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Ibuprofen/famotidine | Ibuprofen/famotidine, sold under the brand name Duexis, is a fixed-dose combination medication used for the treatment of rheumatoid arthritis and osteoarthritis. It contains ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID) and famotidine, a histamine H2-receptor antagonist.
References
Further reading
Deeks ED (September 2013). "Fixed-dose ibuprofen/famotidine: a review of its use to reduce the risk of gastric and duodenal ulcers in patients requiring NSAID therapy". Clin Drug Investig. 33 (9): 689–97. doi:10.1007/s40261-013-0113-x. PMID 23881568. S2CID 24972423.
Schiff M, Peura D (February 2012). "HZT-501 (Duexis; ibuprofen 800 mg/famotidine 26.6 mg) gastrointestinal protection in the treatment of the signs and symptoms of rheumatoid arthritis and osteoarthritis". Expert Rev Gastroenterol Hepatol. 6 (1): 25–35. doi:10.1586/egh.11.88. PMID 22149579. S2CID 46369253.
External links
"Famotidine mixture with ibuprofen". Drug Information Portal. U.S. National Library of Medicine. |
Histrelin | Histrelin acetate, sold under the brand names Vantas and Supprelin LA among others, is a nonapeptide analogue of gonadotropin-releasing hormone (GnRH) with added potency. When present in the bloodstream, it acts on particular cells of the pituitary gland called gonadotropes. Histrelin stimulates these cells to release luteinizing hormone and follicle-stimulating hormone. Thus it is considered a gonadotropin-releasing hormone agonist or GnRH agonist.
Medical uses
Histrelin is used to treat hormone-sensitive cancers of the prostate in men and uterine fibroids in women. In addition, histrelin has been proven to be highly effective in treating central precocious puberty in children.It is available as a daily intramuscular injection.
Histrelin is also available in a 12-month subcutaneous implant (Vantas) for the palliative treatment of advanced prostate cancer, since 2005 in the US, and since Jan 2010 in the UK.
A 12-month subcutaneous implant (Supprelin LA) for central precocious puberty (CPP) was approved on May 3, 2007 by the U.S. Food and Drug Administration.
Histrelin can be part of the primary care protocol in transgender children/youth, which is an off-label use in the USA and the UK, and is used in suppressing cis-sex puberty, until the patient is ready to begin cross-sex hormonal therapy. It is also sometimes prescribed to transgender adults who benefit from having their sex hormone production halted.
Side effects
Side effects are mainly due to low testosterone levels and include headache, hot flashes, reduced libido, and erectile dysfunction.
Pharmacology
In a process known as downregulation, daily stimulation of pituitary gonadotropes causes them to become desensitized to the effects of histrelin. As a consequence, levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) fall after a short period of time. From that point forward, as long as histrelin is administered, the levels of LH and FSH in the blood remain low.This prolonged lowering of LH and FSH levels is the rationale for therapy using GnRH agonists. Since LH and FSH stimulate the gonads to produce estrogens and androgens in females and males respectively, histrelin can effectively be used to decrease the sex steroids in the blood of patients.
See also
Gonadotropin-releasing hormone receptor § Agonists
References
External links
Central Precocious Puberty |
Levorphanol | Levorphanol (brand name Levo-Dromoran) is an opioid medication used to treat moderate to severe pain. It is one of two enantiomers of the compound racemorphan.
It was first described in Germany in 1946. The drug has been in medical use in the United States since 1953.
Pharmacology
Levorphanol acts predominantly as an agonist of the μ-opioid receptor (MOR), but is also an agonist of the δ-opioid receptor (DOR), κ-opioid receptor (KOR), and the nociceptin receptor (NOP), as well as an NMDA receptor antagonist and a serotonin-norepinephrine reuptake inhibitor (SNRI). Levorphanol, similarly to certain other opioids, also acts as a glycine receptor antagonist and GABA receptor antagonist at very high concentrations. Levorphanol is 6 to 8 times as potent as morphine at the MOR.Relative to morphine, levorphanol lacks complete cross-tolerance and possesses greater intrinsic activity at the MOR. The duration of action is generally long compared to other comparable analgesics and varies from 4 hours to as much as 15 hours. For this reason levorphanol is useful in palliation of chronic pain and similar conditions. Levorphanol has an oral to parenteral effectiveness ratio of 2:1, one of the most favorable of the strong narcotics. Its antagonism of the NMDA receptor, similar to those of the phenylheptylamine open-chain opioids such as methadone or the phenylpiperidine ketobemidone, make levorphanol useful for types of pain that other analgesics may not be as effective against, such as neuropathic pain. Levorphanols exceptionally high analgesic efficacy in the treatment of neuropathic pain is also conferred by its action on serotonin and norepinephrine transporters, similar to the opioids tramadol and tapentadol, and mutually complements the analgesic effect of its NMDA receptor antagonism.Levorphanol shows a high rate of psychotomimetic side effects such as hallucinations and delirium, which have been attributed to its binding to and activation of the KOR. At the same time however, activation of this receptor as well as of the DOR have been determined to contribute to its analgesic effects.
Chemistry
Chemically, levorphanol belongs to the morphinan class and is (−)-3-hydroxy-N-methyl-morphinan. It is the "left-handed" (levorotatory) stereoisomer of racemorphan, the racemic mixture of the two stereoisomers with differing pharmacology. The "right-handed" (dextrorotatory) enantiomer of racemorphan is dextrorphan (DXO), an antitussive, potent dissociative hallucinogen (NMDA receptor antagonist), and weakly active opioid. DXO is an active metabolite of the pharmaceutical drug dextromethorphan (DXM), which, analogously to DXO, is an enantiomer of the racemic mixture racemethorphan along with levomethorphan, the latter of which has similar properties to those of levorphanol.
Society and culture
Name
Levorphanol is the INN, BAN, and DCF. As the medically used tartrate salt, the drug is also known as levorphanol tartrate (USAN, BANM). The former developmental code name of levorphanol at Roche was Ro 1-5431.
Availability
As the tartrate salt, levorphanol is marketed by Sentynl Therapeutics and Virtus Pharmaceuticals in the U.S., and Canada under the brand name Levo-Dromoran.
Legality
Levorphanol is listed under the Single Convention On Narcotic Drugs 1961 and is regulated like morphine in most countries. In the U.S., it is a Schedule II Narcotic controlled substance with a DEA ACSCN of 9220 and 2013 annual aggregate manufacturing quota of 4.5 kilos. The salts in use are the tartrate (free base conversion ratio 0.58) and hydrobromide (0.76).
See also
Cough syrup
Racemorphan; Dextrorphan;
Noscapine
Codeine; Pholcodine
Dextromethorphan; Dimemorfan
Butamirate
Pentoxyverine
Tipepidine
Cloperastine; Levocloperastine
== References == |
Paricalcitol | Paricalcitol (chemically it is 19-nor-1,25-(OH)2-vitamin D2. Marketed by Abbott Laboratories under the trade name Zemplar) is a drug used for the prevention and treatment of secondary hyperparathyroidism (excessive secretion of parathyroid hormone) associated with chronic kidney failure. It is an analog of 1,25-dihydroxyergocalciferol, the active form of vitamin D2 (ergocalciferol).
It was patented in 1989 and approved for medical use in 1998.
Medical uses
Its primary use in medicine is in the treatment of secondary hyperparathyroidism associated with chronic kidney disease. However current evidence is not sufficient to demonstrate an advantage of paricalcitol over non-selective vitamin D derivatives for this indication.
Adverse effects
Adverse effects by frequency:Very common (>10% frequency):
NauseaCommon (1-10% frequency):
Uncommon (0.1-1% frequency):
‡ These are adverse effects only seen in patients with grade 3 or 4 chronic kidney disease.
† These are adverse effects only seen in patients with grade 5 chronic kidney disease.
Contraindications
Contraindications include:
Vitamin D intoxication
Hypercalcaemia
Hypersensitivity to paricalcitol or any of its excipientswhereas cautions include:
Impaired liver function
It is also advised that physicians regularly monitor their patients calcium and phosphorus levels.
Interactions
Drugs that may interact with paricalcitol include:
Overdose
Electrolyte abnormalities (e.g. hypercalcaemia and hyperphosphataemia) are common overdose symptoms. Treatment is mostly supportive, with particular attention being paid to correcting electrolyte anomalies and reducing intake of calcium in both the form of supplementation and diet. As it is so heavily bound to plasma proteins haemodialysis is unlikely to be helpful in cases of overdose.Early symptoms of overdose can include:
It is worth noting, however, that may of these symptoms are also indicative of kidney failure and hence may be masked by the patients condition.Late symptoms of overdose include:
Mechanism of action
Like 1,25-dihydroxyergocalciferol, paricalcitol acts as an agonist at the vitamin D receptor and thereby lowers parathyroid hormone levels in the blood.
Pharmacokinetics
The plasma concentration of paricalcitol decreases rapidly and log-linearly within two hours after initial intravenous administration. Therefore, it is not expected to accumulate with multiple dosing, since paricalcitol is usually given no more frequently than every other day (3 times per week).
== References == |
Dimethyl sulfoxide | Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula (CH3)2SO. This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water. It has a relatively high boiling point. DMSO has the unusual property that many individuals perceive a garlic-like taste in the mouth after DMSO makes contact with their skin.In terms of chemical structure, the molecule has idealized Cs symmetry. It has a trigonal pyramidal molecular geometry consistent with other three-coordinate S(IV) compounds, with a nonbonded electron pair on the approximately tetrahedral sulfur atom.
Synthesis and production
Dimethyl sulfoxide was first synthesized in 1866 by the Russian scientist Alexander Zaytsev, who reported his findings in 1867. Dimethyl sulfoxide is produced industrially from dimethyl sulfide, a by-product of the Kraft process, by oxidation with oxygen or nitrogen dioxide.
Reactions
Reactions with electrophiles
The sulfur center in DMSO is nucleophilic toward soft electrophiles and the oxygen is nucleophilic toward hard electrophiles. With methyl iodide it forms trimethylsulfoxonium iodide, [(CH3)3SO]I:
(CH3)2SO + CH3I → [(CH3)3SO]IThis salt can be deprotonated with sodium hydride to form the sulfur ylide:
[(CH3)3SO]I + NaH → (CH3)2S(CH2)O + NaI + H2
Acidity
The methyl groups of DMSO are only weakly acidic, with a pKa = 35. For this reason, the basicities of many weakly basic organic compounds have been examined in this solvent.
Deprotonation of DMSO requires strong bases like lithium diisopropylamide and sodium hydride. Stabilization of the resultant carbanion is provided by the S(O)R group. The sodium derivative of DMSO formed in this way is referred to as dimsyl sodium. It is a base, e.g., for the deprotonation of ketones to form sodium enolates, phosphonium salts to form Wittig reagents, and formamidinium salts to form diaminocarbenes. It is also a potent nucleophile.
Oxidant
In organic synthesis, DMSO is used as a mild oxidant. It forms the basis of several selective sulfonium-based oxidation reactions include the Pfitzner–Moffatt oxidation, Corey–Kim oxidation and the Swern oxidation.
The Kornblum oxidation is conceptually similar. These all involve formation an intermediate sulfonium species (R2S+X where X is a heteroatom)
Ligand and Lewis base
Related to its ability to dissolve many salts, DMSO is a common ligand in coordination chemistry. Illustrative is the complex dichlorotetrakis(dimethyl sulfoxide)ruthenium(II) (RuCl2(dmso)4). In this complex, three DMSO ligands are bonded to ruthenium through sulfur. The fourth DMSO is bonded through oxygen. In general, the oxygen-bonded mode is more common.
In carbon tetrachloride solutions DMSO functions as a Lewis base with a variety of Lewis acids such as I2, phenols, trimethyltin chloride, metalloporphyrins, and the dimer Rh2Cl2(CO)4. The donor properties are discussed in the ECW model. The relative donor strength of DMSO toward a series of acids, versus other Lewis bases, can be illustrated by C-B plots.
Applications
Solvent
DMSO is a polar aprotic solvent and is less toxic than other members of this class, such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, and hexamethylphosphoramide (HMPA). DMSO is frequently used as a solvent for chemical reactions involving salts, most notably Finkelstein reactions and other nucleophilic substitutions. It is also extensively used as an extractant in biochemistry and cell biology. Because DMSO is only weakly acidic, it tolerates relatively strong bases and as such has been extensively used in the study of carbanions. A set of non-aqueous pKa values (C-H, O-H, S-H and N-H acidities) for thousands of organic compounds have been determined in DMSO solution.Because of its high boiling point, 189 °C (372 °F), DMSO evaporates slowly at normal atmospheric pressure. Samples dissolved in DMSO cannot be as easily recovered compared to other solvents, as it is very difficult to remove all traces of DMSO by conventional rotary evaporation. One technique to fully recover samples is removal of the organic solvent by evaporation followed by addition of water (to dissolve DMSO) and cryodesiccation to remove both DMSO and water. Reactions conducted in DMSO are often diluted with water to precipitate or phase-separate products. The relatively high freezing point of DMSO, 18.5 °C (65.3 °F), means that at, or just below, room temperature it is a solid, which can limit its utility in some chemical processes (e.g. crystallization with cooling).
In its deuterated form (DMSO-d6), it is a useful solvent for NMR spectroscopy, again due to its ability to dissolve a wide range of analytes, the simplicity of its own spectrum, and its suitability for high-temperature NMR spectroscopic studies. Disadvantages to the use of DMSO-d6 are its high viscosity, which broadens signals, and its hygroscopicity, which leads to an overwhelming H2O resonance in the 1H-NMR spectrum. It is often mixed with CDCl3 or CD2Cl2 for lower viscosity and melting points.
DMSO is also used to dissolve test compounds in in vitro drug discovery and drug design screening programs, including high-throughput screening programs. This is because it is able to dissolve both polar and nonpolar compounds, can be used to maintain stock solutions of test compounds (important when working with a large chemical library), is readily miscible with water and cell culture media, and has a high boiling point (this improves the accuracy of test compound concentrations by reducing room temperature evaporation). One limitation with DMSO is that it can affect cell line growth and viability, with low DMSO concentrations sometimes stimulating cell growth, and high DMSO concentrations sometimes inhibiting or killing cells.DMSO is used as a vehicle in in vivo studies of test compounds too. It has, for example, been employed as a co-solvent to assist absorption of the flavonol glycoside Icariin in the nematode worm Caenorhabditis elegans. As with its use in in vitro studies, DMSO has some limitations in animal models. Pleiotropic effects can occur and, if DMSO control groups are not carefully planned, then solvent effects can falsely be attributed to the prospective drug. For example, even a very low dose of DMSO has a powerful protective effect against paracetamol (acetaminophen)-induced liver injury in mice.In addition to the above, DMSO is finding increased use in manufacturing processes to produce microelectronic devices. It is widely used to strip photoresist in TFT-LCD flat panel displays and advanced packaging applications (such as wafer-level packaging / solder bump patterning). DMSO is an effective paint stripper too, being safer than many of the others such as nitromethane and dichloromethane.
Biology
DMSO is used in polymerase chain reaction (PCR) to inhibit secondary structures in the DNA template or the DNA primers. It is added to the PCR mix before reacting, where it interferes with the self-complementarity of the DNA, minimizing interfering reactions.DMSO in a PCR is applicable for supercoiled plasmids (to relax before amplification) or DNA templates with high GC-content (to decrease thermostability). For example, 10% final concentration of DMSO in the PCR mixture with Phusion decreases primer annealing temperature (i.e. primer melting temperature) by 5.5–6.0 °C (9.9–10.8 °F).It is well known as a reversible cell cycle arrester at phase G1 of human lymphoid cells.DMSO may also be used as a cryoprotectant, added to cell media to reduce ice formation and thereby prevent cell death during the freezing process. Approximately 10% may be used with a slow-freeze method, and the cells may be frozen at −80 °C (−112 °F) or stored in liquid nitrogen safely.
In cell culture, DMSO is used to induce differentiation of P19 embryonic carcinoma cells into cardiomyocytes and skeletal muscle cells.
Medicine
Use of DMSO in medicine dates from around 1963, when an Oregon Health & Science University Medical School team, headed by Stanley Jacob, discovered it could penetrate the skin and other membranes without damaging them and could carry other compounds into a biological system. In medicine, DMSO is predominantly used as a topical analgesic, a vehicle for topical application of pharmaceuticals, as an anti-inflammatory, and an antioxidant. Because DMSO increases the rate of absorption of some compounds through biological tissues, including skin, it is used in some transdermal drug delivery systems. Its effect may be enhanced with the addition of EDTA. It is frequently compounded with antifungal medications, enabling them to penetrate not just skin but also toenails and fingernails.DMSO has been examined for the treatment of numerous conditions and ailments, but the U.S. Food and Drug Administration (FDA) has approved its use only for the symptomatic relief of patients with interstitial cystitis. A 1978 study concluded that DMSO brought significant relief to the majority of the 213 patients with inflammatory genitourinary disorders that were studied. The authors recommended DMSO for genitourinary inflammatory conditions not caused by infection or tumor in which symptoms were severe or patients failed to respond to conventional therapy.
In interventional radiology, DMSO is used as a solvent for ethylene vinyl alcohol in the Onyx liquid embolic agent, which is used in embolization, the therapeutic occlusion of blood vessels.
In cryobiology DMSO has been used as a cryoprotectant and is still an important constituent of cryoprotectant vitrification mixtures used to preserve organs, tissues, and cell suspensions. Without it, up to 90% of frozen cells will become inactive. It is particularly important in the freezing and long-term storage of embryonic stem cells and hematopoietic stem cells, which are often frozen in a mixture of 10% DMSO, a freezing medium, and 30% fetal bovine serum. In the cryogenic freezing of heteroploid cell lines (MDCK, VERO, etc.) a mixture of 10% DMSO with 90% EMEM (70% EMEM + 30% fetal bovine serum + antibiotic mixture) is used. As part of an autologous bone marrow transplant the DMSO is re-infused along with the patients own hematopoietic stem cells.
DMSO is metabolized by disproportionation to dimethyl sulfide and dimethyl sulfone. It is subject to renal and pulmonary excretion. A possible side effect of DMSO is therefore elevated blood dimethyl sulfide, which may cause a blood borne halitosis symptom.
Alternative medicine
DMSO is marketed as an alternative medicine. Its popularity as an alternative cure is stated to stem from a 60 Minutes documentary in 1980 featuring an early proponent. However, DMSO is an ingredient in some products listed by the U.S. FDA as fake cancer cures and the FDA has had a running battle with distributors. One such distributor is Mildred Miller, who promoted DMSO for a variety of disorders and was consequently convicted of Medicare fraud.The use of DMSO as an alternative treatment for cancer is of particular concern, as it has been shown to interfere with a variety of chemotherapy drugs, including cisplatin, carboplatin, and oxaliplatin. There is insufficient evidence to support the hypothesis that DMSO has any effect, and most sources agree that its history of side effects when tested warrants caution when using it as a dietary supplement, for which it is marketed heavily with the usual disclaimer.
Veterinary medicine
DMSO is commonly used in veterinary medicine as a liniment for horses, alone or in combination with other ingredients. In the latter case, often, the intended function of the DMSO is as a solvent, to carry the other ingredients across the skin. Also in horses, DMSO is used intravenously, again alone or in combination with other drugs. It is used alone for the treatment of increased intracranial pressure and/or cerebral edema in horses.
Taste
The perceived garlic taste upon skin contact with DMSO may be due to nonolfactory activation of TRPA1 receptors in trigeminal ganglia. Unlike dimethyl and diallyl disulfides (which have odors resembling garlic), mono- and tri- sulfides (which typically have foul odors), and similar odiferous sulfur compounds, the pure chemical DMSO is odorless.
Safety
Toxicity
DMSO is a non-toxic solvent with a median lethal dose higher than ethanol (DMSO: LD50, oral, rat, 14,500 mg/kg; ethanol: LD50, oral, rat, 7,060 mg/kg).
Early clinical trials with DMSO were stopped because of questions about its safety, especially its ability to harm the eye. The most commonly reported side effects include headaches and burning and itching on contact with the skin. Strong allergic reactions have been reported. DMSO can cause contaminants, toxins, and medicines to be absorbed through the skin, which may cause unexpected effects. DMSO is thought to increase the effects of blood thinners, steroids, heart medicines, sedatives, and other drugs. In some cases this could be harmful or dangerous.In Australia, it is listed as a Schedule 4 (S4) Drug, and a company has been prosecuted for adding it to products as a preservative.Because DMSO easily penetrates the skin, substances dissolved in DMSO may be quickly absorbed. Glove selection is important when working with DMSO. Butyl rubber, fluoroelastomer, neoprene, or thick (15 mil / 0.4 mm) latex gloves are recommended. Nitrile gloves, which are very commonly used in chemical laboratories, may protect from brief contact but have been found to degrade rapidly with exposure to DMSO.On September 9, 1965, The Wall Street Journal reported that a manufacturer of the chemical warned that the death of an Irish woman after undergoing DMSO treatment for a sprained wrist may have been due to the treatment, although no autopsy was done, nor was a causal relationship established. Clinical research using DMSO was halted and did not begin again until the National Academy of Sciences (NAS) published findings in favor of DMSO in 1972. In 1978, the US FDA approved DMSO for treating interstitial cystitis. In 1980, the US Congress held hearings on claims that the FDA was slow in approving DMSO for other medical uses. In 2007, the US FDA granted "fast track" designation on clinical studies of DMSOs use in reducing brain tissue swelling following traumatic brain injury. DMSO exposure to developing mouse brains can produce brain degeneration. This neurotoxicity could be detected at doses as low as 0.3 mL/kg, a level exceeded in children exposed to DMSO during bone marrow transplant.DMSO disposed into sewers can also cause odor problems in municipal effluents: waste water bacteria transform DMSO under hypoxic (anoxic) conditions into dimethyl sulfide (DMS) that has a strong disagreeable odor, similar to rotten cabbage. However, chemically pure DMSO is odorless because of the lack of C-S-C (sulfide) and C-S-H (mercaptan) linkages. Deodorization of DMSO is achieved by removing the odorous impurities it contains.
Explosion hazard
Dimethyl sulfoxide can produce an explosive reaction when exposed to acyl chlorides; at a low temperature, this reaction produces the oxidant for Swern oxidation.
DMSO can decompose at the boiling temperature of 189 °C at normal pressure, possibly leading to an explosion. The decomposition is catalyzed by acids and bases and therefore can be relevant at even lower temperatures. A strong to explosive reaction also takes place in combination with halogen compounds, metal nitrides, metal perchlorates, sodium hydride, periodic acid and fluorinating agents.
See also
Varying oxidation of sulfur
Dimethyl sulfide (DMS), the corresponding sulfide, also produced by marine phytoplankton and emitted to the oceanic atmosphere where it is oxidized to DMSO, SO2 and sulfate
Dimethyl sulfone, commonly known as methylsulfonylmethane (MSM), a related chemical often marketed as a dietary supplement
Related compounds with methyl on oxygen
Dimethyl sulfite, the corresponding sulfite
Dimethyl sulfate (also DMS), the corresponding sulfate: a mutagenic alkylating compound
Methyl methanesulfonate, another methylating agent
Gloria Ramirez, also known as the "Toxic Woman"
References
External links
International Chemical Safety Card 0459
Dimethyl Sulfoxide Information Center |
Olmesartan/amlodipine/hydrochlorothiazide | Olmesartan/amlodipine/hydrochlorothiazide, sold under the brand name Tribenzor, is a fixed-dose combination medication used to treat high blood pressure. It contains olmesartan medoxomil, an angiotensin-2 receptor antagonist (ARB or A2A), amlodipine, a calcium channel blocker, and hydrochlorothiazide, a diuretic. It is taken by mouth.
