to its receptor, cytoplasmatic domains of CD122 and CD132 heterodimerize. This leads to the activation of Janus kinases JAK1 and JAK3 which subsequently phosphorylate T338 on CD122. This phosphorylation recruits STAT transcription factors, predominantly STAT5, which dimerize and migrate to the cell nucleus where they bind to DNA.Gene expression regulation for IL-2 can be on multiple levels or by different ways. One of the checkpoints is signaling through TCR, antigen receptor of T-lymphocytes after recognizing MHC-peptide complex. Signaling pathway from TCR then goes through phospholipase-C (PLC) dependent pathway. PLC activates 3 major transcription factors and their pathways: NFAT, NFkB and AP-1. After costimulation from CD28 the optimal activation of expression of IL-2 and these pathways is induced.
At the same time Oct-1 is expressed. It helps the activation. Oct1 is expressed in T-lymphocytes and Oct2 is induced after cell activation.
NFAT has multiple family members, all of them are located in cytoplasm and signaling goes through calcineurin, NFAT is dephosphorylated and therefore translocated to the nucleus.
AP-1 is a dimer and is composed of c-Jun and c-Fos proteins. It cooperates with other transcription factors including NFkB and Oct.
NFkB is translocated to the nucleus after costimulation through CD28. NFkB is a heterodimer and there are two binding sites on the IL-2 promoter.
Function
IL-2 has essential roles in key functions of the immune system, tolerance and immunity, primarily via its direct effects on T cells. In the thymus, where T cells mature, it prevents autoimmune diseases by promoting the differentiation of certain immature T cells into regulatory T cells, which suppress other T cells that are otherwise primed to attack normal healthy cells in the body. IL-2 enhances activation-induced cell death (AICD). IL-2 also promotes the differentiation of T cells into effector T cells and into memory T cells when the initial T cell is also stimulated by an antigen, thus helping the body fight off infections. Together with other polarizing cytokines, IL-2 stimulates naive CD4+ T cell differentiation into Th1 and Th2 lymphocytes while it impedes differentiation into Th17 and folicular Th lymphocytes.IL-2 increases the cell killing activity of both natural killer cells and cytotoxic T cells.Its expression and secretion is tightly regulated and functions as part of both transient positive and negative feedback loops in mounting and dampening immune responses. Through its role in the development of T cell immunologic memory, which depends upon the expansion of the number and function of antigen-selected T cell clones, it plays a key role in enduring cell-mediated immunity.
Role in disease
While the causes of itchiness are poorly understood, some evidence indicates that IL-2 is involved in itchy psoriasis.
Medical use
Pharmaceutical analogues
Aldesleukin is a form of recombinant interleukin-2. It is manufactured using recombinant DNA technology and is marketed as a protein therapeutic and branded as Proleukin. It has been approved by the Food and Drug Administration (FDA) and in several European countries for the treatment of cancers (malignant melanoma, renal cell cancer) in large intermittent doses and has been extensively used in continuous doses.Interking is a recombinant IL-2 with a serine at residue 125, sold by Shenzhen Neptunus.Neoleukin 2/15 is a computationally designed mimic of IL-2 that was designed to avoid common side effects. It is currently being commercialized into a therapeutic.
Dosage
Various dosages of IL-2 across the United States and across the world are used. The efficacy and side effects of different dosages is often a point of disagreement.
The commercial interest in local IL-2 therapy has been very low. Because only a very low dose IL-2 is used, treatment of a patient would cost about $ 500 commercial value of the patented IL-2. The commercial return on investment is too low to stimulate additional clinical studies for the registration of intratumoral IL-2 therapy.
United States
Usually, in the U.S., the higher dosage option is used, affected by cancer type, response to treatment and general patient health. Patients are typically treated for five consecutive days, three times a day, for fifteen minutes. The following approximately 10 days help the patient to recover between treatments. IL-2 is delivered intravenously on an inpatient basis to enable proper monitoring of side effects.A lower dose regimen involves injection of IL-2 under the skin typically on an outpatient basis. It may alternatively be given on an inpatient basis over 1–3 days, similar to and often including the delivery of chemotherapy.Intralesional IL-2 is commonly used to treat in-transit melanoma metastases and has a high complete response rate.
Local application
In preclinical and early clinical studies, local application of IL-2 in the tumor has been shown to be clinical more effective in anticancer therapy than systemic IL-2 therapy, over a broad range of doses, without serious side effects.Tumour blood vessels are more vulnerable than normal blood vessels to the actions of IL-2. When injected inside a tumor, i.e. local application, a process mechanistically similar to the vascular leakage syndrome, occurs in tumor tissue only. Disruption of the blood flow inside of the tumor effectively destroys tumor tissue.In local application, the systemic dose of IL-2 is too low to cause side effects, since the total dose is about 100 to 1000 fold lower. Clinical studies showed painful injections at the site of radiation as the most important side effect, reported by patients. In the case of irradiation of nasopharyngeal carcinoma the five-year disease-free survival increased from 8% to 63% by local IL-2 therapy
Toxicity
Systemic IL-2 has a narrow therapeutic window, and the level of dosing usually determines the severity of the side effects. In the case of local IL-2 application, the therapeutic window spans several orders of magnitude.Some common side effects:
flu-like symptoms (fever, headache, muscle and joint pain, fatigue)
nausea/vomiting
dry, itchy skin or rash
weakness or shortness of breath
diarrhea
low blood pressure
drowsiness or confusion
loss of appetiteMore serious and dangerous side effects sometimes are seen, such as breathing problems, serious infections, seizures, allergic reactions, heart problems, kidney failure or a variety of other possible complications. The most common adverse effect of high-dose IL-2 therapy is vascular leak syndrome (VLS; also termed capillary leak syndrome). It is caused by lung endothelial cells expressing high-affinity IL-2R. These cells, as a result of IL-2 binding, causes increased vascular permeability. Thus, intravascular fluid extravasate into organs, predominantly lungs, which leads to life-threatening pulmonary or brain oedema.Other drawbacks of IL-2 cancer immunotherapy are its short half-life in circulation and its ability to predominantly expand regulatory T cells at high doses.Intralesional IL-2 used to treat in-transit melanoma metastases is generally well tolerated. This is also the case for intralesional IL-2 in other forms of cancer, like nasopharyngeal carcinoma.
Pharmaceutical derivative
Eisai markets a drug called denileukin diftitox (trade name Ontak), which is a recombinant fusion protein of the human IL-2 ligand and the diphtheria toxin. This drug binds to IL-2 receptors and introduces the diphtheria toxin into cells that express those receptors, killing the cells. In some leukemias and lymphomas, malignant cells express the IL-2 receptor, so denileukin diftitox can kill them. In 1999 Ontak was approved by the U.S. Food and Drug Administration (FDA) for treatment of cutaneous T cell lymphoma (CTCL).
Preclinical research
IL-2 does not follow the classical dose-response curve of chemotherapeutics. The immunological activity of high and low dose IL-2 show sharp contrast. This might be related to different distribution of IL-2 receptors (CD25, CD122, CD132) on different cell populations, resulting in different cells that are activated by high and low dose IL-2. In general high doses are immune suppressive, while low doses can stimulate type 1 immunity. Low-dose IL-2 has been reported to reduce hepatitis C and B infection.IL-2 has been used in clinical trials for the treatment of chronic viral infections and as a booster (adjuvant) for vaccines. The use of large doses of IL-2 given every 6–8 weeks in HIV therapy, similar to its use in cancer therapy, was found to be ineffective in preventing progression to an AIDS diagnosis in two large clinical trials published in 2009.More recently low dose IL-2 has shown early success in modulating the immune system in disease like type 1 diabetes and vasculitis. There are also promising studies looking to use low dose IL-2 in ischaemic heart disease.
IL-2/anti-IL-2 mAb immune complexes (IL-2 ic)
IL-2 cannot accomplish its role as a promising immunotherapeutic agent due to significant drawbacks which are listed above. Some of the issues can be overcome using IL-2 ic. They are composed of IL-2 and some of its monoclonal antibody (mAb) and can potentiate biologic activity of IL-2 in vivo. The main mechanism of this phenomenon in vivo is due to the prolongation of the cytokine half-life in circulation. Depending on the clone of IL-2 mAb, IL-2 ic can selectively stimulate either CD25high (IL-2/JES6-1 complexes), or CD122high cells (IL-2/S4B6). IL-2/S4B6 immune complexes have high stimulatory activity for NK cells and memory CD8+ T cells and they could thus replace the conventional IL-2 in cancer immunotherapy. On the other hand, IL-2/JES6-1 highly selectively stimulate regulatory T cells and they could be potentially useful for transplantations and in treatment of autoimmune diseases.
History
According to an immunology textbook: "IL-2 is particularly important historically, as it is the first type I cytokine that was cloned, the first type I cytokine for which a receptor component was cloned, and was the first short-chain type I cytokine whose receptor structure was solved. Many general principles have been derived from studies of this cytokine including its being the first cytokine demonstrated to act in a growth factor–like fashion through specific high-affinity receptors, analogous to the growth factors being studied by endocrinologists and biochemists".: 712 In the mid-1960s, studies reported "activities" in leukocyte-conditioned media that promoted lymphocyte proliferation.: 16 In the mid-1970s, it was discovered that T-cells could be selectively proliferated when normal human bone marrow cells were cultured in conditioned medium obtained from phytohemagglutinin-stimulated normal human lymphocytes.: 712 The key factor was isolated from cultured mouse cells in 1979 and from cultured human cells in 1980. The gene for human IL-2 was cloned in 1982 after an intense competition.: 76 Commercial activity to bring an IL-2 drug to market was intense in the 1980s and 90s. By 1983, Cetus Corporation had created a proprietary recombinant version of IL-2 (Aldesleukin, later branded as Proleukin), with the alanine removed from its N-terminal and residue 125 replaced with serine.: 76–77 : 201 Amgen later entered the field with its own proprietary, mutated, recombinant protein and Cetus and Amgen were soon competing scientifically and in the courts; Cetus won the legal battles and forced Amgen out of the field.: 151 By 1990 Cetus had gotten aldesleukin approved in nine European countries but in that year, the U.S. Food and Drug Administration (FDA) refused to approve Cetus application to market IL-2. The failure led to the collapse of Cetus, and in 1991 the company was sold to Chiron Corporation. Chiron continued the development of IL-2, which was finally approved by the FDA as Proleukin for metastatic renal carcinoma in 1992.By 1993 aldesleukin was the only approved version of IL-2, but Roche was also developing a proprietary, modified, recombinant IL-2 called teceleukin, with a methionine added at is N-terminal, and Glaxo was developing a version called bioleukin, with a methionine added at is N-terminal and residue 125 replaced with alanine. Dozens of clinical trials had been conducted of recombinant or purified IL-2, alone, in combination with other drugs, or using cell therapies, in which cells were taken from patients, activated with IL-2, then reinfused. Novartis acquired Chiron in 2006 and licensed the US aldesleukin business to Prometheus Laboratories in 2010 before global rights to Proleukin were subsequently acquired by Clinigen in 2018 and 2019.
References
External links
Proleukin website
IL-2 Signaling Pathway
Rosenberg SA (June 2014). "IL-2: the first effective immunotherapy for human cancer". Journal of Immunology. 192 (12): 5451–8. doi:10.4049/jimmunol.1490019. PMC 6293462. PMID 24907378.
Overview of all the structural information available in the PDB for UniProt: P60568 (Interleukin-2) at the PDBe-KB. |
Clotrimazole | Clotrimazole, sold under the brand name Lotrimin, among others, is an antifungal medication. It is used to treat vaginal yeast infections, oral thrush, diaper rash, tinea versicolor, and types of ringworm including athletes foot and jock itch. It can be taken by mouth or applied as a cream to the skin or in the vagina.Common side effects when taken by mouth include nausea and itchiness. When applied to the skin, common side effects include redness and a burning sensation. In pregnancy, use on the skin or in the vagina is believed to be safe. There is no evidence of harm when used by mouth during pregnancy but this has been less well studied. When used by mouth, greater care should be taken in those with liver problems. It is in the azole class of medications and works by disrupting the fungal cell membrane.Clotrimazole was discovered in 1969. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication.
Medical uses
It is commonly available without a prescription in various dosage forms, such as a topical cream, ointment, or vaginal suppository. It is also available as an oral troche or throat lozenge as a prescription only. Topically, clotrimazole is used for vulvovaginal candidiasis (yeast infection) or yeast infections of the skin. For vulvovaginal candidiasis, clotrimazole tablets and creams are inserted into the vagina. Topical clotrimazole is usually not effective in treatment of fungal infections of the scalp or nails. When using over-the-counter drug clotrimazole products, use should be discontinued if condition does not improve after treatment for 2 weeks for jock itch or after 4 weeks for athletes foot or ringworm.Throat lozenge preparations are used for oropharyngeal candidiasis (oral thrush) or prevention of oral thrush in people with neutropenia.Clotrimazole is usually used five times daily for 14 days for oral thrush, twice daily for 2 to 8 weeks for skin infections, and once daily for 3 or 7 days for vaginal infections.Clotrimazole may be compounded with a glucocorticoid, such as betamethasone, in a topical cream for the treatment of tinea corporis (ringworm), tinea cruris (jock itch) and tinea pedis (athletes foot). Although FDA approved, clotrimazole–betamethasone combination cream is not the preferred treatment for dermatophyte infections due to increased side effects from the topical glucocorticoid.Although temporary relief and partial suppression of symptoms may be observed with the combination therapy, glucocorticoids can elicit an immunosuppressive response and rebound effect that results in more severe infection typically requiring systemic antifungal agents to treat the disease. Combination creams are best avoided in order to improve treatment outcome, reduce the possibility of skin atrophy associated with prolonged topical glucocorticoid use, and to limit the cost of treatment. It can be effective in treating chronic paronychia. The preferred treatment of tinea infections is therefore with clotrimazole monotherapy.Topical and oral clotrimazole can be used in both adults and children.
Additionally, clotrimazole may be used to treat the sickling of cells (related to sickle cell anemia).It can be taken by mouth as a lozenge or troche or applied as a topical cream to the skin or in the vagina.
Pregnancy
Topical clotrimazole is categorized as pregnancy category B. Small amounts of clotrimazole may be absorbed systemically following topical and vaginal administration. However, topical clotrimazole is still considered safe to use to treat yeast infections in pregnant women and is a safer alternative to other antifungals.
Side effects
Side effects of the oral formulation include itching, nausea, and vomiting. Less than 10% of patients using the oral formulation may have abnormal liver function tests. Side effects include rash, hives, blisters, burning, itching, peeling, redness, swelling, pain or other signs of skin irritation. For this reason, liver function tests should be monitored periodically when taking the oral clotrimazole (troche). When used to treat vulvovaginal candidiasis (yeast infection), less than 10% of patients have vulvar or vaginal burning sensation. Less than 1% of patients have the following side effects: burning or itching of penis of sexual partner; polyuria; vulvar itching, soreness, edema, or discharge.Clotrimazole creams and suppositories contain oil which may weaken latex condoms and diaphragms.For topical formulations, should be used externally and should be discontinued if irritation or sensitivity develops at the site of administration.
Interactions
There are no known significant drug interactions with topical clotrimazole. However, with oral (troche) clotrimazole, there are multiple interactions as the medication is a CYP450 enzyme inhibitor, primarily CYP3A4. Thus, any medication that is metabolized by the CYP3A4 enzyme will potentially have elevated levels when oral clotrimazole is used. The prescribing physician should be aware of any medication the patient is taking prior to starting oral clotrimazole. Certain medications should not be taken with oral clotrimazole.
Pharmacology
Pharmacodynamics
Clotrimazole is an imidazole derivative which works by inhibiting the growth of individual Candida or fungal cells by altering the permeability of the fungal cell wall. It binds to phospholipids in the cell membrane and inhibits the biosynthesis of ergosterol and other sterols required for cell membrane production. Clotrimazole may slow fungal growth or result in fungal cell death.
Sales volume
Clotrimazole is available as a generic medication, and in 2016 Canesten brand Clotrimazole was one of the biggest-selling branded over-the-counter medications sold in Great Britain, with sales of £39.2 million.
References
External links
"Clotrimazole". Drug Information Portal. U.S. National Library of Medicine. |
Brigatinib | Brigatinib, sold under the brand name Alunbrig among others, is a small-molecule targeted cancer therapy being developed by Ariad Pharmaceuticals, Inc. Brigatinib acts as both an anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitor.Brigatinib could overcome resistance to osimertinib conferred by the EGFR C797S mutation if it is combined with an anti-EGFR antibody such as cetuximab or panitumumab.
Mechanism of action
Brigatinib is an inhibitor of ALK and mutated EGFR.ALK was first identified as a chromosomal rearrangement in anaplastic large cell lymphoma (ALCL). Genetic studies indicate that abnormal expression of ALK is a key driver of certain types of non-small cell lung cancer (NSCLC) and neuroblastomas, as well as ALCL. Since ALK is generally not expressed in normal adult tissues, it represents a highly promising molecular target for cancer therapy.
Brigatinib inhibits ROS proto-oncogene-1 fusions and EGFR mutations and has a remarkable effect on the central nervous system.Epidermal growth factor receptor (EGFR) is another validated target in NSCLC. Additionally, the T790M "gatekeeper" mutation is linked in approximately 50 percent of patients who grow resistant to first-generation EGFR inhibitors. While second-generation EGFR inhibitors are in development, clinical efficacy has been limited due to toxicity thought to be associated with inhibiting the native (endogenous or unmutated) EGFR. A therapy designed to target EGFR, the T790M mutation but avoiding inhibition of native EGFR is another promising molecular target for cancer therapy.
History
Regulatory approval
Ariad Pharmaceuticals, Inc. filed an investigational new drug (IND) application to the US FDA on August 29, 2016.In 2016, brigatinib was granted orphan drug status by the FDA for treatment of NSCLC.On 28 April 2017, it was granted an accelerated approval from the U.S. Food and Drug Administration (FDA) for metastatic non-small cell lung cancer (NSCLC); as a 2nd-line therapy for ALK-positive NSCLC.In 2020, it was approved as first-line treatment for ALK-positive metastatic NSCLC patients.
Intellectual property
On 22 April 2015, Ariad Pharmaceuticals, Inc. announced the issuance of its first U.S. patent on brigatinib, the protection is through December 30, 2030. The United States Patent and Trademark Office granted U.S. Patent No. 9,012,462 under the title, "Phosphorous Derivatives as Kinase Inhibitors."
Commercialization
Brigatinib is manufactured by Ariad Pharmaceuticals, Inc. (NASDAQ: ARIA) which is focused on rare cancers. Ariad then was acquired by Takeda Pharmaceutical Company Limited (TSE: 4502) in February 2017 through a tender offer (for $24.00 per share in cash) and subsequent merger of Ariad with Kiku Merger Co., Inc., a wholly owned subsidiary of Takeda Pharmaceuticals U.S.A. Ariad is an indirect wholly owned subsidiary of Takeda.
Names
Brigatinib is the INN.
References
External links
"Brigatinib". Drug Information Portal. U.S. National Library of Medicine. |
Carboplatin | Carboplatin, sold under the trade name Paraplatin among others, is a chemotherapy medication used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It is used by injection into a vein.Side effects generally occur. Common side effects include low blood cell levels, nausea, and electrolyte problems. Other serious side effects include allergic reactions and increased future risk of another cancer. Use during pregnancy may result in harm to the baby. Carboplatin is in the platinum-based antineoplastic family of medications and works by interfering with duplication of DNA.Carboplatin was patented in 1972 and approved for medical use in 1989. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Carboplatin is used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It may be used for some types of testicular cancer but cisplatin is generally more effective. It has also been used to treat triple-negative breast cancer.
Side effects
Relative to cisplatin, the greatest benefit of carboplatin is its reduced side effects, particularly the elimination of nephrotoxic effects. Nausea and vomiting are less severe and more easily controlled.
The main drawback of carboplatin is its myelosuppressive effect. This causes the blood cell and platelet output of bone marrow in the body to decrease quite dramatically, sometimes as low as 10% of its usual production levels. The nadir of this myelosuppression usually occurs 21–28 days after the first treatment, after which the blood cell and platelet levels in the blood begin to stabilize, often coming close to its pre-carboplatin levels. This decrease in white blood cells (neutropenia) can cause complications, and is sometimes treated with drugs like filgrastim. The most notable complication of neutropenia is increased probability of infection by opportunistic organisms, which necessitates hospital readmission and treatment with antibiotics.
Chemistry
In terms of its structure, carboplatin differs from cisplatin in that it has a bidentate dicarboxylate (the ligand is CycloButane DiCarboxylic Acid, CBDCA) in place of the two chloride ligands, which are the leaving groups in cisplatin. For this reason, "CBDCA" is sometimes used in the medical literature as an abbreviation referring to carboplatin. Carboplatin exhibits lower reactivity and slower DNA binding kinetics, although it forms the same reaction products in vitro at equivalent doses with cisplatin. Unlike cisplatin, carboplatin may be susceptible to alternative mechanisms. Some results show that cisplatin and carboplatin cause different morphological changes in MCF-7 cell lines while exerting their cytotoxic behaviour. The diminished reactivity limits protein-carboplatin complexes, which are excreted. The lower excretion rate of carboplatin means that more is retained in the body, and hence its effects are longer lasting (a retention half-life of 30 hours for carboplatin, compared to 1.5-3.6 hours in the case of cisplatin).
Mechanism of action
Two theories exist to explain the molecular mechanism of action of carboplatin with DNA:
Aquation, or the like-cisplatin hypothesis.
Activation, or the unlike-cisplatin hypothesis.The former is more accepted owing to the similarity of the leaving groups with its predecessor cisplatin, while the latter hypothesis envisages a biological activation mechanism to release the active Pt2+ species.
Dose
Calverts formula is used to calculate the dose of carboplatin. It takes under consideration the creatinine clearance and the desired area under curve. After 24 hours, close to 70% of carboplatin is excreted in the urine unchanged. This means that the dose of carboplatin must be adjusted for any impairment in kidney function.Calvert formula:
D
o
s
e
(
m
g
)
=
A
U
C
⋅
(
G
F
R
+
25
)
{\displaystyle \mathrm {Dose} (\mathrm {mg} )=\mathrm {AUC} \cdot (\mathrm {GFR} +25)}
The typical area under the curve (AUC) for carboplatin ranges from 3-7 (mg/ml)*min.
History
Carboplatin was discovered at Michigan State University, and developed at the Institute of Cancer Research in London. Bristol-Myers Squibb gained Food and Drug Administration (FDA) approval for carboplatin, under the brand name Paraplatin, in March 1989. Starting in October 2004, generic versions of the drug became available.
Research
Carboplatin has also been used for adjuvant therapy of stage 1 seminomatous testicular cancer. Research has indicated that it is not less effective than adjuvant radiotherapy for this treatment, while having fewer side effects. This has led to carboplatin based adjuvant therapy being generally preferred over adjuvant radiotherapy in clinical practice.Carboplatin combined with hexadecyl chain and polyethylene glycol appears to have increased liposolubility and PEGylation. This is useful in chemotherapy, specifically non-small cell lung cancer.
See also
Cisplatin
Dicycloplatin
References
Additional references
External links
Creatinine Clearence [sic] Calculator
"Carboplatin". Drug Information Portal. U.S. National Library of Medicine. |
Metaxalone | Metaxalone, sold under the brand name Skelaxin, is a muscle relaxant medication used to relax muscles and relieve pain caused by strains, sprains, and other musculoskeletal conditions. Its exact mechanism of action is not known, but it may be due to general central nervous system depression. It is a moderately strong muscle relaxant, with relatively low incidence of side effects.Common side effects include nausea, vomiting, drowsiness, and central nervous system (CNS) side effects, such as dizziness, headache, and irritability.The metabolism of metaxalone involves enzymes CYP1A2 and CYP2C19 in the cytochrome P450 system. Because many medications are metabolized by enzymes in this system, precaution must be taken when administering it with other medications involving the P450 system to avoid interactions.Because of the potential for side effects, this drug is considered a high risk in the elderly.
Pharmacokinetics
Metaxalone exhibits increased bioavailability when taken with food. Specifically, in one study, compared to fasted conditions, the presence of food at the time of drug administration increased Cmax by 77.5%, AUC0-t by 23.5%, and AUC0-∞ by 15.4%. Metaxalone is a substrate of CYP1A2 and CYP2C19, an inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A, and an inducer of CYP1A2 and CYP3A4.
Assay
A literature survey reveals very few methods are reported for the determination of metaxalone to date. Nirogi et al. reported a liquid chromatographic method coupled to tandem mass spectrometry for the quantification of metaxalone in human plasma. A stability-indicating HPLC method was introduced by P.K. Sahu et al. Metaxalone has been used as an internal standard for few analytical methods.
References
External links
"Metaxalone". Drug Information Portal. U.S. National Library of Medicine. |
Adapalene/benzoyl peroxide | Adapalene/benzoyl peroxide, sold under the brand name Epiduo among others, is a fixed-dose combination medication for the treatment of severe acne vulgaris. It consists of a combination of adapalene and benzoyl peroxide in a topical gel formulation.
Medical uses
Adapalene/benzoyl peroxide is indicated for the topical treatment of acne vulgaris.