References
External links
"Amlodipine mixture with hydrochlorothiazide and olmesartan medoxomil". Drug Information Portal. U.S. National Library of Medicine. |
Pantoprazole | Pantoprazole, sold under the brand name Protonix, among others, is a proton pump inhibitor used for the treatment of stomach ulcers, short-term treatment of erosive esophagitis due to gastroesophageal reflux disease (GERD), maintenance of healing of erosive esophagitis, and pathological hypersecretory conditions including Zollinger–Ellison syndrome. It may also be used along with other medications to eliminate Helicobacter pylori. Effectiveness is similar to other proton pump inhibitors (PPIs). It is available by mouth and by injection into a vein.Common side effects include headaches, diarrhea, vomiting, abdominal pain, and joint pain. More serious side effects may include severe allergic reactions, a type of chronic inflammation known as atrophic gastritis, Clostridium difficile colitis, low magnesium, and vitamin B12 deficiency. Use in pregnancy appears to be safe. Pantoprazole is a proton pump inhibitor that decreases gastric acid secretion. It works by inactivating (H+/K+)-ATPase function in the stomach.Study of pantoprazole began in 1985, and it came into medical use in Germany in 1994. It is available as a generic medication. In 2020, it was the twentieth most commonly prescribed medication in the United States, with more than 26 million prescriptions.
Medical uses
Pantoprazole is used for short-term treatment of erosion and ulceration of the esophagus for adults and children five years of age and older caused by gastroesophageal reflux disease. It can be used as a maintenance therapy for long-term use after initial response is obtained, but there have not been any controlled studies about the use of pantoprazole past a duration of 12 months. Pantoprazole may also be used in combination with antibiotics to treat ulcers caused by Helicobacter pylori. It can also be used for long-term treatment of Zollinger-Ellison syndrome. It may be used to prevent gastric ulcers in those taking NSAIDs.For improved efficacy of pantoprazole, the oral tablet formulation is taken half an hour prior to ingestion of food. In the hospital, intravenous administration is indicated when patients are unable to take the medication by mouth.
Children
Pantoprazole is only indicated for the short-term treatment of erosive esophagitis in children ages seven and older; and the safety and effectiveness of pantoprazole have only been established in the treatment of erosive esophagitis in children.
Elderly
The incidence of adverse effects occurring in people aged 65 years and older was similar to that in people aged 65 years and less.
Pregnancy
In reproductive studies using doses largely greater than the recommended doses performed on rats and rabbits, there was no evident harm on the development of the baby.
Breast feeding
Pantoprazole has been found to pass through the breast milk. However, in rodent cancer studies, pantoprazole has been shown to potentially cause tumor growth. The clinical relevance of the finding is unknown, but risks and benefits are recommended for consideration in determining the use of therapy for the mother and child.
Adverse effects
Infection: Stomach acid plays a role in killing ingested bacteria. Use of pantoprazole may increase the chance of developing infections such as pneumonia, particularly in hospitalized patients.
Common
Gastrointestinal: abdominal pain (6%), diarrhea (9%), flatulence (4%), nausea (7%), vomiting (4%)
Neurologic: headache (12%), dizziness (3%)
Neuromuscular and skeletal: arthralgia (3%)
Rare
Gastrointestinal: constipation, dry mouth, hepatitis
Blood problems: low white blood cell count, thrombocytopenia
Immunologic: Stevens–Johnson syndrome, toxic epidermal necrolysis
Metabolic: elevated creatine kinase, elevated cholesterol levels, elevated liver enzymes (AST/ALT), swelling
Musculoskeletal: Muscle disorders, bone fracture and infection, Clostridium difficile infection, osteoporosis-related hip fracture, rhabdomyolysis
Kidneys: interstitial nephritis
Nutrition: may reduce the absorption of important nutrients, vitamins, and minerals, including certain medications, leaving users at increased risk for pneumonia.
Long-term use
Osteoporosis and bone fracture have been observed in people on high-dose and/or long-term (over one year) prescription proton pump inhibitors.
Hypomagnesia has been observed in people on medications like pantoprazole when taken for longer periods of time (generally one year or more, although cases have been reported with regimens as short as three months).
Deficiencies such as vitamin B12 deficiency, iron deficiency, and calcium deficiency may be seen with long term use. Vitamin B12 deficiency is due to the change in the acidic environment within the stomach with the use of pantoprazole which prevents peptidases from being activated. This prevents the cleaving of R-factor from vitamin B12 and prevents its absorption.
Rebound hypergastrinemia may be seen when stopping the medication after long term use.
Discontinuation
In people taking PPIs for longer than six months, a dose taper should be considered prior to discontinuation. For those on a moderate to high dose, this can be done by 50 percent every week until on the lowest dose. After a week it can then be stopped.
Interactions
Due to its effect of reducing stomach acidity, use of pantoprazole can affect absorption of drugs that are pH-sensitive, such as ampicillin esters, ketoconazole, atazanavir, iron salts, amphetamine and mycophenolate mofetil.Additional medications that are affected include bisphosphonate derivatives, fluconazole, clopidogrel, and methotrexate.
Pharmacology
The mechanism of action of pantoprazole is to inhibit the final step in gastric acid production. In the gastric parietal cell of the stomach, pantoprazole covalently binds to the H+/K+ ATP pump to inhibit gastric acid and basal acid secretion. The covalent binding prevents acid secretion for up to 24 hours and longer.Pantoprazole is metabolized in the liver by the cytochrome P450 system. Metabolism mainly consists of demethylation by CYP2C19 followed by sulfation. Another metabolic pathway is oxidation by CYP3A4. Pantoprazole metabolites are not thought to have any pharmacological significance. It is usually given with a prokinetic drug because of inactivity in the acidic environment of the stomach. Pantoprazole binds irreversibly to H+K+ATPase (proton pumps) to suppress the secretion of acid. Due to irreversible binding of the pumps, new pumps have to be made before acid production can be resumed. The drugs plasma half-life is about two hours. After administration, the time for the drug to reach peak plasma concentrations is 2 to 3 hours. The percentage of the drug that is protein bound is 98%.In veterinary medicine, pantoprazole appears to be safe to use in several large animal species. The pharmacokinetics of pantoprazole have been explored in several veterinary species, including calves, alpacas and foals with half lives reported as 2.81, 0.47, and 1.43 hours, respectively. Pantoprazole appears to be eliminated more quickly in goats when compared to calves, with goats having an elimination half-life of less than one hour.
History
Pantoprazole was discovered by scientists at Byk Gulden, a subsidiary of Altana; the drug discovery program started in 1980, producing pantoprazole in 1985. The compound was actually created by chemists working on scale-up of a different chemical that had been chosen as a development candidate.: 117, 129 Byk Gulden partnered with Smith Kline & French in 1984.: 124 The compounds development names were BY1029 and SK&F96022.: 123 By 1986 the companies had created the sodium salt, pantoprazole sodium sesquihydrate, and decided to develop it as it was more soluble and stable, and was more compatible with other ingredients used in the formulation.: 130 It was first marketed in Germany in 1994.: 130 Wyeth licensed the US patent from Altana, and obtained marketing approval from the US FDA in 2000 under the trade name Protonix.In 2004, worldwide sales of the drug were $3.65 billion, about half of which were in the US.In 2007, Altanas drug business was acquired by Nycomed. Nycomed was in turn acquired by Takeda in 2011 and Wyeth was acquired by Pfizer in 2009.The patent protecting the drug was set to expire in 2010, but Teva Pharmaceuticals filed an Abbreviated New Drug Application (ANDA) in 2007, and Wyeth and Nycomed sued Teva for patent infringement, but Teva decided to launch its generic drug "at risk" that year, before the patent had been invalidated. Wyeth launched an authorized generic in 2008. Pfizer and Takedas patent exclusivity expired in 2010, and an administrative exclusivity they had for pediatric use expired in January 2011, and full generic competition began. The litigation between Teva and Pfizer/Takeda was settled in 2013, with Teva paying the patent holders $2.15 billion in damages for its early launch.
Society and culture
As of 2017, the drug was marketed under many brands worldwide, including as a combination drug with domperidone, a combination with itopride, in combination with both clarithromycin and amoxicillin, in combination with levosulpiride, and in combination with naproxen.
Other animals
Pantoprazole has been demonstrated to increase the 3rd compartment pH in alpacas. It has been shown to be generally safe to use in cattle, sheep and goats.
See also
Hyoscine butylbromide
Pirenzepine
References
External links
"Pantoprazole". Drug Information Portal. U.S. National Library of Medicine. |
Inebilizumab | Inebilizumab, sold under the brand name Uplizna, is a medication for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults.The most common adverse reactions include urinary tract infection, headache, joint pain (arthralgia), nausea and back pain.Inebilizumab is a humanized mAb that binds to and depletes CD19+ B cells including plasmablasts and plasma cells.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
Medical uses
Inebilizumab is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with a particular antibody (patients who are anti-aquaporin-4 or AQP4 antibody positive).NMOSD is a rare autoimmune disorder in which immune system cells and autoantibodies attack and damage the optic nerves and spinal cord. NMOSD can be associated with antibodies that bind to a protein called aquaporin-4 (AQP4). Binding of the anti-AQP4 antibody appears to activate other components of the immune system, causing inflammation and damage to the central nervous system. Clinically, the disease is manifested with attacks/relapses that result in neurological impairment such as blindness, paraplegia, sensory loss, bladder dysfunction, and peripheral pain. The disability from each attack is cumulative, making NMOSD a chronically debilitating and potentially life-threatening disease.
Side effects
The label for inebilizumab includes a warning for infusion reactions, potential depletion of certain proteins (hypogammaglobulinemia), and potential increased risk of infection – including Progressive Multifocal Leukoencephalopathy, and potential reactivation of hepatitis B and tuberculosis.The most common adverse reactions in the NMOSD clinical trial were urinary tract infection, headache, joint pain (arthralgia), nausea and back pain.Women who are pregnant should not take inebilizumab because it may cause harm to a developing fetus or newborn baby. The FDA advises health care professionals to inform females of reproductive age to use effective contraception during treatment with inebilizumab and for six months after the last dose.Vaccination with live-attenuated or live vaccines is not recommended during treatment and should be administered at least four weeks prior to initiation of inebilizumab.
History
Inebilizumab was created from the research led by Thomas Tedder at Cellective Therapeutics, and development was continued by Viela Bio and MedImmune.Inebilizumab was approved for medical use in the United States in June 2020.The effectiveness of inebilizumab for the treatment of NMOSD was demonstrated in a clinical study (NCT02200770) of 230 adult participants that evaluated the efficacy and safety of intravenous inebilizumab. In the trial, 213 of the 230 participants had antibodies against AQP4 (anti-AQP4 antibody positive). During the 197-day study, the risk of an NMOSD relapse in the 161 anti-AQP4 antibody positive participants who were treated with inebilizumab was reduced by 77% when compared to the placebo treatment group. There was no evidence of a benefit in participants who were anti-AQP4 antibody negative. The primary efficacy endpoint was the time to the onset of the first adjudicated relapse on or before study day 197 evaluated by a blinded, independent, adjudication committee, who determined whether the attack met protocol-defined criteria. The trial was conducted at 82 sites in 24 countries (including the United States) in North and South America, Europe, Africa, Asia and Australia.The U.S. Food and Drug Administration (FDA) granted the application for inebilizumab orphan drug designation and granted approval of Uplizna to Viela Bio.
Society and culture
Legal status
In November 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Uplizna, intended for the treatment of adults with neuromyelitis optica spectrum disorders (NMOSD) who are anti-aquaporin 4 immunoglobulin G (AQP4-IgG) seropositive. The applicant for this medicinal product is Viela Bio.
Names
Inebilizumab is the international nonproprietary name (INN) and the United States Adopted Name (USAN).
References
Further reading
Cree BA, Bennett JL, Kim HJ, Weinshenker BG, Pittock SJ, Wingerchuk DM, et al. (October 2019). "Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial". Lancet. 394 (10206): 1352–1363. doi:10.1016/S0140-6736(19)31817-3. PMID 31495497. S2CID 201839513.
External links
"Inebilizumab". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02200770 for "A Double-masked, Placebo-controlled Study With Open Label Period to Evaluate MEDI-551 in Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorders" at ClinicalTrials.gov |
Bedaquiline | Bedaquiline, sold under the brand name Sirturo, is a medication used to treat active tuberculosis. Specifically, it is used to treat multi-drug-resistant tuberculosis (MDR-TB) along with other medications for tuberculosis. It is used by mouth.Common side effects include nausea, joint pains, headaches, and chest pain. Serious side effects include QT prolongation, liver dysfunction, and an increased risk of death. While harm during pregnancy has not been found, it has not been well studied in this population. It is in the diarylquinoline antimycobacterial class of medications. It works by blocking the ability of M. tuberculosis to make adenosine 5-triphosphate (ATP).Bedaquiline was approved for medical use in the United States in 2012. It is on the World Health Organizations List of Essential Medicines. The cost for six months is approximately US$900 in low-income countries, US$3,000 in middle-income countries, and US$30,000 in high-income countries.The public sector invested US$455–747 million in developing bedaquiline. This is thought to be 1.6× to 5.1× what the owner, Janssen Biotech, invested (estimated at US$90–240 million). If capitalized and risk-adjusted, these costs become US$647–1,201 million and US$292–772 million, respectively.
Medical uses
Its use was approved in December 2012 by the U.S. Food and Drug Administration (FDA) for use in tuberculosis (TB) treatment, as part of a Fast-Track accelerated approval, for use only in cases of multidrug-resistant tuberculosis, and the more resistant extensively drug resistant tuberculosis.As of 2013 both the World Health Organization (WHO) and US Centers for Disease Control (CDC) have recommended (provisionally) that bedaquiline be reserved for people with multidrug-resistant tuberculosis when an otherwise recommended regimen cannot be designed.
Clinical trials
Bedaquiline has been studied in phase IIb studies for the treatment of multidrug-resistant tuberculosis while phase III studies are currently underway. It has been shown to improve cure rates of smear-positive multidrug-resistant tuberculosis, though with some concern for increased rates of death (further detailed in the Adverse effects section).Small studies have also examined its use as salvage therapy for non-tuberculous mycobacterial infections.It is a component of the experimental BPaMZ combination treatment (bedaquiline + pretomanid + moxifloxacin + pyrazinamide).
Side effects
The most common side effects of bedaquiline in studies were nausea, joint and chest pain, and headache. The drug also has a black-box warning for increased risk of death and arrhythmias, as it may prolong the QT interval by blocking the hERG channel. Everyone on bedaquiline should have monitoring with a baseline and repeated ECGs. If a person has a QTcF of > 500 ms or a significant ventricular arrythmia, bedaquiline and other QT prolonging drugs should be stopped.There is considerable controversy over the approval for the drug, as one of the largest studies to date had more deaths in the group receiving bedaquiline that those receiving placebo. Ten deaths occurred in the bedaquiline group out of 79, while two occurred in the placebo group, out of 81. Of the 10 deaths on bedaquiline, one was due to a motor vehicle accident, five were judged as due to progression of the underlying tuberculosis and three were well after the person had stopped receiving bedaquiline. However, there is still significant concern for the higher mortality in people treated with bedaquiline, leading to the recommendation to limit its use to situations where a four drug regimen cannot otherwise be constructed, limit use with other medications that prolong the QT interval, and the placement of a prominent black box warning.
Drug interactions
Bedaquiline should not be co-administered with other drugs that are strong inducers or inhibitors of CYP3A4, the liver enzyme responsible for oxidative metabolism of the drug. Co-administration with rifampin, a strong CYP3A4 inducer, results in a 52% decrease in the AUC of the drug. This reduces the exposure of the body to the drug and decreases the antibacterial effect. Co-administration with ketoconazole, a strong CYP3A4 inhibitor, results in a 22% increase in the AUC, and potentially an increase in the rate of adverse effects experiencedSince bedaquiline can also prolong the QT interval, use of other QT prolonging drugs should be avoided. Other medications for tuberculosis that can prolong the QT interval include fluoroquinolones and clofazimine.
Mechanism of action
Bedaquiline blocks the proton pump for ATP synthase of mycobacteria. It is the first member of a new class of drugs called the diarylquinolines. Bedaquiline is bactericidal. ATP production is required for cellular energy production and its loss leads inhibition of mycobacterial growth within hours of the addition of bedaquiline. The onset of bedaquiline-induced mycobacterial cell death does not occur until several days after treatment, but nonetheless kills consistently thereafter.
Resistance
The specific part of ATP synthase affected by bedaquiline is subunit c which is encoded by the gene atpE. Mutations in atpE can lead to resistance. Mutations in drug efflux pumps have also been linked to resistance.
Ongoing research
In vitro experiments have indicated that Bedaquiline may also target the mitochondrial ATP synthase of malignant mammalian cells and reduce the rate of metastasis.
History
Bedaquiline was described for the first time in 2004 at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting, after the drug had been in development for over seven years. It was discovered by a team led by Koen Andries at Janssen Pharmaceutica.Bedaquiline was approved for medical use in the United States in 2012.It is manufactured by Johnson & Johnson (J&J), who sought accelerated approval of the drug, a type of temporary approval for diseases lacking other viable treatment options. By gaining approval for a drug that treats a neglected disease, J&J is now able to request expedited FDA review of a future drug.When it was approved by the FDA on 28 December 2012, it was the first new medicine for TB in more than forty years.In 2016, the WHO came under criticism for recommending it as an essential medicine.The WHO TB program director has pointed out that Janssen will donate $30 million worth (30,000 treatment courses) of bedaquiline over a 4-year period.
References
External links
"Bedaquiline". Drug Information Portal. U.S. National Library of Medicine. |
Yasmin | Yasmin, Yasmine or Yasmina may refer to:
Yasmin (given name), a common female nameYasmin - Jasmine Flower
Yasmin (musician), a female British DJ and singer-songwriter
Yasmine (singer), a female Belgian singer, presenter and television personality.
Yasmin (drug), marketing name of a birth control pill
Yasmin, a doll in the Bratz fashion doll line
Film and television
Yasmin (1955 film), a 1955 Hindi film directed by Abdur Rashid Kardar and starring Vyjayanthimala
Yasmin (2004 film), a 2004 English film directed by Kenneth Glenaan and starring Archie Panjabi
Yasmine (film), a 2014 Bruneian film
Yasmins Getting Married, an Australian reality television show
Yasmina (film), a 1927 French silent film
See also
Jasmin (disambiguation)
Jasmine (disambiguation)
Yasemin (disambiguation) |
Fenofibrate | Fenofibrate (sold under the brand names Tricor, Fenobrat etc.), is an oral medication of the fibrate class used to treat abnormal blood lipid levels. It is less commonly used compared than statins because it treats a different type of cholesterol abnormality to statins. While statins have strong evidence for reducing heart disease and death, there is evidence to suggest that fenofibrate also reduces to the risk of heart disease and death. However, this seems only to apply to specific populations of people with elevated triglyceride levels and reduced high-density lipoprotein (HDL) cholesterol. Its use is recommended together with dietary changes.Common side effects include liver problems, breathing problems, abdominal pain, muscle problems, and nausea. Serious side effects may include toxic epidermal necrolysis, rhabdomyolysis, gallstones, and pancreatitis. Use during pregnancy and breastfeeding is not recommended. It works by multiple mechanisms.It was patented in 1969, and came into medical use in 1975. It is available as a generic medication. In 2019, it was the 87th most commonly prescribed medication in the United States with more than 8 million prescriptions.
Medical uses
Fenofibrate is mainly used for primary hypercholesterolemia or mixed dyslipidemia. Fenofibrate may slow the progression of diabetic retinopathy and the need for invasive treatment such as laser therapy in patients with type 2 diabetes with pre-existing retinopathy. It was initially indicated for diabetic retinopathy in patients with type 2 diabetes and diabetic retinopathy in Australia. The large scale, international FIELD and ACCORD-Eye trials found that fenofibrate therapy reduced required laser treatment for diabetic retinopathy by 1.5% over 5 years, as well as reducing progression by 3.7% over 4 years. Further studies looking at the role of fenofibrate in the progression of diabetic retinopathy as the primary outcome is warranted to understand its role in this condition. Although no statistically significant cardiovascular risk benefits were identified in these trials, benefits may accrue to add on therapy to patients with high triglyceride dyslipidaemia currently taking statin medications.Fenofibrate appears to reduce the risk of below ankle amputations in patients with Type 2 diabetes without microvascular disease. The FIELD study reported that fenofibrate at doses of 200 mg daily, reduced the risk for any amputation by 37% independent of glycaemic control, presence or absence of dyslipidaemia and its lipid-lowering mechanism of action. However, the cohort of participants who underwent amputations were more likely to have had previous cardiovascular disease (e.g. angina, myocardial infarction), longer duration of diabetes and had baseline neuropathy.Fenofibrate has an off-label use as an added therapy of high blood uric acid levels in people who have gout.It is used in addition to diet to reduce elevated low-density lipoprotein cholesterol (LDL), total cholesterol, triglycerides (TG), and apolipoprotein B (apo B), and to increase high-density lipoprotein cholesterol (HDL) in adults with primary hypercholesterolemia or mixed dyslipidemia.
Severe hypertriglyceridemia type IV or V
It is used in tandem with diet for treatment of adults with severe hypertriglyceridemia. Improving glycemic control in diabetics showing fasting chylomicronemia usually reduces the need for pharmacologic intervention.Statins remain the first line for treatment of blood cholesterol. AHA guidelines from 2013 did not find evidence for routine use of additional medications.Additionally, in 2016, the FDA filed "Withdrawal of Approval of Indications Related to the Coadministration With Statins in Applications for Niacin Extended-Release Tablets and Fenofibric Acid Delayed Release Capsules" noting "the Agency has concluded that the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events. Consistent with this conclusion, FDA has determined that the benefits of niacin ER tablets and fenofibric acid DR capsules for coadministration with statins no longer outweigh the risks, and the approvals for this indication should be withdrawn."
COVID-19
In August 2021, researchers in the UK and Italy reported laboratory findings that fenofibrate can significantly reduce SARS-CoV-2 infection in vitro.
Contraindications
Fenofibrate is contraindicated in:
Patients with severe renal impairment, including those receiving dialysis (2.7-fold increase in exposure, and increased accumulation during chronic dosing in patients with estimated glomerular filtration rate < 30 mL/min)
Patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function test abnormalities
Patients with preexisting gallbladder disease
Nursing mothers
Hypothyreosis
Patients with known hypersensitivity to fenofibrate or fenofibric acid
Adverse effects
The most common adverse events (>3% of patients with coadministered statins) are
Precautions
When fenofibrate and a statin are given as combination therapy, it is recommended that fenofibrate be given in the morning and the statin at night, so that the peak dosages do not overlap.Musculoskeletal
Myopathy and rhabdomyolysis; increased risk when coadminstered with a statin, particularly in the elderly and patients with diabetes, kidney failure, hypothyroidismHepatotoxicity
Can increase serum transaminases; liver tests should be monitored periodicallyNephrotoxicity
Can increase serum creatinine levels; renal function should be monitored periodically in patients with chronic kidney diseaseBiliary
Can increase cholesterol excretion into the bile, leading to risk of cholelithiasis; if suspected, gallbladder studies are indicated. See "Interaction" section under Bile acid sequestrantCoagulation/Bleeding
Exercise caution in concomitant treatment with oral Coumadin anticoagulants (e.g. warfarin). Adjust the dosage of Coumadin to maintain the prothrombin time/INR at desired level to prevent bleeding complications.
Overdose
"There is no specific treatment for overdose with fenofibric acid delayed-release capsules. General supportive care is indicated, including monitoring of vital signs and observation of clinical status". Additionally, hemodialysis should not be considered as an overdose treatment option because fenofibrate heavily binds to plasma proteins and does not dialyze well.