Side effects
Commonly reported side effects include the following:
Skin redness
Scaling
Dry skin
Contact dermatitis
Skin irritation
Stinging
Burning
Research
Meta-analysis of clinical trials has shown this combined therapy to be more effective than either of its ingredients by themselves.The use of adapalene/benzoyl peroxide in combination with oral antibiotics (lymecycline) has been studied; the combination was well tolerated and showed an improved success rate compared to those receiving only antibiotics (47.6% vs. 33.7%, P = 0.002).
References
External links
"Adapalene mixture with benzoyl peroxide". Drug Information Portal. U.S. National Library of Medicine. |
Caplacizumab | Caplacizumab (INN; trade name Cablivi) is a bivalent single-domain antibody (VHH) designed for the treatment of thrombotic thrombocytopenic purpura and thrombosis.This drug was developed by Ablynx NV. On 30 August 2018, it was approved in the European Union for the "treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression".It is an anti-von Willebrand factor humanized immunoglobulin. It acts by blocking platelet aggregation to reduce organ injury due to ischemia. Results of the phase II TITAN trial have been reported.In February 2019, caplacizumab-yhdp (Cablivi, Ablynx NV) was approved in the United States for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP). The drug is used in combination with plasma exchange and immunosuppressive therapy. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
References
External links
"Caplacizumab". Drug Information Portal. U.S. National Library of Medicine. |
Decitabine | Decitabine, sold under the brand name Dacogen among others, acts as a nucleic acid synthesis inhibitor. It is a medication for the treatment of myelodysplastic syndromes, a class of conditions where certain blood cells are dysfunctional, and for acute myeloid leukemia (AML). Chemically, it is a cytidine analog.
Medical uses
Decitabine is used to treat myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and Intermediate-1, Intermediate-2, and High-Risk International Prognostic Scoring System groups. In patients with chronic kidney disease, Batty and colleagues reported the first case series on the feasibility of therapy with hypomethylating agents in patients with chronic kidney disease.It also has EU approval for acute myeloid leukemia (AML).
Pharmacology
Decitabine is a hypomethylating agent. It hypomethylates DNA by inhibiting DNA methyltransferase.
It functions in a similar manner to azacitidine, although decitabine can only be incorporated into DNA strands while azacitidine can be incorporated into both DNA and RNA chains.
It incorporates into DNA strands upon replication, and then when DNA methyltransferases (DNMTs) such as DNMT1, are engaged to bind the DNA and to replicate the methylation to the daughter strand, DNMTs are bound to decitabine irreversibly and cannot disengage. Therefore, the action of decitabine is division-dependent, meaning the cells have to divide in order for the pharmaceutical to act.
Therefore, cancer cells which divide much more rapidly than most other cells in the body will be more severely affected by decitabine just because they replicate more. In cancer cells, and more specifically in haematological malignancies, it seems that DNA hypermethylation is really critical for their development. Methylation of CpG islands upstream of tumor suppressor genes in order to silence them seems to be critical for these type of cancers. Thus at optimal doses, decitabine blocks this type of methylation and has an anti-neoplastic effect.
Research
Atherosclerosis
A number of investigators have shown a relationship between atherosclerosis and disturbed blood flow. This upregulates DNA methyltransferase expression, which leads to genome-wide DNA methylation alterations and global gene expression changes. These studies have revealed several mechanosensitive genes, such as HoxA5, Klf3, and Klf4, whose promoters were hypermethylated by disturbed blood flow, but rescued by DNA methyltransferases inhibitors such as 5-aza-2-deoxycytidine. It has been found that use of this DNA methyltranferase inhibitor prevents atherosclerosis lesion formation and reduces the production of inflammatory cytokines by macrophages.
References
Further reading
Moon C, Kim SH (June 2009). "Use of epigenetic modification to induce FOXP3 expression in naïve T cells". Transplant. Proc. 41 (5): 1848–1854. doi:10.1016/j.transproceed.2009.02.101. PMID 19545742.
External links
"Decitabine". Drug Information Portal. U.S. National Library of Medicine. |
Eszopiclone | Eszopiclone, sold under the brand-name Lunesta among others such as Night Calm in Egypt, is a medication used in the treatment of insomnia. Evidence supports slight to moderate benefit up to six months. It is taken orally.Common side effects include headache, dry mouth, nausea, and dizziness. Severe side effects may include suicidal thoughts, unhealthy non-medical use, hallucinations, and angioedema. Greater care is recommended in those with liver problems and older people. Rapid decreasing of the dose may result in withdrawal. Eszopiclone is classified as a nonbenzodiazepine sedative hypnotic and as a cyclopyrrolone. It is the S-stereoisomer of zopiclone. It works by interacting with the GABA receptors.Approved for medical use in the United States in 2004, eszopiclone is available as generic medication. In 2019, it was the 223rd most commonly prescribed medication in the United States, with more than 2 million prescriptions. Eszopiclone is not sold in the European Union, as in 2009 the European Medicines Agency (EMA) ruled that it was too similar to zopiclone to be considered a new patentable product.
Medical uses
A 2018 Cochrane review found that it produced moderate improvement in sleep onset and maintenance. The authors suggest that where preferred non-pharmacological treatment strategies have been exhausted, eszopiclone provides an efficient treatment for insomnia. In 2014, the USFDA asked that the starting dose be lowered from 2 milligrams to 1 milligram after it was observed in a study that even 8 hours after taking the drug at night, some people were not able to cope with their next-day activities like driving and other activities that require full alertness.Eszopiclone is slightly effective in the treatment of insomnia where difficulty in falling asleep is the primary complaint. Kirsch et al. found the benefit over placebo to be of questionable clinical significance. Although the drug effect and the placebo response were rather small and of questionable clinical importance, the two together produce a reasonably large clinical response. It is not recommended for chronic use in the elderly.
Elderly
Sedative hypnotic drugs including eszopiclone are more commonly prescribed to the elderly than to younger patients despite benefits of medication being generally unimpressive. Care should be taken in choosing an appropriate hypnotic drug and if drug therapy is initiated it should be initiated at the lowest possible dose to minimise side effects.In 2015, the American Geriatrics Society reviewed the safety information about eszopiclone and similar drugs and concluded that the "nonbenzodiazepine, benzodiazepine receptor agonist hypnotics (eszopiclone, zaleplon, zolpidem) are to be avoided without consideration of duration of use because of their association with harms balanced with their minimal efficacy in treating insomnia."
The review made this determination both because of the relatively large dangers to elderly individuals from zolpidem and other "z-drugs" together with the fact the drugs have "minimal efficacy in treating insomnia." This was a change from the 2012 AGS recommendation, which suggested limiting use to 90 days or less. The review stated: "the 90‐day‐use caveat [was] removed from nonbenzodiazepine, benzodiazepine receptor agonist hypnotics, resulting in an unambiguous avoid statement (without caveats) because of the increase in the evidence of harm in this area since the 2012 update."An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, including eszopiclone appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin receptor agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.A 2009 meta-analysis found a higher rate of infections.
Adverse effects
Sleeping pills, including eszopiclone, have been associated with an increased risk of death.Hypersensitivity to eszopiclone is a contra-indication to its use. Some side effects are more common than others. Recommendations around use of eszopiclone may be altered by other health conditions. These conditions or circumstances may occur in people that have lowered metabolism and other conditions. The presence of liver impairment, lactation and activities requiring mental alertness (e.g., driving) may be considered when determining frequency and dosage.
A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking eszopiclone or other hypnotic drugs compared to those taking a placebo.
Dependence
In the United States eszopiclone is a schedule IV controlled substance under the Controlled Substances Act. Use of eszopiclone may lead to physical and psychological dependence. The risk of non-medical use and dependence increases with the dose and duration of usage and concomitant use of other psychoactive substances. The risk is also greater in patients with a history of alcohol use disorder or other substance use disorder or history of psychiatric disorders. Tolerance may develop after repeated use of benzodiazepines and benzodiazepine-like drugs for a few weeks.
A study funded and carried out by Sepracor, the manufacturer of eszopiclone, found no signs of tolerance or dependence in a group of patients followed for up to six months.
Non-medical use
A study of non-medical use potential of eszopiclone found that in persons with a known history of non-medical benzodiazepine use, eszopiclone at doses of 6 and 12 mg produced effects similar to those of diazepam 20 mg. The study found that at these doses which are two or more times greater than the maximum recommended doses, a dose-related increase in reports of amnesia, sedation, sleepiness, and hallucinations was observed for both eszopiclone (Lunesta) as well as for diazepam (Valium).
Overdose
According to the U.S. Prescribing Information, overdoses of eszopiclone up to 90 times the recommended dose have been reported in which the patient fully recovered. According to the May 2014 edition of the official U.S. Prescribing Information, fatalities have been reported only in cases in which eszopiclone was combined with other drugs or alcohol.Poison control centers reported that between 2005 and 2006 there were 525 total eszopiclone overdoses recorded in the state of Texas, the majority of which were intentional suicide attempts.If consumed within the last hour, eszopiclone overdose can be treated with the administration of activated charcoal or via gastric lavage.
Interactions
There is an increased risk of central nervous system depression when eszopiclone is taken together with other CNS depressant agents, including antipsychotics, sedative hypnotics (like barbiturates or benzodiazepines), antihistamines, opioids, phenothiazines, and some antidepressants. There is also increased risk of central nervous system depression with other medications that inhibit the metabolic activities of the CYP3A4 enzyme system of the liver. Medications that inhibit this enzyme system include nelfinavir, ritonavir, ketoconazole, itraconazole and clarithromycin. Alcohol also has an additive effect when used concurrently with eszopiclone. Eszopiclone is most effective if it is not taken after a heavy meal with high fat content.
Pharmacology
Eszopiclone acts on benzodiazepine binding site situated on GABAA neurons as a positive allosteric modulator.
Eszopiclone is rapidly absorbed after oral administration, with serum levels peaking between .45 and 1.3 hours. The elimination half-life of eszopiclone is approximately 6 hours and it is extensively metabolized by oxidation and demethylation. Approximately 52% to 59% of a dose is weakly bound to plasma protein. Cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1 are involved in the biotransformation of eszopiclone; thus, drugs that induce or inhibit these CYP isozymes may affect the metabolism of eszopiclone. Less than 10% of the orally administered dose is excreted in the urine as racemic zopiclone. In terms of benzodiazepine receptor binding and relevant potency, 3 mg of eszopiclone is equivalent to 10 mg of diazepam.
History
In a controversial 2009 article in the New England Journal of Medicine, "Lost in Transmission — FDA Drug Information That Never Reaches Clinicians", it was reported that the largest of three Lunesta trials found that compared to placebo Lunesta "was superior to placebo" while it only shortened initial time falling asleep by 15 minutes on average. "Clinicians who are interested in the drug’s efficacy cannot find efficacy information in the label: it states only that Lunesta is superior to placebo. The FDA’s medical review provides efficacy data, albeit not until page 306 of the 403-page document. In the longest, largest phase 3 trial, patients in the Lunesta group reported falling asleep an average of 15 minutes faster and sleeping an average of 37 minutes longer than those in the placebo group. However, on average, Lunesta patients still met criteria for insomnia and reported no clinically meaningful improvement in next-day alertness or functioning."
Availability in Europe
On September 11, 2007, Sepracor signed a marketing deal with British pharmaceutical company GlaxoSmithKline for the rights to sell eszopiclone (under the name Lunivia rather than Lunesta) in Europe. Sepracor was expected to receive approximately $155 million if the deal went through. In 2008 Sepracor submitted an application to the EMA (the European Unions equivalent to the U.S. FDA) for authorization to market the drug in the EU, and initially received a favorable response. However, Sepracor withdrew its authorization application in 2009 after the EMA stated it would not be granting eszopiclone new active substance status, as it was essentially pharmacologically and therapeutically too similar to zopiclone to be considered a new patentable product. Since the patent on zopiclone has expired, this ruling would have allowed rival companies to also legally produce cheaper generic versions of eszopiclone for the European market. As of November 2012, Sepracor has not resubmitted its authorization application and eszopiclone is not available in Europe. The deal with GSK fell through, and GSK instead launched a $3.3 billion deal to market Actelions almorexant sleeping tablet, which entered phase 3 medical trials before development was abandoned due to side effects.
References
External links
"Eszopiclone". Drug Information Portal. U.S. National Library of Medicine. |
Calcium citrate | Calcium citrate is the calcium salt of citric acid. It is commonly used as a food additive (E333), usually as a preservative, but sometimes for flavor. In this sense, it is similar to sodium citrate. Calcium citrate is also found in some dietary calcium supplements (e.g. Citracal or Caltrate). Calcium makes up 24.1% of calcium citrate (anhydrous) and 21.1% of calcium citrate (tetrahydrate) by mass. The tetrahydrate occurs in nature as the mineral Earlandite.
In 2019, it was the 225th most commonly prescribed medication in the United States, with more than 2 million prescriptions.
Chemical properties
Calcium citrate is sparingly soluble in water. Needle-shaped crystals of tricalcium dicitrate tetrahydrate [Ca3(C6H5O7)2(H2O)2]·2H2O were obtained by hydrothermal synthesis. The crystal structure comprises a three-dimensional network in which eightfold coordinated Ca2+ cations are linked by citrate anions and hydrogen bonds between two non-coordinating crystal water molecules and two coordinating water molecules.
Production
Calcium citrate is an intermediate in the isolation of citric acid from the fungal fermentation process by which citric acid is produced industrially. The citric acid in the broth solution is neutralized by limewater, precipitating insoluble calcium citrate. This is then filtered off from the rest of the broth and washed to give clean calcium citrate.
3 Ca(OH)2(s) + 2 C6H8O7(l) → Ca3(C6H5O7)2(s) + 6 H2O(l)The calcium citrate thus produced may be sold as-is, or it may be converted to citric acid using dilute sulfuric acid.
Biological role
In many individuals, bioavailability of calcium citrate is found to be equal to that of the cheaper calcium carbonate. However, alterations to the digestive tract may change how calcium is digested and absorbed. Unlike calcium carbonate, which is basic and neutralizes stomach acid, calcium citrate has no effect on stomach acid. Calcium carbonate is harder to digest than calcium citrate, and calcium carbonate carries a risk of "acid rebound" (the stomach overcompensates by producing more acid), so individuals who are sensitive to antacids or who have difficulty producing adequate stomach acid may choose calcium citrate over calcium carbonate for supplementation. According to recent research into calcium absorption after gastric bypass surgery, calcium citrate may have improved bioavailability over calcium carbonate in Roux-en-Y gastric bypass patients who are taking calcium citrate as a dietary supplement after surgery. This is mainly due to the changes related to where calcium absorption occurs in the digestive tract of these individuals.
References
External links
National Cancer Institute |
Morphine | Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (Papaver somniferum). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. There are numerous methods used to administer morphine: oral; sublingual; via inhalation; injection into a muscle; by injection under the skin; intravenously; injection into the space around the spinal cord; transdermal; or via rectal suppository. It acts directly on the central nervous system (CNS) to induce analgesia and alter perception and emotional response to pain. Physical and psychological dependence and tolerance may develop with repeated administration. It can be taken for both acute pain and chronic pain and is frequently used for pain from myocardial infarction, kidney stones, and during labor. Its maximum effect is reached after about 20 minutes when administered intravenously and 60 minutes when administered by mouth, while the duration of its effect is 3–7 hours. Long-acting formulations of morphine are available as MS-Contin, Kadian, and other brand names as well as generically.Potentially serious side effects of morphine include decreased respiratory effort, vomiting, nausea, and low blood pressure. Morphine is addictive and prone to abuse. If ones dose is reduced after long-term use, opioid withdrawal symptoms may occur. Common side effects of morphine include drowsiness, vomiting, and constipation. Caution is advised for use of morphine during pregnancy or breast feeding, as it may affect the health of the baby.Morphine was first isolated between 1803 and 1805 by German pharmacist Friedrich Sertürner. This is generally believed to be the first isolation of an active ingredient from a plant. Merck began marketing it commercially in 1827. Morphine was more widely used after the invention of the hypodermic syringe in 1853–1855. Sertürner originally named the substance morphium, after the Greek god of dreams, Morpheus, as it has a tendency to cause sleep.The primary source of morphine is isolation from poppy straw of the opium poppy. In 2013, approximately 523 tons of morphine were produced. Approximately 45 tons were used directly for pain, an increase of 400% over the last twenty years. Most use for this purpose was in the developed world. About 70 percent of morphine is used to make other opioids such as hydromorphone, oxymorphone, and heroin. It is a Schedule II drug in the United States, Class A in the United Kingdom, and Schedule I in Canada. It is on the World Health Organizations List of Essential Medicines. Morphine is sold under many trade names. In 2019, it was the 163rd most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Medical uses
Pain
Morphine is used primarily to treat both acute and chronic severe pain. Its duration of analgesia is about three to seven hours. Side-effects of nausea and constipation are rarely severe enough to warrant stopping treatment.
It is used for pain due to myocardial infarction and for labor pains. However, concerns exist that morphine may increase mortality in the event of non ST elevation myocardial infarction. Morphine has also traditionally been used in the treatment of acute pulmonary edema. A 2006 review, though, found little evidence to support this practice. A 2016 Cochrane review concluded that morphine is effective in relieving cancer pain.
Shortness of breath
Morphine is beneficial in reducing the symptom of shortness of breath due to both cancer and noncancer causes. In the setting of breathlessness at rest or on minimal exertion from conditions such as advanced cancer or end-stage cardiorespiratory diseases, regular, low-dose sustained-release morphine significantly reduces breathlessness safely, with its benefits maintained over time.
Opioid use disorder
Morphine is also available as a slow-release formulation for opiate substitution therapy (OST) in Austria, Germany, Bulgaria, Slovenia, and Canada for persons with opioid addiction who cannot tolerate either methadone or buprenorphine.
Contraindications
Relative contraindications to morphine include:
respiratory depression when appropriate equipment is not available.
Although it has previously been thought that morphine was contraindicated in acute pancreatitis, a review of the literature shows no evidence for this.
Adverse effects
Constipation
Like loperamide and other opioids, morphine acts on the myenteric plexus in the intestinal tract, reducing gut motility, causing constipation. The gastrointestinal effects of morphine are mediated primarily by μ-opioid receptors in the bowel. By inhibiting gastric emptying and reducing propulsive peristalsis of the intestine, morphine decreases the rate of intestinal transit. Reduction in gut secretion and increased intestinal fluid absorption also contribute to the constipating effect. Opioids also may act on the gut indirectly through tonic gut spasms after inhibition of nitric oxide generation. This effect was shown in animals when a nitric oxide precursor, L-arginine, reversed morphine-induced changes in gut motility.
Hormone imbalance
Clinical studies consistently conclude that morphine, like other opioids, often causes hypogonadism and hormone imbalances in chronic users of both sexes. This side effect is dose-dependent and occurs in both therapeutic and recreational users. Morphine can interfere with menstruation in women by suppressing levels of luteinizing hormone. Many studies suggest the majority (perhaps as many as 90%) of chronic opioid users have opioid-induced hypogonadism. This effect may cause the increased likelihood of osteoporosis and bone fracture observed in chronic morphine users. Studies suggest the effect is temporary. As of 2013, the effect of low-dose or acute use of morphine on the endocrine system is unclear.
Effects on human performance
Most reviews conclude that opioids produce minimal impairment of human performance on tests of sensory, motor, or attentional abilities. However, recent studies have been able to show some impairments caused by morphine, which is not surprising, given that morphine is a central nervous system depressant. Morphine has resulted in impaired functioning on critical flicker frequency (a measure of overall CNS arousal) and impaired performance on the Maddox wing test (a measure of the deviation of the visual axes of the eyes). Few studies have investigated the effects of morphine on motor abilities; a high dose of morphine can impair finger tapping and the ability to maintain a low constant level of isometric force (i.e. fine motor control is impaired), though no studies have shown a correlation between morphine and gross motor abilities.
In terms of cognitive abilities, one study has shown that morphine may have a negative impact on anterograde and retrograde memory, but these effects are minimal and transient. Overall, it seems that acute doses of opioids in non-tolerant subjects produce minor effects in some sensory and motor abilities, and perhaps also in attention and cognition. It is likely that the effects of morphine will be more pronounced in opioid-naive subjects than chronic opioid users.
In chronic opioid users, such as those on Chronic Opioid Analgesic Therapy (COAT) for managing severe, chronic pain, behavioural testing has shown normal functioning on perception, cognition, coordination and behaviour in most cases. One 2000 study analysed COAT patients to determine whether they were able to safely operate a motor vehicle. The findings from this study suggest that stable opioid use does not significantly impair abilities inherent in driving (this includes physical, cognitive and perceptual skills). COAT patients showed rapid completion of tasks that require the speed of responding for successful performance (e.g., Rey Complex Figure Test) but made more errors than controls. COAT patients showed no deficits in visual-spatial perception and organization (as shown in the WAIS-R Block Design Test) but did show impaired immediate and short-term visual memory (as shown on the Rey Complex Figure Test – Recall). These patients showed no impairments in higher-order cognitive abilities (i.e., planning). COAT patients appeared to have difficulty following instructions and showed a propensity toward impulsive behaviour, yet this did not reach statistical significance. It is important to note that this study reveals that COAT patients have no domain-specific deficits, which supports the notion that chronic opioid use has minor effects on psychomotor, cognitive, or neuropsychological functioning.
Reinforcement disorders
Addiction
Morphine is a highly addictive substance. In controlled studies comparing the physiological and subjective effects of heroin and morphine in individuals formerly addicted to opiates, subjects showed no preference for one drug over the other. Equipotent, injected doses had comparable action courses, with no difference in subjects self-rated feelings of euphoria, ambition, nervousness, relaxation, drowsiness, or sleepiness. Short-term addiction studies by the same researchers demonstrated that tolerance developed at a similar rate to both heroin and morphine. When compared to the opioids hydromorphone, fentanyl, oxycodone, and pethidine/meperidine, former addicts showed a strong preference for heroin and morphine, suggesting that heroin and morphine are particularly susceptible to abuse and addiction. Morphine and heroin were also much more likely to produce euphoria and other positive subjective effects when compared to these other opioids. The choice of heroin and morphine over other opioids by former drug addicts may also be because heroin (also known as morphine diacetate, diamorphine, or diacetyl morphine) is an ester of morphine and a morphine prodrug, essentially meaning they are identical drugs in vivo. Heroin is converted to morphine before binding to the opioid receptors in the brain and spinal cord, where morphine causes the subjective effects, which is what the addicted individuals are seeking.
Tolerance
Several hypotheses are given about how tolerance develops, including opioid receptor phosphorylation (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization), μ-opioid receptor internalization or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt.) CCK might mediate some counter-regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs, specifically proglumide, have been shown to slow the development of tolerance to morphine.
Dependence and withdrawal
Cessation of dosing with morphine creates the prototypical opioid withdrawal syndrome, which, unlike that of barbiturates, benzodiazepines, alcohol, or sedative-hypnotics, is not fatal by itself in otherwise healthy people.
Acute morphine withdrawal, along with that of any other opioid, proceeds through a number of stages. Other opioids differ in the intensity and length of each, and weak opioids and mixed agonist-antagonists may have acute withdrawal syndromes that do not reach the highest level. As commonly cited, they are:
Stage I, 6 h to 14 h after last dose: Drug craving, anxiety, irritability, perspiration, and mild to moderate dysphoria
Stage II, 14 h to 18 h after last dose: Yawning, heavy perspiration, mild depression, lacrimation, crying, headaches, runny nose, dysphoria, also intensification of the above symptoms, "yen sleep" (a waking trance-like state)
Stage III, 16 h to 24 h after last dose: Rhinorrhea (runny nose) and increase in other of the above, dilated pupils, piloerection (goose bumps – a purported origin of the phrase, cold turkey, but in fact the phrase originated outside of drug treatment), muscle twitches, hot flashes, cold flashes, aching bones and muscles, loss of appetite, and the beginning of intestinal cramping
Stage IV, 24 h to 36 h after last dose: Increase in all of the above including severe cramping and involuntary leg movements ("kicking the habit" also called restless leg syndrome), loose stool, insomnia, elevation of blood pressure, moderate elevation in body temperature, increase in frequency of breathing and tidal volume, tachycardia (elevated pulse), restlessness, nausea
Stage V, 36 h to 72 h after last dose: Increase in the above, fetal position, vomiting, free and frequent liquid diarrhea, which sometimes can accelerate the time of passage of food from mouth to out of system, weight loss of 2 kg to 5 kg per 24 h, increased white cell count, and other blood changes
Stage VI, after completion of above: Recovery of appetite and normal bowel function, beginning of transition to postacute and chronic symptoms that are mainly psychological, but may also include increased sensitivity to pain, hypertension, colitis or other gastrointestinal afflictions related to motility, and problems with weight control in either directionIn advanced stages of withdrawal, ultrasonographic evidence of pancreatitis has been demonstrated in some patients and is presumably attributed to spasm of the pancreatic sphincter of Oddi.The withdrawal symptoms associated with morphine addiction are usually experienced shortly before the time of the next scheduled dose, sometimes within as early as a few hours (usually 6 h to 12 h) after the last administration. Early symptoms include watery eyes, insomnia, diarrhea, runny nose, yawning, dysphoria, sweating, and in some cases a strong drug craving. Severe headache, restlessness, irritability, loss of appetite, body aches, severe abdominal pain, nausea and vomiting, tremors, and even stronger and more intense drug craving appear as the syndrome progresses. Severe depression and vomiting are very common. During the acute withdrawal period, systolic and diastolic blood pressures increase, usually beyond premorphine levels, and heart rate increases, which have potential to cause a heart attack, blood clot, or stroke.
Chills or cold flashes with goose bumps ("cold turkey") alternating with flushing (hot flashes), kicking movements of the legs ("kicking the habit") and excessive sweating are also characteristic symptoms. Severe pains in the bones and muscles of the back and extremities occur, as do muscle spasms. At any point during this process, a suitable narcotic can be administered that will dramatically reverse the withdrawal symptoms. Major withdrawal symptoms peak between 48 h and 96 h after the last dose and subside after about 8 to 12 days. Sudden withdrawal by heavily dependent users who are in poor health is very rarely fatal. Morphine withdrawal is considered less dangerous than alcohol, barbiturate, or benzodiazepine withdrawal.The psychological dependence associated with morphine addiction is complex and protracted. Long after the physical need for morphine has passed, the addict will usually continue to think and talk about the use of morphine (or other drugs) and feel strange or overwhelmed coping with daily activities without being under the influence of morphine. Psychological withdrawal from morphine is usually a very long and painful process. Addicts often experience severe depression, anxiety, insomnia, mood swings, amnesia (forgetfulness), low self-esteem, confusion, paranoia, and other psychological disorders. Without intervention, the syndrome will run its course, and most of the overt physical symptoms will disappear within 7 to 10 days including psychological dependence. A high probability of relapse exists after morphine withdrawal when neither the physical environment nor the behavioral motivators that contributed to the abuse have been altered. Testimony to morphines addictive and reinforcing nature is its relapse rate. Abusers of morphine (and heroin) have one of the highest relapse rates among all drug users, ranging up to 98% in the estimation of some medical experts.
Toxicity
A large overdose can cause asphyxia and death by respiratory depression if the person does not receive medical attention immediately. Overdose treatment includes the administration of naloxone. The latter completely reverses morphines effects, but may result in immediate onset of withdrawal in opiate-addicted subjects. Multiple doses may be needed as the duration of action of morphine is longer than that of naloxone.The LD50 for humans of morphine sulphate and other preparations is not known with certainty. One poor quality study on morphine overdoses among soldiers reported that the fatal dose was 0.78 mcg/ml in males (~71 mg for an average 90 kg adult man) and 0.98mcg/ml in females (~74 mg for an average 75 kg female). It was not specified whether the dose was oral, parenteral or IV. Laboratory animal studies are usually cited in the literature. In serious drug dependency (high tolerance), 2000–3000 mg per day can be tolerated.
Pharmacology
Pharmacodynamics
Morphine is the prototypical opioid and is the standard against which other opioids are tested. It interacts predominantly with the μ–δ-opioid (Mu-Delta) receptor heteromer. The μ-binding sites are discretely distributed in the human brain, with high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve.Morphine is a phenanthrene opioid receptor agonist – its main effect is binding to and activating the μ-opioid receptor (MOR) in the central nervous system. Its intrinsic activity at the MOR is heavily dependent on the assay and tissue being tested; in some situations it is a full agonist while in others it can be a partial agonist or even antagonist. In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system and gastrointestinal tract. Its primary actions of therapeutic value are analgesia and sedation. Activation of the MOR is associated with analgesia, sedation, euphoria, physical dependence, and respiratory depression. Morphine is also a κ-opioid receptor (KOR) and δ-opioid receptor (DOR) agonist. Activation of the KOR is associated with spinal analgesia, miosis (pinpoint pupils), and psychotomimetic effects. The DOR is thought to play a role in analgesia. Although morphine does not bind to the σ receptor, it has been shown that σ receptor agonists, such as (+)-pentazocine, inhibit morphine analgesia, and σ receptor antagonists enhance morphine analgesia, suggesting downstream involvement of the σ receptor in the actions of morphine.
The effects of morphine can be countered with opioid receptor antagonists such as naloxone and naltrexone; the development of tolerance to morphine may be inhibited by NMDA receptor antagonists such as ketamine or dextromethorphan. The rotation of morphine with chemically dissimilar opioids in the long-term treatment of pain will slow down the growth of tolerance in the longer run, particularly agents known to have significantly incomplete cross-tolerance with morphine such as levorphanol, ketobemidone, piritramide, and methadone and its derivatives; all of these drugs also have NMDA antagonist properties. It is believed that the strong opioid with the most incomplete cross-tolerance with morphine is either methadone or dextromoramide.
Gene expression
Studies have shown that morphine can alter the expression of a number of genes. A single injection of morphine has been shown to alter the expression of two major groups of genes, for proteins involved in mitochondrial respiration and for cytoskeleton-related proteins.
Effects on the immune system
Morphine has long been known to act on receptors expressed on cells of the central nervous system resulting in pain relief and analgesia. In the 1970s and 80s, evidence suggesting that opioid drug addicts show increased risk of infection (such as increased pneumonia, tuberculosis, and HIV/AIDS) led scientists to believe that morphine may also affect the immune system. This possibility increased interest in the effect of chronic morphine use on the immune system.
The first step of determining that morphine may affect the immune system was to establish that the opiate receptors known to be expressed on cells of the central nervous system are also expressed on cells of the immune system. One study successfully showed that dendritic cells, part of the innate immune system, display opiate receptors. Dendritic cells are responsible for producing cytokines, which are the tools for communication in the immune system. This same study showed that dendritic cells chronically treated with morphine during their differentiation produce more interleukin-12 (IL-12), a cytokine responsible for promoting the proliferation, growth, and differentiation of T-cells (another cell of the adaptive immune system) and less interleukin-10 (IL-10), a cytokine responsible for promoting a B-cell immune response (B cells produce antibodies to fight off infection).This regulation of cytokines appear to occur via the p38 MAPKs (mitogen-activated protein kinase)-dependent pathway. Usually, the p38 within the dendritic cell expresses TLR 4 (toll-like receptor 4), which is activated through the ligand LPS (lipopolysaccharide). This causes the p38 MAPK to be phosphorylated. This phosphorylation activates the p38 MAPK to begin producing IL-10 and IL-12. When the dendritic cells are chronically exposed to morphine during their differentiation process then treated with LPS, the production of cytokines is different. Once treated with morphine, the p38 MAPK does not produce IL-10, instead favoring production of IL-12. The exact mechanism through which the production of one cytokine is increased in favor over another is not known. Most likely, the morphine causes increased phosphorylation of the p38 MAPK. Transcriptional level interactions between IL-10 and IL-12 may further increase the production of IL-12 once IL-10 is not being produced. This increased production of IL-12 causes increased T-cell immune response.
Further studies on the effects of morphine on the immune system have shown that morphine influences the production of neutrophils and other cytokines. Since cytokines are produced as part of the immediate immunological response (inflammation), it has been suggested that they may also influence pain. In this way, cytokines may be a logical target for analgesic development. Recently, one study has used an animal model (hind-paw incision) to observe the effects of morphine administration on the acute immunological response. Following hind-paw incision, pain thresholds and cytokine production were measured. Normally, cytokine production in and around the wounded area increases in order to fight infection and control healing (and, possibly, to control pain), but pre-incisional morphine administration (0.1 mg/kg to 10.0 mg/kg) reduced the number of cytokines found around the wound in a dose-dependent manner. The authors suggest that morphine administration in the acute post-injury period may reduce resistance to infection and may impair the healing of the wound.
Pharmacokinetics
Absorption and metabolism
Morphine can be taken orally, sublingually, bucally, rectally, subcutaneously, intranasally, intravenously, intrathecally or epidurally and inhaled via a nebulizer. As a recreational drug, it is becoming more common to inhale ("Chasing the Dragon"), but, for medical purposes, intravenous (IV) injection is the most common method of administration. Morphine is subject to extensive first-pass metabolism (a large proportion is broken down in the liver), so, if taken orally, only 40% to 50% of the dose reaches the central nervous system. Resultant plasma levels after subcutaneous (SC), intramuscular (IM), and IV injection are all comparable. After IM or SC injections, morphine plasma levels peak in approximately 20 min, and, after oral administration, levels peak in approximately 30 min. Morphine is metabolised primarily in the liver and approximately 87% of a dose of morphine is excreted in the urine within 72 h of administration. Morphine is metabolized primarily into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) via glucuronidation by phase II metabolism enzyme UDP-glucuronosyl transferase-2B7 (UGT2B7). About 60% of morphine is converted to M3G, and 6% to 10% is converted to M6G. Not only does the metabolism occur in the liver but it may also take place in the brain and the kidneys. M3G does not undergo opioid receptor binding and has no analgesic effect. M6G binds to μ-receptors and is half as potent an analgesic as morphine in humans. Morphine may also be metabolized into small amounts of normorphine, codeine, and hydromorphone. Metabolism rate is determined by gender, age, diet, genetic makeup, disease state (if any), and use of other medications. The elimination half-life of morphine is approximately 120 min, though there may be slight differences between men and women. Morphine can be stored in fat, and, thus, can be detectable even after death. Morphine can cross the blood–brain barrier, but, because of poor lipid solubility, protein binding, rapid conjugation with glucuronic acid and ionization, it does not cross easily. Heroin, which is derived from morphine, crosses the blood–brain barrier more easily, making it more potent.
Extended-release
There are extended-release formulations of orally administered morphine whose effect last longer, which can be given once per day. Brand names for this formulation of morphine include Avinza, Kadian, MS Contin and Dolcontin. For constant pain, the relieving effect of extended-release morphine given once (for Kadian) or twice (for MS Contin) every 24 hours is roughly the same as multiple administrations of immediate release (or "regular") morphine. Extended-release morphine can be administered together with "rescue doses" of immediate-release morphine as needed in case of breakthrough pain, each generally consisting of 5% to 15% of the 24-hour extended-release dosage.
Detection in body fluids
Morphine and its major metabolites, morphine-3-glucuronide and morphine-6-glucuronide, can be detected in blood, plasma, hair, and urine using an immunoassay. Chromatography can be used to test for each of these substances individually. Some testing procedures hydrolyze metabolic products into morphine before the immunoassay, which must be considered when comparing morphine levels in separately published results. Morphine can also be isolated from whole blood samples by solid phase extraction (SPE) and detected using liquid chromatography-mass spectrometry (LC-MS).
Ingestion of codeine or food containing poppy seeds can cause false positives.A 1999 review estimated that relatively low doses of heroin (which metabolizes immediately into morphine) are detectable by standard urine tests for 1–1.5 days after use. A 2009 review determined that, when the analyte is morphine and the limit of detection is 1 ng/ml, a 20 mg intravenous (IV) dose of morphine is detectable for 12–24 hours. A limit of detection of 0.6 ng/ml had similar results.
Chirality and biological activity
Morphine has a highly challenging chemical structure. It is a pentacyclic 3°amine (alkaloid) with 5 stereogenic centers and exists in 32 stereoisomeric forms. But the desired analgesic activity resides exclusively in the natural product, the (-)-enantiomer with the configuration ((5R,6S,9R,13S,14R).
Natural occurrence
Morphine is the most abundant opiate found in opium, the dried latex extracted by shallowly scoring the unripe seedpods of the Papaver somniferum poppy. Morphine is generally 8–14% of the dry weight of opium, although specially bred cultivars reach 26% or produce little morphine at all (under 1%, perhaps down to 0.04%). The latter varieties, including the Przemko and Norman cultivars of the opium poppy, are used to produce two other alkal |
Morphine | oids, thebaine and oripavine, which are used in the manufacture of semi-synthetic and synthetic opioids like oxycodone and etorphine and some other types of drugs. P. bracteatum does not contain morphine or codeine, or other narcotic phenanthrene-type, alkaloids. This species is rather a source of thebaine. Occurrence of morphine in other Papaverales and Papaveraceae, as well as in some species of hops and mulberry trees has not been confirmed. Morphine is produced most predominantly early in the life cycle of the plant. Past the optimum point for extraction, various processes in the plant produce codeine, thebaine, and in some cases negligible amounts of hydromorphone, dihydromorphine, dihydrocodeine, tetrahydro-thebaine, and hydrocodone (these compounds are rather synthesized from thebaine and oripavine).
In the brain of mammals, morphine is detectable in trace steady-state concentrations. The human body also produces endorphins, which are chemically related endogenous opioid peptides that function as neuropeptides and have similar effects to morphine.
Human biosynthesis
Morphine is an endogenous opioid in humans that can be synthesized by and released from various human cells, including white blood cells. CYP2D6, a cytochrome P450 isoenzyme, catalyzes the biosynthesis of morphine from codeine and dopamine from tyramine along the biosynthetic pathway of morphine in humans. The morphine biosynthetic pathway in humans occurs as follows:L-tyrosine → para-tyramine or L-DOPA → dopamine → (S)-norlaudanosoline → (S)-reticuline → 1,2-dehydroretinulinium → (R)-reticuline → salutaridine → salutaridinol → thebaine → neopinone → codeinone → codeine → morphine (S)-Norlaudanosoline (also known as tetrahydropapaveroline) can also be synthesized from 3,4-dihydroxyphenylacetaldehyde (DOPAL), a metabolite of L-DOPA and dopamine. Urinary concentrations of endogenous codeine and morphine have been found to significantly increase in individuals taking L-DOPA for the treatment of Parkinsons disease.
Biosynthesis in the opium poppy
Morphine is biosynthesized in the opium poppy from the tetrahydroisoquinoline reticuline. It is converted into salutaridine, thebaine, and oripavine. The enzymes involved in this process are the salutaridine synthase, salutaridine:NADPH 7-oxidoreductase and the codeinone reductase. Researchers are attempting to reproduce the biosynthetic pathway that produces morphine in genetically engineered yeast. In June 2015 the S-reticuline could be produced from sugar and R-reticuline could be converted to morphine, but the intermediate reaction could not be performed. In August 2015 the first complete synthesis of thebaine and hydrocodone in yeast were reported, but the process would need to be 100,000 times more productive to be suitable for commercial use.
Chemistry
Elements of the morphine structure have been used to create completely synthetic drugs such as the morphinan family (levorphanol, dextromethorphan and others) and other groups that have many members with morphine-like qualities. The modification of morphine and the aforementioned synthetics has also given rise to non-narcotic drugs with other uses such as emetics, stimulants, antitussives, anticholinergics, muscle relaxants, local anaesthetics, general anaesthetics, and others. Morphine-derived agonist–antagonist drugs have also been developed.
Structure description
Morphine is a benzylisoquinoline alkaloid with two additional ring closures. As Jack DeRuiter of the Department of Drug Discovery and Development (formerly, Pharmacal Sciences), Harrison School of Pharmacy, Auburn University stated in his Fall 2000 course notes for that earlier departments "Principles of Drug Action 2" course, "Examination of the morphine molecule reveals the following structural features important to its pharmacological profile...
A rigid pentacyclic structure consisting of a benzene ring (A), two partially unsaturated cyclohexane rings (B and C), a piperidine ring (D) and a tetrahydrofuran ring (E). Rings A, B and C are the phenanthrene ring system. This ring system has little conformational flexibility...
Two hydroxyl functional groups: a C3-phenolic [hydroxyl group] (pKa 9.9) and a C6-allylic [hydroxyl group],
An ether linkage between C4 and C5,
Unsaturation between C7 and C8,
A basic, [tertiary]-amine function at position 17, [and]
[Five] centers of chirality (C5, C6, C9, C13 and C14) with morphine exhibiting a high degree of stereoselectivity of analgesic action."
Morphine and most of its derivatives do not exhibit optical isomerism, although some more distant relatives like the morphinan series (levorphanol, dextorphan and the racemic parent chemical racemorphan) do, and as noted above stereoselectivity in vivo is an important issue.
Uses and derivatives
Most of the licit morphine produced is used to make codeine by methylation. It is also a precursor for many drugs including heroin (3,6-diacetylmorphine), hydromorphone (dihydromorphinone), and oxymorphone (14-hydroxydihydromorphinone). Most semi-synthetic opioids, both of the morphine and codeine subgroups, are created by modifying one or more of the following:
Halogenating or making other modifications at positions 1 or 2 on the morphine carbon skeleton.
The methyl group that makes morphine into codeine can be removed or added back, or replaced with another functional group like ethyl and others to make codeine analogues of morphine-derived drugs and vice versa. Codeine analogues of morphine-based drugs often serve as prodrugs of the stronger drug, as in codeine and morphine, hydrocodone and hydromorphone, oxycodone and oxymorphone, nicocodeine and nicomorphine, dihydrocodeine and dihydromorphine, etc.
Saturating, opening, or other changes to the bond between positions 7 and 8, as well as adding, removing, or modifying functional groups to these positions; saturating, reducing, eliminating, or otherwise modifying the 7–8 bond and attaching a functional group at 14 yields hydromorphinol; the oxidation of the hydroxyl group to a carbonyl and changing the 7–8 bond to single from double changes codeine into oxycodone.
Attachment, removal or modification of functional groups to positions 3 or 6 (dihydrocodeine and related, hydrocodone, nicomorphine); in the case of moving the methyl functional group from position 3 to 6, codeine becomes heterocodeine, which is 72 times stronger, and therefore six times stronger than morphine
Attachment of functional groups or other modification at position 14 (oxymorphone, oxycodone, naloxone)
Modifications at positions 2, 4, 5 or 17, usually along with other changes to the molecule elsewhere on the morphine skeleton. Often this is done with drugs produced by catalytic reduction, hydrogenation, oxidation, or the like, producing strong derivatives of morphine and codeine.Many morphine derivatives can also be manufactured using thebaine or codeine as a starting material. Replacement of the N-methyl group of morphine with an N-phenylethyl group results in a product that is 18 times more powerful than morphine in its opiate agonist potency. Combining this modification with the replacement of the 6-hydroxyl with a 6-methylene group produces a compound some 1,443 times more potent than morphine, stronger than the Bentley compounds such as etorphine (M99, the Immobilon tranquilliser dart) by some measures. Closely related to morphine are the opioids morphine-N-oxide (genomorphine), which is a pharmaceutical that is no longer in common use; and pseudomorphine, an alkaloid that exists in opium, form as degradation products of morphine.As a result of the extensive study and use of this molecule, more than 250 morphine derivatives (also counting codeine and related drugs) have been developed since the last quarter of the 19th century. These drugs range from 25% the analgesic strength of codeine (or slightly more than 2% of the strength of morphine) to several thousand times the strength of morphine, to powerful opioid antagonists, including naloxone (Narcan), naltrexone (Trexan), diprenorphine (M5050, the reversing agent for the Immobilon dart) and nalorphine (Nalline). Some opioid agonist-antagonists, partial agonists, and inverse agonists are also derived from morphine. The receptor-activation profile of the semi-synthetic morphine derivatives varies widely and some, like apomorphine are devoid of narcotic effects.
Salts
Both morphine and its hydrated form are sparingly soluble in water. For this reason, pharmaceutical companies produce sulfate and hydrochloride salts of the drug, both of which are over 300 times more water-soluble than their parent molecule. Whereas the pH of a saturated morphine hydrate solution is 8.5, the salts are acidic. Since they derive from a strong acid but weak base, they are both at about pH = 5; as a consequence, the morphine salts are mixed with small amounts of NaOH to make them suitable for injection.A number of salts of morphine are used, with the most common in current clinical use being the hydrochloride, sulfate, tartrate, and citrate; less commonly methobromide, hydrobromide, hydroiodide, lactate, chloride, and bitartrate and the others listed below. Morphine diacetate (heroin) is not a salt, but rather a further derivative, see above.Morphine meconate is a major form of the alkaloid in the poppy, as is morphine pectinate, nitrate, sulfate, and some others. Like codeine, dihydrocodeine and other (especially older) opiates, morphine has been used as the salicylate salt by some suppliers and can be easily compounded, imparting the therapeutic advantage of both the opioid and the NSAID; multiple barbiturate salts of morphine were also used in the past, as was/is morphine valerate, the salt of the acid being the active principle of valerian. Calcium morphenate is the intermediate in various latex and poppy-straw methods of morphine production, more rarely sodium morphenate takes its place. Morphine ascorbate and other salts such as the tannate, citrate, and acetate, phosphate, valerate and others may be present in poppy tea depending on the method of preparation.The salts listed by the United States Drug Enforcement Administration for reporting purposes, in addition to a few others, are as follows:
Production
In the opium poppy, the alkaloids are bound to meconic acid. The method is to extract from the crushed plant with diluted sulfuric acid, which is a stronger acid than meconic acid, but not so strong to react with alkaloid molecules. The extraction is performed in many steps (one amount of crushed plant is extracted at least six to ten times, so practically every alkaloid goes into the solution). From the solution obtained at the last extraction step, the alkaloids are precipitated by either ammonium hydroxide or sodium carbonate. The last step is purifying and separating morphine from other opium alkaloids. The somewhat similar Gregory process was developed in the United Kingdom during the Second World War, which begins with stewing the entire plant, in most cases save the roots and leaves, in plain or mildly acidified water, then proceeding through steps of concentration, extraction, and purification of alkaloids. Other methods of processing "poppy straw" (i.e., dried pods and stalks) use steam, one or more of several types of alcohol, or other organic solvents.
The poppy straw methods predominate in Continental Europe and the British Commonwealth, with the latex method in most common use in India. The latex method can involve either vertical or horizontal slicing of the unripe pods with a two-to five-bladed knife with a guard developed specifically for this purpose to the depth of a fraction of a millimetre and scoring of the pods can be done up to five times. An alternative latex method sometimes used in China in the past is to cut off the poppy heads, run a large needle through them, and collect the dried latex 24 to 48 hours later.In India, opium harvested by licensed poppy farmers is dehydrated to uniform levels of hydration at government processing centers, and then sold to pharmaceutical companies that extract morphine from the opium. However, in Turkey and Tasmania, morphine is obtained by harvesting and processing the fully mature dry seed pods with attached stalks, called poppy straw. In Turkey, a water extraction process is used, while in Tasmania, a solvent extraction process is used.Opium poppy contains at least 50 different alkaloids, but most of them are of very low concentration. Morphine is the principal alkaloid in raw opium and constitutes roughly 8–19% of opium by dry weight (depending on growing conditions). Some purpose-developed strains of poppy now produce opium that is up to 26% morphine by weight. A rough rule of thumb to determine the morphine content of pulverised dried poppy straw is to divide the percentage expected for the strain or crop via the latex method by eight or an empirically determined factor, which is often in the range of 5 to 15. The Norman strain of P. Somniferum, also developed in Tasmania, produces down to 0.04% morphine but with much higher amounts of thebaine and oripavine, which can be used to synthesise semi-synthetic opioids as well as other drugs like stimulants, emetics, opioid antagonists, anticholinergics, and smooth-muscle agents.In the 1950s and 1960s, Hungary supplied nearly 60% of Europes total medication-purpose morphine production. To this day, poppy farming is legal in Hungary, but poppy farms are limited by law to 2 acres (8,100 m2). It is also legal to sell dried poppy in flower shops for use in floral arrangements.
It was announced in 1973 that a team at the National Institutes of Health in the United States had developed a method for total synthesis of morphine, codeine, and thebaine using coal tar as a starting material. A shortage in codeine-hydrocodone class cough suppressants (all of which can be made from morphine in one or more steps, as well as from codeine or thebaine) was the initial reason for the research.
Most morphine produced for pharmaceutical use around the world is actually converted into codeine as the concentration of the latter in both raw opium and poppy straw is much lower than that of morphine; in most countries, the usage of codeine (both as end-product and precursor) is at least equal or greater than that of morphine on a weight basis.
Chemical synthesis
The first morphine total synthesis, devised by Marshall D. Gates, Jr. in 1952, remains a widely used example of total synthesis. Several other syntheses were reported, notably by the research groups of Rice, Evans, Fuchs, Parker, Overman, Mulzer-Trauner, White, Taber, Trost, Fukuyama, Guillou, and Stork. Because of the stereochemical complexity and consequent synthetic challenge presented by this polycyclic structure, Michael Freemantle has expressed the view that it is "highly unlikely" that a chemical synthesis will ever be cost-effective such that it could compete with the cost of producing morphine from the opium poppy.
Precursor to other opioids
Pharmaceutical
Morphine is a precursor in the manufacture in a number of opioids such as dihydromorphine, hydromorphone, hydrocodone, and oxycodone as well as codeine, which itself has a large family of semi-synthetic derivatives.
Illicit
Illicit morphine is produced, though rarely, from codeine found in over-the-counter cough and pain medicines. Another illicit source is morphine extracted from extended-release morphine products. Chemical reactions can then be used to convert morphine, dihydromorphine, and hydrocodone into heroin or other opioids [e.g., diacetyldihydromorphine (Paralaudin), and thebacon]. Other clandestine conversions—of morphine, into ketones of the hydromorphone class, or other derivatives like dihydromorphine (Paramorfan), desomorphine (Permonid), metopon, etc., and of codeine into hydrocodone (Dicodid), dihydrocodeine (Paracodin), etc. —require greater expertise, and types and quantities of chemicals and equipment that are more difficult to source, and so are more rarely used, illicitly (but cases have been recorded).