Interactions
These drug interactions with fenofibrate are considered major and may need therapy modifications:
Bile acid sequestrants (e.g. cholestyramine, colestipol, etc.): If taken together, bile acid resins may bind to fenofibrate, resulting in a decrease in fenofibrate absorption. To maximize absorption, patients need to separate administration by at least 1 h before or 4 h to 6 h after taking the bile acid sequestrant.
Immunosuppressants (e.g. ciclosporin or tacrolimus): An increased risk of renal dysfunction exists with concomitant use of immunosuppressants and fenofibrate. Approach with caution when coadministering additional medications that decrease renal function.
Vitamin K antagonists (e.g. warfarin): As previously mentioned, fenofibrate interacts with coumadin anticoagulants to increase the risk of bleeding. Dosage adjustment of vitamin K antagonist may be necessary.
Statins: Combination of statins and fenofibrate may increase the risk of rhabdomyolysis or myopathy.
Mechanism of action
"In summary, enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL underlie the hypotriglyceridemic effect of fibrates, whereas their effect on HDL metabolism is associated with changes in HDL apolipoprotein expression."Fenofibrate is a fibrate derivative, a prodrug comprising fenofibric acid linked to an isopropyl ester. It lowers lipid levels by activating peroxisome proliferator-activated receptor alpha (PPARα). PPARα activates lipoprotein lipase and reduces apoprotein CIII, which increases lipolysis and elimination of triglyceride-rich particles from plasma.PPARα also increases apoproteins AI and AII, reduces VLDL- and LDL-containing apoprotein B, and increases HDL-containing apoprotein AI and AII.
Formulations
Fenofibrate is available in several formulations and is sold under several brand names, including:
Tricor by AbbVie
Lipofen by Kowa Pharmaceuticals America Inc
Lofibra by Teva
Lipanthyl, Lipidil, Lipantil micro and Supralip by Abbott Laboratories
Fenocor-67 by Ordain Health Care
Fibractiv 105/35 by Cogentrix Pharma (India)
Fenogal by SMB Laboratories
Antara by Oscient Pharmaceuticals
Tricheck by Zydus (CND)
Atorva TG by Zydus Medica
Golip by GolgiUSA
Stanlip by Ranbaxy (India)The formulations may differ in terms of pharmacokinetic properties, particularly bioavailability; some must be taken with meals, whereas others may be taken without regard to food.The choline salt of fenofibrate is available in the United States, sold as Trilipix, and may be taken without regard to meals.
Environmental presence
Fenofibric acid was one of the 12 compounds identified in sludge samples taken from 12 wastewater treatment plants in California that were associated with estrogenic activity in in vitro.
History
Fenofibrate was first synthesized in 1974, as a derivative of clofibrate, and was initially offered in France. It was initially known as procetofen, and was later renamed fenofibrate to comply with World Health Organization International Nonproprietary Name guidelines.Fenofibrate was developed by Groupe Fournier SA of France.
In the United States, Tricor was reformulated in 2005. This reformulation was controversial, seen as an attempt to stifle competition from generic equivalents, and was the subject of antitrust litigation by Teva.
References
External links
"Fenofibrate". Drug Information Portal. U.S. National Library of Medicine. |
Flucytosine | Flucytosine, also known as 5-fluorocytosine (5-FC), is an antifungal medication. It is specifically used, together with amphotericin B, for serious Candida infections and cryptococcosis. It may be used by itself or with other antifungals for chromomycosis. Flucytosine is used by mouth and by injection into a vein.Common side effects include bone marrow suppression, loss of appetite, diarrhea, vomiting, and psychosis. Anaphylaxis and other allergic reactions occasionally occur. It is unclear if use in pregnancy is safe for the baby. Flucytosine is in the fluorinated pyrimidine analogue family of medications. It works by being converted into fluorouracil inside the fungus, which impairs its ability to make protein.Flucytosine was first made in 1957. It is on the World Health Organizations List of Essential Medicines. As of 2016, in the United States the medication cost about US$2,000 per day while in the United Kingdom it is about US$22 per day. It is not available in much of the developing world.
Medical uses
Flucytosine by mouth is used for the treatment of serious infections caused by susceptible strains of Candida or Cryptococcus neoformans. It can also be used for the treatment of chromomycosis (chromoblastomycosis), if susceptible strains cause the infection. Flucytosine must not be used as a sole agent in life-threatening fungal infections due to relatively weak antifungal effects and fast development of resistance, but rather in combination with amphotericin B and/or azole antifungals such as fluconazole or itraconazole. Minor infections such as candidal cystitis may be treated with flucytosine alone. In some countries, treatment with slow intravenous infusions for no more than a week is also a therapeutic option, particular if the disease is life-threatening.
Serious fungal infections may occur in those who are immunocompromised. These people benefit from combination therapy including flucytosine, but the incidence of side-effects of a combination therapy, particular with amphotericin B, may be higher.
Pregnancy and breastfeeding
In animal models (rats), flucytosine has been found to be teratogenic. Sufficient human data does not exist. Pregnant women should be given flucytosine only if the potential benefits exceed the potential harm to the fetus.
It is not known if flucytosine is distributed in human breast milk. Given the potential risk to the child, the patient should not breastfeed during treatment with flucytosine.
Children
The efficacy and safety in patients under 18 years of age has not been determined.
Side effects
Patients treated with drugs compromising bone marrow function (e.g. cytostatics) should be treated carefully. Blood cell counts should be taken very frequently.
Patients with renal disease should receive flucytosine cautiously and in reduced doses. Guidelines for proper dosing exist. Serum level determinations are mandatory for these patients.
All patients receiving flucytosine should be under strict medical supervision.
Hematological, renal and liver function studies should be done frequently during therapy (initially daily, twice a week for the rest of treatment).
Patients with preexisting bone marrow depression and liver impairment should be treated with caution.
Antiproliferative actions on bone marrow and GI tissue: Due to the drugs preference for rapidly proliferating tissues, bone marrow depression (anemia, leukopenia, pancytopenia, or even rarely agranulocytosis) may occur. Aplastic anemia has also been seen. Bone marrow toxicity can be irreversible and may cause death, particularly in immunocompromised patients. GI toxicity may be severe or rarely fatal and consists of anorexia, abdominal bloating, abdominal pain, diarrhea, dry mouth, duodenal ulcer, GI hemorrhage, nausea, vomiting, and ulcerative colitis.
Liver function: Elevations of liver enzymes and bilirubin, hepatic dysfunction, jaundice and, in one patient, liver necrosis have all been seen. Some fatal cases have been reported; however, the majority of cases was reversible.
Renal function: Increased BUN and serum creatinine have been noted. Crystalluria (formation of crystals and excretion in the urine) and acute kidney injury have also been seen.
Adverse central nervous system effects are frequent and include confusion, hallucinations, psychosis, ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, vertigo and sedation.
Skin reactions: Rash, pruritus, and photosensitivity have all been noticed. Toxic epidermal necrolysis (Lyells syndrome) may also be encountered and may be life-threatening.
Anaphylaxis: Sometimes cases of anaphylaxis consisting of diffuse erythema, pruritus, conjunctival injection, fever, abdominal pain, edema, hypotension and bronchospastic reactions are observed.It is not known if flucytosine is a human carcinogen. The issue has been raised because traces of 5-fluorouracil, which is a known carcinogen, are found in the colon resulting from the metabolization of flucytosine.
Interactions
Flucytosine may increase the toxicity of amphotericin B and vice versa, although the combination may be life-saving and should be used whenever indicated (e.g., cryptococcal meningitis). The cytostatic cytarabine inhibits the antimycotic activity of flucytosine.
Overdose
Symptoms and their severities are unknown, because flucytosine is used under close medical supervision, but expected to be an excess of the usually encountered side effects on the bone marrow, gastrointestinal tract, liver and kidney function. Vigorous hydration and hemodialysis may be helpful in removing the drug from the body. Hemodialysis is particular useful in patients with impaired renal function.
Pharmacology
Mechanisms of action
Two major mechanisms of action have been elucidated:
Flucytosine is intrafungally converted into the cytostatic fluorouracil which undergoes further steps of activation and finally interacts as 5-fluorouridinetriphosphate with RNA biosynthesis thus disturbing the building of certain essential proteins.
Flucytosine also undergoes conversion into 5-fluorodeoxyuridinemonophosphate which inhibits fungal DNA synthesis.
Spectrum of susceptible fungi and resistance
Flucytosine is active in vitro as well as in vivo against some strains of Candida and Cryptococcus. Limited studies demonstrate that flucytosine may be of value against infections with Sporothrix, Aspergillus, Cladosporium, Exophiala, and Phialophora.
Resistance is quite commonly seen as well in treatment-naive patients and under current treatment with flucytosine. In different strains of Candida resistance has been noted to occur in 1 to 50% of all specimens obtained from patients.
Pharmacokinetic data
Flucytosine is well absorbed (75 to 90%) from the gastrointestinal tract. Intake with meals slows the absorption, but does not decrease the amount absorbed. Following an oral dose of 2 grams peak serum levels are reached after approximately 6 hours. The time to peak level decreases with continued therapy. After 4 days peak levels are measured after 2 hours. The drug is eliminated renally. In normal patients flucytosine has reportedly a half-life of 2.5 to 6 hours. In patients with impaired renal function higher serum levels are seen and the drug tends to accumulate. The drug is mainly excreted unchanged in the urine (90% of an oral dose) and only traces are metabolized and excreted in the feces. Therapeutic serum levels range from 25 to 100 μg/ml. Serum levels in excess of 100 μg are associated with a higher incidence of side effects. Periodic measurements of serum levels are recommended for all patients and are a must in patients with renal damage.
Economics
Although a generic, off patent medication in the U.S., as of January 2016, there was only one FDA-approved pharmaceutical supplier, Valeant Pharmaceuticals. Due to this monopoly, the cost per 250 mg tablet was $70.46 per tablet for a daily treatment cost of ~$2110/day for a 75 kg adult (165 pounds) adult and $29,591 for a two-week treatment course as of December 2015. This cost of flucytosine is more than 100-fold higher in the U.S. than in the United Kingdom and Europe via Meda AB Pharmaceuticals. Flucytosine tablets are available in India for US$2.00 per tablet via Jolly Healthcare Pvt. Ltd. and are available in 100 tablet packs.
Other animals
In some countries, such as Switzerland, flucytosine has been licensed to treat cats, dogs and birds (in most cases together with amphotericin B) for the same indications as in humans.
References
External links
"Flucytosine". Drug Information Portal. U.S. National Library of Medicine. |
Methyclothiazide | Methyclothiazide is a thiazide diuretic.
== References == |
1-Docosanol | 1-Docosanol, also known as behenyl alcohol, is a saturated fatty alcohol containing 22 carbon atoms, used traditionally as an emollient, emulsifier, and thickener in cosmetics.In July 2000, docosanol was approved for medical use in the United States as an antiviral agent for reducing the duration of cold sores. It is an over-the-counter medication (OTC). It is sold under the brand name Abreva among others.
Side effects
One of the most common side effects that has been reported from docosanol is headache. Headaches caused by the medication tend to be mild and can occur in any region of the head. In clinical trials, headache occurred in 10.4% of people treated with docosanol cream and 10.7% of people treated with placebo.The most serious side effects, although rare, are allergic reactions. Some of the patients experienced the symptoms of allergic reactions, including difficulty breathing, confusion, angioedema (facial swelling), fainting, dizziness, hives or chest pain.Other side effects may include: acne, burning, dryness, itching, rash, redness, acute diarrhea, soreness, swelling.
Mechanism of action
Docosanol is thought to act by inhibiting the fusion of the human host cell with the viral envelope of the herpes virus, thus preventing its replication.
History
The drug was approved as a cream for oral herpes after clinical trials by the FDA in July 2000.
It was shown to shorten the healing by 17.5 hours on average (95% confidence interval: 2 to 22 hours) in a placebo-controlled trial. Another trial showed no effect when treating the infected backs of guinea pigs.Two experiments with n-docosanol cream failed to show statistically significant differences by any parameter between n-docosanol cream and vehicle control–treated sites or between n-docosanol and untreated infection sites.
Society and culture
Controversy
In March 2007, it was the subject of a US nationwide class-action suit against Avanir and GlaxoSmithKline as the claim that it cut recovery times in half was found to have been misleading in a California court, but the case was eventually settled and the "cuts healing time in half" claim had not been used in product advertising for some years.
References
External links
"Docosanol". Drug Information Portal. U.S. National Library of Medicine. |
Felodipine | Felodipine is a medication of the calcium channel blocker type which is used to treat high blood pressure.
It was patented in 1978 and approved for medical use in 1988.
Medical uses
Felodipine is used to treat high blood pressure and stable angina.It should not be used for people who are pregnant, have acute heart failure, are having a heart attack, have an obstructed heart valve, or have obstructions that block bloodflow out of the heart.For people with liver failure the dose needs to be lowered, because felodipine is cleared by the liver.
Adverse effects
The only very common side effect, occurring in more than 1/10 people, is pain and swelling in the arms and legs.Common side effects, occurring in between 1% and 10% of people, include flushing, headache, heart palpitations, dizziness and fatigue.Felodipine can exacerbate gingivitis.
Interactions
Felodipine is metabolized by cytochrome P450 3A4, so substances that inhibit or activate CYP3A4 can strongly effect how much felodipine is present.CYP3A4 inhibitors, which increase the amount of felodipine available per dose, include cimetidine, erythromycin, itraconazole, ketoconazole, HIV protease inhibitors, and grapefruit juice.CYP3A4 activators, which decrease the amount of felodipine available per dose, include phenytoin, carbamazepine, rifampicin, barbiturates, efavirenz, nevirapine, and Saint Johns wort.
Mechanism of action
Felodipine is a calcium channel blocker. Felodipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid.Different calcium channels are present in vascular tissue and cardiac tissue; an in vitro study on human vascular and cardiac tissues comparing how selective various calcium channel blockers are for vascular compared to cardiac tissue found the following vascular/cardiac tissue ratios: mibefradil 41, felodipine 12; nifedipine 7, amlodipine 5, and verapamil 0.2.: 172
Chemistry
Felodipine is a member of the 1,4-dihydropyridine class of calcium channel blockers.: 20–21 It is a racemic mixture, and is insoluble in water but is soluble in dichloromethane and ethanol.: 25
History
The Swedish company Hässle, a division of Astra AB, discovered felodipine; it filed a patent application in 1979 claiming felodipine as an antihypertensive drug. Astra partnered this drug and others with Merck & Co. in the US under a 1982 agreement between the companies. The drug was approved by the FDA in 1991 after a three and a half year review; the drug entered a very crowded market the included the other calcium channel blockers nifedipine, verapamil, nicardipine, and isradipine. The FDA gave the drug a 1C rating, meaning that it found little difference between felodipine and the drugs already approved for the same use.In 1994 Astra AB and Merck changed their partnership to a joint venture called Astra Merck, and in 1998 Astra (by that time, AstraZeneca) bought out Mercks rights in the joint venture.The first generics became available in Sweden in 2003 and in the US in 2004.: 155 In April 2016, AstraZeneca announced that they were selling the right to market felodipine in China to China Medical System Holdings for $310 million; AZ would continue to manufacture the drug.
Society and culture
As of 2016, felodipine was marketed under many brand names worldwide: Auronal, Cardioplen, Catrazil, Dewei, Dilahex, Enfelo, Erding, Fedil, Fedisyn, Feldil, Felicipin, Felo, Felocard, Felocor, Feloday, Felodil, Felodin, Felodip, Felodipin, Felodipina, Felodipine, Felodipino, Felodistad, Felogard, Felohexal, Felop, Felopine, Felostad, Feloten, Felotens, Felpin, Flodicar, Flodil, Keliping, Keydipin, Lodistad, Modip, Munobal, Nirmadil, Parmid, Penedil, Perfudal, Phelop, Phenodical, Plendil, Plentopine, Polo, Presid, Preslow, Prevex, Renedil, Sistar, Splendil, Stapin, Topidil, Vascalpha, Versant, and XiaoDing.The combination of felodipine and candesartan was marketed as Atacand.The combination of felodipine and ramipril was marketed as Delmuno, Tazko, Triacor, Triapin, Triasyn, Tri-Plen, Unimax, and Unitens.The combination of felodipine and enalapril was marketed as Lexxel.The combination of felodipine and metoprolol was marketed as Logimat, Logimax, and Mobloc.
== References == |
Pramlintide | Pramlintide (trade name Symlin) is an injectable amylin analogue drug for diabetes (both type 1 and 2), developed by Amylin Pharmaceuticals (now a wholly owned subsidiary of AstraZeneca). Pramlintide is sold as an acetate salt.
Pharmacology
Pramlintide is an analogue of amylin, a small peptide hormone that is released into the bloodstream by the β cells of the pancreas along with insulin after a meal. Like insulin, amylin is completely absent in individuals with Type I diabetes.In synergy with endogenous amylin, pramlintide aids in the regulation of blood glucose by slowing gastric emptying, promoting satiety via hypothalamic receptors (different receptors than for GLP-1), and inhibiting inappropriate secretion of glucagon, a catabolic hormone that opposes the effects of insulin and amylin. Pramlintide also has effects in raising the acute first-phase insulin response threshold following a meal.
Both a reduction in glycated hemoglobin and weight loss have been shown in insulin-treated patients with type 2 diabetes taking pramlintide as an adjunctive therapy.
Research Applications
In the research field, pramlintide has been experimented with and used as a potential treatment drug. Pramlintide has demonstrated its ability to decrease amyloid beta plaques in Alzheimers disease mouse models.
Approval
Pramlintide has been approved by the FDA, for use by type 1 and type 2 diabetic patients who use insulin. Pramlintide allows patients to use less insulin, lowers average blood sugar levels, and substantially reduces what otherwise would be a large unhealthy rise in blood sugar that occurs in diabetics right after eating.
Apart from insulin analogs, pramlintide is the only drug approved by the FDA to lower blood sugar in type 1 diabetics since insulin in the early 1920s.
Design and structure
Since native human amylin is highly amyloidogenic and potentially toxic, the strategy for designing pramlintide was to substitute residues from rat amylin, which is less amyloidogenic although not completely
(but would presumably retain clinical activity). Proline residues are known to be structure-breaking residues, so these were directly grafted into the human sequence. Despite its enhanced stability compared to human amylin, pramlintide is still able to organize into amyloid material.Amino acid sequences:
Pramlintide as protein is (positively charged).
References
External links
www.symlin.com - product website
www.amylin.com - Symlin page on the Amylin Pharmaceuticals website |
Dicycloverine | Dicycloverine, also known as dicyclomine, sold under the brand name Bentyl in the US, is a medication that is used to treat spasms of the intestines such as occur in irritable bowel syndrome. It is taken by mouth or by injection into a muscle. While it has been used in baby colic and enterocolitis, evidence does not support these uses.Common side effects include dry mouth, blurry vision, weakness, sleepiness, and lightheadedness. Serious side effects may include psychosis and breathing problems in babies. Use in pregnancy appears to be safe while use during breastfeeding is not recommended. How it works is not entirely clear.Dicycloverine was approved for medical use in the United States in 1950. It is available as a generic medication. In 2019, it was the 165th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Medical uses
Dicyclomine is used to treat the symptoms of irritable bowel syndrome, specifically hypermotility, in adults. As of 2016, clinical guidelines recommended dicycloverine and other antispasmodics for IBS with diarrhea as a first line treatment.
Contraindications
This medicine should not be used for people who have an obstructive GI or urinary condition, severe ulcerative colitis, reflux, any unstable cardiac condition, glaucoma, myasthenia gravis, and anyone who is acutely bleeding.It should not be given to children or infants with colic due to the risks of convulsions, difficult breathing, irritability, and restlessness, and there is little evidence to support the efficacy in such use in any case.Because dicycloverine is known to impair thinking and coordination, people taking the drug should avoid driving or operating machinery.The effect on the baby during pregnancy or breastfeeding is not well understood.
Adverse effects
Dicycloverine can cause a range of anticholinergic side effects such as dry mouth, nausea, blurred vision, dizziness, confusion, severe constipation, stomach pain, heart palpitations, difficulty urinating, and seizures.
Pharmacology
Dicycloverine blocks the action of acetylcholine on cholinergic receptors on smooth muscles in the GI tract, relaxing the smooth muscle.
History
Dicycloverine was first synthesized chemically in the United States circa 1945 by scientists at William S. Merrell Company.It was first marketed in 1952 for gastrointestinal disorders, including colic in infants. The INN name "dicycloverine" was recommended in 1959. It was included in the combination drug for morning sickness called Bendectin, along with doxylamine and vitamin B6 which was launched in the US 1956; dicyclomine was removed from the formulation in 1976 after Merrell determined that it added no value. Bendectin became the subject of many lawsuits due to allegations that it had caused birth defects similar to thalidomide, which Merrell had also marketed in the US and Canada.In the mid-1980s several governments restricted its use in infants due to reports of convulsions, difficult breathing, irritability, and restlessness in infants given the drug.In 1994 the US Federal Trade Commission ordered Marion Merrell Dow, which had recently acquired Rugby Darby, the only generic manufacturer of dicycloverine in the US, to promise to grant licenses to its intellectual property on the drug to any company that wanted it, based on antitrust concerns. The US market for the drug at that time was around $8 million; Dow had 60% of it and Rugby had 40%. The next year, Hoechst Marion Roussel, which by that time had acquired the business, granted a license to Endo Pharmaceuticals. By 2000 several other generic competitors had started selling the drug. The case was part of the reshaping of the US pharmaceutical market that occurred in the 1990s, to favor generic entry.
Society and culture
Although rarely, there have been reports of dicycloverine abuse. Dicycloverine is an antagonist at sigma-1 and 5-HT2A receptor sites, though its affinities for these targets are roughly one-fifth to one-tenth as strong as its affinities for CHRM1 and CHRM4 (its clinical targets). It is also a relatively non-polar tertiary amine, able to cross the blood-brain barrier, leading to delirium at high concentrations.
References
External links
"Dicyclomine". Drug Information Portal. U.S. National Library of Medicine. |
Naphazoline/pheniramine | Naphazoline/pheniramine, sold under the brand name Naphcon-A among others, is a combination eye drop used to help the symptoms of allergic conjunctivitis such as from hay fever. It contains naphazoline and pheniramine. It is used as an eye drop. Use is not recommended for more than three days.Side effects may include allergic reactions, eye pain, and dilated pupils. It is unclear if use in pregnancy is safe. Nephazoline works by resulting in constriction of blood vessels thus decreasing redness while pheniramine works by blocking the effects of histamine to stop itching.The combination was approved for medical use in the United States in 1994. It is available over the counter. In 2017, it was the 203rd most commonly prescribed medication in the United States, with more than two million prescriptions.
Medical use
It is administered topically with one to two drops applied to the affected eye(s) up to four times daily.