History
An opium-based elixir has been ascribed to alchemists of Byzantine times, but the specific formula was lost during the Ottoman conquest of Constantinople (Istanbul). Around 1522, Paracelsus made reference to an opium-based elixir that he called laudanum from the Latin word laudāre, meaning "to praise" He described it as a potent painkiller, but recommended that it be used sparingly. The recipe given differs substantially from that of modern-day laudanum.Morphine was discovered as the first active alkaloid extracted from the opium poppy plant in December 1804 in Paderborn by German pharmacist Friedrich Sertürner. In 1817, Sertürner reported experiments in which he administered morphine to himself, three young boys, three dogs, and a mouse; all four people almost died. Sertürner originally named the substance morphium after the Greek god of dreams, Morpheus, as it has a tendency to cause sleep. Sertürners morphium was six times stronger than opium. He hypothesized that, because lower doses of the drug were needed, it would be less addictive. However Sertürner became addicted to the drug, warning that "I consider it my duty to attract attention to the terrible effects of this new substance I called morphium in order that calamity may be averted."The drug was first marketed to the general public by Sertürner and Company in 1817 as a pain medication, and also as a treatment for opium and alcohol addiction. It was first used as a poison in 1822 when Dr. Edme Castaing of France was convicted of murdering a patient. Commercial production began in Darmstadt, Germany, in 1827 by the pharmacy that became the pharmaceutical company Merck, with morphine sales being a large part of their early growth. In the 1850s, Alexander Wood reported that he had injected morphine into his wife Rebecca as an experiment; the myth goes that this killed her because of respiratory depression, but she outlived her husband by ten years.Later it was found that morphine was more addictive than either alcohol or opium, and its extensive use during the American Civil War allegedly resulted in over 400,000 people with the "soldiers disease" of morphine addiction. This idea has been a subject of controversy, as there have been suggestions that such a disease was in fact a fabrication; the first documented use of the phrase "soldiers disease" was in 1915.Diacetylmorphine (better known as heroin) was synthesized from morphine in 1874 and brought to market by Bayer in 1898. Heroin is approximately 1.5 to 2 times more potent than morphine weight for weight. Due to the lipid solubility of diacetylmorphine, it can cross the blood–brain barrier faster than morphine, subsequently increasing the reinforcing component of addiction. Using a variety of subjective and objective measures, one study estimated the relative potency of heroin to morphine administered intravenously to post-addicts to be 1.80–2.66 mg of morphine sulfate to 1 mg of diamorphine hydrochloride (heroin).
Morphine became a controlled substance in the US under the Harrison Narcotics Tax Act of 1914, and possession without a prescription in the US is a criminal offense.
Morphine was the most commonly abused narcotic analgesic in the world until heroin was synthesized and came into use. In general, until the synthesis of dihydromorphine (c. 1900), the dihydromorphinone class of opioids (1920s), and oxycodone (1916) and similar drugs, there were no other drugs in the same efficacy range as opium, morphine, and heroin, with synthetics still several years away (pethidine was invented in Germany in 1937) and opioid agonists among the semi-synthetics were analogues and derivatives of codeine such as dihydrocodeine (Paracodin), ethylmorphine (Dionine), and benzylmorphine (Peronine). Even today, morphine is the most sought after prescription narcotic by heroin addicts when heroin is scarce, all other things being equal; local conditions and user preference may cause hydromorphone, oxymorphone, high-dose oxycodone, or methadone as well as dextromoramide in specific instances such as 1970s Australia, to top that particular list. The stop-gap drugs used by the largest absolute number of heroin addicts is probably codeine, with significant use also of dihydrocodeine, poppy straw derivatives like poppy pod and poppy seed tea, propoxyphene, and tramadol.
The structural formula of morphine was determined by 1925 by Robert Robinson. At least three methods of total synthesis of morphine from starting materials such as coal tar and petroleum distillates have been patented, the first of which was announced in 1952, by Dr. Marshall D. Gates, Jr. at the University of Rochester. Still, the vast majority of morphine is derived from the opium poppy by either the traditional method of gathering latex from the scored, unripe pods of the poppy, or processes using poppy straw, the dried pods and stems of the plant, the most widespread of which was invented in Hungary in 1925 and announced in 1930 by Hungarian pharmacologist János Kabay.In 2003, there was discovery of endogenous morphine occurring naturally in the human body. Thirty years of speculation were made on this subject because there was a receptor that, it appeared, reacted only to morphine: the μ3-opioid receptor in human tissue. Human cells that form in reaction to cancerous neuroblastoma cells have been found to contain trace amounts of endogenous morphine.
Society and culture
Legal status
In Australia, morphine is classified as a Schedule 8 drug under the variously titled State and Territory Poisons Acts.
In Canada, morphine is classified as a Schedule I drug under the Controlled Drugs and Substances Act.
In France, morphine is in the strictest schedule of controlled substances, based upon the December 1970 French controlled substances law.
In Germany, morphine is a verkehrsfähiges und verschreibungsfähiges Betäubungsmittel listed under Anlage III (the equivalent of CSA Schedule II) of the Betäubungsmittelgesetz.
In Switzerland, morphine is scheduled similarly to Germanys legal classification of the drug.
In Japan, morphine is classified as a narcotic under the Narcotics and Psychotropics Control Act (麻薬及び向精神薬取締法, mayaku oyobi kōseishinyaku torishimarihō).
In the Netherlands, morphine is classified as a List 1 drug under the Opium Law.
In New Zealand, morphine is classified as a Class B drug under the Misuse of Drugs Act 1975.
In the United Kingdom, morphine is listed as a Class A drug under the Misuse of Drugs Act 1971 and a Schedule 2 Controlled Drug under the Misuse of Drugs Regulations 2001.
In the United States, morphine is classified as a Schedule II controlled substance under the Controlled Substances Act under main Administrative Controlled Substances Code Number 9300. Morphine pharmaceuticals are subject to annual manufacturing quotas; in 2017 these quotas were 35.0 tonnes of production for sale, and 27.3 tonnes of production as an intermediate, or chemical precursor, for conversion into other drugs. Morphine produced for use in extremely dilute formulations is excluded from the manufacturing quota.
Internationally (UN), morphine is a Schedule I drug under the Single Convention on Narcotic Drugs.
Non-medical use
The euphoria, comprehensive alleviation of distress and therefore all aspects of suffering, promotion of sociability and empathy, "body high", and anxiolysis provided by narcotic drugs including the opioids can cause the use of high doses in the absence of pain for a protracted period, which can impart a morbid craving for the drug in the user. As the prototype of the entire opioid class of drugs, morphine has properties that may lead to its misuse. Morphine addiction is the model upon which the current perception of addiction is based.Animal and human studies and clinical experience back up the contention that morphine is one of the most euphoric drugs known, and via all but the IV route heroin and morphine cannot be distinguished according to studies because heroin is a prodrug for the delivery of systemic morphine. Chemical changes to the morphine molecule yield other euphorigenics such as dihydromorphine, hydromorphone (Dilaudid, Hydal), and oxymorphone (Numorphan, Opana), as well as the latter threes methylated equivalents dihydrocodeine, hydrocodone, and oxycodone, respectively; in addition to heroin, there are dipropanoylmorphine, diacetyldihydromorphine, and other members of the 3,6 morphine diester category like nicomorphine and other similar semi-synthetic opiates like desomorphine, hydromorphinol, etc. used clinically in many countries of the world but also produced illicitly in rare instances.In general, non-medical use of morphine entails taking more than prescribed or outside of medical supervision, injecting oral formulations, mixing it with unapproved potentiators such as alcohol, cocaine, and the like, or defeating the extended-release mechanism by chewing the tablets or turning into a powder for snorting or preparing injectables. The latter method can be as time-consuming and involved as traditional methods of smoking opium. This and the fact that the liver destroys a large percentage of the drug on the first pass impacts the demand side of the equation for clandestine re-sellers, as many customers are not needle users and may have been disappointed with ingesting the drug orally. As morphine is generally as hard or harder to divert than oxycodone in a lot of cases, morphine in any form is uncommon on the street, although ampoules and phials of morphine injection, pure pharmaceutical morphine powder, and soluble multi-purpose tablets are very popular where available.Morphine is also available in a paste that is used in the production of heroin, which can be smoked by itself or turned |
Morphine | to a soluble salt and injected; the same goes for the penultimate products of the Kompot (Polish Heroin) and black tar processes. Poppy straw as well as opium can yield morphine of purity levels ranging from poppy tea to near-pharmaceutical-grade morphine by itself or with all of the more than 50 other alkaloids. It also is the active narcotic ingredient in opium and all of its forms, derivatives, and analogues as well as forming from breakdown of heroin and otherwise present in many batches of illicit heroin as the result of incomplete acetylation.
Names
Morphine is marketed under many different brand names in various parts of the world. It was formerly called Morphia in British English.Informal names for morphine include: Cube Juice, Dope, Dreamer, Emsel, First Line, Gods Drug, Hard Stuff, Hocus, Hows, Lydia, Lydic, M, Miss Emma, Mister Blue, Monkey, Morf, Morph, Morphide, Morphie, Morpho, Mother, MS, Ms. Emma, Mud, New Jack Swing (if mixed with heroin), Sister, Tab, Unkie, Unkie White, and Stuff.MS Contin tablets are known as misties, and the 100 mg extended-release tablets as greys and blockbusters. The "speedball" can use morphine as the opioid component, which is combined with cocaine, amphetamines, methylphenidate, or similar drugs. "Blue Velvet" is a combination of morphine with the antihistamine tripelennamine (Pyrabenzamine, PBZ, Pelamine) taken by injection, or less commonly the mixture when swallowed or used as a retention enema; the name is also known to refer to a combination of tripelennamine and dihydrocodeine or codeine tablets or syrups taken by mouth. "Morphia" is an older official term for morphine also used as a slang term. "Driving Miss Emma" is intravenous administration of morphine. Multi-purpose tablets (readily soluble hypodermic tablets that can also be swallowed or dissolved under the tongue or betwixt the cheek and jaw) are known, as are some brands of hydromorphone, as Shake & Bake or Shake & Shoot.
Morphine can be smoked, especially diacetylmorphine (heroin), the most common method being the "Chasing The Dragon" method. To perform acetylation to turn the morphine into heroin and related drugs immediately prior to use is known as AAing (for Acetic Anhydride) or home-bake, and the output of the procedure also known as home-bake or, Blue Heroin (not to be confused with Blue Magic heroin, or the linctus known as Blue Morphine or Blue Morphone, or the Blue Velvet mixture described above).
Access in developing countries
Although morphine is cheap, people in poorer countries often do not have access to it. According to a 2005 estimate by the International Narcotics Control Board, six countries (Australia, Canada, France, Germany, the United Kingdom, and the United States) consume 79% of the worlds morphine. The less affluent countries, accounting for 80% of the worlds population, consumed only about 6% of the global morphine supply. Some countries import virtually no morphine, and in others the drug is rarely available even for relieving severe pain while dying.Experts in pain management attribute the under-distribution of morphine to an unwarranted fear of the drugs potential for addiction and abuse. While morphine is clearly addictive, Western doctors believe it is worthwhile to use the drug and then wean the patient off when the treatment is over.
References
External links
"Morphine". Drug Information Portal. U.S. National Library of Medicine.
Morphine and Heroin at The Periodic Table of Videos (University of Nottingham)
Video: Intravenous morphine loading (Vimeo) (YouTube) – A short education video teaching health professionals the main points about intravenous loading of analgesics, in particular morphine. |
Palifermin | Palifermin (trade name Kepivance, marketed by Biovitrum) is a truncated human recombinant keratinocyte growth factor (KGF) produced in Escherichia coli. KGF stimulates the growth of cells that line the surface of the mouth and intestinal tract.
Therapeutic use(s)
When patients with blood cancers (leukemia and lymphoma) receive high dose chemotherapy and radiation therapy to undergo bone marrow transplantation, they usually get severe oral mucositis.
Palifermin reduces the incidence and duration of severe oral mucositis by protecting those cells and stimulating the growth of new epithelial cells to build up the mucosal barrier.
Palifermin is also being studied in the prevention and treatment of oral mucositis and dysphagia (difficulty swallowing) in other types of cancer.
Drug target and mechanism of action
Keratinocyte growth factor (KGF) resides in the family of fibroblast growth factor (FGF). The drugs target is the KGF receptor. Through the binding of this drug to the aforementioned receptor, Palifermin stimulates epithelial cell proliferation, differentiation, and upregulation of cytoprotective mechanisms to reduce the symptoms of oral mucositis.
Side effects
Common side effects often seen in conjunction with the use of Palifermin include, but are not limited to:
Some of the more serious side effects can be seen below:
Administration
Palifermin is administered via intravenous bolus injection. The drug comes as a lyophilized powder that must be reconstituted with sterile water for injection before it may be administered. It is given for three days before, and three days after chemotherapy is undergone. However, it is important that the drug is not administered within 24 hours of the actual chemotherapy process. This drug is most commonly dosed in a hospital setting, but can be taken at home as per specific instructions regarding preparation and storage from a doctor. The recommended dosage consists of 60 μg/kg/day.
Drug interactions
Co-administration of Palifermin with Heparin should be avoided. Drug interactions with Heparin include a significantly increased systemic exposure to Palifermin. Avoid administration of Palifermin within 24 hours of myelotoxic chemotherapy, as this could result in increased oral mucositis.
Pre-clinical trials
Toxicology studies
Toxicology studies were conducted by use of animal models, utilizing a variety of species, including mice, rats, and monkeys. Singles doses in rats and monkeys were given up to 30,000 and 50,000 micrograms/kg, respectively. Daily doses of 1,000 and 300 micrograms/kg, respectively, were given to rats and monkeys for 28 consecutive days. Toxic effects noted included exaggerated pharmacological effects of the drug, such as hyperkeratosis of skin and tongue and goblet cell hyperplasia in the GI tract. It was noted that the rats were more sensitive to these effects than the monkeys. Induced genetic abnormality assays including microchromosome reverse mutation and E. coli mutagenicity assays were completed using mice. There were no genotoxic effects noted from this study.
Clinical trials
Phase I
Study 950170: The first in human study included administration via the subcutaneous route. This study was ended early due to the large number of adverse reactions observed around/in the injection site.
Study 960136: (Dose-escalation). Intended to determine safety and tolerability, biologic activity, and pharmacokinetic profile in 61 healthy volunteers. The study included a single dose as well as a combination of 3 daily doses (ranging from 0.2 to 20 micrograms/kg) given consecutively. It was determined that single doses did not result in noteworthy production of epithelial cells.
Study 970136 (Randomized, double-blind, placebo-controlled, dose-escalation). Intended to determine the safety and tolerability, and pharmacokinetics of a single dose, administered intravenously (ranging from 5–20 micrograms/kg) in 24 healthy volunteers. It was found that systematic exposure was proportional to the administered dose. Extravascular distribution of the drug was noted.
Study 970290 (Open-label). Intended to evaluate pharmacokinetic properties intersubject variability of the drug in four, healthy male volunteers. It was determined that a high intersubject variability was not the cause of dosing errors in previous studies.
Study 970276 (Dose-escalation). Intended to determine the safety and tolerability, pharmacokinetic and pharmacodynamics properties of the drug versus a placebo in 18 healthy volunteers. The study consisted of daily IV doses in three consecutive days (20 or 40 micrograms/kg). It was determined that subjects that received three daily doses of 40 micrograms/kg demonstrated adequate production of epithelial cells in the buccal mucosa. Predicted elevation in amylase and lipase were also determined.
Study 20010192 (Randomized, double-blind, placebo-controlled, dose-escalation). Intended to determine safety and tolerability, pharmacokinetic and pharmacodynamics properties of the drug versus a placebo by utilization of a single IV dose (ranging from 60 to 250 micrograms/kg) in 84 healthy volunteers. It was determined that after the first 30 minutes (after IV dose was administered) a rapid decline in concentration occurred, followed by a subsequent plateau once 1.5 hours had been achieved. A decline in concentration was consistently observed once 6 hours post-dose had been reached. It was also noted that with a 4X increase in dose, a 3X increase in AUC was achieved. Half-life values of 4–6 hours were noted; extravascular distribution of the drug was noted as well.
Phase II
Study 980231 (Randomized, double-blind, placebo-controlled). Three dose regimens were included: "pre-post", "pre", and placebo Palifermin administration (60 micrograms/kg) by IV for three consecutive days before chemotherapy and after autologous peripheral blood progenitor cell (PBPC). Efficacy was demonstrated in the drug versus the placebo.
Phase III
Study 2000162 (Randomized, double-blind, placebo-controlled). Intended to evaluate Palifermin efficacy in reducing oral mucositis in subjects with hematologic malignancy undergoing chemotherapy with autologous peripheral blood progenitor cell transplantation. Patients were administered with 3 daily, consecutive IV doses (or placebo) of Palifermin (60 micrograms/kg) before chemotherapy and Filgrastim (60 micrograms/kg) was administered after transplantation for three days consecutively. Efficacy was demonstrated in the drug versus the placebo.
Costs
Palifermin costs approximately 5,000 euros per treatment for a 70 kg patient.
Annual sales
The worldwide profits for years the 2008–2011 are provided below.
2008: $5.7 million
2009: $109.9 million
2010: $94.8 million
2011: $77.9 million
References
This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute.
External links
Kepivance homepage |
Halog | Halog may refer to:
Halog (city), the capital of the former Princely State of Dhami in India
a tradename for Halcinonide
Two islands in the Quiniluban Group in Palawan Province, Philippines
See also
Halogen (disambiguation) |
Glycopyrronium bromide | Glycopyrronium bromide is a medication of the muscarinic anticholinergic group. It does not cross the blood–brain barrier and consequently has few to no central effects. It is available in oral, intravenous, topical, and inhaled forms. It is a synthetic quaternary ammonium compound.The cation, which is the active moiety, is called glycopyrronium (INN) or glycopyrrolate (USAN).
In June 2018, glycopyrronium was approved by the US Food and Drug Administration (FDA) to treat excessive underarm sweating, becoming the first drug developed specifically to reduce excessive sweating. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Glycopyrronium was first used in 1961 to treat peptic ulcers. Since 1975, intravenous glycopyrronium has been used before surgery to reduce salivary, tracheobronchial, and pharyngeal secretions. It is also used in conjunction with neostigmine, a neuromuscular blocking reversal agent, to prevent neostigmines muscarinic effects such as bradycardia. It can be administered to raise the heart rate in bradycardia, which often will also increase the blood pressure.
It is also used to reduce excessive saliva (sialorrhea), and Ménières disease.It has been used topically and orally to treat hyperhidrosis, in particular, gustatory hyperhidrosis.In inhalable form it is used to treat chronic obstructive pulmonary disease (COPD). Doses for inhalation are much lower than oral ones, so that swallowing a dose will not have an effect.In end-of-life care, this medication will often be administered to patients that become encumbered by their bronchial secretions and are no longer able to clear their own airway through insufficient coughing reflex.
Side effects
Dry mouth, urinary retention, headaches, vomiting, diarrhea, constipation, blurry vision are possible side effects of the medication. Since glycopyrronium reduces the bodys sweating ability, it can even cause hyperthermia and heat stroke in hot environments. The medication also induces drowsiness, an effect exacerbated by the consumption of alcohol.
Pharmacology
Mechanism of action
Glycopyrronium competitively blocks muscarinic receptors, thus inhibiting cholinergic transmission.
Pharmacokinetics
Glycopyrronium bromide affects the gastrointestinal tracts, liver and kidney but has a very limited effect on the brain and the central nervous system. In horse studies, after a single intravenous infusion, the observed tendencies of glycopyrronium followed a tri-exponential equation, by rapid disappearance from the blood followed by a prolonged terminal phase. Excretion was mainly in urine and in the form of an unchanged drug. Glycopyrronium has a relatively slow diffusion rate, and in a standard comparison to atropine, is more resistant to penetration through the blood-brain barrier and placenta.
Research
It has been studied in asthma.
References
External links
"Glycopyrronium bromide". Drug Information Portal. U.S. National Library of Medicine.
"Glycopyrronium". Drug Information Portal. U.S. National Library of Medicine. |
Tinidazole | Tinidazole is a drug used against protozoan infections. It is widely known throughout Europe and the developing world as a treatment for a variety of anaerobic amoebic and bacterial infections. It was developed in 1972 and is a prominent member of the nitroimidazole antibiotic class.It is on the World Health Organizations List of Essential Medicines.Tinidazole is marketed by Mission Pharmacal under the brand name Tindamax, by Pfizer under the names Fasigyn and Simplotan, and in some Asian countries as Sporinex.
Uses
Tinidazole may be a therapeutic alternative in the setting of metronidazole intolerance. Tinidazole is used to treat Helicobacter pylori, Amoebic dysentery, Giardia and Trichomonas vaginalis.
Side effects
Drinking alcohol while taking tinidazole causes an unpleasant disulfiram-like reaction, which includes nausea, vomiting, headache, increased blood pressure, flushing, and shortness of breath.
Half-life
Elimination half-life is 13.2 ± 1.4 hours. Plasma half-life is 12 to 14 hours.
References
External links
MedlinePlus Drug Information: Tinidazole
Drug Bank Facts on Tinidazole |
Aprepitant | Aprepitant, sold under the brand name Emend among others, is a medication used to prevent chemotherapy-induced nausea and vomiting (CINV) and to prevent postoperative nausea and vomiting (PONV). It may be used together with ondansetron and dexamethasone. It is taken by mouth or administered by intravenous injection.Common side effects include tiredness, loss of appetite, diarrhea, abdominal pain, hiccups, itchiness, pneumonia, and blood pressure changes. Other severe side effects may include anaphylaxis. While use in pregnancy does not appear to be harmful, such use has not been well studied. Aprepitant belongs to the class of neurokinin-1 receptor antagonists medications. It works by blocking substance P from attaching to the NK1 receptors.Aprepitant was approved for medical use in the European Union and the United States in 2003. It is made by Merck & Co. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Aprepitant is used to prevent chemotherapy-induced nausea and vomiting (CINV) and to prevent postoperative nausea and vomiting (PONV). It may be used together with ondansetron and dexamethasone.
Mechanism of action
Aprepitant is classified as an NK1 antagonist because it blocks signals given off by NK1 receptors. This, therefore, decreases the likelihood of vomiting in patients.
NK1 is a G protein-coupled receptor located in the central and peripheral nervous system. This receptor has a dominant ligand known as Substance P (SP). SP is a neuropeptide, composed of 11 amino acids, which sends impulses and messages from the brain. It is found in high concentrations in the vomiting center of the brain, and, when activated, it results in a vomiting reflex. In addition to this it also plays a key part in the transmission of pain impulses from the peripheral receptors to the central nervous system.
Aprepitant has been shown to inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutic drugs by blocking substance P landing on receptors in the brains neurons. Positron emission tomography (PET) studies, have demonstrated that aprepitant can cross the blood brain barrier and bind to NK1 receptors in the human brain. It has also been shown to increase the activity of the 5-HT3 receptor antagonists ondansetron and the corticosteroid dexamethasone, which are also used to prevent nausea and vomiting caused by chemotherapy.Before clinical testing, a new class of therapeutic agent has to be characterized in terms of preclinical metabolism and excretion studies. Average bioavailability is found to be around 60-65%. Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma. As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of co-administered medicinal products that are metabolized through CYP3A4. Specific interaction has been demonstrated with oxycodone, where aprepitant both increased the efficacy and worsened the side effects of oxycodone; however it is unclear whether this is due to CPY3A4 inhibition or through its NK-1 antagonist action. Following IV administration of a 14C-labeled prodrug of aprepitant (L-758298), which is converted rapidly and completely to aprepitant, approximately 57% of the total radioactivity is excreted in the urine and 45% in feces. No unchanged substance is excreted in urine.
Structure and properties
Aprepitant is made up of a morpholine core with two substituents attached to adjacent ring carbons. These substitute groups are trifluoromethylated 1-phenylethanol and fluorophenyl group. Aprepitant also has a third substituent (triazolinone), which is joined to the morpholine ring nitrogen. It has three chiral centres very close together, which combine to produce an amino acetal arrangement. Its empirical formula is C23H21F7N4O3.
Synthesis
Shortly after Merck initiated research into reducing the severity and likelihood of CINV, researchers discovered that aprepitant is effective in prevention. Researchers worked on coming up with a process to create aprepitant, and within a short period they came up with effective synthesis of the substance. This original synthesis was deemed to be workable and proved to be a crucial step in achieving commercialization; however, Merck decided that the process was not environmentally sustainable. This was due to the original synthesis requiring six steps, many of which needed dangerous chemicals such as sodium cyanide, dimethyltitanocene, and gaseous ammonia. In addition to this, for the process to be effective cryogenic temperatures were needed for some of the steps and other steps produced hazardous byproducts such as methane. The environmental concerns of the synthesis of aprepitant became so great that Merck research team decided to withdraw the drug from clinical trials and attempt to create a different synthesis of aprepitant.The gamble of taking the drug out of clinical trials proved to be successful when shortly afterwards the team of Merck researchers came up with an alternative and more environmentally friendly synthesis of aprepitant. The new process works by four compounds of similar size and complexity being fused together. This therefore is a much simpler process and requires only three steps, half the number of the original synthesis.
The new process begins by enantiopure trifluoromethylated phenyl ethanol being joined to a racemic morpholine precursor. This results in the wanted isomer crystallizing on the top of the solution and the unwanted isomer remaining in the solution. The unwanted isomer is then converted to the wanted one by the chemist controlling the reaction conditions and a process known as crystallization-induced asymmetric transformation occurring. By the end of this step a secondary amine, the base of the drug, is formed.
The second step involves the fluorophenyl group being attached to the morpholine ring. Once this has been achieved the third and final step can initiated. This step involved a side chain of triazolinone being added to the ring. Once this step has been successfully completed a stable molecule of aprepitant has been produced.This more streamlined route yields around 76% more aprepitant than the original process and reduces the operating cost by a significant amount. In addition, the new process also reduces the amount of solvent and reagents required by about 80% and saving an estimated 340,000L per ton of aprepitant produced.The improvements in the synthesis process have also decreased the long-term detriment to the natural environment associated with the original procedure, due to eliminating the use of several hazardous chemicals.
History
It was approved by the US Food and Drug Administration (FDA) in 2003. In 2008, fosaprepitant, an intravenous form of aprepitant was approved in the United States.
Research
Major depression
Plans to develop aprepitant as an antidepressant have been withdrawn. Subsequently, other trials with NK1 receptor antagonists, casopitant and orvepitant, have shown promising results.Beyond suggestions that PET receptor occupancy must not be used routinely to cap dosing for new medical indications for this class, or that > 99% human receptor occupancy might be required for consistent psycho-pharmacological or other therapeutic effects, critical scientific dissection and debate of the above data might be needed to enable aprepitant, and the class of NK1 antagonists as a whole, to fulfill preclinically predicted utilities beyond CINV (i.e., for other psychiatric disorders, addictions, neuropathic pain, migraine, osteoarthritis, overactive bladder, inflammatory bowel disease and other disorders with suspected inflammatory or immunological components. However, most data remain proprietary and thus reviews on the expanded clinical potential for drugs like aprepitant range from optimistic to poor.
References
External links
"Aprepitant". Drug Information Portal. U.S. National Library of Medicine. |
Dapagliflozin/saxagliptin | Dapagliflozin/saxagliptin, sold under the brand name Qtern, is a fixed-dose combination anti-diabetic medication used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. It is a combination of dapagliflozin and saxagliptin. It is taken by mouth.The most common side effects include upper respiratory tract infection (such as nose and throat infections) and, when used with a sulphonylurea, hypoglycaemia (low blood glucose levels).Dapagliflozin/saxagliptin was approved for medical use in the European Union in July 2016, and in the United States in February 2017.
Medical uses
In the United States dapagliflozin/saxagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.In the European Union it is indicated in adults aged 18 years and older with type 2 diabetes mellitus:
to improve glycemic control when metformin with or without sulphonylurea (SU) and either saxagliptin or dapagliflozin does not provide adequate glycemic control.
when already being treated with saxagliptin and dapagliflozin.
References
External links
"Dapagliflozin propanediol". Drug Information Portal. U.S. National Library of Medicine.
"Saxagliptin". Drug Information Portal. U.S. National Library of Medicine.
"Dapagliflozin". MedlinePlus.
"Saxagliptin". MedlinePlus. |
Melphalan | Melphalan, sold under the brand name Alkeran among others, is a chemotherapy medication used to treat multiple myeloma, ovarian cancer, melanoma, and AL amyloidosis. It is taken by mouth or by injection into a vein.Common side effects include nausea and bone marrow suppression. Other severe side effects may include anaphylaxis and the development of other cancers. Use during pregnancy may result in harm to the fetus. Melphalan belongs to the class of nitrogen mustard alkylating agents. It works by interfering with the creation of DNA and RNA.Melphalan 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.
Medical uses
It is used to treat multiple myeloma, ovarian cancer, AL amyloidosis, and occasionally malignant melanoma.
The agent was first investigated as a possible drug for use in melanoma, it was not found to be effective.In 2016, it was approved in the U.S. for:
use as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in multiple myeloma (MM) patients
the palliative treatment of MM patients for whom oral therapy is not appropriateMelphalan is used to treat ocular retinoblastoma, a pediatric solid tumor. This is accomplished via transarterial catheter based slow pulsed infusion into the ophthalmic artery.
Side effects
Common side effects include:
Nausea
Bone marrow suppression, including
Decreased white blood cell count causing increased risk of infection
Decreased platelet count causing increased risk of bleedingLess common side effects include:
Severe allergic reactions
Pulmonary fibrosis (scarring of lung tissue) including fatal outcomes (usually only with prolonged use)
Hair loss
Interstitial pneumonitis
Rash
Itching
Irreversible bone marrow failure due to melphalan not being withdrawn early enough
Cardiac arrest
Mechanism of action
Melphalan chemically alters the DNA nucleotide guanine through alkylation, and causes linkages between strands of DNA. This chemical alteration inhibits DNA synthesis and RNA synthesis, functions necessary for cells to survive. These changes cause cytotoxicity in both dividing and non-dividing tumor cells. Tumor cells spend less time in resting phases than normal cells so at any given time, they are more likely to be metabolically active than most normal host cells. The rationale behind incorporating an alkylating function in a molecule resembling a primary cellular metabolite was to get a greater safety margin by fooling tumor cells into taking up the toxin preferentially.
Synthesis
4-Nitro-L-phenylalanine (1) was converted to its phthalimide by heating with phthalic anhydride, and this was converted to its ethyl ester (2). Catalytic hydrogenation produced the corresponding aniline. Heating in acid with oxirane, followed by treatment with phosphorus oxychloride provided the bischloride, and removal of the protecting groups by heating in hydrochloric acid gave melphalan (3).
Society and culture
Legal status
On 17 September 2020, 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 melphalan. The applicant for this medicinal product is ADIENNE S.r.l. S.U. Melphalan was approved for medical use in the European Union in November 2020.
References
External links
"Melphalan". Drug Information Portal. U.S. National Library of Medicine. |
Zonisamide | Zonisamide, sold under the brand name Zonegran among others, is a medication used to treat the symptoms of epilepsy and Parkinsons disease. Chemically it is a sulfonamide. It serves as an anticonvulsant used primarily as an adjunctive therapy in adults with Parkinsons disease, partial-onset seizures; infantile spasm, mixed seizure types of Lennox–Gastaut syndrome, myoclonic and generalized tonic clonic seizure. Despite this it is also sometimes used as a monotherapy for partial-onset seizures.
Medical uses
Epilepsy
Zonisamide is approved in the United States, and United Kingdom for adjunctive treatment of partial seizures in adults and Japan for both adjunctive and monotherapy for partial seizures (simple, complex, secondarily generalized), generalized (tonic, tonic-clonic (grand mal), and atypical absence) and combined seizures. In Australia it is marketed as both an adjunctive therapy and monotherapy for partial seizures only.
Parkinsons disease
It has been approved for the treatment of the motor symptoms of Parkinsons disease (PD), as an adjunct to levodopa, in a few countries such as Japan. In Japan, zonisamide has been used as an adjunct to levodopa treatment since 2009. In addition, there is clinical evidence that zonisamide in combination with levodopa control of motor symptoms of PD but evidence for the treatment of the non motor symptoms of PD lacking.
Adverse effects
Adverse effects by incidence:Very common (>10% incidence) adverse effects include:
Common (1-10% incidence) adverse effects include:
Interactions
Zonisamide and other carbonic anhydrase inhibitors such as topiramate, furosemide, and hydrochlorothiazide have been known to interfere with amobarbital, which has led to inadequate anesthetization during the Wada test. Zonisamide may also interact with other carbonic anhydrase inhibitors to increase the potential for metabolic acidosis.Additionally, the metabolism of zonisamide is inhibited by ketoconazole, ciclosporin, miconazole, fluconazole and carbamazepine (in descending order of inhibition) due to their effects on the CYP3A4 enzyme.Zonisamide is not known to inhibit cytochrome P450 enzymes when present at therapeutic concentrations.
Mechanism of action
Zonisamide is an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The precise mechanism by which zonisamide exerts its antiseizure effect is unknown, although it is believed that the drug blocks sodium and T-type calcium channels, which leads to the suppression of neuronal hypersynchronization (that is, seizure-form activity). It is also known to be a weak carbonic anhydrase inhibitor (similarly to the anticonvulsant topiramate). It is also known to modulate GABAergic and glutamatergic neurotransmission.
Pharmacokinetics
Absorption
Variable, yet relatively rapid rate of absorption with a time to peak concentration of 2.8-3.9 hours. Bioavailability is close to 100% and food has no effect on the bioavailability of zonisamide but may affect the rate of absorption.
Metabolism
Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5, to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.
History
Zonisamide was discovered by Uno and colleagues in 1972 and launched by Dainippon Sumitomo Pharma (formerly Dainippon Pharmaceutical) in 1989 as Excegran in Japan. It was marketed by Élan in the United States starting in 2000 as Zonegran, before Élan transferred their interests in zonisamide to Eisai Co., Ltd. in 2004. Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others) and Europe (starting in Germany and the United Kingdom).
Research
Tardive dyskinesia
In an open-label trial zonisamide attenuated the symptoms of tardive dyskinesia.
Obesity
It has also been studied for obesity with significant positive effects on body weight loss and there are three ongoing clinical trials for this indication. It was to be sold, when combined with bupropion, under the brand name Empatic, until its development was discontinued.
Migraine
Zonisamide has been studied for and used as a migraine preventative medication, when topiramate is either ineffective or cannot be continued due to side effects.
Bipolar depression
It has also been used off-label by psychiatrists as a mood stabilizer to treat bipolar depression.
References
External links
"Zonisamide". Drug Information Portal. U.S. National Library of Medicine. |
Nitazoxanide | Nitazoxanide, sold under the brand name Alinia among others, is a broad-spectrum antiparasitic and broad-spectrum antiviral medication that is used in medicine for the treatment of various helminthic, protozoal, and viral infections. It is indicated for the treatment of infection by Cryptosporidium parvum and Giardia lamblia in immunocompetent individuals and has been repurposed for the treatment of influenza. Nitazoxanide has also been shown to have in vitro antiparasitic activity and clinical treatment efficacy for infections caused by other protozoa and helminths; evidence as of 2014 suggested that it possesses efficacy in treating a number of viral infections as well.Chemically, nitazoxanide is the prototype member of the thiazolides, a class of drugs which are synthetic nitrothiazolyl-salicylamide derivatives with antiparasitic and antiviral activity. Tizoxanide, an active metabolite of nitazoxanide in humans, is also an antiparasitic drug of the thiazolide class.Nitazoxanide tablets were approved as a generic medication in the United States in 2020.
Uses
Nitazoxanide is an effective first-line treatment for infection by Blastocystis species and is indicated for the treatment of infection by Cryptosporidium parvum or Giardia lamblia in immunocompetent adults and children. It is also an effective treatment option for infections caused by other protozoa and helminths (e.g., Entamoeba histolytica, Hymenolepis nana, Ascaris lumbricoides, and Cyclospora cayetanensis).
Chronic hepatitis B
Nitazoxanide alone has shown preliminary evidence of efficacy in the treatment of chronic hepatitis B over a one-year course of therapy. Nitazoxanide 500 mg twice daily resulted in a decrease in serum HBV DNA in all of 4 HBeAg-positive patients, with undetectable HBV DNA in 2 of 4 patients, loss of HBeAg in 3 patients, and loss of HBsAg in one patient. Seven of 8 HBeAg-negative patients treated with nitazoxanide 500 mg twice daily had undetectable HBV DNA and 2 had loss of HBsAg. Additionally, nitazoxanide monotherapy in one case and nitazoxanide plus adefovir in another case resulted in undetectable HBV DNA, loss of HBeAg and loss of HBsAg. These preliminary studies showed a higher rate of HBsAg loss than any currently licensed therapy for chronic hepatitis B. The similar mechanism of action of interferon and nitazoxanide suggest that stand-alone nitazoxanide therapy or nitazoxanide in concert with nucleos(t)ide analogs have the potential to increase loss of HBsAg, which is the ultimate end-point of therapy. A formal phase 2 study is being planned for 2009.
Chronic hepatitis C
Romark initially decided to focus on the possibility of treating chronic hepatitis C with nitazoxanide. The drug garnered interest from the hepatology community after three phase II clinical trials involving the treatment of hepatitis C with nitazoxanide produced positive results for treatment efficacy and similar tolerability to placebo without any signs of toxicity. A meta-analysis from 2014 concluded that the previous held trials were of low-quality and with held with a risk of bias. The authors concluded that more randomized trials with low risk of bias are needed to determine if Nitazoxanide can be used as an effective treatment for chronic hepatitis C patients.
Contraindications
Nitazoxanide is contraindicated only in individuals who have experienced a hypersensitivity reaction to nitazoxanide or the inactive ingredients of a nitazoxanide formulation.
Adverse effects
The side effects of nitazoxanide do not significantly differ from a placebo treatment for giardiasis; these symptoms include stomach pain, headache, upset stomach, vomiting, discolored urine, excessive urinating, skin rash, itching, fever, flu syndrome, and others. Nitazoxanide does not appear to cause any significant adverse effects when taken by healthy adults.
Overdose
Information on nitazoxanide overdose is limited. Oral doses of 4 grams in healthy adults do not appear to cause any significant adverse effects. In various animals, the oral LD50 is higher than 10 g/kg.
Interactions
Due to the exceptionally high plasma protein binding (>99.9%) of nitazoxanides metabolite, tizoxanide, the concurrent use of nitazoxanide with other highly plasma protein-bound drugs with narrow therapeutic indices (e.g., warfarin) increases the risk of drug toxicity. In vitro evidence suggests that nitazoxanide does not affect the CYP450 system.
Pharmacology
Pharmacodynamics
The anti-protozoal activity of nitazoxanide is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron-transfer reaction that is essential to anaerobic energy metabolism. PFOR inhibition may also contribute to its activity against anaerobic bacteria.It has also been shown to have activity against influenza A virus in vitro. The mechanism appears to be by selectively blocking the maturation of the viral hemagglutinin at a stage preceding resistance to endoglycosidase H digestion. This impairs hemagglutinin intracellular trafficking and insertion of the protein into the host plasma membrane.
Nitazoxanide modulates a variety of other pathways in vitro, including glutathione-S-transferase and glutamate-gated chloride ion channels in nematodes, respiration and other pathways in bacteria and cancer cells, and viral and host transcriptional factors.
Pharmacokinetics
Following oral administration, nitazoxanide is rapidly hydrolyzed to the pharmacologically active metabolite, tizoxanide, which is 99% protein bound. Tizoxanide is then glucuronide conjugated into the active metabolite, tizoxanide glucuronide. Peak plasma concentrations of the metabolites tizoxanide and tizoxanide glucuronide are observed 1–4 hours after oral administration of nitazoxanide, whereas nitazoxanide itself is not detected in blood plasma.Roughly 2⁄3 of an oral dose of nitazoxanide is excreted as its metabolites in feces, while the remainder of the dose excreted in urine. Tizoxanide is excreted in the urine, bile and feces. Tizoxanide glucuronide is excreted in urine and bile.
Chemistry
Nitazoxanide is the prototype member of the thiazolides, which is a drug class of structurally-related broad-spectrum antiparasitic compounds. Nitazoxanide is a light yellow crystalline powder. It is poorly soluble in ethanol and practically insoluble in water.
History
Nitazoxanide was originally discovered in the 1980s by Jean-François Rossignol at the Pasteur Institute. Initial studies demonstrated activity versus tapeworms. In vitro studies demonstrated much broader activity. Dr. Rossignol co-founded Romark Laboratories, with the goal of bringing nitazoxanide to market as an anti-parasitic drug. Initial studies in the USA were conducted in collaboration with Unimed Pharmaceuticals, Inc. (Marietta, GA) and focused on development of the drug for treatment of cryptosporidiosis in AIDS. Controlled trials began shortly after the advent of effective anti-retroviral therapies. The trials were abandoned due to poor enrollment and the FDA rejected an application based on uncontrolled studies.
Subsequently, Romark launched a series of controlled trials. A placebo-controlled study of nitazoxanide in cryptosporidiosis demonstrated significant clinical improvement in adults and children with mild illness. Among malnourished children in Zambia with chronic cryptosporidiosis, a three-day course of therapy led to clinical and parasitologic improvement and improved survival. In Zambia and in a study conducted in Mexico, nitazoxanide was not successful in the treatment of cryptosporidiosis in advanced infection with human immunodeficiency virus at the doses used. However, it was effective in patients with higher CD4 counts. In treatment of giardiasis, nitazoxanide was superior to placebo and comparable to metronidazole. Nitazoxanide was successful in the treatment of metronidazole-resistant giardiasis. Studies have suggested efficacy in the treatment of cyclosporiasis, isosporiasis, and amebiasis. Recent studies have also found it to be effective against beef tapeworm(Taenia saginata).
Pharmaceutical products
Dosage forms
Nitazoxanide is currently available in two oral dosage forms: a tablet (500 mg) and an oral suspension (100 mg per 5 ml when reconstituted).An extended release tablet (675 mg) has been used in clinical trials for chronic hepatitis C; however, this form is not currently marketed or available for prescription.
Brand names
Nitazoxanide is sold under the brand names Adonid, Alinia, Allpar, Annita, Celectan, Colufase, Daxon, Dexidex, Diatazox, Kidonax, Mitafar, Nanazoxid, Parazoxanide, Netazox, Niazid, Nitamax, Nitax, Nitaxide, Nitaz, Nizonide, NT-TOX, Pacovanton, Paramix, Toza, and Zox.
Research
As of September 2015, nitazoxanide was in phase 3 clinical trials for the treatment influenza due to its inhibitory effect on a broad range of influenza virus subtypes and efficacy against influenza viruses that are resistant to neuraminidase inhibitors like oseltamivir. Nitazoxanide is also being researched as a potential treatment for COVID-19, chronic hepatitis B, chronic hepatitis C, rotavirus and norovirus gastroenteritis.
References
Further reading
"Parasitic infections". Am J Transplant. 4 (Suppl 10): 142–55. October 2004. doi:10.1111/j.1600-6135.2004.00677.x. PMID 15504227. S2CID 5742723.
External links
"Nitazoxanide". Drug Information Portal. U.S. National Library of Medicine. |
Mitapivat | Mitapivat, sold under the brand name Pyrukynd, is a medication used to treat hemolytic anemia. It is taken as the sulfate hydrate salt by mouth. Mitapivat is a pyruvate kinase activator.Mitapivat was approved for medical use in the United States in February 2022.
Medical uses
Mitapivat is indicated for the treatment of hemolytic anemia in adults with pyruvate kinase deficiency.
Pharmacology
Mechanism of action
Mitapivat binds to and activates pyruvate kinase, thereby enhancing glycolytic pathway activity, improving adenosine triphosphate (ATP) levels and reducing 2,3-diphosphoglycerate (2,3-DPG) levels. Mutations in pyruvate kinase cause deficiency in pyruvate kinase which prevents adequate red blood cell (RBC) glycolysis, leading to a buildup of the upstream glycolytic intermediate 2,3-DPG and deficiency in the pyruvate kinase product ATP.
Society and culture
Legal status
On 15 September 2022, 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 Pyrukynd, intended for the treatment of an inherited condition called pyruvate kinase deficiency. The applicant for this medicinal product is Agios Netherlands B.V.
Names
Mitapivat is the international nonproprietary name (INN).
References
Further reading
Kung C, Hixon J, Kosinski PA, Cianchetta G, Histen G, Chen Y, et al. (September 2017). "AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency". Blood. 130 (11): 1347–1356. doi:10.1182/blood-2016-11-753525. PMC 5609468. PMID 28760888.
Rab MA, Van Oirschot BA, Kosinski PA, Hixon J, Johnson K, Chubukov V, et al. (January 2021). "AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes". Haematologica. 106 (1): 238–249. doi:10.3324/haematol.2019.238865. PMC 7776327. PMID 31974203.
External links
"Mitapivat sulfate". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03548220 for "A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)" at ClinicalTrials.gov
Clinical trial number NCT03559699 for "A Study Evaluating the Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)" at ClinicalTrials.gov |
Metyrapone | Metyrapone, sold under the brand name Metopirone, is a medication which is used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushings syndrome (hypercortisolism).
Medical uses
Metyrapone can be used in the diagnosis of adrenal insufficiency. Metyrapone 30 mg/kg, maximum dose 3,000 mg, is administered at midnight usually with a snack. The plasma cortisol and 11-deoxycortisol are measured the next morning between 8:00 and 9:00 am. A plasma cortisol less than 220 nmol/L indicates adequate inhibition of 11β-hydroxylase. In patients with intact Hypothalamo-pituitary-adrenal axis, CRH and ACTH levels rise as a response to the falling cortisol levels. This results in an increase of the steroid precursors in the pathway. Therefore, if 11-deoxycortisol levels do not rise and remain less than 7 µg/dL (202 nmol/L) and adrenocorticotropic hormone (ACTH) rises, then it is highly suggestive of adrenal insufficiency. If neither 11-deoxycortisol nor ACTH rise, it is highly suggestive of an impaired hypothalamic–pituitary–adrenal axis at either the pituitary or hypothalamus.
The metyrapone test may aid in verifying the cause of Cushings syndrome. Most patients with pituitary dysfunction and/or pituitary microadenoma will increase ACTH secretion in response to metyrapone, while most ectopic ACTH-producing tumors will not. Pituitary macroadenomas do not always respond to metyrapone.
Metyrapone is used for the medical control of hypercortisolism in Cushings syndrome (ACTH dependent or independent). The aim for medical treatment is to achieve pre-operative control of hypercortisolism, or for control of residual disease persisting post-operatively (TSS, adrenalectomy). It is not for long term definitive treatment/cure, only as an adjunct (surgery is the aim for cure in most causes of Cushings syndrome). Metyrapone hence acts by inhibiting adrenal steroidogenesis. One side effect is hirsutism (in women) because of the excess androgen precursors created. The other commonly used agent for medical treatment of Cushings is ketoconazole (an anti-fungal agent). This does not exhibit the side effect of hirsutism.
Pharmacology
Pharmacodynamics
Metyrapone blocks cortisol steroidogenesis by acting as a reversible inhibitor of 11β-hydroxylase. This stimulates adrenocorticotropic hormone (ACTH) secretion, which in turn increases plasma 11-deoxycortisol levels.
Chemistry
Analogues of metyrapone include aminoglutethimide, amphenone B, and mitotane.
Research
Metyrapone has been found in early human trials to reduce recollection of emotional memories in normal volunteers. The volunteers showed significant impairment in ability to retrieve memories with negative emotional content while not impairing memories with neutral content. This has significant implication in the study of the process of emotional healing in post traumatic stress disorder.Due to the permissive action of cortisol on glucagon, partial blockade of cortisol may reduce
the effects of circulating glucagon in chronically increasing blood glucose in metabolic syndrome (syndrome X) and type 2 diabetes.
See also
ACTH stimulation test
== References == |
Fomepizole | Fomepizole, also known as 4-methylpyrazole, is a medication used to treat methanol and ethylene glycol poisoning. It may be used alone or together with hemodialysis. It is given by injection into a vein.Common side effects include headache, nausea, sleepiness, and unsteadiness. It is unclear if use during pregnancy is safe for the baby. Fomepizole works by blocking the enzyme that converts methanol and ethylene glycol to their toxic breakdown products.Fomepizole was approved for medical use in the United States in 1997. It is on the World Health Organizations List of Essential Medicines.
Medical use
Fomepizole is used to treat ethylene glycol and methanol poisoning. It acts to inhibit the breakdown of these toxins into their active toxic metabolites. Fomepizole is a competitive inhibitor of the enzyme alcohol dehydrogenase, found in the liver. This enzyme plays a key role in the metabolism of ethylene glycol, and of methanol.
Ethylene glycol is first metabolized to glycolaldehyde by alcohol dehydrogenase. Glycolaldehyde then undergoes further oxidation to glycolate, glyoxylate, and oxalate. Glycolate and oxalate are the primary toxins responsible for the metabolic acidosis, and for the renal damage, seen in ethylene glycol poisoning.
Methanol is first metabolized to formaldehyde by alcohol dehydrogenase. Formaldehyde then undergoes further oxidation, via formaldehyde dehydrogenase, to become formic acid. Formic acid is the primary toxin responsible for the metabolic acidosis, and for the visual disturbances, associated with methanol poisoning.By competitively inhibiting the first enzyme, alcohol dehydrogenase, in the metabolism of ethylene glycol and methanol, fomepizole slows the production of the toxic metabolites. The slower rate of metabolite production allows the liver to process and excrete the metabolites as they are produced, limiting the accumulation in tissues such as the kidney and eye. As a result, much of the organ damage is avoided.Fomepizole is most effective when given soon after ingestion of ethylene glycol or methanol. Delaying its administration allows for the generation of harmful metabolites.