Adverse effects
Pupils may become enlarged temporarily
Overuse may cause more redness
Those with heart disease, high blood pressure, narrow angle glaucoma or who have urination trouble are discouraged from using the product
It is recommended to remove contact lenses before use. Use with contact lenses can lead to reduced oxygenation of the underlying cornea
If infants or children accidentally ingest the drops, it may lead to coma and significant reduction in body temperature. If such ingestion occurs, immediately calling a poison control center is recommended
References
External links
"Naphazoline hydrochloride mixture with pheniramine maleate". Drug Information Portal. U.S. National Library of Medicine. |
Relugolix | Relugolix, sold under the brand names Orgovyx and Relumina and as one component of Myfembree, is a gonadotropin-releasing hormone antagonist (GnRH receptor antagonist) medication which is used in the treatment of prostate cancer in men and uterine fibroids in women. It is also under development for use in the treatment of endometriosis. It is taken by mouth once per day.Side effects of relugolix include menstrual abnormalities, hot flashes, excessive sweating, headache, and decreased bone mineral density. Relugolix is a GnRH antagonist, or an antagonist of the gonadotropin-releasing hormone receptor. Unlike most other GnRH modulators, but similarly to elagolix (brand name Orilissa), relugolix is a non-peptide, small-molecule compound and is orally active. It suppresses sex hormone levels to the postmenopausal or castrate range in both women and men with administration once per day.As of February 2019, relugolix is in phase III clinical trials for endometriosis. It was approved for use for the treatment of uterine fibroids in Japan in January 2019, and for the treatment of prostate cancer in the United States in December 2020.
Medical uses
Relugolix is approved in the United States for the treatment of prostate cancer in men and in Japan for the treatment of uterine fibroids (uterine leiomyoma) in women. It is used at a dosage of 120 mg once daily by mouth in the treatment of prostate cancer (after a single 360 mg loading dose on the first day of therapy) and at a dosage of 40 mg once daily in the treatment of uterine fibroids.
Available forms
Relugolix is available in the form of 40 and 120 mg oral tablets.
Side effects
The main side effects of relugolix for uterine fibroids include abnormal uterine bleeding (24.6–48.6% vs. 6.3% for placebo), hot flashes (42.8–45.5% vs. 0% for placebo), heavy menstrual bleeding (12.1–49.3% vs. 9.4% for placebo), headache (12.3–15.2%), and excessive sweating (9.4–15.2% vs. 0% for placebo). In addition, decreased bone mineral density occurs with relugolix (21.7% decrease by week 12, 24.4% decrease by week 24).
Pharmacology
Pharmacodynamics
Relugolix is a selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR), with a half-maximal inhibitory concentration (IC50) of 0.12 nM.A dosage of relugolix of 40 mg once per day has been found to suppress estradiol levels to postmenopausal levels (<20 pg/mL) within 24 hours in premenopausal women. In the control group of women, estradiol levels fluctuated between 50 and 250 pg/mL. Estradiol levels have been found to return to normal concentrations within 4 weeks of discontinuation of relugolix in premenopausal women. The medication additionally suppresses levels of progesterone, luteinizing hormone, and follicle-stimulating hormone in premenopausal women. Relugolix at a dosage of 40 mg or more once per day has been found to reduce testosterone levels to sustained castrate levels (<20 ng/dL) in men. It additionally suppresses luteinizing hormone and follicle-stimulating hormone levels in men.Lower doses of relugolix (<40 mg/day) are under investigation for achieving partial sex hormone suppression in the treatment of endometriosis and uterine fibroids. This is intended to reduce the incidence and severity of menopausal symptoms such as hot flushes and decreased bone mineral density that are secondary to estrogen deficiency.
Pharmacokinetics
A single 40-mg oral dose of relugolix has been found to result in peak levels of relugolix of 29 ng/mL (47 nmol/L) after 1.5 hours. Steady-state levels are reached within 7 days with 40 mg/day relugolix administration. There is an approximate 2-fold accumulation of relugolix by 2 weeks of continuous administration. Food diminishes the oral bioavailability of relugolix by about 50%.Relugolix is a substrate for P-glycoprotein, which may have a limiting effect on its absorption and distribution. The plasma protein binding of relugolix is approximately 68 to 71% over a concentration range of 0.05 to 5 μg/mL.Relugolix is not a substrate for CYP3A4. The elimination half-life of relugolix is 36 to 65 hours across a dosage range of 20 to 180 mg/day. There is moderate to high interindividual variability in systemic exposure to relugolix.Relugolix is excreted mainly in feces (83%) and to a small degree in urine (4%). Only about 6% of a dose of relugolix is excreted unchanged.
Chemistry
Relugolix is a non-peptide, small-molecule compound, and is structurally distinct from GnRH analogues. It is an N-phenylurea derivative.
History
Relugolix was first described in 2004. It superseded sufugolix (developmental code name TAK-013), which was developed by the same researchers. Relugolix was approved for the treatment of uterine fibroids in Japan on 8 January 2019. It was the second orally active GnRH antagonist to be introduced for medical use, following elagolix (brand name Orilissa) in July 2018. Relugolix was approved for the treatment of prostate cancer in the United States on 18 December 2020.The FDA approved relugolix based on evidence from a clinical trial (NCT03085095) of 930 participants 48 to 97 years old with advanced prostate cancer. The trial was conducted at 155 sites in the United States, Canada, and countries in South America, Europe and the Asia Pacific region. All participants in the trial had advanced prostate cancer. Participants were randomly assigned to receive either one relugolix tablet daily (on the first day they received three tables) or an active control (leuprolide acetate) which was given as an injection under the skin every three months. The participants and healthcare providers were aware of which treatment was being given. The treatment lasted for 48 weeks. The efficacy of relugolix was assessed by the percentage of participants who achieved and maintained low testosterone level equal to castration.
Society and culture
Names
Relugolix is the generic name of the drug and its INN, USAN, and JAN. It is also known by its former developmental code names RVT-601 and TAK-385.Relugolix is sold under the brand name Orgovyx for the treatment of prostate cancer and under the brand name Relumina for the treatment of uterine fibroids. Relugolix compounded with ethinyl estradiol and norethindrone is sold under the brand name Myfembree for the treatment of uterine fibroids.
Availability
Relugolix is available in the United States and in Japan.
Legal status
On 24 February 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Orgovyx, intended for the treatment of prostate cancer. The applicant for this medicinal product is Myovant Sciences Ireland Limited.
Research
Relugolix is under development by Myovant Sciences and Takeda for the treatment of uterine fibroids in countries besides Japan such as the United States. Relugolix is also under development for the treatment of endometriosis in the United States and other countries.
References
Further reading
Markham, Anthony (April 2019). "Relugolix: First Global Approval". Drugs. 79 (6): 675–679. doi:10.1007/s40265-019-01105-0. ISSN 0012-6667. PMID 30937733. S2CID 89616869.
Elsharoud, A.; Ali, M.; Al-Hendy, A. (2019). "Relugolix. GnRH (LHRH) receptor antagonist, Treatment of uterine fibroids, Treatment of endometriosis-related pain, Treatment of prostate cancer". Drugs of the Future. 44 (2): 131. doi:10.1358/dof.2019.44.2.2927590. ISSN 0377-8282. S2CID 87369995.
Barra F, Seca M, Della Corte L, Giampaolino P, Ferrero S (August 2019). "Relugolix for the treatment of uterine fibroids". Drugs Today. 55 (8): 503–512. doi:10.1358/dot.2019.55.8.3020179. PMID 31461087. S2CID 201654739.
External links
"Relugolix". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03085095 for "A Study to Evaluate the Safety and Efficacy of Relugolix in Men With Advanced Prostate Cancer (HERO)" at ClinicalTrials.gov |
Sonata | Sonata (; Italian: [soˈnaːta], pl. sonate; from Latin and Italian: sonare [archaic Italian; replaced in the modern language by suonare], "to sound"), in music, literally means a piece played as opposed to a cantata (Latin and Italian cantare, "to sing"), a piece sung.: 17 The term evolved through the history of music, designating a variety of forms until the Classical era, when it took on increasing importance. Sonata is a vague term, with varying meanings depending on the context and time period. By the early 19th century, it came to represent a principle of composing large-scale works. It was applied to most instrumental genres and regarded—alongside the fugue—as one of two fundamental methods of organizing, interpreting and analyzing concert music. Though the musical style of sonatas has changed since the Classical era, most 20th- and 21st-century sonatas still maintain the same structure.
The term sonatina, pl. sonatine, the diminutive form of sonata, is often used for a short or technically easy sonata.
Instrumentation
In the Baroque period, a sonata was for one or more instruments almost always with continuo. After the Baroque period most works designated as sonatas specifically are performed by a solo instrument, most often a keyboard instrument, or by a solo instrument accompanied by a keyboard instrument.
Sonatas for a solo instrument other than keyboard have been composed, as have sonatas for other combinations of instruments.
History
Baroque
In the works of Arcangelo Corelli and his contemporaries, two broad classes of sonata were established, and were first described by Sébastien de Brossard in his Dictionaire de musique (third edition, Amsterdam, ca. 1710): the sonata da chiesa (that is, suitable for use in church), which was the type "rightly known as Sonatas", and the sonata da camera (proper for use at court), which consists of a prelude followed by a succession of dances, all in the same key.: 21, 40 Although the four, five, or six movements of the sonata da chiesa are also most often in one key, one or two of the internal movements are sometimes in a contrasting tonality.The sonata da chiesa, generally for one or more violins and bass, consisted normally of a slow introduction, a loosely fugued allegro, a cantabile slow movement, and a lively finale in some binary form suggesting affinity with the dance-tunes of the suite. This scheme, however, was not very clearly defined, until the works of Arcangelo Corelli when it became the essential sonata and persisted as a tradition of Italian violin music.
The sonata da camera consisted almost entirely of idealized dance-tunes. On the other hand, the features of sonata da chiesa and sonata da camera then tended to be freely intermixed. Although nearly half of Bachs 1,100 surviving compositions, arrangements, and transcriptions are instrumental works, only about 4% are sonatas.The term sonata is also applied to the series of over 500 works for harpsichord solo, or sometimes for other keyboard instruments, by Domenico Scarlatti, originally published under the name Essercizi per il gravicembalo (Exercises for the Harpsichord). Most of these pieces are in one binary-form movement only, with two parts that are in the same tempo and use the same thematic material, though occasionally there will be changes in tempo within the sections. They are frequently virtuosic, and use more distant harmonic transitions and modulations than were common for other works of the time. They were admired for their great variety and invention.
Both the solo and trio sonatas of Vivaldi show parallels with the concerti he was writing at the same time. He composed over 70 sonatas, the great majority of which are of the solo type; most of the rest are trio sonatas, and a very small number are of the multivoice type.The sonatas of Domenico Paradies are mild and elongated works with a graceful and melodious little second movement included.
Classical period
The practice of the Classical period would become decisive for the sonata; the term moved from being one of many terms indicating genres or forms, to designating the fundamental form of organization for large-scale works. This evolution stretched over fifty years. The term came to apply both to the structure of individual movements (see Sonata form and History of sonata form) and to the layout of the movements in a multi-movement work. In the transition to the Classical period there were several names given to multimovement works, including divertimento, serenade, and partita, many of which are now regarded effectively as sonatas. The usage of sonata as the standard term for such works began somewhere in the 1770s. Haydn labels his first piano sonata as such in 1771, after which the term divertimento is used sparingly in his output. The term sonata was increasingly applied to either a work for keyboard alone (see piano sonata), or for keyboard and one other instrument, often the violin or cello. It was less and less frequently applied to works with more than two instrumentalists; for example, piano trios were not often labelled sonata for piano, violin, and cello.
Initially the most common layout of movements was:
Allegro, which at the time was understood to mean not only a tempo, but also some degree of "working out", or development, of the theme.
A middle movement, most frequently a slow movement: an Andante, an Adagio or a Largo; or less frequently a Minuet or Theme and Variations form.
A closing movement was generally an Allegro or a Presto, often labeled Finale. The form was often a Rondo or Minuet.However, two-movement layouts also occur, a practice Haydn uses as late as the 1790s. There was also in the early Classical period the possibility of using four movements, with a dance movement inserted before the slow movement, as in Haydns Piano sonatas No. 6 and No. 8. Mozarts sonatas were also primarily in three movements. Of the works that Haydn labelled piano sonata, divertimento, or partita in Hob XIV, seven are in two movements, thirty-five are in three, and three are in four; and there are several in three or four movements whose authenticity is listed as "doubtful." Composers such as Boccherini would publish sonatas for piano and obbligato instrument with an optional third movement—–in Boccherinis case, 28 cello sonatas.
But increasingly instrumental works were laid out in four, not three movements, a practice seen first in string quartets and symphonies, and reaching the sonata proper in the early sonatas of Beethoven. However, two- and three-movement sonatas continued to be written throughout the Classical period: Beethovens opus 102 pair has a two-movement C major sonata and a three-movement D major sonata. Nevertheless, works with fewer or more than four movements were increasingly felt to be exceptions; they were labelled as having movements "omitted," or as having "extra" movements.
Thus, the four-movement layout was by this point standard for the string quartet, and overwhelmingly the most common for the symphony. The usual order of the four movements was:
An allegro, which by this point was in what is called sonata form, complete with exposition, development, and recapitulation.
A slow movement, an Andante, an Adagio or a Largo.
A dance movement, frequently Minuet and trio or—especially later in the classical period—a Scherzo and trio.
A finale in faster tempo, often in a sonata–rondo form.When movements appeared out of this order they would be described as "reversed", such as the scherzo coming before the slow movement in Beethovens 9th Symphony. This usage would be noted by critics in the early 19th century, and it was codified into teaching soon thereafter.
It is difficult to overstate the importance of Beethovens output of sonatas: 32 piano sonatas, plus sonatas for cello and piano or violin and piano, forming a large body of music that would over time increasingly be thought essential for any serious instrumentalist to master.
Romantic period
In the early 19th century, the current usage of the term sonata was established, both as regards form per se, and in the sense that a fully elaborated sonata serves as a norm for concert music in general, which other forms are seen in relation to. From this point forward, the word sonata in music theory labels as much the abstract musical form as particular works. Hence there are references to a symphony as a sonata for orchestra. This is referred to by William Newman as the sonata idea.
Among works expressly labeled sonata for the piano, there are the three of Frédéric Chopin, those of Felix Mendelssohn, the three of Robert Schumann, Franz Liszts Sonata in B minor, and later the sonatas of Johannes Brahms and Sergei Rachmaninoff.
In the early 19th century, the sonata form was defined, from a combination of previous practice and the works of important Classical composers, particularly Haydn, Mozart, Beethoven, but composers such as Clementi also. It is during this period that the differences between the three- and the four-movement layouts became a subject of commentary, with emphasis on the concerto being laid out in three movements, and the symphony in four.
Ernest Newman wrote in the essay "Brahms and the Serpent":
That, perhaps, will be the ideal of the instrumental music of the future; the way to it, indeed, seems at last to be opening out before modern composers in proportion as they discard the last tiresome vestiges of sonata form. This, from being what it was originally, the natural mode of expression of a certain eighteenth century way of thinking in music, became in the nineteenth century a drag upon both individual thinking and the free unfolding of the inner vital force of an idea, and is now simply a shop device by which a bad composer may persuade himself and the innocent reader of textbooks that he is a good one.
After the Romantic period
The role of the sonata as an extremely important form of extended musical argument would inspire composers such as Hindemith, Prokofiev, Shostakovich, Tailleferre, Ustvolskaya, and Williams to compose in sonata form, and works with traditional sonata structures continue to be composed and performed.
Scholarship and musicology
Sonata idea or principle
Research into the practice and meaning of sonata form, style, and structure has been the motivation for important theoretical works by Heinrich Schenker, Arnold Schoenberg, and Charles Rosen among others; and the pedagogy of music continued to rest on an understanding and application of the rules of sonata form as almost two centuries of development in practice and theory had codified it.
The development of the classical style and its norms of composition formed the basis for much of the music theory of the 19th and 20th centuries. As an overarching formal principle, sonata was accorded the same central status as Baroque fugue; generations of composers, instrumentalists, and audiences were guided by this understanding of sonata as an enduring and dominant principle in Western music. The sonata idea begins before the term had taken on its present importance, along with the evolution of the Classical periods changing norms. The reasons for these changes, and how they relate to the evolving sense of a new formal order in music, is a matter to which research is devoted. Some common factors which were pointed to include: the shift of focus from vocal music to instrumental music; changes in performance practice, including the loss of the continuo.Crucial to most interpretations of the sonata form is the idea of a tonal center; and, as the Grove Concise Dictionary of Music puts it: "The main form of the group embodying the sonata principle, the most important principle of musical structure from the Classical period to the 20th century: that material first stated in a complementary key be restated in the home key".(The sonata idea has been thoroughly explored by William Newman in his monumental three-volume work Sonata in the Classic Era (A History of the Sonata Idea), begun in the 1950s and published in what has become the standard edition of all three volumes in 1972.
20th-century theory
Heinrich Schenker argued that there was an Urlinie or basic tonal melody, and a basic bass figuration. He held that when these two were present, there was basic structure, and that the sonata represented this basic structure in a whole work with a process known as interruption.As a practical matter, Schenker applied his ideas to the editing of the piano sonatas of Beethoven, using original manuscripts and his own theories to "correct" the available sources. The basic procedure was the use of tonal theory to infer meaning from available sources as part of the critical process, even to the extent of completing works left unfinished by their composers. While many of these changes were and are controversial, that procedure has a central role today in music theory, and is an essential part of the theory of sonata structure as taught in most music schools.
Notable sonatas
Baroque (c. 1600 – c. 1760)
Johann Sebastian Bach
Sonatas for solo violin (BWV 1001, 1003 and 1005)
Sonatas for flute and continuo (BWV 1034, 1035)
Trio sonatas: for organ (BWV 525–530); for violin and harpsichord (BWV 1014–1019); for viola da gamba and harpsichord (BWV 1027–1029); for flute and harpsichord (BWV 1030, 1032); for flute, violin and continuo (Sonata sopril Soggetto Reale included in The Musical Offering)
Heinrich Ignaz Franz Biber
Rosary Sonatas
George Frideric Handel
Sonata for Violin and Continuo in D major (HWV 371)
Giuseppe Tartini
Devils Trill Sonata
Domenico Scarlatti
List of solo keyboard sonatas by Domenico Scarlatti
Classical (c. 1760 – c. 1830)
Wolfgang Amadeus Mozart
Piano Sonata No. 8 in A minor (K. 310)
Piano Sonata No. 11 in A major (K. 331/300i)
Piano Sonata No. 12 in F major (K. 332)
Piano Sonata No. 13 in B-flat major (K. 333)
Piano Sonata No. 14 in C minor (K. 457)
Piano Sonata No. 15 in F major (K. 533/494)
Piano Sonata No. 16 in C major (K. 545)
Sonata in A for Violin and Keyboard (K. 526)
Franz Joseph Haydn
Sonata No. 1 in C major, Hob. XVI:1 – Piano Sonata No. 62, Hob.XVI:52
Franz Schubert
Sonata in C minor, D. 958
Sonata in A major, D. 959
Sonata in B♭ major, D. 960
Romantic (c. 1795 – c. 1900)
Ludwig van Beethoven
Piano Sonata No. 8 "Pathétique"
Piano Sonata No. 14 "Moonlight" (Sonata quasi una fantasia)
Piano Sonata No. 17 "Tempest"
Piano Sonata No. 19 "Leichte"
Piano Sonata No. 21 "Waldstein"
Piano Sonata No. 23 "Appassionata"
Piano Sonata No. 29 "Hammerklavier"
Piano Sonata No. 32 in C minor, Op. 111
Violin Sonata No. 5 "Spring"
Violin Sonata No. 9 "Kreutzer"
Cello Sonata No. 1 in F major Op. 5
Cello Sonata No. 2 in G minor Op. 5
Cello Sonata No. 3 in A major Op. 69
Johannes Brahms
Cello Sonata No. 1
Cello Sonata No. 2
Clarinet Sonatas No. 1 and No.2
Violin Sonata No. 1
Violin Sonata No. 2
Violin Sonata No. 3
Johannes Brahms, Albert Dietrich, and Robert Schumann
F-A-E Sonata
Frédéric Chopin
Piano Sonata No. 2 in B♭ minor
Piano Sonata No. 3 in B minor
Paul Dukas
Piano Sonata in E-flat minor (1900)
George Enescu
Sonata No. 1 for violin and piano in D major, Op. 2 (1897)
Sonata No. 2 for violin and piano in F minor, Op. 6 (1899)
Edvard Grieg
Three sonatas for Violin and Piano
Franz Liszt
Sonata after a Reading of Dante (Fantasia Quasi Sonata)
Sonata in B minor
Robert Schumann
Violin Sonata No. 1 in A minor, Op. 105
20th-century and contemporary (c. 1910–present)
Samuel Barber
Cello Sonata Op. 6
Piano Sonata Op. 26 (1949)
Jean Barraqué
Piano Sonata (1950–52)
Béla Bartók
Sonata for Two Pianos and Percussion
Sonata for Piano (1926)
Sonata for Solo Violin
Sonata No. 1 for Violin and Piano
Sonata No. 2 for Violin and Piano
Alban Berg
Sonata for Piano, Op. 1
Leonard Bernstein
Sonata for Clarinet and Piano
Pierre Boulez
Piano Sonata No. 1
Piano Sonata No. 2
Piano Sonata No. 3
Benjamin Britten
Sonata for Cello and Piano, Op. 65
John Cage
Sonata for Unaccompanied Clarinet
Sonatas and Interludes for Prepared Piano (1946–48)
Claude Debussy
Sonata No. 1, for cello and piano (1915)
Sonata No. 2, for flute, viola and harp (1915)
Sonata No. 3, for violin and piano (1916–1917)
George Enescu
Sonata No. 3 for violin and piano, in A minor, dans le caractère populaire roumain Op. 25 (1926)
Sonata No. 2 for cello and piano in C major, Op. 26, No. 2 (1935)
Piano Sonata No. 1 in F♯ minor, Op. 24, No. 1 (1924)
Piano Sonata No. 3 in D major, Op. 24, No. 3 (1933–1935)
Karel Goeyvaerts
Sonata for Two Pianos, Op. 1
Hans Werner Henze
Royal Winter Music, Guitar Sonatas No. 1 and 2
Paul Hindemith
Sonata for Viola and Piano, Op. 11, No. 4 (1919)
Charles Ives
Piano Sonata No. 2, Concord, Mass., 1840–60
Leoš Janáček
1. X. 1905 (Janáčeks Sonata for Piano)
Ben Johnston
Sonata for Microtonal Piano
György Ligeti
Sonata, for solo cello (1948/1953)
Darius Milhaud
Sonata for flute, oboe, clarinet, and piano, Op. 47 (1918)
Sergei Prokofiev
Piano Sonatas—six juvenile (1904, 1907, 1907, 1907–08, 1908, 1908–09)
Piano Sonata No. 1 in F minor, Op. 1 (1907–09)
Piano Sonata No. 2 in D minor, Op. 14 (1912)
Piano Sonata No. 3 in A minor, Op. 28 (1907–17)
Piano Sonata No. 4 in C minor, Op. 29 (1917)
Piano Sonata No. 5 in C major (original version), Op. 38 (1923)
Violin Sonata No. 1 in F minor, Op. 80 (1938–46)
Piano Sonata No. 6 in A major, Op. 82 (1939–40)
Piano Sonata No. 7 in B-flat major, Stalingrad, Op. 83 (1939–42)
Piano Sonata No. 8 in B-flat major, Op. 84 (1939–44)
Flute Sonata in D major, Op. 94 (1943)
Violin Sonata No. 2 in D major, Op. 94 bis (1943)
Piano Sonata No. 9 in C major, Op. 103 (1947)
Sonata for Solo Violin (Unison Violins) in D major, Op. 115
Cello Sonata in C major, Op. 119
Sonata for Solo Cello in C-sharp minor, Op. 133
Piano Sonata No. 5 in C major (revised version), Op. 135 (1952–53)
Sergei Rachmaninoff
Piano Sonata No. 2 in B-flat minor, Op. 36 (1913, revised in 1931)
Sonata for Cello and Piano in G minor, Op. 19 (1901)
Alexander Scriabin
Piano Sonata No. 2 (Sonata-Fantasy)
Piano Sonata No. 3
Piano Sonata No. 4
Piano Sonata No. 5
Piano Sonata No. 6
Piano Sonata No. 7 "White Mass"
Piano Sonata No. 8
Piano Sonata No. 9 "Black Mass"
Piano Sonata No. 10
Kaikhosru Shapurji Sorabji
Piano Sonata No. 0
Piano Sonata No. 1
Piano Sonata No. 2
Piano Sonata No. 3
Piano Sonata No. 4
Piano Sonata No. 5 "Opus Archimagicum"
Igor Stravinsky
Sonata for Two Pianos (1943)
Eugène Ysaÿe
Six Sonatas for solo violin (1923)
References
Sources
== Further reading == |
Lactitol | Lactitol is a sugar alcohol used as a replacement bulk sweetener for low calorie foods with 30–40% of the sweetness of sucrose. It is also used medically as a laxative. Lactitol is produced by two manufacturers, Danisco and Purac Biochem.