Interaction with alcohol
Concurrent use with ethanol is contraindicated because fomepizole is known to prolong the half-life of ethanol via inhibiting its metabolism. Extending the half-life of ethanol may increase and extend the intoxicating effects of ethanol, allowing for greater (potentially dangerous) levels of intoxication at lower doses. Fomepizole slows the production of acetaldehyde by inhibiting alcohol dehydrogenase, which in turn allows more time to further convert acetaldehyde into acetic acid by acetaldehyde dehydrogenase. The result is a patient with a prolonged and deeper level of intoxication for any given dose of ethanol, and reduced "hangover" symptoms (since these adverse symptoms are largely mediated by acetaldehyde build up).
In a chronic alcoholic who has built up a tolerance to ethanol, this removes some of the disincentives to ethanol consumption ("negative reinforcement") while allowing them to become intoxicated with a lower dose of ethanol. The danger is that the alcoholic will then overdose on ethanol (possibly fatally). If alcoholics instead very carefully reduce their doses to reflect the now slower metabolism, they may get the "rewarding" stimulus of intoxication at lower doses with less adverse "hangover" effects - leading potentially to increased psychological dependency. However, these lower doses may therefore produce less chronic toxicity and provide a harm minimization approach to chronic alcoholism.
It is, in essence, the antithesis of a disulfiram approach which tries to increase the buildup of acetaldehyde resulting in positive punishment for the patient. Compliance, and adherence, is a substantial problem in disulfiram-based approaches. Disulfiram also has a considerably longer half-life than that of fomepizole, requiring the person to not drink ethanol in order to avoid severe effects. If the person is not adequately managed on a benzodiazepine, barbiturate, acamprosate, or another GABAA receptor agonist, the alcohol withdrawal syndrome, and its attendant, life-threatening risk of delirium tremens "DT", may occur. Disulfiram treatment should never be initiated until the risk of DT has been evaluated, and mitigated appropriately. Fomepizole treatment may be initiated while the DT de-titration sequence is still being calibrated based upon the persons withdrawal symptoms and psychological health.
Adverse effects
Common side effects associated with fomepizole use include headache and nausea.
Kinetics
Absorption and distribution
Fomepizole distributes rapidly into total body water. The volume of distribution is between 0.6 and 1.02 L/kg. The therapeutic concentration is from 8.2 to 24.6 mg (100 to 300 micromoles) per liter. Peak concentration following single oral doses of 7 to 50 mg/kg of body weight occurred in 1 to 2 hours. The half-life varies with dose, so has not been calculated.
Metabolism and elimination
Hepatic; the primary metabolite is 4-carboxypyrazole (about 80 to 85% of an administered dose). Other metabolites include the pyrazoles 4-hydroxymethylpyrazole and the N -glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole.
Following multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed-function oxidase system.
In healthy volunteers, 1.0 to 3.5% of an administered dose was excreted unchanged in the urine. The metabolites also are excreted unchanged in the urine.
Fomepizole is dialyzable.
Other uses
Apart from medical uses, the role of 4-methylpyrazole in coordination chemistry has been studied.
See also
Alcohol (medicine)
Disulfiram-like drug
References
External links
"Fomepizole". Drug Information Portal. U.S. National Library of Medicine. |
Ramelteon | Ramelteon, sold under the brand name Rozerem among others, is a melatonin agonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset. It reduces the time taken to fall asleep, but the degree of clinical benefit is small. The medication is approved for long-term use. Ramelteon is taken by mouth.Side effects of ramelteon include somnolence, dizziness, fatigue, nausea, exacerbated insomnia, and changes in hormone levels. Ramelteon is an analogue of melatonin and is a selective agonist of the melatonin MT1 and MT2 receptors. The half-life and duration of ramelteon are much longer than those of melatonin. Ramelteon is not a benzodiazepine or Z-drug and does not interact with GABA receptors, instead having a distinct mechanism of action.Ramelteon was first described in 2002 and was approved for medical use in 2005. Unlike certain other sleep medications, ramelteon is not a controlled substance and has no known potential for misuse.
Medical uses
Insomnia
Ramelteon is approved for the treatment of insomnia characterized by difficulty with sleep onset in adults. In regulatory clinical trials, it was found to significantly reduce latency to persistent sleep (LPS). A 2009 pooled analysis of four clinical trials found that ramelteon at a dose of 8 mg reduced sleep onset by 13 minutes (30% decrease) relative to placebo on the first and second nights of use. Subsequent meta-analyses of longer-duration use have found that ramelteon decreases subjective sleep latency by about 4 to 7 minutes. Meta-analyses are mixed on whether ramelteon increases total sleep time. Ramelteon also improves sleep quality (SMD –0.074, 95% CI –0.13 to –0.02) and sleep efficiency. The clinical improvement in insomnia with ramelteon is small and of questionable benefit.Ramelteon is approved in the United States but was not approved in the European Union owing to concerns that it lacked effectiveness. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) noted that ramelteon had only been found to improve sleep onset and not other sleep outcomes, only one of three clinical trials actually found that it improved sleep onset, and that the improvement in sleep onset was too small to be clinically meaningful. The CHMP also noted that the long-term effectiveness of ramelteon had not been demonstrated.The American Academy of Sleep Medicines 2017 clinical practice guidelines recommended the use of ramelteon in the treatment of sleep-onset insomnia. It rated the recommendation as weak and the quality of evidence as very low but concluded that the potential benefits outweighed the potential harms. The guidelines found that ramelteon reduces sleep latency by 9 minutes (95% CI 6–12 minutes) but does not improve sleep quality. In contrast to ramelteon, the guidelines did not recommend the use of melatonin.
Circadian rhythm sleep disorders
Melatonin receptor agonists like melatonin and tasimelteon are considered to be effective in regulating sleep–wake cycles and in the treatment of circadian rhythm sleep disorders like delayed sleep phase disorder. Ramelteon has been assessed in only a few studies in the treatment of circadian rhythm sleep disorders, including jet lag disorder, shift work disorder, and non-24-hour sleep–wake disorder. These studies have been of varying quality and their findings in terms of effectiveness have been mixed. Ramelteon is approved only for treatment of insomnia and is not approved for treatment of circadian rhythm sleep disorders. It was previously under development for treatment of circadian rhythm sleep disorders, but development for these indications was discontinued.
Other uses
Delirium
A systematic review, published in 2014, concluded "ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo." A 2022 systematic review and meta-analysis found that the combination of ramelteon and the orexin receptor antagonist suvorexant may reduce the incidence of delirium in adults hospitalized patients whereas suvorexant alone was ineffective.
Bipolar disorder
Ramelteon has received attention in psychiatry as a possible add-on treatment for mania in bipolar disorder. However, to date, the scarce available evidence fails to support the clinical utility of ramelteon and other melatonin receptor agonists such as melatonin for mania.
Available forms
Ramelteon is available in the form of 8 mg oral film-coated tablets.
Contraindications
Ramelteon is not recommended for use in people with severe sleep apnea.
Adverse effects
Side effects of ramelteon include somnolence (3% vs. 2% for placebo), fatigue (3% vs. 2% for placebo), dizziness (4% vs. 3% for placebo), nausea (3% vs. 2% for placebo), and exacerbated insomnia (3% vs. 2% for placebo). Overall, side effects occurred in 6% with ramelteon and 2% with placebo in clinical trials. Side effects leading to discontinuation occurred in 1% or fewer people. Rarely, anaphylactic reactions, abnormal thinking, and worsening of depression or suicidal thinking in patients with pre-existing depression may occur with ramelteon. Ramelteon has been found to slightly increase prolactin levels in women (+34% vs. –4% with placebo) but not in men and to decrease free testosterone levels (by 3–6% in younger men and by 13–18% in older men).Ramelteon has not been shown to produce dependence and has shown no potential for abuse. The withdrawal and rebound insomnia that is typical with GABAA receptor positive modulators like benzodiazepines and Z-drugs is not present in ramelteon.Increased incidence of liver and testicular tumors have been observed with ramelteon in rodents but only at doses equivalent to at least 20 times greater than the recommended dose in humans.
Overdose
Ramelteon has been assessed at doses of up to 64 mg in clinical studies.
Interactions
Ramelteon has been evaluated for potential drug interactions with the following medications and showed no significant effects: omeprazole, theophylline, dextromethorphan, and midazolam, digoxin and warfarin. There were no clinically meaningful effects when ramelteon was coadministered with any of these drugs.A drug interaction study showed that there were no clinically meaningful effects or an increase in adverse events when ramelteon and the SSRI Prozac (fluoxetine) were coadministered. When coadministered with ramelteon, fluvoxamine (strong CYP1A2 inhibitor) increased AUC approximately 190-fold, and the Cmax increased approximately 70-fold, compared to ramelteon administered alone. Ramelteon and fluvoxamine should not be coadministered.Ramelteon has significant drug–drug interaction with the following drugs: amiodarone, ciprofloxacin, fluvoxamine, ticlopidine.
Ramelteon should be administered with caution in patients taking other CYP1A2 inhibitors, strong CYP3A4 inhibitors such as ketoconazole, and strong CYP2C9 inhibitors such as fluconazole.Efficacy may be reduced when ramelteon is used in combination with potent CYP enzyme inducers such as rifampin, since ramelteon concentrations may be decreased.
Pharmacology
Pharmacodynamics
Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the non-human MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors, and high selectivity for human MT1 and MT2 receptors compared to the non-human MT3 receptor. The affinity of ramelteon for the MT1 and MT2 receptors is 3 to 16 times higher than that of melatonin. Ramelteon has 8-fold higher affinity for the MT1 receptor over the MT2 receptor. The binding profile of ramelteon distinguishes it from melatonin, tasimelteon, and agomelatine.The major metabolite of ramelteon, M-II, is active and has approximately one-tenth and one-fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is 17- to 25-fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes.Ramelteon has no appreciable affinity for the GABA receptors or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opioids. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel.
Mechanism of action
The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep–wake cycle.
Pharmacokinetics
Absorption
The total absorption of ramelteon is 84% while its oral bioavailability is 1.8%. The low bioavailability of ramelteon is due to extensive first-pass metabolism. The absorption of ramelteon is rapid, with peak levels being reached after approximately 0.75 hours (range 0.5–1.5 hours). Food increases peak concentrations of ramelteon by 22% and overall exposure by 31% and delays the time to peak levels by approximately 0.75 hours. The pharmacokinetics of ramelteon are linear across a dose range of 4 to 64 mg. There is substantial interindividual variability in the peak concentrations and area-under-the-curve levels of ramelteon which is consistent with high first-pass metabolism.
Distribution
The volume of distribution of ramelteon is 73.6 L, which suggests substantial tissue distribution. The plasma protein binding of ramelteon is 82% independently of concentration. Ramelteon is primarily bound to albumin (70%). The medication is not selectively distributed to red blood cells.
Metabolism
Ramelteon is metabolized in the liver primarily by oxidation via hydroxylation and carbonylation. It is also secondarily metabolized to produce glucuronide conjugates. Ramelteon is metabolized mainly by CYP1A2 while CYP2C enzymes and CYP3A4 are involved to a minor extent. The metabolites of ramelteon include M-I, M-II, M-III, and M-IV. Exposure to M-II is approximately 20- to 100-fold higher than to ramelteon.
Elimination
Ramelteon is excreted 84% in urine and 4% in feces. Less than 0.1% of drug is excreted as unchanged ramelteon. Elimination of ramelteon is essentially complete by 96 hours following a single dose.The elimination half-life of ramelteon is 1 to 2.6 hours while the half-life of M-II, the major active metabolite of ramelteon, is 2 to 5 hours. The half-lives of ramelteon and M-II are substantially longer than that of melatonin, which has a half-life in the range of 20 to 45 minutes. Levels of ramelteon and its metabolites at or below the limit of detectability within 24 hours following a dose.
Special populations
Peak levels of ramelteon and overall exposure are about 86% and 97% higher, respectively, in elderly adults compared to younger adults. Conversely, peak levels of M-II are 13% and overall exposure 30% higher in elderly adults than in younger adults. The elimination half-life of ramelteon is 2.6 hours in elderly adults.
History
Ramelteon was first described in the medical literature in 2002. It was approved for use in the United States in July 2005.
Society and culture
Legal status
Ramelteon has no potential for abuse or drug dependence and is not a controlled substance.
Research
Psychiatry
Ramelteon, along with other melatonin receptor agonists like melatonin, has been repurposed in clinical trials as an adjunctive treatment for acute manic episodes in subjects with bipolar disorder. Nonetheless, meta-analytic evidence is based on very few trials and does not allow supporting the use of melatonin receptor agonists as adjunctive options for mania in clinical practice, although the small sample size do not allow ruling out their beneficial effect.
References
External links
"Ramelteon". Drug Information Portal. U.S. National Library of Medicine. |
Upadacitinib | Upadacitinib, sold under the brand name Rinvoq, is a Janus kinase (JAK) inhibitor medication for the treatment of moderately to severely active rheumatoid arthritis and psoriatic arthritis in adults where methotrexate (a drug used to treat active arthritis) did not work well or could not be tolerated. It was approved for medical use in the United States and in the European Union in 2019, and was developed by the biotech company AbbVie.
Common side effects include upper respiratory tract infections (common cold, sinus infections), nausea, cough, and fever.Upadacitinib works by blocking the action of enzymes called Janus kinases. These enzymes are involved in setting up processes that lead to inflammation, and blocking their effect brings inflammation in the joints under control.
Medical uses
Upadacitinib is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs (DMARDs). Upadacitinib may be used as monotherapy or in combination with methotrexate.
Contraindications
The drug is contraindicated in people with active tuberculosis and other severe infections, severe liver impairment (Child–Pugh score C), and during pregnancy.The use of upadacitinib in combination with other Janus kinase inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and ciclosporin is not recommended.
Interactions
Substances that strongly inhibit the liver enzyme CYP3A4, such as ketoconazole, itraconazole or clarithromycin, increase upadacitinib concentrations in the body. In a study, ketoconazole increased its AUC by 75%. Conversely, substances that strongly induce CYP3A4 lower upadacitinib concentrations. For example, rifampicin reduced the AUC by 60% in a study.Upadacitinib seems to be a weak inducer of CYP3A4, as it lowers concentrations of other substrates of this enzyme (such as the midazolam AUC by 26%). It has no effect on substrates of CYP1A2, CYP2B6, CYP2C9, CYP2C19 or CYP2D6.
Side effects
Common side effects are upper respiratory tract infections such as common cold and sinus infections (13.5% of patients in studies), nausea (3.5%), cough (2.2%), fever, and increased liver enzymes. Serious side effects include infections, including life-threatening ones, such as pneumonia, cellulitis, tuberculosis, as well as shingles and other herpes infections.
Pharmacology
Mechanism of action
The Janus kinases (JAKs) are a family of cytoplasmic tyrosine kinases whose function is to transduce cytokine-mediated signals via the JAK-STAT pathway. There are four JAK subtypes, each of which has overlapping receptor responsibilities. Inhibitors of this enzyme family (jakinibs) have shown efficacy in treating certain inflammatory and autoimmune diseases such as rheumatoid arthritis and Crohns disease. However, the first generation of these drugs, tofacitinib and ruxolitinib, lacked subtype selectivity, affecting JAK1/JAK3 and JAK1/JAK2 respectively. This has led to dose-limiting side effects in this otherwise promising class of drugs. Upadacitinib is a second generation Janus kinase inhibitor that is selective for the JAK1 subtype of this enzyme over the JAK2 (74-fold), JAK3 (58-fold) and tyrosine kinase 2 subtypes.
Pharmacokinetics
After oral intake, upadacitinib reaches highest concentrations in the blood plasma after two to four hours. A fatty meal has no clinically relevant effect on its resorption. Steady-state conditions are reached after four days; accumulation is minimal. There is no significant first pass effect. When in the bloodstream, 52% of the substance are bound to plasma proteins. It is mainly metabolized by CYP3A4, and possibly to a minor extent by CYP2D6. The most important pathway consists of oxidation to a carboxylic acid and subsequent glucuronidation, yielding a metabolite called M4. However, 79% of the drug are circulating in form of upadacitinib itself, and only 13% as M4. Other metabolites are only present in small fractions. None are pharmacologically active.The drug is excreted mainly as the original substance, of which 38% are found in the feces and 24% in the urine. The mean terminal half-life is 9 to 14 hours.
Clinical trials
Phase I studies
A phase I study revealed that upadacitinib followed a bi-exponential disposition with a terminal half-life of 6–16 hours. There was no significant accumulation over the dose range of 3–36 mg per day. No interaction was found in rheumatoid arthritis patients taking methotrexate. The most common adverse event was headache but its incidence was similar to that when taking placebo (15.6% for upadacitinib vs. 16.7% for placebo). An investigation into absorption and metabolism found that dosing after a high-fat meal had no effect on upadacitinib total drug exposure over time (area under the curve or AUC).
Phase II studies
Two phase IIb studies were initiated to study the efficacy and safety of upadacitinib in patients with rheumatoid arthritis and one phase II study was initiated in patients with Crohns disease.
BALANCE I
In the first study, 276 rheumatoid arthritis patients were recruited who had previously experienced inadequate response to anti–tumor necrosis factor (TNF) therapy and were currently on a stable dose of methotrexate. Patients were randomized to receive 3, 6, 12, or 18 mg twice daily or placebo. The primary endpoint was a 20% improvement in symptoms according to the American College of Rheumatology improvement criteria (ACR20). At the completion of the study it was found that response rates were significantly higher in those receiving upadacitinib versus in those receiving placebo alone (36–42% and 22– 26%, respectively). Adverse events included headache, nausea, and infection but no infections were serious.
BALANCE II
In the second phase IIb study, 300 rheumatoid arthritis patients were recruited who have had an inadequate response to methotrexate. Patients were randomized to receive 3, 6, 12, or 18 mg twice daily or placebo. The primary endpoint was a 20% improvement in symptoms according to the American College of Rheumatology improvement criteria (ACR20). At the completion of the study it was found that response rates were significantly higher in those receiving upadacitinib versus in those receiving placebo alone. (62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively) than with placebo (46%). Improvement in symptoms was rapid, with significant changes in disease scores by week 2. Adverse events were mild with infection being the most serious. One case of community-acquired pneumonia occurred at 12 mg.
CELEST
In this 16-week study, 220 patients were recruited with moderately to severely active Crohns disease. Participants must have also experienced an inadequate response to or intolerance to Immunotherapy or TNF inhibitors. Patients were randomized to therapy with upadacitinib at 3, 6, 12, 24 mg twice daily or 24 mg once daily for 16 weeks or placebo, followed by blinded extension therapy for 36 weeks. The co-primary endpoints were the proportion of patients who achieved clinical remission (soft stool frequency or daily abdominal pain score) at week 16 and endoscopic remission at week 12 or 16. Secondary endpoints included significant clinical response (≥30% reduction in symptoms) at week 16 and endoscopic response (≥25% decrease in symptoms) at week 12 or 16. At 16 weeks 22% of patients taking the 24 mg twice daily dose achieved endoscopic remission with upadacitinib compared to 0% of patients taking placebo. 27% of patients taking the 6 mg twice daily dose achieved clinical remission compared to 11% of patients taking placebo. Adverse events did not appear to be dose-related. A single case of non-melanoma skin cancer was reported in the 24 mg twice daily group.
Phase III studies
Abbvie has planned a total of six phase III trials that will evaluate over 4,000 patients with moderate to severe rheumatoid arthritis. Two Phase III trials are planned studying participants with psoriatic arthritis and one in participants with ulcerative colitis.
SELECT-COMPARE
In SELECT-COMPARE 1629 patients with moderate to severe rheumatoid arthritis and inadequate response to methotrexate were randomized (2:2:1) to once-daily upadacitinib 15mg, placebo, or adalimumab 40mg, on stable background methotrexate. Primary endpoints were ACR20 and DAS28CRP<2.6 versus placebo at week 12; inhibition of radiographic progression was evaluated at week 26. The study was designed and powered to test for non-inferiority and superiority of upadacitinib versus adalimumab clinically and functionally. At week 12, both primary endpoints were met for upadacitinib versus placebo (p≤0.001). ACR20 was achieved by 71% versus 36%, and DAS28CRP<2.6 by 29% versus 6%. Upadacitinib was superior to adalimumab for ACR50, DAS28CRP≤3.2, ΔPain and ΔHAQDI. At week 26, more patients on upadacitinib vs placebo or adalimumab achieved low disease activity or remission (p≤0.001). Radiographic progression was less and observed in fewer patients receiving upadacitinib versus placebo (p≤0.001). Up to week 26, adverse events (AEs) including serious infections were comparable for upadacitinib and adalimumab. The proportions of patients with serious AEs and AEs leading to discontinuation were highest for adalimumab; the proportion with herpes zoster and CPK elevations was highest for upadacitinib. Three malignancies, five MACE, and four deaths were reported, none on upadacitinib. Six venous thromboembolic events were reported [placebo, one; upadacitinib, two; adalimumab, three].
Upadacitinib was superior to placebo and adalimumab for improving signs, symptoms and physical function in RA patients on background methotrexate, and significantly inhibited radiographic progression versus placebo, while the overall safety profile was generally similar to adalimumab, except for higher rates of herpes zoster and CPK elevations on upadacitinib.
SELECT-CHOICE
SELECT-CHOICE was a phase III trial comparing upadacitinib and abatacept in 612 people whose rheumatoid arthritis did not respond to biologic DMARDs. It compared their ability to reduce Disease Activity Score-28 with CRP (DAS-28 CRP), a measure of rheumatoid arthritis disease severity that includes number of tender and swollen joints, C-reactive protein level (a marker of inflammation), and overall health reported on a standardized scale. The trial found that after 12 weeks of treatment, people treated with upadacitinib had lower DAS-28 CRP scores and a higher rate of remission. There was also a higher rate of serious and opportunistic infections, elevated liver enzymes, and thromboembolism in the upadacitinib group.
History
Upadacitinib was approved for medical use in the United States in August 2019.The US Food and Drug Administration (FDA) approved upadacitinib based on evidence from five clinical trials (Trial 1/NCT02706873, Trial 2/NCT02706951, Trial 3/NCT02675426, Trial 4/NCT02629159, Trial 5/NCT02706847) of 3,141 participants with active rheumatoid arthritis (RA). The trials were conducted in Australia, New Zealand, Israel, South Africa, Asia, North/Central/South America, and Europe.Five trials established the benefits and side effects of upadacitinib. Trials enrolled participants with moderate to severe active RA in whom disease-modifying antirheumatic drugs (DMARDS) did not work well or could not be tolerated. All participants had at least six tender and six swollen joints, and increased levels of high sensitivity C-reactive protein (hsCRP). hsCRP is a substance produced by the body to protect itself from illness. Trials lasted up to 5 years.Trial 1 enrolled participants who had never been treated with MTX. Participants were randomly assigned to receive one of two doses of upadacitinib or MTX daily for 24 weeks. Neither the subject nor the healthcare providers knew which medication was being given until after this 24-week treatment period.Trial 2 enrolled participants in whom MTX did not work well. Participants were randomly assigned to receive one of two doses of upadacitinib daily by mouth or continue their usual dose of MTX for 14 weeks. At week 14, participants who were assigned to MTX received upadacitinib by mouth daily. Neither the subject nor the healthcare providers knew which medication was being given.Trial 3 enrolled participants in whom DMARDS did not work well. Participants were randomly assigned to receive one of two doses of upadacitinib or placebo daily by mouth in addition to DMARDS for 12 weeks. At week 12, participants who received placebo were reassigned to upadacitinib daily. Neither the subject nor the healthcare providers knew which medication was being given.Trial 4 enrolled participants in whom MTX did not work well. Participants were randomly assigned to receive upadacitinib or placebo daily by mouth in addition to MTX for 14 weeks. Participants receiving placebo who did not have adequate improvement of signs and/or symptoms could be switched to upadacitinib after week 14. At week 26, all participants receiving placebo were switched to upadacitinib once daily by mouth. Neither the subject nor the healthcare providers knew which medication was being given.Trial 5 enrolled participants in whom DMARDS did not work well or could not be tolerated. Participants were randomly assigned to receive one of two doses of upadacitinib or placebo treatment daily added to DMARDs for 12 weeks. At week 12, participants who received placebo were reassigned to upadacitinib daily.The benefit of upadacitinib was measured by comparing the proportion of participants treated with upadacitinib who achieved an American College of Rheumatology 20 (ACR20) response at week 12 or week 14 to the proportion of participants treated with MTX or placebo who achieved an ACR20 response. ACR20 is a 20% improvement in signs and symptoms of RA.Upadacitinib was approved for medical use in the European Union in December 2019.
Research
Upadacitinib has also demonstrated success in treating moderate to severe atopic dermatitis and has been found to have superior efficacy compared with placebo and dupilumab.