Applications
Lactitol is used in a variety of low food energy or low fat foods. High stability makes it popular for baking. It is used in sugar-free candies, cookies (biscuits), chocolate, and ice cream, with a sweetness of 30–40% that of sucrose. Lactitol also promotes colon health as a prebiotic. Because of poor absorption, lactitol only has 2–2.5 kilocalories (8.4–10.5 kilojoules) per gram, compared to 4 kilocalories (17 kJ) per gram for typical saccharides. Hence, lactitol is about 60% as caloric as typical saccharides.
Medical
Lactitol is listed as an excipient in some prescription drugs.Lactitol is a laxative and is used to prevent or treat constipation, e.g., under the trade name Importal.In February 2020, Lactitol was approved for use in the United States as an osmotic laxative for the treatment of chronic idiopathic constipation (CIC) in adults.Lactitol in combination with Ispaghula husk is an approved combination for idiopathic constipation as a laxative and is used to prevent or treat constipation.
Safety and health
Lactitol, erythritol, sorbitol, xylitol, mannitol, and maltitol are all sugar alcohols. The U.S. Food and Drug Administration (FDA) classifies sugar alcohols as "generally recognized as safe" (GRAS). They are approved as food additives, and are recognized as not contributing to tooth decay or causing increases in blood glucose. Lactitol is also approved for use in foods in most countries around the world.Like other sugar alcohols, lactitol causes cramping, flatulence, and diarrhea in some individuals who consume it. This is because humans lack a suitable beta-galactosidase in the upper gastrointestinal (GI) tract, and a majority of ingested lactitol reaches the large intestine, where it then becomes fermentable to gut microbes (prebiotic) and can pull water into the gut by osmosis. Those with health conditions should consult their GP or dietician prior to consumption.
History
The U.S. Food and Drug Administration (FDA) approved Pizensy based on evidence from a clinical trial (Trial 1/ NCT02819297) of 594 subjects with CIC conducted in the United States. The FDA also considered other supportive evidence including data from Trial 2 (NCT02481947) which compared Pizensy to previously approved drug (lubiprostone) for CIC, and Trial 3 (NCT02819310) in which subjects used Pizensy for one year as well as data from published literature.The benefit and side effects of Pizensy were evaluated in a clinical trial (Trial 1) of 594 subjects with CIC. In this trial, subjects received treatment with either Pizensy or placebo once daily for 6 months. Neither the subjects nor the health care providers knew which treatment was being given until after the trials were completed.In the second trial (Trial 2) of three months duration, improvement in CSBMs was used to compare Pizensy to the drug lubiprostone which was previously approved for CIC. The third trial (Trial 3) was used to collect the side effects in subjects treated with Pizensy for one year.
References
External links
Media related to Lactitol at Wikimedia Commons
"Lactitol". Drug Information Portal. U.S. National Library of Medicine. |
Stavudine | Stavudine (d4T), sold under the brand name Zerit among others, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. However, it is not a first-line treatment. It is given by mouth.Common side effects include headache, diarrhea, vomiting, rash, and peripheral nerve problems. Severe side effects include high blood lactate, pancreatitis, and an enlarged liver. It is not generally recommended in pregnancy. Stavudine is in the nucleoside analog reverse-transcriptase inhibitor (NRTI) class of medication.Stavudine was first described in 1966 and approved for use in the United States in 1994. It is available as a generic medication.
Medical uses
Stavudine is used in the treatment of HIV-1 infection, but is not a cure. It is not normally recommended as initial treatment. Stavudine can also reduce the risk of developing HIV-1 infection after coming into contact with the virus either at work (e.g., needlestick) or through exposure to infected blood or other bodily fluids. It is always used in combination with other HIV medications for the better control of the infection and a reduction in HIV complications.The World Health Organization (WHO) recommends stavudine to be phased out to due to its high toxicity levels. If the drug must be used, it is recommended to use low dosages to reduce the occurrence of side effects; however, a 2015 Cochrane review found no clear advantage between high and low dosage regimens.
Pregnancy and breastfeeding
Stavudine has been demonstrated to affect the fetus in animal studies but no data are available from human studies. Pregnant women should therefore be given stavudine only if the potential benefits outweigh the potential harm to the fetus. Additionally, there have been case reports of fatal lactic acidosis in pregnant women receiving combination therapy of stavudine and didanosine with other antiviral agents.The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, in order to avoid the risk of HIV transmission through breast milk. There is also evidence that stavudine gets into animal breast milk, although no data are available for human breast milk.
Children
Stavudine is safe for use in children infected with HIV from birth through adolescence. Adverse effects and safety profile are the same as adults.
Elderly
There is no data available for stavudine use in HIV-infected adults aged 65 years or older. However, among 12,000 people over the age of 65, 30% developed peripheral neuropathy. Additionally, since the elderly are more likely to have decreased renal function, they are more likely to develop toxic side effects.
Adverse events
Common side effects
Nausea
Vomiting
Diarrhea
Headache
Upset stomachSevere side effects
Peripheral neuropathy
Lactic acidosis
Pancreatitis
Hepatotoxicity
Hepatomegaly with steatosis
Lipoatrophy/lipodystrophy (fat redistribution/accumulation)Individuals are monitored for the development of these serious adverse effects. The development of peripheral neuropathy is shown to be dose related, and may be resolved if the drug is discontinued. Individuals with advanced HIV-1 disease, a history of peripheral neuropathy, or individuals on other drugs that have association with neuropathy develop this side effect more often.Stavudine has been shown in laboratory test to be genotoxic, but with clinical doses its carcinogenic effects are non-existent. Hyperlactatemia, bone mineral density (BMD) loss, reduction in limb fat and an increase in triglycerides were found when administered in high dosages. It is also one of the most likely antiviral drugs to cause lipodystrophy, and for this reason it is no longer considered an appropriate treatment for most patients in developed countries.
HLA-B*4001 may be used as a genetic marker to predict which patients will develop stavudine-associated lipodystrophy, to avoid or shorten the duration of stavudine according to a study in Thailand.It is still used as first choice in first line therapy in resource poor settings such as in India. Only in case of development of peripheral neuropathy or pregnancy is it changed to the next choice, zidovudine. Safety and effectiveness of dosage titration was not reported in treatment naive patients. It was only reported in those patients with sustained virologic suppression. These findings are not generalized to Stavudine used in ART naive patients who have high viral loads.
On Monday 30 November 2009, the World Health Organization stated that "[The WHO] recommends that countries phase out the use of Stavudine, or d4T, because of its long-term, irreversible side-effects. Stavudine is still widely used in first-line therapy in developing countries due to its low cost and widespread availability. Zidovudine (AZT) or tenofovir (TDF) are recommended as less toxic and equally effective alternatives."
Mechanism of action
Stavudine is a nucleoside analog of thymidine. It is phosphorylated by cellular kinases into an active triphosphate. Stavudine triphosphate inhibits HIVs reverse transcriptase by competing with the natural substrate, thymidine triphosphate. Reverse transcriptase is the enzyme the virus uses to make a DNA copy of its RNA in order to insert its genetic material into the hosts DNA. Upon incorporation into the DNA strand, stavudine triphosphate causes termination of DNA replication.
Pharmacokinetics
Absorption: Stavudine has rapid absorption and good oral bioavailability (F = 0.86).Distribution: Stavudine does not bind to proteins in the blood.Metabolism: The clearance of stavudine is affected minimally by hepatic metabolism. Oxidation and glucuronidation produce minor metabolites.Elimination: Stavudine is mostly eliminated in the urine and mostly in its unchanged form.
Drug interactions
Simultaneous use of zidovudine is not recommended, as it can inhibit the intracellular phosphorylation of stavudine. Other anti-HIV drugs do not possess this property.
Stavudine is not protein-bound nor does it inhibit the major cytochrome P450 isoforms. Thus, significant drug interactions with drugs metabolized through these pathways or drugs that are protein-bound are unlikely.
History
Stavudine was first created by Jerome Horwitz in the 1960s and was originally named D4T. When the AIDS epidemic occurred in the 1980s, William Prusoff and Dr. Tai-Shun Lin discovered the anti-HIV properties of Stavudine. The pharmaceutical company Bristol-Myers Squibb manufactures the drug under the trade name Zerit.It is also the first drug to be granted parallel track status in 1992, by the US Food and Drug Administration (FDA), which allowed for the agency to make Stavudine available to patients before being approved. Stavudine was submitted under the FDAs accelerated approval process. Through this process, Stavudines effectiveness was measured by its effect on the surrogate marker, CD4, instead of clinical endpoints. The FDA concluded that an increase in CD4 cell counts was an indicator of how effective the drug would be against AIDS and HIV infection. Stavudine was the fourth drug to be approved for the treatment of AIDS and HIV infection by the FDA on June 27, 1994. Even after approval, studies were continued to evaluate the clinical benefit of the drug. If there is no indication of clinical benefits, the accelerated approval may be withdrawn.In 2018, Mylan Pharmaceuticals discontinued manufacturing stavudine 20 mg, 30 mg, and 40 mg capsules.
References
External links
"Stavudine". Drug Information Portal. U.S. National Library of Medicine. |
Selexipag | Selexipag, sold under the brand name Uptravi, is a medication developed by Actelion for the treatment of pulmonary arterial hypertension (PAH). Selexipag and its active metabolite, ACT-333679 (or MRE-269, the free carboxylic acid), are agonists of the prostacyclin receptor, which leads to vasodilation in the pulmonary circulation. It is taken by mouth or administered intravenously.
Contraindications
In Europe, use of selexipag together with strong inhibitors of the liver enzyme CYP2C8, such as gemfibrozil, is contraindicated because it increases concentrations of selexipag twofold, and its active metabolite 11-fold, potentially leading to more adverse effects.
Adverse effects
The adverse effects of selexipag are similar to those of intravenous prostacyclins used for pulmonary arterial hypertension. Common side effects include headache and jaw pain. An increased risk for hyperthyroidism has also been noted in people taking selexipag.
Pharmacology
Mechanism of action
Selexipag and its active metabolite ACT-333679 act on the prostacyclin receptor of lung tissue, with the latter being 37-fold more potent. They are selective for the prostacyclin receptor. Binding to this receptor leads to three major effects: increased vasodilation of the arteries, decreased cell proliferation and inhibition of platelet aggregation, all beneficial in the treatment of pulmonary arterial hypertension.
Pharmacokinetics
Selexipag is quickly absorbed from the gut and hydrolyzed in the intestines and the liver to ACT-333679 by carboxylesterases. Absolute bioavailability is about 49%, most likely because of a high first-pass effect. Highest concentrations in the blood plasma are reached after one to three hours for selexipag and after three to four hours for the active metabolite. When in the circulation, about 99% of both substances are bound to plasma proteins, namely to albumin and alpha-1-acid glycoprotein to equal amounts.The liver enzymes CYP2C8 and, to a lesser extent, CYP3A4, hydroxylate and dealkylate the active substance, thereby inactivating it. Besides, ACT-333679 is glucuronidized by the enzymes UGT1A3 and UGT2B7. The terminal half-life of selexipag is 0.8 to 2.5 hours, that of the active metabolite is 6.2 to 13.5 hours.
History
The U.S. Food and Drug Administration (FDA) granted selexipag orphan drug status for PAH. It was approved by the FDA on 22 December 2015.In Europe, the drug was approved in May 2016.
Society and culture
Economics
The expected price for the drug in the US is $160,000 to $170,000 per patient before rebates.
References
External links
"Selexipag". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03187678 for "Safety Study of the Switch From Oral Selexipag to Intravenous Selexipag in Subjects With Stable Pulmonary Arterial Hypertension" at ClinicalTrials.gov |
Folinic acid | Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.Side effects may include trouble sleeping, allergic reactions, or fever. Use in pregnancy or breastfeeding is generally regarded as safe. When used for anemia it is recommended that pernicious anemia as a cause be ruled out first. Folinic acid is a form of folic acid that does not require activation by dihydrofolate reductase to be useful to the body.Folinic acid was first made in 1945. It is on the World Health Organizations List of Essential Medicines.
Medical use
Folinic acid is given following methotrexate as part of a total chemotherapeutic plan, where it may protect against bone marrow suppression or gastrointestinal mucosa inflammation. No apparent effect is seen on pre-existing methotrexate-induced nephrotoxicity. Folinic acid can be taken as a pill (orally) or injected into a vein (intravenously) or muscle (intramuscularly).While not specifically an antidote for methotrexate, folinic acid may also be useful in the treatment of acute methotrexate overdose. Different dosing protocols are used, but folinic acid should be redosed until the methotrexate level is less than 5 x 10−8 M.Additionally, folinic acid is sometimes used to reduce the side effects of methotrexate in rheumatoid arthritis patients. This includes reductions in nausea, abdominal pain, abnormal liver blood tests, and mouth sores.Folinic acid is also used in combination with the chemotherapy agent 5-fluorouracil in treating colon cancer. In this case, folinic acid is not used for "rescue" purposes; rather, it enhances the effect of 5-fluorouracil by inhibiting thymidylate synthase.
Folinic acid is also sometimes used to prevent toxic effects of high doses of antimicrobial dihydrofolate reductase inhibitors such as trimethoprim and pyrimethamine. It may be prescribed in the treatment of toxoplasmosis retinitis, in combination with the folic acid antagonists pyrimethamine and sulfadiazine.
Folinic acid is also used in the treatment of cerebral folate deficiency, a syndrome in which the use of folic acid cannot normalize cerebrospinal fluid levels of 5-MTHF.
Side effects
Folinic acid should not be administered intrathecally. This may produce severe adverse effects or even death.In cancer patients, rare hypersensitivity reactions to folinic acid have been described.
Drug interactions
Fluorouracil: Folinic acid may increase the toxicity associated with fluorouracil if the two are administered together. Some adverse effects that have occurred, particularly in elderly patients, include severe enterocolitis, diarrhea, and dehydration.Sulfamethoxazole-trimethoprim: A potential drug interaction exists with concomitant use of sulfamethoxazole-trimethoprim and folinic acid. Folinic acid has been shown to decrease the efficacy of sulfamethoxazole-trimethoprim in the treatment of Pneumocystis jirovecii (formerly known as Pneumocystis carinii), a common cause of pneumonia in AIDS patients.
Mechanism of action
Folinic acid is a 5-formyl derivative of tetrahydrofolic acid. It is readily converted to other reduced folic acid derivatives (e.g., 5,10-methylenetetrahydrofolate, 5-methyltetrahydrofolate), thus has vitamin activity equivalent to that of folic acid. Since it does not require the action of dihydrofolate reductase for its conversion, its function as a vitamin is unaffected by inhibition of this enzyme by drugs such as methotrexate. This is the classical view of folinic acid rescue therapy. In 1980s, however, folinic acid was found to reactivate the dihydrofolate reductase itself even when methotrexate exists.
Although the mechanism is not very clear, the polyglutamylation of methotrexate and dihydrofolate in malignant cells is considered to play an important role in the selective reactivation of dihydrofolate reductase by folinic acid in normal cells.Folinic acid, therefore, allows for some purine/pyrimidine synthesis to occur in the presence of dihydrofolate reductase inhibition, so some normal DNA replication processes can proceed.
Folinic acid has dextro- and levorotary isomers. Both levoleucovorin (the levorotary isomer) and racemic folinic acid (a mixture of both isomers) have similar efficacy and tolerability. Levoleucovorin was approved by the FDA in 2008.
History
Folinic acid was discovered as a needed growth factor for the bacterium Leuconostoc citrovorum in 1948, by Sauberlich and Baumann. This resulted in it being called "citrovorum factor," meaning citrovorum growth factor. It had an unknown structure, but was found to be a derivative of folate that had to be metabolized in the liver before it could support growth of L. citrovorum. The synthesis of citrovorum factor by liver cells in culture was eventually accomplished from pteroylglutamic acid in the presence of suitable concentrations of ascorbic acid. The simultaneous addition of sodium formate to such systems resulted in increased citrovorum factor activity in the cell-free supernatants (producing, as now known, the 5-formyl derivative), and from this method of preparation of large amounts of the factor, its structure as levo-folinic acid (5-formyl tetrahydrofolic acid) was eventually deduced.
Names
Folinic acid should be distinguished from folic acid (vitamin B9). However, folinic acid is a vitamer for folic acid and has the full vitamin activity of this vitamin. Levofolinic acid and its salts are the 2S- form of the molecule. They are the only forms of the molecule that are known to be biologically active.
It is generally administered as the calcium or sodium salt (calcium folinate (INN), sodium folinate, leucovorin calcium, leucovorin sodium).
References
External links
"Leucovorin". Drug Information Portal. U.S. National Library of Medicine.
"Leucovorin". MedlinePlus. |
Physostigmine | Physostigmine (also known as eserine from éséré, the West African name for the Calabar bean) is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean and the fruit of the Manchineel tree.
The chemical was synthesized for the first time in 1935 by Percy Lavon Julian and Josef Pikl. It is available in the U.S. under the trade names Antilirium and Isopto Eserine, and as eserine salicylate and eserine sulfate. Today, physostigmine is most commonly used for its medicinal value. However, before its discovery by Sir Robert Christison in 1846, it was much more prevalent as an ordeal poison. The positive medical applications of the drug were first suggested in the gold medal-winning final thesis of Thomas Richard Fraser at the University of Edinburgh in 1862.
Medical uses
Physostigmine is used to treat glaucoma and delayed gastric emptying. Because it enhances the transmission of acetylcholine signals in the brain and can cross the blood–brain barrier, physostigmine salicylate is used to treat anticholinergic poisoning (that is, poisoning by substances that interfere with the transmission of acetylcholine signaling, such as atropine, scopolamine, and other anticholinergic drug overdoses). It is also used to reverse neuromuscular blocking. Physostigmine is the antidote of choice for Datura stramonium poisoning. It is also an antidote for Atropa belladonna poisoning, the same as for atropine. It has also been used as an antidote for poisoning with GHB, but is poorly effective and often causes additional toxicity, so is not a recommended treatment. It can also be used as an antidote for dimenhydrinate poisoning.It has been shown to improve long-term memory, and was once explored as a therapy for Alzheimers disease, but in clinical trials it was not shown to confer convincing benefits, and it led to very common moderate to severe side-effects such as nausea, vomiting, diarrhea, loss of appetite, abdominal pain, and tremors, resulting in a high rate of withdrawal. Physostigmines poor tolerability led to it being abandoned in favor of later acetylcholinesterase inhibitors, three of which are currently in use: donepezil, galantamine, and rivastigmine. Recently, it has begun to be used in the treatment of orthostatic hypotension.
Recently, physostigmine has been proposed as an antidote for intoxication with gamma hydroxybutyrate (GHB, a potent sedative-hypnotic agent that can cause loss of consciousness, loss of muscle control, and death). Physostigmine may counteract GHB by producing a nonspecific state of arousal. However, not enough scientific evidence shows physostigmine properly treats GHB toxicity. Furthermore, lower doses of GHB produce a stronger action at the GHB receptor than at the GABAB-receptor, resulting in a stimulating effect which would act synergistically with physostigmine and produce hyperstimulation when the GHB blood levels begin to drop.
Physostigmine also has other proposed uses: it could reverse undesired side effects of benzodiazepines such as diazepam, alleviating anxiety and tension. Another proposed use of physostigmine is to reverse the effects of barbiturates (any of a group of barbituric acids derived for use as sedatives or hypnotics).
Pharmacology
Physostigmine acts by interfering with the metabolism of acetylcholine. It is a reversible inhibitor of acetylcholinesterase, the enzyme responsible for the breakdown of acetylcholine in the synaptic cleft of the neuromuscular junction. It indirectly stimulates both nicotinic and muscarinic acetylcholine receptors. Physostigmine has an LD50 of 3 mg/kg in mice.
Bioactivity
Physostigmine functions as an acetylcholinesterase inhibitor. Its mechanism is to prevent the hydrolysis of acetylcholine by acetylcholinesterase at the transmitted sites of acetylcholine. This inhibition enhances the effect of acetylcholine, making it useful for the treatment of cholinergic disorders and myasthenia gravis. More recently, physostigmine has been used to improve the memory of Alzheimers patients due to its potent anticholinesterase activity. However, its drug form, physostigmine salicylate, has poor bioavailability.
Physostigmine also has a miotic function, causing pupillary constriction. It is useful in treating mydriasis. Physostigmine also increases outflow of the aqueous humor in the eye, making it useful in the treatment of glaucoma.
Side effects
An overdose can cause cholinergic syndrome. Other side effects may include nausea, vomiting, diarrhea, anorexia, dizziness, headache, stomach pain, sweating, dyspepsia, and seizures. The carbamate functional group readily hydrolyses in water, and in bodily conditions. The metabolite thus formed from physostigmine and some other alkaloids (e.g. cymserine) is eseroline, which research has suggested may be neurotoxic to humans. Death can occur rapidly following overdose as a result of respiratory arrest and paralysis of the heart.
Synthesis
Physostigmine has two stereocenters—the two carbons where the five-membered rings join—so any attempt at the total synthesis must pay attention to obtaining the correct stereoisomer. The 71 syntheses of physostigmine yield 33 racemic mixtures and 38 products of a single enantiomer. The first total synthesis of physostigmine was achieved by Julian and Pikl in 1935. The main goal of Julians formal physostigmine synthesis was to prepare the key compound (L)-eseroline (compound 10 in the adjacent diagram), the conversion of which to physostigmine would be straightforward. In one of his earlier works Julian synthesized the ring of physostigmine from 1-methyl-3-formyl-oxindole as starting material, which was discovered by Paul Friedländer. However, the starting material was expensive, and the reduction of a nitrile to an amine (similar to the reaction of compound 6 to give compound 7 in the diagram) with sodium and alcohol did not proceed in good yield. In his second work “Studies in the Indole Series III,” he had improved the yield of amine from nitrile significantly by using palladium and hydrogen. Although he succeeded in the synthesis of the target compound, the route had several drawbacks. First, the chemical resolution of compound 8 is unreliable, and the chemical resolution of rac-eserethole gives optically pure product only after eight recrystallizations of its tartrate salt. Second, the reductive amination going from compound 8 to compound 9 requires a large amount of Na. In the years since this initial work, many other groups have used a variety of approaches to construct the ring system and showcase new synthetic methods.
Biosynthesis
Physostigmine biosynthesis is proposed from tryptamine methylation and post-heterocyclization catalyzed by an unknown enzyme:
History
The Calabar bean
The Efik people, living in Cross River State and the Ibibio people in Akwa Ibom State, in what is now the south-south of Nigeria, were the first to come in contact with physostigmine, the active ingredient in the Calabar bean. The Calabar bean, or chopping nut, was very prevalent in Efik culture as an ordeal poison. Individuals accused of witchcraft would drink the white, milky extract of the bean, made by crushing the bean in a mortar and soaking the remains in water. If the accused died, it was considered proof of their use of witchcraft. If they lived, usually due to vomiting up the poison, then they were declared innocent and sent free.