References
External links
"Upadacitinib". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02706873 for "A Study to Compare Upadacitinib (ABT-494) Monotherapy to Methotrexate (MTX) Monotherapy in Adults With Rheumatoid Arthritis (RA) Who Have Not Previously Taken Methotrexate (SELECT-EARLY)" at ClinicalTrials.gov
Clinical trial number NCT02706951 for "A Study Comparing Upadacitinib (ABT-494) Monotherapy to Methotrexate (MTX) Monotherapy in Adults With Rheumatoid Arthritis (RA) Who Have an Inadequate Response to MTX (SELECT-MONOTHERAPY)" at ClinicalTrials.gov
Clinical trial number NCT02675426 for "A Study Comparing Upadacitinib (ABT-494) to Placebo in Adults With Rheumatoid Arthritis on a Stable Dose of Conventional Synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) Who Have an Inadequate Response to csDMARDs Alone (SELECT-NEXT)" at ClinicalTrials.gov
Clinical trial number NCT02629159 for "A Study Comparing Upadacitinib (ABT-494) to Placebo and to Adalimumab in Adults With Rheumatoid Arthritis Who Are on a Stable Dose of Methotrexate and Who Have an Inadequate Response to Methotrexate (SELECT-COMPARE)" at ClinicalTrials.gov
Clinical trial number NCT02706847 for "A Study to Compare Upadacitinib (ABT-494) to Placebo in Adults With Rheumatoid Arthritis on Stable Dose of Conventional Synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) With an Inadequate Response or Intolerance to Biologic DMARDs (SELECT-BEYOND)" at ClinicalTrials.gov |
Ipratropium bromide/salbutamol | Ipratropium bromide/salbutamol, is sold under the brand name DuoNeb as a nebulized solution, is a combination medication used to treat chronic obstructive pulmonary disease (COPD). It contains ipratropium (an anticholinergic) and salbutamol (albuterol, a β2-adrenergic agonist).Common side effects include sore throat, muscle cramps, and nausea. Other side effects may include bronchospasm, allergic reactions, and upper respiratory tract infections. Safety in pregnancy is unclear. Each medication typically decreases bronchospasm and does so via different mechanisms.The combination was approved for medical use in the United States in 1996. It is available as a generic medication. In 2019, it was the 151st most commonly prescribed medication in the United States, with more than 4 million prescriptions.
Society and culture
Since Combivent contains a chlorofluorocarbon-based propellant, its use was discontinued in 2013 in the United States and other countries. This was because Chloroflourocarbons (CFC) are attributed to depletion of the ozone layer.
References
External links
DailyMed
Consumer Medication Information from PubMed Archived 2012-12-03 at the Wayback Machine
Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute. 2007. |
Esmolol | Esmolol, sold under the brand name Brevibloc, is a cardio selective beta1 receptor blocker with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilising activity at therapeutic dosages.
It is a class II antiarrhythmic. Esmolol decreases the force and rate of heart contractions by blocking beta-adrenergic receptors of the sympathetic nervous system, which are found in the heart and other organs of the body. Esmolol prevents the action of two naturally occurring substances: epinephrine and norepinephrine.It was patented in 1980 and approved for medical use in 1987.
Medical uses
To terminate supraventricular tachycardia,
Episodic atrial fibrillation or flutter,
Arrhythmia during anaesthesia,
To reduce HR and BP during and after cardiac surgery, and
In early treatment of myocardial infarction.
Esmolol is also used in blunting the hemodynamic response to laryngoscopy and intubation.
Dosing
A loading dose of 0.5 mg/kg is given followed
by 0.05–0.2 mg/kg/min infusion.
Metabolism
Esmolol is considered a soft drug, one that is rapidly metabolized to an inactive form. Esmolol is rapidly metabolized by hydrolysis of the ester linkage, chiefly by the esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase. Total body clearance in man was found to be about 20 L/kg/hr, which is greater than cardiac output; thus the metabolism of esmolol is not limited by the rate of blood flow to metabolizing tissues such as the liver or affected by hepatic or renal blood flow. Esmolols short duration of action is based on the ester-methyl side chain which allows for quick hydrolysis. Esmolols structure is reflected in its name, es-molol as in ester-methyl. Plasma cholinesterases and red cell membrane acetylcholinesterase do not have any action. This metabolism results in the formation of a free acid and methanol. The amount of methanol produced is similar to endogenous methanol production. Esmolol has a rapid distribution half-life of about two minutes and an elimination half-life of about nine minutes.
References
External links
"Esmolol". Drug Information Portal. U.S. National Library of Medicine. |
Ethosuximide | Ethosuximide, sold under the brand name Zarontin among others, is a medication used to treat absence seizures. It may be used by itself or with other antiseizure medications such as valproic acid. Ethosuximide is taken by mouth.Ethosuximide is usually well tolerated. Common side effects include loss of appetite, abdominal pain, diarrhea, and feeling tired. Serious side effects include suicidal thoughts, low blood cell levels, and lupus erythematosus. It is unclear if it is safe for the baby during pregnancy. Ethosuximide is in the succinimide family of medications. Its mechanism of action is thought to be due to antagonism of the postsynaptic T-type voltage-gated calcium channel.Ethosuximide was approved for medical use in the United States in 1960. It is on the World Health Organizations List of Essential Medicines. Ethosuximide is available as a generic medication. As of 2019 its availability was limited in many countries with concerns of price fixing in the United States.
Medical uses
It is approved for absence seizures. Ethosuximide is considered the first choice drug for treating absence seizures in part because it lacks the idiosyncratic hepatotoxicity of the alternative anti-absence drug, valproic acid.
Adverse effects
As with other anticonvulsants, ethosuximide carries a warning about use during pregnancy. Although a causal relationship with birth defects has not be established, the potential for harm to the baby is weighed against the known harm caused by a mother having even minor seizures.
Central nervous system
Common
drowsiness
mental confusion
insomnia
headache
ataxia
Rare
paranoid psychosis
increased libido
exacerbation of depression
Gastrointestinal
dyspepsia
vomiting
nausea
cramps
constipation
diarrhea
stomach pain
loss of appetite
weight loss
gum enlargement
swelling of tongue
abnormal liver function
Genitourinary
microscopic hematuria
vaginal bleeding
Blood
The following can occur with or without bone marrow loss:
pancytopenia
agranulocytosis
leukopenia
eosinophilia
Skin
urticaria
systemic lupus erythematosus
Stevens–Johnson syndrome
hirsutism
pruritic erythematous rashes
Eyes
myopia
Drug interactions
Valproates can either decrease or increase the levels of ethosuximide; however, combinations of valproates and ethosuximide had a greater protective index than either drug alone.It may elevate serum phenytoin levels.
Mechanism of action
The mechanism by which ethosuximide affects neuronal excitability includes block of T-type calcium channels, and may include effects of the drug on other classes of ion channel. The primary finding that ethosuximide is a T-type calcium channel blocker gained widespread support, but initial attempts to replicate the finding were inconsistent. Subsequent experiments on recombinant T-type channels in cell lines demonstrated conclusively that ethosuximide blocks all T-type calcium channel isoforms. Significant T-type calcium channel density occurs in dendrites of neurons, and recordings from reduced preparations that strip away this dendritic source of T-type calcium channels may have contributed to reports of ethosuximide ineffectiveness.
In March 1989, Coulter, Huguenard and Prince showed that ethosuximide and dimethadione, both effective anti-absence agents, reduced low-threshold Ca2+ currents in T-type calcium channels in freshly removed thalamic neurons. In June of that same year, they also found the mechanism of this reduction to be voltage-dependent, using acutely dissociated neurons of rats and guinea pigs; it was also noted that valproic acid, which is also used in absence seizures, did not do that. The next year, they showed that anticonvulsant succinimides did this and that the pro-convulsant ones did not. The first part was supported by Kostyuk et al. in 1992, who reported a substantial reduction in current in dorsal root ganglia at concentrations ranging from 7 μmol/L to 1 mmol/L.That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mmol/L. The year after, a study conducted on human neocortical cells removed during surgery for intractable epilepsy, the first to use human tissue, found that ethosuximide had no effect on Ca2+ currents at the concentrations typically needed for a therapeutic effect.In 1998, Slobodan M. Todorovic and Christopher J. Lingle of Washington University reported a 100% block of T-type current in dorsal root ganglia at 23.7 ± 0.5 mmol/L, far higher than Kostyuk reported. That same year, Leresche et al. reported that ethosuximide had no effect on T-type currents, but did decrease noninactivating Na+ current by 60% and the Ca2+-activated K+ currents by 39.1 ± 6.4% in rat and cat thalamocortical cells. It was concluded that the decrease in Na+ current is responsible for the anti-absence properties.In the introduction of a paper published in 2001, Dr. Juan Carlos Gomora and colleagues at the University of Virginia in Charlottesville pointed out that past studies were often done in isolated neurons that had lost most of their T-type channels. Using cloned α1G, α1H, and α1I T-type calcium channels, Gomoras team found that ethosuximide blocked the channels with an IC50 of 12 ± 2 mmol/L and that of N-desmethylmethsuximide (the active metabolite of mesuximide) is 1.95 ± 0.19 mmol/L for α1G, 1.82 ± 0.16 mmol/L for α1I, and 3.0 ± 0.3 mmol/L for α1H. It was suggested that the blockade of open channels is facilitated by ethosuximides physically plugging the channels when current flows inward.
Stereochemistry
Ethosuximide is a chiral drug with a stereocenter. Therapeutically, the racemate, the 1: 1 mixture of ( S ) and ( R ) - isomers used.
Society and culture
Cost
As of 2019 there were concerns in the United States that the price of ethosuximide was inflated by manufacturers.
Availability
Availability of ethosuximide is limited in many countries. It was marketed under the trade names Emeside and Zarontin. However, both capsule preparations were discontinued from production, leaving only generic preparations available. Emeside capsules were discontinued by their manufacturer, Laboratories for Applied Biology, in 2005. Similarly, Zarontin capsules were discontinued by Pfizer in 2007. Syrup preparations of both brands remained available.
See also
Phensuximide
Methsuximide
References
External links
"Ethosuximide". Drug Information Portal. U.S. National Library of Medicine. |
Dantrolene | Dantrolene sodium, sold under the brand name Dantrium among others, is a postsynaptic muscle relaxant that lessens excitation-contraction coupling in muscle cells. It achieves this by inhibiting Ca2+ ions release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors. It is the primary drug used for the treatment and prevention of malignant hyperthermia, a rare, life-threatening disorder triggered by general anesthesia or drugs. It is also used in the management of neuroleptic malignant syndrome, muscle spasticity (e.g. after strokes, in paraplegia, cerebral palsy, or patients with multiple sclerosis), and poisoning by 2,4-dinitrophenol or by the related compounds dinoseb and dinoterb.The most frequently occurring side effects include drowsiness, dizziness, weakness, general malaise, fatigue, and diarrhea.It is marketed by Par Pharmaceuticals LLC as Dantrium (in North America) and by Norgine BV as Dantrium, Dantamacrin, or Dantrolen (in Europe). A hospital is recommended to keep a minimum stock of 36 dantrolene vials totaling 720 mg, sufficient for a 70-kg person.
Adverse effects
Central nervous system side effects are quite frequently noted and encompass speech and visual disturbances, mental depression and confusion, hallucinations, headache, insomnia and exacerbation or precipitation of seizures, and increased nervousness. Infrequent cases of respiratory depression or a feeling of suffocation have been observed. Dantrolene often causes sedation severe enough to incapacitate the patient to drive or operate machinery.Gastrointestinal effects include bad taste, decreased appetite, nausea, vomiting, abdominal cramps, and diarrhea.Liver side effects may be seen either as asymptomatic elevation of liver enzymes and/or bilirubin or, most severe, as fatal and nonfatal liver inflammation. The risk of liver inflammation is associated with the duration of treatment and the daily dose. In patients treated for hyperthermia, no liver toxicity has been observed so far. Patients on chronic dantrolene therapy should routinely have LFTs monitored.Pleural effusion with inflammation of the fibrous sac around the heart (oral treatment only), rare cases of bone marrow damage, diffuse muscle pains, backache, dermatologic reactions, transient cardiovascular reactions, and crystals in the urine have additionally been seen. Muscle weakness may persist for several days following treatment.
Mutagenicity and carcinogenity
It is unclear whether dantrolene has carcinogenic effects.
Contraindications
Oral dantrolene cannot be used by:
people with a pre-existing liver disease
people with compromised lung function
people with severe cardiovascular impairment
people with a known hypersensitivity to dantrolene
pediatric patients under five years of age
people who need good muscular balance or strength to maintain an upright position, motoric function, or proper neuromuscular balanceIf the indication is a medical emergency, such as malignant hyperthermia, the only significant contraindication is hypersensitivity.
Pregnancy and breastfeeding
If needed in pregnancy, adequate human studies are lacking, therefore the drug should be given in pregnant women only if clearly indicated. It may cause hypotonia in the newborn if given closely before delivery.Dantrolene should not be given to breastfeeding mothers. If a treatment is necessary, breastfeeding should be terminated.
Interactions
Dantrolene may interact with the following drugs:
Calcium channel blockers of the diltiazem/verapamil type: Intravenous treatment with dantrolene and concomitant calcium channel blocker treatment may lead to severe cardiovascular collapse, abnormal heart rhythms, myocardial depressions, and high blood potassium.
Nondepolarizing neuromuscular blocking agents, such as vecuronium bromide: Neuromuscular blockade is potentiated.
CNS depressants: Sedative action is potentiated. Benzodiazepines may also cause additive muscle weakness.
Combined oral contraceptives and hormone replacement therapy with estrogens may enhance liver toxicity of dantrolene, particularly in women over 35 years of age.
Pharmacology
Dantrolene depresses excitation-contraction coupling in skeletal muscle by acting as a receptor antagonist to the ryanodine receptor, and decreasing free intracellular calcium concentration.
Chemistry
Chemically it is a hydantoin derivative, but does not exhibit antiepileptic activity like other hydantoin derivates such as phenytoin.The poor water solubility of dantrolene leads to certain difficulties in its use. A more water-soluble analog of dantrolene, azumolene, is under development for similar indications. Azumolene has a bromine residue instead of the nitro group found in dantrolene, and is 30 times more water-soluble.
Synthesis
The original patent synthesis started with para-nitroaniline which undergoes diazotization followed by a copper(II) chloride catalyzed arylation with furfural (essentially a modified Meerwein arylation). This then reacts with 1-aminohydantoin to form the final product.
History
Dantrolene was first described in the scientific literature in 1967, as one of several hydantoin derivatives proposed as a new class of muscle relaxant. Dantrolene underwent extensive further development, and its action on skeletal muscle was described in detail in 1973.Dantrolene was widely used in the management of spasticity before its efficacy in treating malignant hyperthermia was discovered by South African anesthesiologist Gaisford Harrison and reported in a landmark 1975 article published in the British Journal of Anaesthesia. Harrison experimentally induced malignant hyperthermia with halothane anesthesia in genetically susceptible pigs, and obtained an 87.5% survival rate, where seven of his eight experiments survived after intravenous administration of dantrolene. The efficacy of dantrolene in humans was later confirmed in a large, multicenter study published in 1982, and confirmed epidemiologically in 1993. Before dantrolene, the only available treatment for malignant hyperthermia was procaine, which was associated with a 60% mortality rate in animal models.
References
External links
"Dantrolene". Drug Information Portal. U.S. National Library of Medicine.
"Dantrolene sodium". Drug Information Portal. U.S. National Library of Medicine. |
Indometacin | Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of prostaglandins, endogenous signaling molecules known to cause these symptoms. It does this by inhibiting cyclooxygenase, an enzyme that catalyzes the production of prostaglandins.It was patented in 1961 and approved for medical use in 1963. It is on the World Health Organizations List of Essential Medicines. It is marketed under more than twelve different trade names. In 2017, it was the 291st most commonly prescribed medication in the United States, with more than one million prescriptions.
Medical uses
As an NSAID, indometacin is an analgesic, anti-inflammatory, and antipyretic. Clinical indications for indometacin include:Joint diseases
rheumatoid arthritis
ankylosing spondylitis
osteoarthritis
gouty arthritis
acute painful shoulder bursitis or tendinitisHeadaches
Trigeminal autonomic cephalgias
Paroxysmal hemicranias
Chronic paroxysmal hemicrania
Episodic paroxysmal hemicrania
Hemicrania continua
Valsalva-induced headaches
Primary cough headache
Primary exertional headache
Primary headache associated with sexual activity (preorgasmic and orgasmic)
Primary stabbing headache (jabs and jolts syndrome)
Hypnic headacheOthers
Patent ductus arteriosus
Contraindications
Concurrent peptic ulcer, or history of ulcer disease
Allergy to indometacin, aspirin, or other NSAIDs
Roux-en-Y gastric bypass and gastric sleeve patients
Patients with nasal polyps reacting with an angioedema to other NSAIDs
Children under 2 years of age (with the exception of neonates with patent ductus arteriosus)
Severe pre-existing renal and liver damage
Caution: pre-existing bone marrow damage (frequent blood cell counts are indicated)
Caution: bleeding tendencies of unknown origin (indometacin inhibits platelet aggregation)
Caution: Parkinsons disease, epilepsy, psychotic disorders (indometacin may worsen these conditions)
Concurrent with potassium sparing diuretics
Patients who have a patent ductus arteriosus dependent heart defect (such as transposition of the great vessels)
Significant hypertension (high blood pressure)
Concomitant administration of lithium salts (such as lithium carbonate)
Adverse effects
In general, adverse effects seen with indometacin are similar to all other NSAIDs. For instance, indometacin inhibits both cyclooxygenase-1 and cyclooxygenase-2, which then inhibits the production of prostaglandins in the stomach and intestines responsible for maintaining the mucous lining of the gastrointestinal tract. Indometacin, therefore, like other non-selective COX inhibitors, can cause peptic ulcers. These ulcers can result in serious bleeding or perforation, requiring hospitalization of the patient.
To reduce the possibility of peptic ulcers, indometacin should be prescribed at the lowest dosage needed to achieve a therapeutic effect, usually between 50 and 200 mg/day. It should always be taken with food. Nearly all patients benefit from an ulcer protective drug (e.g. highly dosed antacids, ranitidine 150 mg at bedtime, or omeprazole 20 mg at bedtime). Other common gastrointestinal complaints, including dyspepsia, heartburn and mild diarrhea are less serious and rarely require discontinuation of indometacin.
Many NSAIDs, but particularly indometacin, cause lithium retention by reducing its excretion by the kidneys. Thus indometacin users have an elevated risk of lithium toxicity. For patients taking lithium (e.g. for treatment of depression or bipolar disorder), less toxic NSAIDs such as sulindac or aspirin are preferred.
All NSAIDs, including indometacin, also increase plasma renin activity and aldosterone levels, and increase sodium and potassium retention. Vasopressin activity is also enhanced. Together these may lead to:
Edema (swelling due to fluid retention)
Hyperkalemia (high potassium levels)
Hypernatremia (high sodium levels)
HypertensionElevations of serum creatinine and more serious renal damage such as acute kidney failure, chronic nephritis and nephrotic syndrome, are also possible. These conditions also often begin with edema and high potassium levels in the blood.
Paradoxically yet uncommonly, indometacin can cause headache (10 to 20%), sometimes with vertigo and dizziness, hearing loss, tinnitus, blurred vision (with or without retinal damage). There are unsubstantiated reports of worsening Parkinsons disease, epilepsy, and psychiatric disorders. Cases of life-threatening shock (including angioedema, sweating, severe hypotension and tachycardia as well as acute bronchospasm), severe or lethal hepatitis and severe bone marrow damage have all been reported. Skin reactions and photosensitivity are also possible side effects.
The frequency and severity of side effects and the availability of better tolerated alternatives make indometacin today a drug of second choice. Its use in acute gout attacks and in dysmenorrhea is well-established because in these indications the duration of treatment is limited to a few days only, therefore serious side effects are not likely to occur.
People should undergo regular physical examination to detect edema and signs of central nervous side effects. Blood pressure checks will reveal development of hypertension. Periodic serum electrolyte (sodium, potassium, chloride) measurements, complete blood cell counts and assessment of liver enzymes as well as of creatinine (renal function) should be performed. This is particularly important if Indometacin is given together with an ACE inhibitor or with potassium-sparing diuretics, because these combinations can lead to hyperkalemia and/or serious kidney failure. No examinations are necessary if only the topical preparations (spray or gel) are applied.
Rare cases have shown that use of this medication by pregnant women can have an effect on the fetal heart, possibly resulting in fetal death via premature closing of the Ductus arteriosus.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.
Mechanism of action
Indometacin, a non-steroidal anti-inflammatory drug (NSAID), has similar mode of action when compared to other drugs in this group. It is a nonselective inhibitor of cyclooxygenase (COX) 1 and 2, the enzymes that participate in prostaglandin synthesis from arachidonic acid. Prostaglandins are hormone-like molecules normally found in the body, where they have a wide variety of effects, some of which lead to pain, fever, and inflammation. By inhibiting the synthesis of prostaglandins, indometacin can reduce pain, fever, and inflammation. Indometacin mechanism of action, along with several other NSAIDs that inhibit COX, was described in 1971.Additionally, indometacin has recently been found to be a positive allosteric modulator (PAM) of the CB1 cannabinoid receptor. By enhancing the binding and signalling of endogenous cannabinoids such as anandamide, PAMs may elicit increased cannabinergic signalling in a tissue specific manner, reducing the incidence of problematic side effects such as psychoactivity while maintaining some antinociceptive activity.Besides, indometacin has logarithmic acid dissociation constant pKa of 3 to 4.5. Since the physiologic body pH is well above the pKa range of indometacin, most of the indometacin molecules will be dissociated into ionized form, leaving very little un-ionized form of indometacin to cross a cell membrane. If the pH gradient across a cell membrane is high, most of the indometacin molecules will be trapped in one side of the membrane with higher pH. This phenomenon is called "ion trapping". The phenomenon of ion trapping is particularly prominent in the stomach as pH at the stomach mucosa layer is extremely acidic, while the parietal cells are more alkaline. Therefore, indometacin are trapped inside the parietal cells in ionized form, damaging the stomach cells, causing stomach irritation. This stomach irritation can reduce if the stomach acid pH is reduced.Indometacins role in treating certain headaches is unique compared to other NSAIDs. In addition to the class effect of COX inhibition, there is evidence that indometacin has the ability to reduce cerebral blood flow not only through modulation of nitric oxide pathways but also via intracranial precapillary vasoconstriction. Indometacin property of reducing cerebral blood flow is useful in treating raised intracranial pressure. A case report has shown that an intravenous bolus dose of indometacin given with 2 hours of continuous infusion is able to reduce intracranial pressure by 37% in 10 to 15 minutes and increases cerebral perfusion pressure by 30% at the same time. This reduction in cerebral pressure may be responsible for the remarkable efficacy in a group of headaches that is referred to as "indometacin-responsive headaches", such as idiopathic stabbing headache, chronic paroxysmal hemicranial, and exertional headaches. On the other hand, the activation of superior salivary nucleus in the brainstem is used to stimulate the trigeminal autonomic reflex arc, causing a type of headache called trigeminal autonomic cephalgia. Indometacin inhibits the superior salivatory nucleus, thus relieving this type of headache.Prostaglandins also cause uterine contractions in pregnant women. Indometacin is an effective tocolytic agent, able to delay premature labor by reducing uterine contractions through inhibition of prostaglandin synthesis in the uterus and possibly through calcium channel blockade.
Indometacin readily crosses the placenta and can reduce fetal urine production to treat polyhydramnios. It does so by reducing renal blood flow and increasing renal vascular resistance, possibly by enhancing the effects of vasopressin on the fetal kidneys.
Other modes of action for indometacin are:
it inhibits motility of polymorphonuclear leukocytes, similar to colchicine
it uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, like salicylates
it has been found to specifically inhibit MRP (multidrug resistance proteins) in murine and human cells
Nomenclature
Indometacin is the INN, BAN, and JAN of the drug while indomethacin is the USAN, and former AAN and BAN.
See also
Indometacin farnesil
Indometacin morpholinylamide
Pravadoline
GW-405,833
References
External links
Effects of Perinatal Indomethacin Treatment on Preterm Infants, academic dissertation (PDF)
Indomethacin, from MedicineNet
Indomethacin, from Drugs.com
Indocin: Description, chemistry, ingredients, from RxList.com |
Mycophenolic acid | Mycophenolic acid (MPA) is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat autoimmune conditions such as Crohns disease and lupus. Specifically it is used following kidney, heart, and liver transplantation. It can be given by mouth or by injection into a vein. It comes as mycophenolate sodium and mycophenolate mofetil.Common side effects include nausea, infections, and diarrhea. Other serious side effects include an increased risk of cancer, progressive multifocal leukoencephalopathy, anemia, and gastrointestinal bleeding. Use during pregnancy may harm the baby. It works by blocking inosine monophosphate dehydrogenase (IMPDH), which is needed by lymphocytes to make guanosine.Mycophenolic acid was initially discovered by Italian Bartolomeo Gosio in 1893. It was rediscovered in 1945 and 1968. It was approved for medical use in the United States in 1995 following the discovery of its immunosuppressive properties in the 1990s. It is available as a generic medication. In 2017, it was the 254th most commonly prescribed medication in the United States, with more than one million prescriptions.
Medical uses
Organ transplant
Mycophenolate is used for the prevention of organ transplant rejection. Mycophenolate mofetil is indicated for the prevention of organ transplant rejection in adults and kidney transplantation rejection in children over 2 years; whereas mycophenolate sodium is indicated for the prevention of kidney transplant rejection in adults. Mycophenolate sodium has also been used for the prevention of rejection in liver, heart, or lung transplants in children older than two years.