Western medicines discovery
In 1846, European missionaries arrived in what was referred to as Old Calabar, now part of Nigeria. These missionaries wrote about the use of the Calabar bean as a test for witchcraft. These beans eventually made their way back to Scotland, the home of these particular missionaries, where in 1855 Robert Christison, a toxicologist, tested the toxicity of the poison on himself by eating one. He survived to document the experience. The bean was studied throughout the 1860s by a few different Edinburgh scientists, including Douglas Argyll Robertson who wrote a paper on the use of Calabar bean extract on the eye and was the first to use it medicinally, and Thomas Richard Fraser, who researched how to best extract the active principle, which was later determined to be physostigmine. Fraser also studied the antagonism between physostigmine and atropine extremely rigorously, at a time when the concept of antagonism had little if any experimental support. Frasers research is still the basis of todays knowledge about the interactions between atropine and physostigmine at many different and specific doses. Physostigmines first use as a treatment for glaucoma was by Ludwig Laqueur in 1876. Laqueur himself had glaucoma so, like Christison, he experimented on himself, although Laqueur was much more scientific and methodical in his self-treatment.
In the 1920s, Otto Loewi determined the biomechanical mechanism for the effects of physostigmine on the body. Loewi was studying how actions that we now consider to be controlled by the parasympathetic nervous system, were directed by chemicals. During his studies, Loewi discovered acetylcholine and that physostigmine acted by preventing acetylcholine inhibition. In 1936, Loewi was awarded the Nobel Prize for his work on discovering acetylcholine and biological chemical transmitters. More important discoveries surrounding physostigmine were made at the University of Edinburgh in 1925. Edgar Stedman and George Barger determined the structure of physostigmine using a method called chemical degradation. In 1935 Percy Lavon Julian was later the first to synthesize physostigmine. English scientist Robert Robinson was also working on the synthesis of physostigmine, but surprisingly Julian, a relatively unknown scientist at the time, was the successful one.In 1934, while working at St Alfeges Hospital in London, Dr Mary Walker discovered that a subcutaneous injection of physostigmine could temporarily reverse the muscle weakness found in patients with myasthenia gravis. She had noted that the symptoms and signs of myasthenia were similar to those found in curare poisoning, and physostigmine was used as an antidote to curare poisoning at that time. Her article explaining the first case of myasthenia gravis being successfully treated with physostigmine was published in The Lancet in June 1934.
See also
Neostigmine
Miotine
T-1123
TL-1238
== References == |
Nizatidine | Nizatidine is a histamine H2 receptor antagonist that inhibits stomach acid production, and is commonly used in the treatment of peptic ulcer disease and gastroesophageal reflux disease.It was patented in 1980 and approved for medical use in 1988. It was developed by Eli Lilly. Brand names include Tazac and Axid.
Medical use
Nizatidine is used to treat duodenal ulcers, gastric ulcers, and gastroesophageal reflux disease (GERD/GORD), and to prevent stress ulcers.
Adverse effects
Side effects are uncommon, usually minor, and include diarrhea, constipation, fatigue, drowsiness, headache, and muscle aches.
History and development
Nizatidine was developed by Eli Lilly, and was first marketed in 1988. It is considered to be equipotent with ranitidine and differs by the substitution of a thiazole ring in place of the furan ring in ranitidine. In September 2000, Eli Lilly announced they would sell the sales and marketing rights for Axid to Reliant Pharmaceuticals. Subsequently, Reliant developed the oral solution of Axid, marketing this in 2004, after gaining approval from the U.S. Food and Drug Administration (FDA). However, a year later, they sold rights of the Axid Oral Solution (including the issued patent protecting the product) to Braintree Laboratories.Nizatidine proved to be the last new histamine H2 receptor antagonist introduced prior to the advent of proton pump inhibitors.Axid (nizatidine) drug recalled due to presence of NDMA.
See also
Famotidine (Pepcid) — another popular H2 receptor antagonist
References
External links
"Nizatidine". Drug Information Portal. U.S. National Library of Medicine. |
Chlorpromazine | Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar disorder, severe behavioral problems in children including those with attention deficit hyperactivity disorder, nausea and vomiting, anxiety before surgery, and hiccups that do not improve following other measures. It can be given by mouth, by injection into a muscle, or into a vein.Chlorpromazine is in the typical antipsychotic class, and, chemically, is one of the phenothiazines. Its mechanism of action is not entirely clear but believed to be related to its ability as a dopamine antagonist. It also has anti-serotonergic and antihistaminergic properties.Common side effects include movement problems, sleepiness, dry mouth, low blood pressure upon standing, and increased weight. Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, neuroleptic malignant syndrome, severe lowering of the seizure threshold, and low white blood cell levels. In older people with psychosis as a result of dementia it may increase the risk of death. It is unclear if it is safe for use in pregnancy.Chlorpromazine was developed in 1950 and was the first antipsychotic on the market. It is on the World Health Organizations List of Essential Medicines. Its introduction has been labeled as one of the great advances in the history of psychiatry. It is available as a generic medication.
Medical uses
Chlorpromazine is used in the treatment of both acute and chronic psychoses, including schizophrenia and the manic phase of bipolar disorder, as well as amphetamine-induced psychosis.
In a 2013 comparison of fifteen antipsychotics in schizophrenia, chlorpromazine demonstrated mild-standard effectiveness. It was 13% more effective than lurasidone and iloperidone, approximately as effective as ziprasidone and asenapine, and 12–16% less effective than haloperidol, quetiapine, and aripiprazole.A 2014 systematic review carried out by Cochrane included 55 trials that compared the effectiveness of chlorpromazine versus placebo for the treatment of schizophrenia. Compared to the placebo group, patients under chlorpromazine experienced less relapse during 6 months to 2 years follow-up. No difference was found between the two groups beyond two years of follow-up. Patients under chlorpromazine showed a global improvement in symptoms and functioning. The systematic review also highlighted the fact that the side effects of the drug were severe and debilitating, including sedation, considerable weight gain, a lowering of blood pressure, and an increased risk of acute movement disorders. They also noted that the quality of evidence of the 55 included trials was very low and that 315 trials could not be included in the systematic review due to their poor quality. They called for further research on the subject, as chlorpromazine is a cheap benchmark drug and one of the most used treatments for schizophrenia worldwide.Chlorpromazine has also been used in porphyria and as part of tetanus treatment. It still is recommended for short-term management of severe anxiety and psychotic aggression. Resistant and severe hiccups, severe nausea/emesis, and preanesthetic conditioning are other uses. Symptoms of delirium in hospitalized AIDS patients have been effectively treated with low doses of chlorpromazine.
Other
Chlorpromazine is occasionally used off-label for treatment of severe migraine. It is often, particularly as palliation, used in small doses to reduce nausea by opioid-treated cancer patients and to intensify and prolong the analgesia of the opioids as well. Efficacy has been shown in treatment of symptomatic hypertensive emergency.
In Germany, chlorpromazine still carries label indications for insomnia, severe pruritus, and preanesthesia.Chlorpromazine and other phenothiazines have been demonstrated to possess antimicrobial properties, but are not currently used for this purpose except for a very small number of cases. For example, Miki et al. 1992 trialed daily doses of chlorpromazine, reversing chloroquine resistance in Plasmodium chabaudi isolates in mice.Chlorpromazine is an antagonist of several insect monoamine receptors. It is the most active antagonist known of silk moth (Bombyx mori) octopamine receptor α, intermediate for Bm tyramine receptors 1 & 2, weak for Drosophila octopamine receptor β, high for Drosophila tyramine receptor 1, intermediate for migratory locust (Locusta migratoria) tyramine receptor 1, and high for American cockroach (Periplaneta americana) octopamine receptor α and tyramine receptor 1.
Adverse effects
There appears to be a dose-dependent risk for seizures with chlorpromazine treatment. Tardive dyskinesia (involuntary, repetitive body movements) and akathisia (a feeling of inner restlessness and inability to stay still) are less commonly seen with chlorpromazine than they are with high potency typical antipsychotics such as haloperidol or trifluoperazine, and some evidence suggests that, with conservative dosing, the incidence of such effects for chlorpromazine may be comparable to that of newer agents such as risperidone or olanzapine.Chlorpromazine may deposit in ocular tissues when taken in high dosages for long periods of time.
Contraindications
Absolute contraindications include:
Previous hypersensitivity (including jaundice, agranulocytosis, etc.) to phenothiazines, especially chlorpromazine, or any of the excipients in the formulation being used.Relative contraindications include:
Very rarely, elongation of the QT interval may occur, increasing the risk of potentially fatal arrhythmias.
Interactions
Consuming food prior to taking chlorpromazine orally limits its absorption; likewise, cotreatment with benztropine can also reduce chlorpromazine absorption. Alcohol can also reduce chlorpromazine absorption. Antacids slow chlorpromazine absorption. Lithium and chronic treatment with barbiturates can increase chlorpromazine clearance significantly. Tricyclic antidepressants (TCAs) can decrease chlorpromazine clearance and hence increase chlorpromazine exposure. Cotreatment with CYP1A2 inhibitors like ciprofloxacin, fluvoxamine or vemurafenib can reduce chlorpromazine clearance and hence increase exposure and potentially also adverse effects. Chlorpromazine can also potentiate the CNS depressant effects of drugs like barbiturates, benzodiazepines, opioids, lithium and anesthetics and hence increase the potential for adverse effects such as respiratory depression and sedation.Chlorprozamine is also a moderate inhibitor of CYP2D6 and a substrate for CYP2D6, and hence can inhibit its own metabolism. It can also inhibit the clearance of CYP2D6 substrates such as dextromethorphan, potentiating their effects. Other drugs like codeine and tamoxifen, which require CYP2D6-mediated activation into their respective active metabolites, may have their therapeutic effects attenuated. Likewise, CYP2D6 inhibitors such as paroxetine or fluoxetine can reduce chlorpromazine clearance, increasing serum levels of chlorpromazine and potentially its adverse effects. Chlorpromazine also reduces phenytoin levels and increases valproic acid levels. It also reduces propranolol clearance and antagonizes the therapeutic effects of antidiabetic agents, levodopa (a Parkinsons medication. This is likely due to the fact that chlorpromazine antagonizes the D2 receptor which is one of the receptors dopamine, a levodopa metabolite, activates), amphetamines and anticoagulants. It may also interact with anticholinergic drugs such as orphenadrine to produce hypoglycaemia (low blood sugar).Chlorpromazine may also interact with epinephrine (adrenaline) to produce a paradoxical fall in blood pressure. Monoamine oxidase inhibitors (MAOIs) and thiazide diuretics may also accentuate the orthostatic hypotension experienced by those receiving chlorpromazine treatment. Quinidine may interact with chlorpromazine to increase myocardial depression. Likewise, it may also antagonize the effects of clonidine and guanethidine. It also may reduce the seizure threshold and hence a corresponding titration of anticonvulsant treatments should be considered. Prochlorperazine and desferrioxamine may also interact with chlorpromazine to produce transient metabolic encephalopathy.Other drugs that prolong the QT interval, such as quinidine, verapamil, amiodarone, sotalol and methadone, may also interact with chlorpromazine to produce additive QT interval prolongation.
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly, there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely, tardive dyskinesia can occur when the medication is stopped.
Pharmacology
Chlorpromazine is classified as a low-potency typical antipsychotic. Low-potency antipsychotics have more anticholinergic side effects, such as dry mouth, sedation, and constipation, and lower rates of extrapyramidal side effects, while high-potency antipsychotics (such as haloperidol) have the reverse profile.
Pharmacokinetics
Pharmacodynamics
Chlorpromazine is a very effective antagonist of D2 dopamine receptors and similar receptors, such as D3 and D5. Unlike most other drugs of this genre, it also has a high affinity for D1 receptors. Blocking these receptors causes diminished neurotransmitter binding in the forebrain, resulting in many different effects. Dopamine, unable to bind with a receptor, causes a feedback loop that causes dopaminergic neurons to release more dopamine. Therefore, upon first taking the drug, patients will experience an increase in dopaminergic neural activity. Eventually, dopamine production of the neurons will drop substantially and dopamine will be removed from the synaptic cleft. At this point, neural activity decreases greatly; the continual blockade of receptors only compounds this effect.Chlorpromazine acts as an antagonist (blocking agent) on different postsynaptic and presynaptic receptors:
Dopamine receptors (subtypes D1, D2, D3 and D4), which account for its different antipsychotic properties on productive and unproductive symptoms, in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extrapyramidal effects
Serotonin receptors (5-HT2, 5-HT6 and 5-HT7), with anxiolytic, antidepressant and antiaggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain and ejaculation difficulties.
Histamine receptors (H1 receptors, accounting for sedation, antiemetic effect, vertigo, and weight gain)
α1- and α2-adrenergic receptors (accounting for sympatholytic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism – controversial. Also associated with weight gain as a result of blockage of the adrenergic alpha 1 receptor)
M1 and M2 muscarinic acetylcholine receptors (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, sinus tachycardia, electrocardiographic changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects).The presumed effectiveness of the antipsychotic drugs relied on their ability to block dopamine receptors. This assumption arose from the dopamine hypothesis that maintains that both schizophrenia and bipolar disorder are a result of excessive dopamine activity. Furthermore, psychomotor stimulants like cocaine that increase dopamine levels can cause psychotic symptoms if taken in excess.Chlorpromazine and other typical antipsychotics are primarily blockers of D2 receptors. In fact an almost perfect correlation exists between the therapeutic dose of a typical antipsychotic and the drugs affinity for the D2 receptor. Therefore, a larger dose is required if the drugs affinity for the D2 receptor is relatively weak. A correlation exists between average clinical potency and affinity of the antipsychotics for dopamine receptors.
Chlorpromazine tends to have greater effect at serotonin receptors than at D2 receptors, which is notably the opposite effect of the other typical antipsychotics. Therefore, chlorpromazine with respect to its effects on dopamine and serotonin receptors is more similar to the atypical antipsychotics than to the typical antipsychotics.Chlorpromazine and other antipsychotics with sedative properties such as promazine and thioridazine are among the most potent agents at α-adrenergic receptors. Furthermore, they are also among the most potent antipsychotics at histamine H1 receptors. This finding is in agreement with the pharmaceutical development of chlorpromazine and other antipsychotics as anti-histamine agents. Furthermore, the brain has a higher density of histamine H1 receptors than any body organ examined which may account for why chlorpromazine and other phenothiazine antipsychotics are as potent at these sites as the most potent classical antihistamines.In addition to influencing the neurotransmitters dopamine, serotonin, epinephrine, norepinephrine, and acetylcholine it has been reported that antipsychotic drugs could achieve glutamatergic effects. This mechanism involves direct effects on antipsychotic drugs on glutamate receptors. By using the technique of functional neurochemical assay chlorpromazine and phenothiazine derivatives have been shown to have inhibitory effects on NMDA receptors that appeared to be mediated by action at the Zn site. It was found that there is an increase of NMDA activity at low concentrations and suppression at high concentrations of the drug. No significant difference in glutamate and glycine activity from the effects of chlorpromazine were reported. Further work will be necessary to determine if the influence in NMDA receptors by antipsychotic drugs contributes to their effectiveness.Chlorpromazine does also act as a FIASMA (functional inhibitor of acid sphingomyelinase).
Peripheral effects
Chlorpromazine is an antagonist to H1 receptors (provoking antiallergic effects), H2 receptors (reduction of forming of gastric juice), M1 and M2 receptors (dry mouth, reduction in forming of gastric juice) and some 5-HT receptors (different anti-allergic/gastrointestinal actions).
Because it acts on so many receptors, chlorpromazine is often referred to as a "dirty drug".
History
In 1933, the French pharmaceutical company Laboratoires Rhône-Poulenc began to search for new anti-histamines. In 1947, it synthesized promethazine, a phenothiazine derivative, which was found to have more pronounced sedative and antihistaminic effects than earlier drugs. A year later, the French surgeon Pierre Huguenard used promethazine together with pethidine as part of a cocktail to induce relaxation and indifference in surgical patients. Another surgeon, Henri Laborit, believed the compound stabilized the central nervous system by causing "artificial hibernation", and described this state as "sedation without narcosis". He suggested to Rhône-Poulenc that they develop a compound with better stabilizing properties. In December 1950, the chemist Paul Charpentier produced a series of compounds that included RP4560 or chlorpromazine. Simone Courvoisier conducted behavioural tests and found chlorpromazine produced indifference to aversive stimuli in rats.Chlorpromazine was distributed for testing to physicians between April and August 1951. Laborit trialled the medicine on at the Val-de-Grâce military hospital in Paris, using it as an anaesthetic booster in intravenous doses of 50 to 100 mg on surgery patients and confirming it as the best drug to date in calming and reducing shock, with patients reporting improved well being afterwards. He also noted its hypothermic effect and suggested it may induce artificial hibernation. Laborit thought this would allow the body to better tolerate major surgery by reducing shock, a novel idea at the time. Known colloquially as "Laborits drug", chlorpromazine was released onto the market in 1953 by Rhône-Poulenc and given the trade name Largactil, derived from large "broad" and acti* "activity".Following on, Laborit considered whether chlorpromazine may have a role in managing patients with severe burns, Raynauds phenomenon, or psychiatric disorders. At the Villejuif Mental Hospital in November 1951, he and Montassut administered an intravenous dose to psychiatrist Cornelia Quarti who was acting as a volunteer. Quarti noted the indifference, but fainted upon getting up to go to the toilet, and so further testing was discontinued (orthostatic hypotension is a known side effect of chlorpromazine). Despite this, Laborit continued to push for testing in psychiatric patients during early 1952. Psychiatrists were reluctant initially, but on 19 January 1952, it was administered (alongside pethidine, pentothal and ECT) to Jacques Lh. a 24-year-old manic patient, who responded dramatically, and was discharged after three weeks having received 855 mg of the drug in total.Pierre Deniker had heard about Laborits work from his brother-in-law, who was a surgeon, and ordered chlorpromazine for a clinical trial at the Sainte-Anne Hospital Center in Paris where he was Mens Service Chief. Together with the Director of the hospital, Professor Jean Delay, they published their first clinical trial in 1952, in which they treated 38 psychotic patients with daily injections of chlorpromazine without the use of other sedating agents. The response was dramatic; treatment with chlorpromazine went beyond simple sedation with patients showing improvements in thinking and emotional behaviour. They also found that doses higher than those used by Laborit were required, giving patients 75–100 mg daily.Deniker then visited America, where the publication of their work alerted the American psychiatric community that the new treatment might represent a real breakthrough. Heinz Lehmann of the Verdun Protestant Hospital in Montreal trialled it in 70 patients and also noted its striking effects, with patients symptoms resolving after many years of unrelenting psychosis. By 1954, chlorpromazine was being used in the United States to treat schizophrenia, mania, psychomotor excitement, and other psychotic disorders.
Rhône-Poulenc licensed chlorpromazine to Smith Kline & French (todays GlaxoSmithKline) in 1953. In 1955 it was approved in the United States for the treatment of emesis (vomiting). The effect of this drug in emptying psychiatric hospitals has been compared to that of penicillin and infectious diseases. But the popularity of the drug fell from the late 1960s as newer drugs came on the scene. From chlorpromazine a number of other similar antipsychotics were developed. It also led to the discovery of antidepressants.Chlorpromazine largely replaced electroconvulsive therapy, hydrotherapy, psychosurgery, and insulin shock therapy. By 1964, about 50 million people worldwide had taken it. Chlorpromazine, in widespread use for 50 years, remains a "benchmark" drug in the treatment of schizophrenia, an effective drug although not a perfect one. The relative strengths or potencies of other antipsychotics are often ranked or measured against chlorpromazine in aliquots of 100 mg, termed chlorpromazine equivalents or CPZE.In the movie: "Shutter Island", chlorpromazine is presented as being the new medicament for psychosis treatment however with adverse effects like tremors or abstinence syndrome.
Society and culture
Names
Brand names include Thorazine, Largactil, Hibernal, and Megaphen (sold by Bayer in West-Germany since July 1953).)
Research
Chlorpromazine has tentative benefit in animals infected with Naegleria fowleri, and shows antifungal and antibacterial activity in vitro.
Veterinary use
The veterinary use of chlorpromazine has generally been superseded by use of acepromazine.Chlorpromazine may be used as an antiemetic in dogs and cats, or, less often, as sedative before anesthesia. In horses, it often causes ataxia and lethargy, and is therefore seldom used.It is commonly used to decrease nausea in animals that are too young for other common anti-emetics. It is also sometimes used as a preanesthetic and muscle relaxant in cattle, swine, sheep, and goats.The use of chlorpromazine in food-producing animals is not permitted in the EU, as a maximum residue limit could not be determined following assessment by the European Medicines Agency.
References
External links
"Chlorpromazine". Drug Information Portal. U.S. National Library of Medicine.
"Chlorpromazine hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Dihydroergotamine | Dihydroergotamine (DHE), sold under the brand names D.H.E. 45 and Migranal among others, is an ergot alkaloid used to treat migraines. It is a derivative of ergotamine. It is administered as a nasal spray or injection and has an efficacy similar to that of sumatriptan. Nausea is a common side effect.It has similar actions to the triptans, acting as an agonist to the serotonin receptors and causing vasoconstriction of the intracranial blood vessels, but also interacts centrally with dopamine and adrenergic receptors. It can be used to treat acute intractable headache or withdrawal from analgesics.
Medical uses
Subcutaneous and intramuscular injections are generally more effective than the nasal spray and can be self-administered by patients. Intravenous injection is considered very effective for severe migraine or status migrainosus. DHE is also used in the treatment of medication overuse headache.
Side effects
Nausea is a common side effect of IV administration and less common in other modes. Antiemetics can be given prior to DHE to counteract the nausea. Risks and contraindications are similar to the triptans. DHE and triptans should never be taken within 24 hours of each other due to the potential for coronary artery vasospasm. DHE produces no dependence.
Contraindications
DHE is contraindicated with potent CYP3A4 inhibitors, like macrolide antibiotics.
Pharmacology
Mechanism of action
DHEs antimigraine activity is due to its action as an agonist at the serotonin 5-HT1B, 5-HT1D, and 5-HT1F receptors. It also interacts with other serotonin, adrenergic, and dopamine receptors.DHE is an agonist of the serotonin 5-HT2B receptor and has been associated with cardiac valvulopathy.
Pharmacodynamic
Pharmacokinetics
Oral bioavailability is poor and it is not available in oral form in the US. DHE is available as a nasal spray and in ampules for subcutaneous, intramuscular and intravenous injection. Efficacy is variable in the nasal spray form with relative bioavailability of 32% compared to injection.
Contraindications
Contraindications for DHE include: pregnancy, renal or hepatic failure, coronary, cerebral, and peripheral vascular disease, hypersensitivity reactions, sepsis, and uncontrolled hypertension.
History
Dihydroergotamine (DHE) is a semi-synthetic form of ergotamine approved in the US in 1946.
Society and culture
Brand names
Brand names of DHE include Diergo, Dihydergot, D.H.E. 45, Ergont, Ikaran, Migranal, Orstanorm, and Seglor, among others.
European Union
In 2013 the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that medicines containing ergot derivatives no longer be used to treat several conditions involving problems with memory, sensation or blood circulation, or to prevent migraine headaches because the risks (increased risk of fibrosis and ergotism) were said to be greater than the benefits in these indications.
References
External links
"Dihydroergotamine". Drug Information Portal. U.S. National Library of Medicine.
"Dihydroergotamine mesylate". Drug Information Portal. U.S. National Library of Medicine. |
Pneumococcal conjugate vaccine | Pneumococcal conjugate vaccine is a pneumococcal vaccine and a conjugate vaccine used to protect infants, young children, and adults against disease caused by the bacterium Streptococcus pneumoniae (pneumococcus). It contains purified capsular polysaccharide of pneumococcal serotypes conjugated to a carrier protein to improve antibody response compared to the pneumococcal polysaccharide vaccine. The World Health Organization (WHO) recommends the use of the conjugate vaccine in routine immunizations given to children.Vaccine-mediated immunity is "conferred mainly by opsonophagocytic killing of S. pneumoniae."The most common side effects in children are decreased appetite, fever (only very common in children aged six weeks to five years), irritability, reactions at the site of injection (reddening or hardening of the skin, swelling, pain or tenderness), somnolence (sleepiness) and poor quality sleep. In adults and the elderly, the most common side effects are decreased appetite, headaches, diarrhea, fever (only very common in adults aged 18 to 29 years), vomiting (only very common in adults aged 18 to 49 years), rash, reactions at the site of injection, limitation of arm movement, arthralgia and myalgia (joint and muscle pain), chills and fatigue.
Brands
Pneumosil
Pneumosil is a decavalent pneumococcal conjugate vaccine produced by the Serum Institute of India. It contains the serotypes 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, and 23F, and was prequalified by WHO in January 2020.
Prevnar
Prevnar 13 (PCV13) is produced by Pfizer (formerly Wyeth) and it replaced Prevnar, the pneumococcal 7-valent conjugate vaccine (PCV7). It is a tridecavalent vaccine and thus contains thirteen serotypes of pneumococcus (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F). These serotype sugars are conjugated to diphtheria carrier protein because this makes the antigenic and protective effect stronger (in most cases). Prevnar 13 was approved for use in the European Union in December 2009. In February 2010, Prevnar 13 was approved in the United States to replace Prevnar, the pneumococcal 7-valent conjugate vaccine (PCV7). After waiting for the outcome of a trial underway in the Netherlands, the Centers for Disease Control and Prevention (CDC) recommended the vaccine for adults over age 65 in August 2014.Prevnar (PCV7) was a heptavalent vaccine, meaning that it contains the cell capsule sugars of seven serotypes of the bacteria S. pneumoniae (4, 6B, 9V, 14, 18C, 19F, and 23F) conjugated with diphtheria proteins. It was manufactured by Wyeth (which was acquired by Pfizer). Prevnar (PCV7) was approved for use in the United States in February 2000, and vaccination with Prevnar was recommended for all children younger than two years and for unvaccinated children between 24 and 59 months old who were at high risk for pneumococcal infections.Prevnar was produced from the seven most prevalent strains of Streptococcus pneumoniae bacteria in the U.S. The bacterial capsule sugars, a characteristic of these pathogens, are linked (conjugated) to CRM197, a nontoxic recombinant variant of diphtheria toxin (from cultures of Corynebacterium diphtheriae). This produces a more robust immune response (in most healthy persons). Further, aluminum is also added to the vaccine serum because it is an adjuvant, meaning it further enhances the immune response.The vaccines polysaccharide sugars are grown separately in soy peptone broths. Through reductive amination, the sugars are directly conjugated to the protein carrier CRM197 to form the glycoconjugate. CRM197 is grown in C. diphtheriae strain C7 in a medium of casamino acids and yeast extracts.The Prevnar seven-valent formulation contained serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, and resulted in a 98% probability of protection against these strains, which caused 80% of the pneumococcal disease in infants in the U.S. PCV7 is no longer produced.In 2010, Pfizer introduced Prevnar 13, which contains six additional strains (1, 3, 5, 6A, 19A and 7F), which protect against the majority of the remaining pneumococcal infections.In June 2021, the U.S. Food and Drug Administration (FDA) approved Prevnar 20, an icosavalent pneumococcal conjugate vaccine, which includes the serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F for adults 18 years of age and older. As of August 2022, seven serotypes remain experimental and were authorized only under "accelerated approval" by FDA, based on opsonophagocytic activity ("OPA") assay. Maintenance of this approval is ongoing and "may be contingent upon verification and description of clinical benefit in a confirmatory trial."In February 2022, the European Medicines Agency Approves Pfizers Prevnar 20 (PVC20) under the brand name Apexxnar.
Synflorix
Synflorix (PCV10) is produced by GlaxoSmithKline. It is a decavalent vaccine and thus contains ten serotypes of pneumococcus (1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F) which are conjugated to a carrier protein. Synflorix received a positive opinion from the European Medicines Agency (EMA) for use in the European Union in January 2009, and GSK received European Commission authorization to market Synflorix in March 2009.
Vaxneuvance
Vaxneuvance is a pneumococcal 15-valent conjugate vaccine created by Merck that was approved for medical use in the United States in July 2021. The vaccine was developed under the code name "V114". It is identical to PCV13, except that it adds serotypes 22F and 33F. These two serotypes are particularly important because, after "widespread use of the PCV13…[vaccine] in many countries," these two serotypes are now "among leading serotypes causing IPD in children and adults."Vaxneuvance is indicated for the active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F in adults 18 years of age and older.On 14 October 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 Vaxneuvance, intended for prophylaxis against pneumococcal pneumonia and associated invasive disease. The applicant for this medicinal product is Merck Sharp & Dohme B.V. Vaxneuvance was approved for medical use in the European Union in December 2021.
Schedule of vaccination
As with all immunizations, whether it is available or required, and under what circumstances, varies according to the decisions made by local public health agencies.
Children under the age of two years fail to mount an adequate response to the 23-valent adult vaccine, and so a pneumococcal conjugate vaccine is used. While this covers only seven strains out of more than ninety strains, these seven strains cause 80% to 90% of cases of severe pneumococcal disease, and it is considered to be nearly 100% effective against these strains.
United Kingdom
The UK childhood vaccination schedule for infants born after 31 December 2019, consists of a primary course of one dose at twelve weeks of age with a second dose at one year of age. For infants born before 1 January 2020 and those in Scotland, the childhood vaccination schedule consists of a primary course of two doses at eight and sixteen weeks of age with a final third dose at one year of age.Children at special risk (e.g., sickle cell disease and asplenia) require as full protection as can be achieved using the conjugated vaccine, with the more extensive polysaccharide vaccine given after the second year of life:
United States
In 2001, the Centers for Disease Control and Prevention (CDC), upon advice from its Advisory Committee on Immunization Practices (ACIP), recommended the vaccine be administered to every infant and young child in the United States. The resulting demand outstripped production, creating shortages not resolved until 2004. All children, according to the U.S. vaccination schedule, should receive four doses, at two months, four months, six months, and again between one year and fifteen months of age.The CDC updated the pneumococcal vaccine guidelines for adults 65 years of age or older in 2019.In October 2021, the CDC recommended that adults 65 years of age or older who have not previously received a pneumococcal conjugate vaccine or whose previous vaccination history is unknown should receive a pneumococcal conjugate vaccine (either PCV20 or PCV15). If PCV15 is used, this should be followed by a dose of PPSV23. The CDC recommended that adults aged 19 to 64 years with certain underlying medical conditions or other risk factors who have not previously received a pneumococcal conjugate vaccine or whose previous vaccination history is unknown should receive a pneumococcal conjugate vaccine (either PCV20 or PCV15). If PCV15 is used, this should be followed by a dose of PPSV23.
Efficacy
Prevnar-7 is designed to stop seven of about ninety pneumococcal serotypes which have the potential to cause invasive pneumococcal disease (IPD). In 2010, a 13-valent vaccine was introduced. Each year, IPD kills approximately one million children worldwide. Since approval, Prevnars efficacy in preventing IPD has been documented by a number of epidemiologic studies. There is evidence that other people in the same household as a vaccinee also become relatively protected.
There is evidence that routine childhood vaccination reduces the burden of pneumococcal disease in adults and especially high-risk adults, such as those living with HIV/AIDS.The vaccine is, however, primarily developed for the U.S. and European epidemiological situation, and therefore it has only a limited coverage of serotypes causing serious pneumococcal infections in most developing countries.
Evidence supporting addition to routine vaccination schedules
After introduction of the pneumococcal conjugate vaccine in 2000, several studies described a decrease in invasive pneumococcal disease in the United States. One year after its introduction, a group of investigators found a 69% drop in the rate of invasive disease in those of less than two years of age. By 2004, all-cause pneumonia admission rates had declined by 39% (95% CI 22–52) and rates of hospitalizations for pneumococcal meningitis decreased by 66% (95% CI 56.3-73.5) in children younger than 2.Rates of invasive pneumococcal disease among adults have also declined since the introduction of the vaccine.
Vaccination in low-income countries
Pneumococcal disease is the leading vaccine-preventable killer of young children worldwide, according to the World Health Organization (WHO). It killed more than 500,000 children younger than five years of age in 2008 alone. Approximately ninety percent of these deaths occur in the developing world. Historically 15–20 years pass before a new vaccine reaches one quarter of the population of the developing world.Pneumococcal vaccines Accelerated Development and Introduction Plan (PneumoADIP) was a GAVI Alliance (GAVI) funded project to accelerate the introduction of pneumococcal vaccinations into low-income countries through partnerships between countries, donors, academia, international organizations and industry. GAVI continues this work and as of March 2013, 25 GAVI-eligible and supported countries have introduced the pneumococcal conjugate vaccine. Further, 15 additional GAVI countries have plans to introduce the vaccine into their national immunization program and 23 additional countries have approved GAVI support to introduce the vaccine.
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 Apexxnar, intended for prophylaxis against pneumococcal pneumonia and associated invasive disease. The applicant for this medicinal product is Pfizer Europe MA EEIG. Apexxnar was approved for medical use in the European Union in February 2022.
Economics
Prevnar 13 is Pfizers best-selling product. It had annual sales of US$5.85 billion in 2020.
Brand names
The vaccines are marketed under several brand names including Prevnar 20, Prevnar 13, Synflorix, Pneumosil, and Vaxneuvance.
Research
Merck is investigating a 21-valent vaccine (code named V116) against pneumococcus serotypes. The vaccine is geared towards persons living with HIV.
References
Further reading
Centers for Disease Control and Prevention (2015). "Chapter 17: Pneumococcal Disease". In Hamborsky J, Kroger A, Wolfe S (eds.). Epidemiology and Prevention of Vaccine-Preventable Diseases (13th ed.). Washington, D.C.: Public Health Foundation.
External links
"13-Valent Pneumococcal Vaccine". Drug Information Portal. U.S. National Library of Medicine.
"Heptavalent pneumococcal conjugate vaccine". Drug Information Portal. U.S. National Library of Medicine.
"Pneumococcal Conjugate (PCV13) Vaccine Information Statement". Centers for Disease Control and Prevention (CDC). 10 August 2021. |
Penicillamine | Penicillamine, sold under the brand name of Cuprimine among others, is a medication primarily used for the treatment of Wilsons disease. It is also used for people with kidney stones who have high urine cystine levels, rheumatoid arthritis, and various heavy metal poisonings. It is taken by mouth.
Medical uses
Penicillamine was approved for medical use in the United States in 1970. It is on the World Health Organizations List of Essential Medicines.It is used as a chelating agent:
In Wilsons disease, a rare genetic disorder of copper metabolism, penicillamine treatment relies on its binding to accumulated copper and elimination through urine.
Penicillamine was the second line treatment for arsenic poisoning, after dimercaprol (BAL). It is no longer recommended.In cystinuria, a hereditary disorder in which high urine cystine levels lead to the formation of cystine stones, penicillamine binds with cysteine to yield a mixed disulfide which is more soluble than cystine.Penicillamine has been used to treat scleroderma.Penicillamine can be used as a disease-modifying antirheumatic drug (DMARD) to treat severe active rheumatoid arthritis in patients who have failed to respond to an adequate trial of conventional therapy, although it is rarely used today due to availability of TNF inhibitors and other agents, such as tocilizumab and tofacitinib. Penicillamine works by reducing numbers of T-lymphocytes, inhibiting macrophage function, decreasing IL-1, decreasing rheumatoid factor, and preventing collagen from cross-linking.
Adverse effects
Common side effects include rash, loss of appetite, nausea, diarrhea, and low blood white blood cell levels. Other serious side effects include liver problems, obliterative bronchiolitis, and myasthenia gravis. It is not recommended in people with lupus erythematosus. Use during pregnancy may result in harm to the baby. Penicillamine works by binding heavy metals; the resulting penicillamine–metal complexes are then removed from the body in the urine.Bone marrow suppression, dysgeusia, anorexia, vomiting, and diarrhea are the most common side effects, occurring in ~20–30% of the patients treated with penicillamine.Other possible adverse effects include:
Nephropathy
Hepatotoxicity
Membranous glomerulonephritis
Aplastic anemia (idiosyncratic)
Antibody-mediated myasthenia gravis and Lambert–Eaton myasthenic syndrome, which may persist even after its withdrawal
Drug-induced systemic lupus erythematosus
Elastosis perforans serpiginosa
Toxic myopathies
Unwanted breast growth
Oligospermia
Chemistry
Penicillamine is a trifunctional organic compound, consisting of a thiol, an amine, and a carboxylic acid. It is structurally similar to the α-amino acid cysteine, but with geminal dimethyl substituents α to the thiol. Like most amino acids, it is a colorless solid that exists in the zwitterionic form at physiological pH.
Penicillamine is a chiral drug with one stereogenic center and exist as a pair of enantiomers. Refer the image for the structure of penicillamine enantiomers. The (S)-enantiomer, the eutomer, is antiarthritic while the distomer (R)-penicillamine is extremely toxic. Of its two enantiomers, L-penicillamine (having R absolute configuration) is toxic because it inhibits the action of pyridoxine (also known as vitamin B6). That enantiomer is a metabolite of penicillin but has no antibiotic properties itself. A variety of penicillamine–copper complex structures are known.
History
John Walshe first described the use of penicillamine in Wilsons disease in 1956. He had discovered the compound in the urine of patients (including himself) who had taken penicillin, and experimentally confirmed that it increased urinary copper excretion by chelation. He had initial difficulty convincing several world experts of the time (Denny Brown and Cumings) of its efficacy, as they held that Wilsons disease was not primarily a problem of copper homeostasis but of amino acid metabolism, and that dimercaprol should be used as a chelator. Later studies confirmed both the copper-centered theory and the efficacy of D-penicillamine. Walshe also pioneered other chelators in Wilsons such as triethylene tetramine and tetrathiomolybdate.Penicillamine was first synthesized by John Cornforth under supervision of Robert Robinson.Penicillamine has been used in rheumatoid arthritis since the first successful case in 1964.
Cost
In the United States, Valeant raised the cost of the medication from about US$500 to US$24,000 per month in 2016.
References
External links
"Penicillamine". Drug Information Portal. U.S. National Library of Medicine. |
Fludrocortisone | Fludrocortisone, sold under the brand name Florinef, among others, is a corticosteroid used to treat adrenogenital syndrome, postural hypotension, and adrenal insufficiency. In adrenal insufficiency, it is generally taken together with hydrocortisone. Fludrocortisone is taken by mouth and is most commonly used in its acetate form.Common side effects of fludrocortisone include high blood pressure, swelling, heart failure, and low blood potassium. Other serious side effects can include low immune-system function, cataracts, muscle weakness, and mood changes. Whether use of fludrocortisone during pregnancy is safe for the fetus is unknown. Fludrocortisone is mostly a mineralocorticoid, but it also has glucocorticoid effects.Fludrocortisone was patented in 1953. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Fludrocortisone has been used in the treatment of cerebral salt-wasting syndrome. It is used primarily to replace the missing hormone aldosterone in various forms of adrenal insufficiency such as Addisons disease and the classic salt-wasting (21-hydroxylase deficiency) form of congenital adrenal hyperplasia. Due to its effects on increasing Na+ levels, and therefore blood volume, fludrocortisone is the first-line of treatment for orthostatic intolerance and postural orthostatic tachycardia syndrome (POTS).
It can be used to treat low blood pressure.Fludrocortisone is also a confirmation test for diagnosing Conns syndrome (aldosterone-producing adrenal adenoma), the fludrocortisone suppression test. Loading the patient with fludrocortisone would suppress serum aldosterone level in a normal patient, whereas the level would remain elevated in a Conns patient. The fludrocortisone suppression test is an alternative to the NaCl challenge (which would use normal saline or salt tablets).
Side effects
Sodium and water retention
Swelling due to fluid retention (edema)
High blood pressure (hypertension)
Headache
Low blood potassium level (hypokalemia)
Muscle weakness
Fatigue
Increased susceptibility to infection
Impaired wound healing
Increased sweating
Increased hair growth (hirsutism)
Thinning of skin and stretch marks
Disturbances of the gut such as indigestion (dyspepsia), distention of the abdomen and ulceration (peptic ulcer)
Decreased bone density and increased risk of fractures of the bones
Difficulty in sleeping (insomnia)
Depression
Weight gain
Raised blood sugar level
Changes to the menstrual cycle
Partial loss of vision due to opacity in the lens of the eye (cataracts)
Raised pressure in the eye (glaucoma)
Increased pressure in the skull (intracranial pressure)
Pharmacology
Fludrocortisone is a corticosteroid and acts as a powerful mineralocorticoid, along with some additional but comparatively very weak glucocorticoid activity. Relative to cortisol, it is said to have 10 times the glucocorticoid potency but 250 to 800 times the mineralocorticoid potency. Fludrocortisone acetate is a prodrug of fludrocortisone, which is the active form of the drug.Plasma renin, sodium, and potassium are checked through blood tests to verify that the correct dosage is reached.
Chemistry
Fludrocortisone, also known as 9α-fluorocortisol (9α-fluorohydrocortisone) or as 9α-fluoro-11β,17α,21-trihydroxypregn-4-ene-3,20-dione, is a synthetic pregnane steroid and a halogenated derivative of cortisol (11β,17α,21-trihydroxypregn-4-ene-3,20-dione). Specifically, it is a modification of cortisol with a fluorine atom substituted in place of one hydrogen atom at the C9α position. Fluorine is a good bioisostere for hydrogen because it is similar in size, with the major difference being in its electronegativity. The acetate form of fludrocortisone, fludrocortisone acetate, is the C21 acetate ester of fludrocortisone, and is hydrolyzed into fludrocortisone in the body.
History
Fludrocortisone was described in the literature in 1953 and was introduced for medical use (as the acetate ester) in 1954. It was the first synthetic corticosteroid to be marketed, and followed the introduction of cortisone in 1948 and hydrocortisone (cortisol) in 1951. Fludrocortisone was also the first fluorine-containing pharmaceutical drug to be marketed.
Society and culture
Generic name
Fludrocortisone is the generic name of fludrocortisone and its INN, USAN, BAN, DCF, and DCIT, whereas fludrocortisone acetate is the generic name of fludrocortisone acetate and its USP, BANM and JAN.
Brand names
Fludrocortisone is marketed mainly under the brand names Astonin and Astonin-H, whereas the more widely used fludrocortisone acetate is sold mainly as Florinef, but also under several other brand names including Cortineff, Florinefe, and Fludrocortison.
Availability
Fludrocortisone is marketed in Austria, Croatia, Denmark, Germany, Luxembourg, Romania, and Spain, whereas fludrocortisone acetate is more widely available throughout the world and is marketed in the United States, Canada, the United Kingdom, various other European countries, Australia, Japan, China, Brazil, and many other countries.
References
External links
"Fludrocortisone". Drug Information Portal. U.S. National Library of Medicine. |
Levofloxacin | Levofloxacin, sold under the brand name Levaquin among others, is an antibiotic medication. It is used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, H. pylori (in combination with other medications), urinary tract infections, chronic prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis, meningitis, or pelvic inflammatory disease. Use is generally recommended only when other options are not available. It is available by mouth, intravenously, and in eye drop form.Common side effects include nausea, diarrhea, and trouble sleeping. Serious side effects may include tendon rupture, tendon inflammation, seizures, psychosis, and potentially permanent peripheral nerve damage. Tendon damage may appear months after treatment is completed. People may also sunburn more easily. In people with myasthenia gravis, muscle weakness and breathing problems may worsen. While use during pregnancy is not recommended, risk appears to be low. The use of other medications in this class appear to be safe while breastfeeding; however, the safety of levofloxacin is unclear. Levofloxacin is a broad-spectrum antibiotic of the fluoroquinolone drug class. It usually results in death of the bacteria. It is the left-handed isomer of the medication ofloxacin.Levofloxacin was patented in 1985 and approved for medical use in the United States in 1996. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 182nd most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Medical uses
Levofloxacin is used to treat infections including: respiratory tract infections, cellulitis, urinary tract infections, prostatitis, anthrax, endocarditis, meningitis, pelvic inflammatory disease, travelers diarrhea, tuberculosis, and plague and is available by mouth, intravenously, and in eye drop form.As of 2016, the US Food and Drug Administration (FDA) recommended that "serious side effects associated with fluoroquinolone antibacterial drugs generally outweigh the benefits for patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections who have other treatment options. For patients with these conditions, fluoroquinolones should be reserved for those who do not have alternative treatment options."Levofloxacin is used for the treatment of pneumonia, urinary tract infections, and abdominal infections. As of 2007 the Infectious Disease Society of America (IDSA) and the American Thoracic Society recommended levofloxacin and other respiratory fluoroquinolines as first line treatment for community acquired pneumonia when co-morbidities such as heart, lung, or liver disease are present or when in-patient treatment is required. Levofloxacin also plays an important role in recommended treatment regimens for ventilator-associated and healthcare-associated pneumonia.As of 2010 it was recommended by the IDSA as a first-line treatment option for catheter-associated urinary tract infections in adults. In combination with metronidazole it is recommended as one of several first-line treatment options for adult patients with community-acquired intra-abdominal infections of mild-to-moderate severity. The IDSA also recommends it in combination with rifampicin as a first-line treatment for prosthetic joint infections. The American Urological Association recommends levofloxacin as a first-line treatment to prevent bacterial prostatitis when the prostate is biopsied. and as of 2004 it was recommended to treat bacterial prostatitis by the NIH research network studying the condition.Levofloxacin and other fluoroquinolones have also been widely used for the treatment of uncomplicated community-acquired respiratory and urinary tract infections, indications for which major medical societies generally recommend the use of older, narrower spectrum drugs to avoid fluoroquinolone resistance development. Due to its widespread use, common pathogens such as Escherichia coli and Klebsiella pneumoniae have developed resistance. In many countries as of 2013, resistance rates among healthcare-associated infections with these pathogens exceeded 20%.Levofloxacin is also used as antibiotic eye drops to prevent bacterial infection. Usage of levofloxacin eye drops, along with an antibiotic injection of cefuroxime or penicillin during cataract surgery, has been found to lower the chance of developing endophthalmitis, compared to eye drops or injections alone.
Pregnancy and breastfeeding
According to the FDA approved prescribing information, levofloxacin is pregnancy category C. This designation indicates that animal reproduction studies have shown adverse effects on the fetus and there are no adequate and well-controlled studies in humans, but the potential benefit to the mother may in some cases outweigh the risk to the fetus. Available data point to a low risk for the unborn child. 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.Levofloxacin does penetrate into breastmilk, though the concentration of levofloxacin in the breastfeeding infant is expected to be low. Due to potential risks to the baby, the manufacturer does not recommend that nursing mothers take levofloxacin. However, the risk appears to be very low, and levofloxacin can be used in breastfeeding mothers with proper monitoring of the infant, combined with delaying breastfeeding for 4–6 hours after taking levofloxacin.
Children
Levofloxacin is not approved in most countries for the treatment of children except in unique and life-threatening infections because it is associated with an elevated risk of musculoskeletal injury in this population, a property it shares with other fluoroquinolones.