Autoimmune disease
Mycophenolate is increasingly utilized as a steroid sparing treatment in autoimmune diseases and similar immune-mediated disorders including Behçets disease, pemphigus vulgaris, immunoglobulin A nephropathy, small vessel vasculitides, and psoriasis. It is also used for retroperitoneal fibrosis along with a number of other medications. Specifically it has also be used for psoriasis not treatable by other methods.Its increasing application in treating lupus nephritis has demonstrated more frequent complete response and less frequent complications compared to cyclophosphamide bolus therapy, a regimen with risk of bone marrow suppression, infertility, and malignancy. Further work addressing maintenance therapy demonstrated mycophenolate superior to cyclophosphamide, again in terms of response and side-effects. Walsh proposed that mycophenolate should be considered as a first-line induction therapy for treatment of lupus nephritis in people without kidney dysfunction.
Comparison to other agents
Compared with azathioprine it has higher incidence of diarrhea, and no difference in risk of any of the other side effects in transplant patients. Mycophenolic acid is 15 times more expensive than azathioprine.
Adverse effects
Common adverse drug reactions (≥ 1% of people) include diarrhea, nausea, vomiting, joint pain; infections, leukopenia, or anemia reflect the immunosuppressive and myelosuppressive nature of the drug. Mycophenolate sodium is also commonly associated with fatigue, headache, cough and/or breathing issues. Intravenous (IV) administration of mycophenolate mofetil is also commonly associated with thrombophlebitis and thrombosis. Infrequent adverse effects (0.1–1% of people) include esophagitis, gastritis, gastrointestinal tract hemorrhage, and/or invasive cytomegalovirus (CMV) infection. More rarely, pulmonary fibrosis or various neoplasia occur: melanoma, lymphoma, other malignancies having an occurrences of 1 in 20 to 1 in 200, depending on the type, with neoplasia in the skin being the most common site.
Several cases of pure red cell aplasia (PRCA) have also been reported.The U.S. Food and Drug Administration (FDA) issued an alert that people are at increased risk of opportunistic infections, such as activation of latent viral infections, including shingles, other herpes infections, cytomegalovirus, and BK virus associated nephropathy. In addition the FDA is investigating 16 people that developed a rare neurological disease while taking the drug. This is a viral infection known as progressive multifocal leukoencephalopathy; it attacks the brain and is usually fatal.
Pregnancy
Mycophenolic acid is associated with miscarriage and congenital malformations when used during pregnancy, and should be avoided whenever possible by women trying to get pregnant.
Blood tests
Among the most common effects of this drug is increased blood cholesterol levels. Other changes in blood chemistry such as hypomagnesemia, hypocalcemia, hyperkalemia, and an increase in blood urea nitrogen (BUN) can occur.
Mechanism of action
Purines (including the nucleosides guanosine and adenosine) can either be synthesized de novo using ribose 5-phosphate or they can be salvaged from free nucleotides. Mycophenolic acid is a potent, reversible, non-competitive inhibitor of inosine-5′-monophosphate dehydrogenase (IMPDH), an enzyme essential to the de novo synthesis of guanosine-5-monophosphate (GMP) from inosine-5-monophosphate (IMP). IMPDH inhibition particularly affects lymphocytes since they rely almost exclusively on de novo purine synthesis. In contrast, many other cell types use both pathways, and some cells, such as terminally differentiated neurons, depend completely on purine nucleotide salvage. Thus, use of mycophenolic acid leads to a relatively selective inhibition of DNA replication in T cells and B cells.
Pharmacology
Mycophenolate can be derived from the fungi Penicillium stoloniferum, P. brevicompactum and P. echinulatum. Mycophenolate mofetil is metabolised in the liver to the active moiety mycophenolic acid. It reversibly inhibits inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes. Other cells recover purines via a separate salvage pathway and are thus able to escape the effect.Mycophenolate is potent and can, in many contexts, be used in place of the older anti-proliferative azathioprine. It is usually used as part of a three-compound regimen of immunosuppressants, also including a calcineurin inhibitor (ciclosporin or tacrolimus) and a glucocorticoid (e.g. dexamethasone or prednisone).
Chemistry
Mycophenolate mofetil is the morpholino ethyl ester of mycophenolic acid; the ester masks the carboxyl group. Mycophenolate mofetil is reported to have a pKa values of 5.6 for the morpholino moiety and 8.5 for the phenolic group.
History
Mycophenolic acid was discovered by Italian medical scientist Bartolomeo Gosio. Gosio collected a fungus from spoiled corn and named it Penicillium glaucum. (The species is now called P. brevicompactum.) In 1893 he found that the fungus had antibacterial activity. In 1896 he isolated crystals of the compound, which he successfully demonstrated as the active antibacterial compound against the anthrax bacterium. This was the first antibiotic that was isolated in pure and crystalline form. But the discovery was forgotten. It was rediscovered by two American scientists C.L. Alsberg and O.M. Black in 1912, and given the name mycophenolic acid. The compound was eventually demonstrated to have antiviral, antifungal, antibacterial, anticancer, and antipsoriasis activities. Although it is not commercialised as antibiotic due to its adverse effects, its modified compound (ester derivative) is an approved immunosuppressant drug in kidney, heart, and liver transplantations, and is marketed under the brands CellCept (mycophenolate mofetil by Roche) and Myfortic (mycophenolate sodium by Novartis).Cellcept was developed by a South African geneticist Anthony Allison and his wife Elsie M. Eugui. In the 1970s while working at the Medical Research Council, Allison investigated the biochemical causes of immune deficiency in children. He discovered the metabolic pathway involving an enzyme, inosine monophosphate dehydrogenase, which is responsible for undesirable immune response in autoimmune diseases, as well as for immune rejection in organ transplantation. He conceived an idea that if a molecule that could block the enzyme is discovered, then, it would become an immunosuppressive drug that could be used for autoimmune diseases and in organ transplantation. In 1981 he decided to go for drug discovery and approached several pharmaceutical companies, which turned him down one by one as he had no primary knowledge of drug research. However, Syntex liked his plans and asked him to join the company with his wife. He became vice president for the research. In one of their experiments the Allisons used an antibacterial compound, mycophenolate mofetil, which was abandoned in clinical use due to its adverse effects. They discovered that the compound had immunosuppressive activity. They synthesised a chemical variant for increased activity and reduced adverse effects. They subsequently demonstrated that it was useful in organ transplantation in experimental rats. After successful clinical trials, the compound was approved for use in kidney transplant by the U.S. Food and Drug Administration on 3 May 1995, and was sold under the brand name CellCept. It was approved for use in the European Union in February 1996.
Names
It was initially introduced as the prodrug mycophenolate mofetil (MMF, trade name CellCept) to improve oral bioavailability. The salt mycophenolate sodium has also been introduced. Enteric-coated mycophenolate sodium (EC-MPS) is an alternative MPA formulation.
MMF and EC-MPS appear to be equal in benefits and safety.
Research
Mycophenolate mofetil is beginning to be used in the management of auto-immune disorders such as idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), scleroderma (systemic sclerosis or SSc), and pemphigus vulgaris (PV) with success for some patients.It is also currently being used as a long-term therapy for maintaining remission of granulomatosis with polyangiitis, though thus far, studies have found it inferior to azathioprine. A combination of mycophenolate and ribavirin has been found to stop infection by and replication of dengue virus in vitro. It has also shown promising antiviral activity against MERS, especially in combination with interferon.Preliminary data suggests that mycophenolate mofetil might have benefits in people with multiple sclerosis. However the evidence is insufficient to determine the effects as an add‐on therapy for interferon beta-1a in people with RRMS.
References
External links
"Mycophenolic acid". Drug Information Portal. U.S. National Library of Medicine.
"Mycophenolate mofetil". Drug Information Portal. U.S. National Library of Medicine.
"Mycophenolate sodium". Drug Information Portal. U.S. National Library of Medicine. |
Alglucosidase alfa | Alglucosidase alfa, sold under the brand name Myozyme among others, is an enzyme replacement therapy (ERT) orphan drug for treatment of Pompe disease (Glycogen storage disease type II), a rare lysosomal storage disorder (LSD).
Chemically speaking, the drug is an analog of the enzyme that is deficient in patients affected by Pompe disease, alpha-glucosidase. It is the first drug available to treat this disease.It was approved for medical use in the United States in April 2006, as Myozyme and in May 2010, as Lumizyme.
Medical uses
Alglucosidase alfa is indicated for people with Pompe disease (GAA deficiency).In 2014 the U.S. Food and Drug Administration announced the approval of alglucosidase alfa for treatment of people with infantile-onset Pompe disease, including people who are less than eight years of age. In addition, the Risk Evaluation and Mitigation Strategy (REMS) is being eliminated.
Side effects
Common observed adverse reactions to alglucosidase alfa treatment are pneumonia, respiratory complications, infections and fever. More serious reactions reported include heart and lung failure and allergic shock. Myozyme boxes carry warnings regarding the possibility of life-threatening allergic response.
Cost
Some health plans have refused to subsidize Myozyme for adults because it lacks approval for treatment in adults, as well as its high cost (US$300,000 per year for life).In 2015, Lumizyme was ranked the costliest drug per patient, with an average charge of $630,159.
References
External links
"Alglucosidase Alfa". Drug Information Portal. U.S. National Library of Medicine. |
Anidulafungin | Anidulafungin (INN): 42 (trade names Eraxis, Ecalta) is a semisynthetic echinocandin used as an antifungal drug. It was previously known as LY303366. It may also have application in treating invasive Aspergillus infection when used in combination with voriconazole. It is a member of the class of antifungal drugs known as the echinocandins; its mechanism of action is by inhibition of (1→3)-β-D-glucan synthase, an enzyme important to the synthesis of the fungal cell wall.It is on the World Health Organizations List of Essential Medicines.
Indications
Candidemia and other forms of invasive Candida infections (intra-abdominal abscess and peritonitis)
Esophageal candidiasisAnidulafungin has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida, and has not been studied in sufficient numbers of neutropenic patients to determine efficacy in this group.
Pharmacodynamics and pharmacokinetics
Anidulafungin significantly differs from other antifungals in that it undergoes chemical degradation to inactive forms at body pH and temperature. Because it does not rely on enzymatic degradation or hepatic or renal excretion, the drug is safe to use in patients with any degree of hepatic or renal impairment.Volume of distribution: 30–50 L.
Anidulafungin is not evidently metabolized by the liver. This specific drug undergoes slow chemical hydrolysis to an open-ring peptide which lacks antifungal activity. The half-life of the drug is 27 hours. About 30% is excreted in the feces (10% as unchanged drug). Less than 1% is excreted in the urine.
Mechanism of action
Anidulafungin inhibits glucan synthase, an enzyme important in the formation of (1→3)-β-D-glucan, a major fungal cell wall component. Glucan synthase is not present in mammalian cells, so it is an attractive target for antifungal activity.
Semisynthesis
Anidulafungin is manufactured via semi-synthesis. The starting material is echinocandin B (a lipopeptide fermentation product of Aspergillus nidulans or the closely related species, A. rugulosus), which undergoes deacylation (cleavage of the linoleoyl side chain) by the action of a deacylase enzyme from the bacterium Actinoplanes utahensis; in three subsequent synthetic steps, including a chemical reacylation, the antifungal drug anidulafungin is synthesized.
History
Anidulafungin was originally discovered at Lilly laboratories by Turner and Debono and licensed to Vicuron Pharmaceuticals who submitted it to the FDA. Pfizer acquired the drug upon its acquisition of Vicuron in the fall of 2005. Pfizer gained approval by the Food and Drug Administration (FDA) on February 21, 2006.
== References == |
Ketoconazole | Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candidiasis, pityriasis versicolor, dandruff, and seborrheic dermatitis. Taken by mouth it is a less preferred option and only recommended for severe infections when other agents cannot be used. Other uses include treatment of excessive male-patterned hair growth in women and Cushings syndrome.Common side effects when applied to the skin include redness. Common side effects when taken by mouth include nausea, headache, and liver problems. Liver problems may result in death or the need for a liver transplantation. Other severe side effects when taken by mouth include QT prolongation, adrenocortical insufficiency, and anaphylaxis. It is an imidazole and works by hindering the production of ergosterol required for the fungal cell membrane, thereby slowing growth.Ketoconazole was patented in 1977 by Belgian pharmaceutical company Janssen, and came into medical use in 1981. It is available as a generic medication and formulations that are applied to the skin are over the counter in the United Kingdom. In 2019, it was the 171st most commonly prescribed medication in the United States, with more than 3 million prescriptions. The formulation that is taken by mouth was withdrawn in the European Union and in Australia in 2013, and in China in 2015. In addition, its use was restricted in the United States and Canada in 2013.
Medical uses
Topical antifungal
Topically administered ketoconazole is usually prescribed for fungal infections of the skin and mucous membranes, such as athletes foot, ringworm, candidiasis (yeast infection or thrush), jock itch, and tinea versicolor. Topical ketoconazole is also used as a treatment for dandruff (seborrheic dermatitis of the scalp) and for seborrheic dermatitis on other areas of the body, perhaps acting in these conditions by suppressing levels of the fungus Malassezia furfur on the skin.
Systemic antifungal
Ketoconazole has activity against many kinds of fungi that may cause human disease, such as Candida, Histoplasma, Coccidioides, and Blastomyces (although it is not active against Aspergillus), chromomycosis and paracoccidioidomycosis. First made in 1977, ketoconazole was the first orally-active azole antifungal medication. However, ketoconazole has largely been replaced as a first-line systemic antifungal medication by other azole antifungal agents, such as itraconazole, because of ketoconazoles greater toxicity, poorer absorption, and more limited spectrum of activity.Ketoconazole is used orally in dosages of 200 to 400 mg per day in the treatment of superficial and deep fungal infections.
Off-label uses
Hair loss
Ketoconazole shampoo in conjunction with an oral 5α-reductase inhibitor such as finasteride or dutasteride has been used off label to treat androgenic alopecia. It was speculated that antifungal properties of ketoconazole reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia.Limited clinical studies suggest ketoconazole shampoo used either alone or in combination with other treatments may be useful in reducing hair loss in some cases.
Hormonal
The side effects of ketoconazole are sometimes harnessed in the treatment of non-fungal conditions. While ketoconazole blocks the synthesis of the sterol ergosterol in fungi, in humans, at high dosages (>800 mg/day), it potently inhibits the activity of several enzymes necessary for the conversion of cholesterol to steroid hormones such as testosterone and cortisol. Specifically, ketoconazole has been shown to inhibit cholesterol side-chain cleavage enzyme, which converts cholesterol to pregnenolone, 17α-hydroxylase and 17,20-lyase, which convert pregnenolone into androgens, and 11β-hydoxylase, which converts 11-deoxycortisol to cortisol. All of these enzymes are mitochondrial cytochrome p450 enzymes. Based on these antiandrogen and antiglucocorticoid effects, ketoconazole has been used with some success as a second-line treatment for certain forms of advanced prostate cancer and for the suppression of glucocorticoid synthesis in the treatment of Cushings syndrome. However, in the treatment of prostate cancer, concomitant glucocorticoid administration is needed to prevent adrenal insufficiency. Ketoconazole has additionally been used, in lower dosages, to treat hirsutism and, in combination with a GnRH analogue, male-limited precocious puberty. In any case, the risk of hepatotoxicity with ketoconazole limits its use in all of these indications, especially in those that are benign such as hirsutism.Ketoconazole has been used to prevent the testosterone flare at the initiation of GnRH agonist therapy in men with prostate cancer.
Contraindications
Oral ketoconazole has various contraindications, such as concomitant use with certain other drugs due to known drug interactions. Other contraindications of oral ketoconazole include liver disease, adrenal insufficiency, and known hypersensitivity to oral ketoconazole.
Side effects
Gastrointestinal
Vomiting, diarrhea, nausea, constipation, abdominal pain, upper abdominal pain, dry mouth, dysgeusia, dyspepsia, flatulence, tongue discoloration may occur.
Endocrine
The drug may cause adrenal insufficiency so the level of the adrenocortical hormones should be monitored while taking it. Oral ketoconazole at a dosage range of 400 to 2,000 mg/day has been found to result in a rate of gynecomastia of 21%.
Liver
In July 2013, the U.S. Food and Drug Administration (FDA) issued a warning that taking ketoconazole by mouth can cause severe liver injuries and adrenal gland problems: adrenal insufficiency and worsening of other related to the gland conditions. It recommends oral tablets should not be a first-line treatment for any fungal infection. It should be used for the treatment of certain fungal infections, known as endemic mycoses, only when alternative antifungal therapies are not available or tolerated. As contraindication it should not be used in people with acute or chronic liver disease.
Hypersensitivity
Anaphylaxis after the first dose may occur. Other cases of hypersensitivity include urticaria.
Topical formulations
The topical formulations have not been associated with liver damage, adrenal problems, or drug interactions. These formulations include creams, shampoos, foams, and gels applied to the skin, unlike the ketoconazole tablets, which are taken by mouth.
Pregnancy
Ketoconazole is categorized as pregnancy category C in the US. Research in animals has shown it to cause teratogenesis when administered in high doses. A subsequent trial in Europe failed to show a risk to infants of mothers receiving ketoconazole.
Overdose
In the event of an overdose of oral ketoconazole, treatment should be supportive and based on symptoms. Activated charcoal may be administered within the first hour following overdose of oral ketoconazole.
Interactions
The concomitant use of the following medications is contraindicated with ketoconazole tablets:
methadone, disopyramide, dronedarone
irinotecan, lurasidone, colchicine
alprazolam, oral midazolam, oral triazolam
felodipine, ranolazine, tolvaptan, eplerenone
HMG-CoA reductase inhibitors: lovastatin, simvastatin
ergot alkaloids: ergotamine, dihydroergotamine, ergometrine, methylergometrine
Others: cisapride, nisoldipine, dofetilide, pimozideAnd is not recommended:
carbamazepine, phenytoin
gastric acid suppressants: antacids, antimuscarinics, histamine H2 blockers, proton pump inhibitors
sucralfate
rifampin, rifabutin, isoniazid
efavirenz, nevirapineRitonavir is known for increasing activity of the ketoconazole so it is recommended to reduce dosage.There is also a list of drugs which significantly decrease systemic exposure to the ketoconazole and drugs whose systemic exposure is increased by the ketoconazole.
Pharmacology
Pharmacodynamics
Antifungal activity
As an antifungal, ketoconazole is structurally similar to imidazole, and interferes with the fungal synthesis of ergosterol, a constituent of fungal cell membranes, as well as certain enzymes. As with all azole antifungal agents, ketoconazole works principally by inhibiting the enzyme cytochrome P450 14α-demethylase (CYP51A1). This enzyme participates in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Lower doses of fluconazole and itraconazole are required to kill fungi compared to ketoconazole, as they have been found to have a greater affinity for fungal cell membranes.
Resistance to ketoconazole has been observed in a number of clinical fungal isolates, including Candida albicans. Experimentally, resistance usually arises as a result of mutations in the sterol biosynthesis pathway. Defects in the sterol 5-6 desaturase enzyme reduce the toxic effects of azole inhibition of the 14-alpha demethylation step. Multidrug-resistance (MDR) genes can also play a role in reducing cellular levels of the drug. As azole antifungals all act at the same point in the sterol pathway, resistant isolates are normally cross-resistant to all members of the azole family.
Antihormonal activity
As an antiandrogen, ketoconazole operates through at least two mechanisms of action. First, and most notably, high oral doses of ketoconazole (e.g. 40 mg three times per day) block both testicular and adrenal androgen biosynthesis, leading to a reduction in circulating testosterone levels. It produces this effect through inhibition of 17α-hydroxylase and 17,20-lyase, which are involved in the synthesis and degradation of steroids, including the precursors of testosterone. Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used with some success as a treatment for androgen-dependent prostate cancer. Second, ketoconazole is an androgen receptor antagonist, competing with androgens such as testosterone and dihydrotestosterone (DHT) for binding to the androgen receptor. This effect is thought to be quite weak however, even with high oral doses of ketoconazole.Ketoconazole, along with miconazole, has been found to act as an antagonist of the glucocorticoid receptor.Ketoconazole is a racemic mixture consisting of cis-(2S,4R)-(−) and cis-(2R,4S)-(+) enantiomers. The cis-(2S,4R) isomer was more potent in inhibiting progesterone 17α,20-lyase than its enantiomer (IC50 values of 0.05 and 2.38 μM, respectively) and in inhibiting 11β-hydroxylase (IC50 values of 0.152 and 0.608 μM, respectively). Both isomers were relatively weak inhibitors of human placental aromatase.Oral ketoconazole has been used clinically as a steroidogenesis inhibitor in men, women, and children at dosages of 200 to 1,200 mg/day. Numerous small studies have investigated the effects of oral ketoconazole on hormone levels in humans. It has been found in men to significantly decrease testosterone and estradiol levels and to significantly increase luteinizing hormone, progesterone, and 17α-hydroxyprogesterone levels, whereas levels of androstenedione, follicle-stimulating hormone, and prolactin were unaffected. The ratio of testosterone to estradiol is also decreased during oral ketoconazole therapy in men. Suppression of testosterone levels by ketoconazole is generally partial and has often been found to be transient. Better effects on suppression of testosterone levels have been observed in men when ketoconazole is combined with a GnRH agonist to suppress the hypothalamic–pituitary–gonadal axis, which prevents compensatory upregulation of luteinizing hormone secretion and consequent activation of gonadal testosterone production. In premenopausal women with polycystic ovary syndrome, ketoconazole has been found to significantly decrease levels of androstenedione and testosterone and significantly increase levels of 17α-hydroxyprogesterone and estradiol. Studies in postmenopausal women with breast cancer have found that ketoconazole significantly decreases androstenedione levels, slightly decreases estradiol levels, and does not affect estrone levels. This indicates minimal inhibition of aromatase by ketoconazole in vivo in humans. Ketoconazole has also been found to decrease levels of endogenous corticosteroids, such as cortisol, corticosterone, and aldosterone, as well as vitamin D.Ketoconazole has been found to displace dihydrotestosterone and estradiol from sex hormone-binding globulin in vitro, but this was not found to be relevant in vivo.
Other activities
Ketoconazole has been found to inhibit the activity of the cation channel TRPM5.
Pharmacokinetics
When administered orally, ketoconazole is best absorbed at highly acidic levels, so antacids or other causes of decreased stomach acid levels will lower the drugs absorption. Absorption can be increased by taking it with an acidic beverage, such as cola. Ketoconazole is very lipophilic and tends to accumulate in fatty tissues.
Chemistry
Ketoconazole is a synthetic imidazole. It is a nonsteroidal compound. It is a racemic mixture of two enantiomers, levoketoconazole ((2S,4R)-(−)-ketoconazole) and dextroketoconazole ((2R,4S)-(+)-ketoconazole). Levoketoconazole is under development for potential clinical use as a steroidogenesis inhibitor with better tolerability and less toxicity than ketoconazole. Other steroidogenesis inhibitors besides ketoconazole and levoketoconazole include the nonsteroidal compound aminoglutethimide and the steroidal compound abiraterone acetate.
History
Ketoconazole was discovered in 1976 at Janssen Pharmaceuticals. It was patented in 1977, followed by introduction in the United States in July 1981. Following its introduction, ketoconazole was the only systemic antifungal available for almost a decade. Ketoconazole was introduced as the prototypical medication of the imidazole group of antifungals. Oral ketoconazole has been replaced with oral itraconazole for many mycoses.Due to incidence of serious liver toxicity, the use of oral ketoconazole was suspended in France in July 2011 following review. This event triggered an evaluation of oral ketoconazole throughout the rest of the European Union as well. In 2013, oral ketoconazole was withdrawn in Europe and Australia, and strict restrictions were placed on the use of oral ketoconazole in the United States and Canada. Oral ketoconazole is now only indicated for use in these countries when the indication is a severe or life-threatening systemic infection and alternatives are unavailable. However, topical ketoconazole, which does not distribute systemically, is safe and widely used still.Ketoconazole HRA was approved for use in the European Union for treatment of Cushings syndrome in November 2013.As of March 2019, oral levoketoconazole (developmental code name COR-003, tentative brand name Recorlev) is phase III clinical trials for the treatment of Cushings syndrome. Oral levoketoconazole may have a lower risk of liver toxicity than oral ketoconazole.
Society and culture
Generic names
Ketoconazole is the generic name of the drug and its INN, USAN, BAN, and JAN.
Brand names
Ketoconazole has been marketed under a large number of brand names.
Availability
Ketoconazole is available widely throughout the world.In 2013, the European Medicines Agencys Committee on Medicinal Products for Human Use (CHMP) recommended that a ban be imposed on the use of oral ketoconazole for systemic use in humans throughout the European Union, after concluding that the risk of serious liver injury from systemic ketoconazole outweighs its benefits.
Veterinary use
Ketoconazole is sometimes prescribed as an antifungal by veterinarians for use in pets, often as unflavored tablets that may need to be cut to smaller size for correct dosage.
References
External links
"Ketoconazole". Drug Information Portal. U.S. National Library of Medicine. |
Subsets and Splits
No saved queries yet
Save your SQL queries to embed, download, and access them later. Queries will appear here once saved.