In the United States levofloxacin is approved for the treatment of anthrax and plague in children over six months of age.Levofloxacin is recommended by the Pediatric Infectious Disease Society and the Infectious Disease Society of America as a first-line treatment for pediatric pneumonia caused by penicillin-resistant Streptococcus pneumoniae, and as a second-line agent for the treatment of penicillin-sensitive cases.In one study, 1534 juvenile patients (age 6 months to 16 years) treated with levofloxacin as part of three efficacy trials were followed up to assess all musculoskeletal events occurring up to 12 months post-treatment. At 12 months follow-up the cumulative incidence of musculoskeletal adverse events was 3.4%, compared to 1.8% among 893 patients treated with other antibiotics. In the levafloxacin-treated group, approximately two-thirds of these musculoskeletal adverse events occurred in the first 60 days, 86% were mild, 17% were moderate, and all resolved without long-term sequelae.
Spectrum of activity
Levofloxacin and later generation fluoroquinolones are collectively referred to as "respiratory quinolones" to distinguish them from earlier fluoroquinolones which exhibited modest activity toward the important respiratory pathogen Streptococcus pneumoniae.The drug exhibits enhanced activity against the important respiratory pathogen Streptococcus pneumoniae relative to earlier fluoroquinolone derivatives like ciprofloxacin. For this reason, it is considered a "respiratory fluoroquinolone" along with more recently developed fluoroquinolones such as moxifloxacin and gemifloxacin. It is less active than ciprofloxacin against Gram-negative bacteria, especially Pseudomonas aeruginosa, and lacks the anti-methicillin-resistant Staphylococcus aureus (MRSA) activity of moxifloxacin and gemifloxacin. Levofloxacin has shown moderate activity against anaerobes, and is about twice as potent as ofloxacin against Mycobacterium tuberculosis and other mycobacteria, including Mycobacterium avium complex.Its spectrum of activity includes most strains of bacterial pathogens responsible for respiratory, urinary tract, gastrointestinal, and abdominal infections, including Gram negative (Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Proteus mirabilis, and Pseudomonas aeruginosa), Gram positive (methicillin-sensitive but not methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, Staphylococcus epidermidis, Enterococcus faecalis, and Streptococcus pyogenes), and atypical bacterial pathogens (Chlamydophila pneumoniae and Mycoplasma pneumoniae). Compared to earlier antibiotics of the fluoroquinoline class such as ciprofloxacin, levofloxacin exhibits greater activity towards Gram-positive bacteria but lesser activity toward Gram-negative bacteria, especially Pseudomonas aeruginosa.
Resistance
Resistance to fluoroquinolones is common in staphylococcus and pseudomonas. Resistance occurs in multiple ways. One mechanism is by an alteration in topoisomerase IV enzyme. A double mutant form of S. pneumoniae Gyr A + Par C bearing Ser-81-->Phe and Ser-79-->Phe mutations were eight to sixteen times less responsive to ciprofloxacin.
Contraindications and interactions
Package inserts mention that levofloxacin is to be avoided in patients with a known hypersensitivity to levofloxacin or other quinolone drugs.Like all fluoroquinolines, levofloxacin is contraindicated in patients with epilepsy or other seizure disorders, and in patients who have a history of quinolone-associated tendon rupture.Levofloxacin may prolong the QT interval in some people, especially the elderly, and levofloxacin should not be used for people with a family history of Long QT syndrome, or who have long QT, chronic low potassium, it should not be prescribed with other drugs that prolong the QT interval.Unlike ciprofloxacin, levofloxacin does not appear to deactivate the drug metabolizing enzyme CYP1A2. Therefore, drugs that use that enzyme, like theophylline, do not interact with levofloxacin. It is a weak inhibitor of CYP2C9, suggesting potential to block the breakdown of warfarin and phenprocoumon. This can result in more action of drugs like warfarin, leading to more potential side effects, such as bleeding.The use of non-steroidal anti-inflammatory drugs (NSAIDs) in combination with high dose fluoroquinolone therapy may lead to seizures.When levofloxacin is taken with anti-acids containing magnesium hydroxide or aluminum hydroxide, the two combine to form insoluble salts that are difficult to absorb from the intestines. Peak serum concentrations of levofloxacin may be reduced by 90% or more, which can prevent the levofloxacin from working. Similar results have been reported when levofloxacin is taken with iron supplements and multi-vitamins containing zinc.A 2011 review examining musculoskeletal complications of fluoroquinolones proposed guidelines with respect to administration to athletes, that called for avoiding all use of fluoroquinolone antibiotics if possible, and if they are used: ensure there is informed consent about the musculoskeletal risks, and inform coaching staff; do not use any corticosteroids if fluoroquinolones are used; consider dietary supplements of magnesium and antioxidants during treatment; reduce training until the course of antibiotic is finished and then carefully increase back to normal; and monitor for six months after the course is finished, and stop all athletic activity if symptoms emerge.
Adverse effects
Adverse effects are typically mild to moderate. However, severe, disabling, and potentially irreversible adverse effects sometimes occur, and for this reason it is recommended that use of fluoroquinolones be limited.
Prominent among these are adverse effects that became the subject of a black box warning by the FDA in 2016. The FDA wrote: "An FDA safety review has shown that fluoroquinolones when used systemically (i.e. tablets, capsules, and injectable) are associated with disabling and potentially permanent serious adverse effects that can occur together. These adverse effects can involve the tendons, muscles, joints, nerves, and central nervous system." Rarely, tendinitis or tendon rupture may occur due to fluoroquinolone antibiotics, including levofloxacin. Such injuries, including tendon rupture, has been observed up to 6 months after cessation of treatment; higher doses of fluoroquinolones, being elderly, transplant patients, and those with a current or historical corticosteroid use are at elevated risk. The U.S. label for levofloxacin also contains a black box warning for the exacerbation of the symptoms of the neurological disease myasthenia gravis. Similarly, the UK Medicines and Healthcare Products Regulatory Agency recommendations warn of rare but disabling and potentially irreversible adverse effects, and to recommend limiting use of these drugs. Increasing age and corticosteroid use appears to increase the risk of musculoskeletal complications.A wide variety of other uncommon but serious adverse events have been associated with fluoroquinolone use, with varying degrees of evidence supporting causation. These include anaphylaxis, hepatotoxicity, central nervous system effects including seizures and psychiatric effects, prolongation of the QT interval, blood glucose disturbances, and photosensitivity, among others. Levofloxacin may produce fewer of these rare serious adverse effects than other fluoroquinolones.There is some disagreement in the medical literature regarding whether and to what extent levofloxacin and other fluoroquinolones produce serious adverse effects more frequently than other broad spectrum antibacterial drugs.There are some case reports of levofloxacin associated with idiopathic intracranial hypertension.With regard to more usual adverse effects, in pooled results from 7537 patients exposed to levofloxacin in 29 clinical trials, 4.3% discontinued treatment due to adverse drug reactions. The most common adverse reactions leading to discontinuation were gastrointestinal, including nausea, vomiting, and constipation. Overall, 7% of patients experienced nausea, 6% headache, 5% diarrhea, 4% insomnia, along with other adverse reactions experienced at lower rates.Administration of levofloxacin or other broad spectrum antibiotics is associated with Clostridium difficile associated diarrhea which may range in severity from mild diarrhea to fatal colitis. Fluoroquinoline administration may be associated with the acquisition and outgrowth of a particularly virulent Clostridium strain.More research is needed to determine the best dose and length of treatment.
Overdose
Overdosing experiments in animals showed loss of body control and drooping, difficulty breathing, tremors, and convulsions. Doses in excess of 1500 mg/kg orally and 250 mg/kg IV produced significant mortality in rodents.In the event of an acute overdosage, authorities recommend unspecific standard procedures such as emptying the stomach, observing the patient and maintaining appropriate hydration. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.
Pharmacology
Mechanism of action
Levofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. Like all quinolones, it functions by inhibiting the DNA gyrase and topoisomerase IV, two bacterial type II topoisomerases. Topoisomerase IV is necessary to separate DNA that has been replicated (doubled) prior to bacterial cell division. With the DNA not being separated, the process is stopped, and the bacterium cannot divide. DNA gyrase, on the other hand, is responsible for supercoiling the DNA, so that it will fit in the newly formed cells. Both mechanisms amount to killing the bacterium. Levofloxacin acts as a bactericide.As of 2011, the mechanism of action for the drugs musculoskeletal complications were not clear.
Pharmacokinetics
Levofloxacin is rapidly and essentially completely absorbed after oral administration, with a plasma concentration profile over time that is essentially identical to that obtained from intravenous administration of the same amount over 60 minutes. As such, the intravenous and oral formulations of levofloxacin are considered interchangeable. Levofloxacins ability to bind to proteins in the body ranges from 24 to 38%.The drug undergoes widespread distribution into body tissues. Peak levels in skin are achieved 3 hours after administration and exceed those in plasma by a factor of 2. Similarly, lung tissue concentrations range from two-fold to five-fold higher than plasma concentrations in the 24 hours after a single dose.
The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally or intravenously. Elimination occurs mainly via excretion of unmetabolized drug in the urine. Following oral administration, 87% of an administered dose was recovered in the urine as unchanged drug within 2 days. Less than 5% was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans.
Chemistry
Like all fluoroqinolones, levofloxacin is a fluorinated quinolone carboxylic acid. It is a chiral molecule and the pure (−)-(S)-enantiomer of the racemic drug ofloxacin. This enantiomer binds more effectively to the DNA gyrase enzyme and to topoisomerase IV than its (+)-(R)-counterpart. Levofloxacin is referred to as a chiral switch: These are chiral drugs that have already been patent claimed, approved and marketed as racemates (or as mixtures of diastereomers but have since been redeveloped as pure enantiomers. Distinct functional groups on this molecules include a hydroxyl group, carbonyl group, and an aromatic ring.The substance is used as the hemihydrate, which has the empirical formula C18H20FN3O4 · 1⁄2 H2O and a molecular mass of 370.38 g/mol. Levofloxacin is a light-yellowish-white to yellow-white crystal or crystalline powder. A major issue in the synthesis of levofloxacin is identifying correct entries into the benzoxazine core in order to produce the correct chiral form.
History
Levofloxacin is a third-generation fluoroquinolone, being one of the isomers of ofloxacin, which was a broader-spectrum conformationally locked analog of norfloxacin; both ofloxacin and levofloxaxin were synthesized and developed by scientists at Daiichi Seiyaku. The Daiichi scientists knew that ofloxacin was racemic, but tried unsuccessfully to separate the two isomers; in 1985 they succeeded in separately synthesizing the pure levo form and showed that it was less toxic and more potent than the other form.It was first approved for marketing in Japan in 1993, for oral administration, and Daiichi marketed it there under the brand name Cravit. Daiichi, working with Johnson & Johnson as it had with ofloxacin, obtained FDA approval in 1996 under the brand name Levaquin to treat bacterial sinusitus, bacterial exacerbations of bronchitis, community-acquired pneumonia, uncomplicated skin infections, complicated urinary tract infections, and acute pyelonephritis.Levofloxacin is marketed by Sanofi-Aventis under a license agreement signed with Daiichi in 1993, under the brand name "Tavanic".Levofloxacin had reached blockbuster status by this time; combined worldwide sales of levofloxacin and ofloxacin for J&J alone were US$1.6 billion in 2009.The term of the levofloxacin United States patent was extended by the U.S. Patent and Trademark Office 810 days under the provisions of the Hatch Waxman Amendment so that the patent would expire in 2010 instead of 2008. This extension was challenged by generic drug manufacturer Lupin Pharmaceuticals, which did not challenge the validity of the patent, but only the validity of the patent extension, arguing that the patent did not cover a "product" and so Hatch-Waxman was not available for extensions. The federal patent court ruled in favor of J&J and Daiichi, and generic versions of levofloxacin did not enter the U.S. market until 2009.
Society and culture
Availability
Levofloxacin is available in tablet form, injection, and oral solution.
Usage
The FDA estimated that in 2011, over 23 million outpatient prescriptions for fluoroquinolones, of which levofloxacin made up 28%, were filled in the United States.
Litigation
As of 2012, Johnson and Johnson was facing around 3400 state and federal lawsuits filed by people who claimed tendon damage from levofloxacin; about 1900 pending in a class action at the United States District Court in Minnesota and about 1500 pending at a district court in New Jersey.In October 2012, J&J settled 845 cases in the Minnesota action, after Johnson and Johnson prevailed in three of the first four cases to go to trial. By May 2014, all but 363 cases had been settled or adjudicated.
References
External links
"Levofloxacin". Drug Information Portal. U.S. National Library of Medicine. |
Chlorhexidine | Chlorhexidine (CHX) (commonly known by the salt forms chlorhexidine gluconate and chlorhexidine digluconate (CHG) or chlorhexidine acetate) is a disinfectant and antiseptic that is used for skin disinfection before surgery and to sterilize surgical instruments. It may be used both to disinfect the skin of the patient and the hands of the healthcare providers. It is also used for cleaning wounds, preventing dental plaque, treating yeast infections of the mouth, and to keep urinary catheters from blocking. It is used as a liquid or powder.Side effects may include skin irritation, teeth discoloration, and allergic reactions, although the risk appears to be the same as other topical antiseptics. It may cause eye problems if direct contact occurs. Use in pregnancy appears to be safe. Chlorhexidine may come mixed in alcohol, water, or surfactant solution. It is effective against a range of microorganisms, but does not inactivate spores.Chlorhexidine came into medical use in the 1950s. Chlorhexidine is available over the counter (OTC) in the United States. It is on the World Health Organizations List of Essential Medicines. In 2017, it was the 286th most commonly prescribed medication in the United States, with more than one million prescriptions.The name "chlorhexidine" breaks down as chlor(o) + hex(ane) + id(e) + (am)ine.
Uses
Chlorhexidine is used in disinfectants (disinfection of the skin and hands), cosmetics (additive to creams, toothpaste, deodorants, and antiperspirants), and pharmaceutical products (preservative in eye drops, active substance in wound dressings and antiseptic mouthwashes). A 2019 Cochrane review concluded that based on very low certainty evidence in those who are critically ill "it is not clear whether bathing with chlorhexidine reduces hospital‐acquired infections, mortality, or length of stay in the ICU, or whether the use of chlorhexidine results in more skin reactions."In endodontics, chlorhexidine is used for root canal irrigation and as an intracanal dressing, but has been replaced by the use of sodium hypochlorite bleach in much of the developed world.
Antiseptic
CHG is active against Gram-positive and Gram-negative organisms, facultative anaerobes, aerobes, and yeasts. It is particularly effective against Gram-positive bacteria (in concentrations ≥ 1 μg/L). Significantly higher concentrations (10 to more than 73 μg/mL) are required for Gram-negative bacteria and fungi. Chlorhexidine is ineffective against polioviruses and adenoviruses. The effectiveness against herpes viruses has not yet been established unequivocally.There is strong evidence that chlorhexidine is more effective than povidone-iodine for clean surgery. Evidence shows that it is the most effective antiseptic for upper limb surgery, and there is no data to suggest that alcoholic chlorhexidine increases the risk of tourniquet-related burns, ignition fires or allergic episodes during surgery.
Chlorhexidine, like other cation-active compounds, remains on the skin. It is frequently combined with alcohols (ethanol and isopropyl alcohol).
Dental use
Use of a CHG-based mouthwash in combination with normal tooth care can help reduce the build-up of plaque and improve mild gingivitis. There is not enough evidence to determine the effect in moderate to severe gingivitis. About 20 mL twice a day of concentrations of 0.1% to 0.2% is recommended for mouth-rinse solutions with a duration of at least 30 seconds. Such mouthwash also has a number of adverse effects including damage to the mouth lining, tooth discoloration, tartar build-up, and impaired taste. Extrinsic tooth staining occurs when chlorhexidine rinse has been used for 4 weeks or longer.Mouthwashes containing chlorhexidine which stain teeth less than the classic solution have been developed, many of which contain chelated zinc.Using chlorhexidine as a supplement to everyday mechanical oral hygiene procedures for 4 to 6 weeks and 6 months leads to a moderate reduction in gingivitis compared to placebo, control or mechanical oral hygiene alone.Chlorhexidine is a cation which interacts with anionic components of toothpaste, such as sodium lauryl sulfate and sodium monofluorophosphate, and forms salts of low solubility and antibacterial activity. Hence, to enhance the antiplaque effect of chlorhexidine, "it seems best that the interval between toothbrushing and rinsing with CHX [chlorhexidine] be more than 30 minutes, cautiously close to 2 hours after brushing".
Topical
Chlorhexidine gluconate is used as a skin cleanser for surgical scrubs, as a cleanser for skin wounds, for preoperative skin preparation, and for germicidal hand rinses. Chlorhexidine eye drops have been used as a treatment for eyes affected by Acanthamoeba keratitis.Chlorhexidine is very effective for poor countries like Nepal and its use is growing in the world for treating the umbilical cord. A 2015 Cochrane review has yielded high-quality evidence that within the community setting, chlorhexidine skin or cord care can reduce the incidence of omphalitis (inflammation of the umbilical cord) by 50% and neonatal mortality by 12%.
Side effects
CHG is ototoxic; if put into an ear canal which has a ruptured eardrum, it can lead to deafness.CHG does not meet current European specifications for a hand disinfectant. Under the test conditions of the European Standard EN 1499, no significant difference in the efficacy was found between a 4% solution of chlorhexidine digluconate and soap. In the U.S., between 2007 and 2009, Hunter Holmes McGuire Veterans Administration Medical Center conducted a cluster-randomized trial and concluded that daily bathing of patients in intensive care units with washcloths saturated with chlorhexidine gluconate reduced the risk of hospital-acquired infections.Whether prolonged exposure over many years may have carcinogenic potential is still not clear. The US Food and Drug Administration recommendation is to limit the use of a chlorhexidine gluconate mouthwash to a maximum of six months.When ingested, CHG is poorly absorbed in the gastrointestinal tract and can cause stomach irritation or nausea. If aspirated into the lungs at high enough concentration, as reported in one case, it can be fatal due to the high risk of acute respiratory distress syndrome.
Mechanism of action
At physiologic pH, chlorhexidine salts dissociate and release the positively charged chlorhexidine cation. The bactericidal effect is a result of the binding of this cationic molecule to negatively charged bacterial cell walls. At low concentrations of chlorhexidine, this results in a bacteriostatic effect; at high concentrations, membrane disruption results in cell death.
Chemistry
It is a cationic polybiguanide (bisbiguanide). It is used primarily as its salts (e.g., the dihydrochloride, diacetate, and digluconate).
Deactivation
Chlorhexidine is deactivated by forming insoluble salts with anionic compounds, including the anionic surfactants commonly used as detergents in toothpastes and mouthwashes, anionic thickeners such as carbomer, and anionic emulsifiers such as acrylates/C10-30 alkyl acrylate crosspolymer, among many others. For this reason, chlorhexidine mouth rinses should be used at least 30 minutes after other dental products. For best effectiveness, food, drink, smoking, and mouth rinses should be avoided for at least one hour after use. Many topical skin products, cleansers, and hand sanitizers should also be avoided to prevent deactivation when chlorhexidine (as a topical by itself or as a residue from a cleanser) is meant to remain on the skin.
Synthesis
The structure is based on two molecules of proguanil, linked with a hexamethylenediamine spacer.
Brands
Chlorhexidine topical is sold as Betasept, Biopatch, Calgon Vesta, ChloraPrep One-Step, Dyna-Hex, Hibiclens, Hibistat Towelette, Scrub Care Exidine, Spectrum-4 among others.Chlorhexidine gluconate mouthwash is sold as Dentohexinm, Paroex, Peridex, PerioChip, Corsodyl and Periogard, among others.Hexoralettene N contains benzocaine, menthol and chlorhexidine hydrochloride. It is used as oral antiseptic candies.
Veterinary medicine
In animals, chlorhexidine is used for topical disinfection of wounds, and to manage skin infections. Chlorhexidine-based disinfectant products are used in the dairy farming industry.Post-surgical respiratory problems have been associated with the use of chlorhexidine products in cats.
See also
Polyaminopropyl biguanide
Polyhexanide
Triclosan
References
External links
"Chlorhexidine". Drug Information Portal. U.S. National Library of Medicine. |
Telotristat ethyl | Telotristat ethyl (USAN, brand name Xermelo) is a prodrug of telotristat, which is an inhibitor of tryptophan hydroxylase. It is formulated as telotristat etiprate — a hippurate salt of telotristat ethyl.On February 28, 2017, the U.S. Food and Drug Administration (FDA) approved telotristat ethyl in combination with somatostatin analog (SSA) therapy for the treatment of adults with diarrhea associated with carcinoid syndrome that SSA therapy alone has inadequately controlled. Telotristat ethyl was approved for use in the European Union in September 2017.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
Pharmacology
Telotristat is an inhibitor of tryptophan hydroxylase, which mediates the rate-limiting step in serotonin biosynthesis.
Adverse effects
Common adverse effects noted in clinical trials include nausea, headache, elevated liver enzymes, depression, accumulation of fluid causing swelling (peripheral edema), flatulence, decreased appetite, and fever. Constipation is also common, and may be serious or life-threatening (especially in overdose).
Formulations
It is marketed by Lexicon Pharmaceuticals (as telotristat etiprate). 328 mg telotristat etiprate is equivalent to 250 mg telotristate ethyl.
References
Further reading
Kulke MH, ODorisio T, Phan A, Bergsland E, Law L, Banks P, et al. (October 2014). "Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide". Endocrine-Related Cancer. 21 (5): 705–14. doi:10.1530/ERC-14-0173. PMC 4295770. PMID 25012985.
External links
"Telotristat ethyl". Drug Information Portal. U.S. National Library of Medicine.
"Telotristat etiprate". Drug Information Portal. U.S. National Library of Medicine. |
Diclofenac | Diclofenac, sold under the brand name Voltaren, among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout. It is taken by mouth or rectally in a suppository, used by injection, or applied to the skin. Improvements in pain last for as much as eight hours. It is also available in combination with misoprostol in an effort to decrease stomach problems.Common side effects include abdominal pain, gastrointestinal bleeding, nausea, dizziness, headache, and swelling. Serious side effects may include heart disease, stroke, kidney problems, and stomach ulceration. Use is not recommended in the third trimester of pregnancy. It is likely safe during breastfeeding. It is believed to work by decreasing the production of prostaglandin. It blocks both COX-1 (like aspirin) and COX-2 (like celecoxib), hence is a COX-2 inhibitor.Diclofenac was patented in 1965 by Ciba-Geigy; it came into medical use in the United States in 1988. It is available as a generic medication. In 2019, it was the 74th most commonly prescribed medication in the United States, with more than 10 million prescriptions. It is available as a sodium or potassium salt. It is also widely used for livestock; such use was responsible for the Indian vulture crisis, during which in a few years 95% of the countrys vulture population was killed, and in many countries agricultural use is now forbidden.
Medical uses
Diclofenac is used to treat pain, inflammatory disorders, and dysmenorrhea.
Pain
Inflammatory disorders may include musculoskeletal complaints, especially arthritis, rheumatoid arthritis, polymyositis, dermatomyositis, osteoarthritis, dental pain, temporomandibular joint (TMJ) pain, spondylarthritis, ankylosing spondylitis, gout attacks, and pain management in cases of kidney stones and gallstones. An additional indication is the treatment of acute migraines. Diclofenac is used commonly to treat mild to moderate postoperative or post-traumatic pain, in particular when inflammation is also present, and is effective against menstrual pain and endometriosis.
Diclofenac is also available in topical forms and has been found to be useful for osteoarthritis but not other types of long-term musculoskeletal pain.It may also help with actinic keratosis, and acute pain caused by minor strains, sprains, and contusions (bruises).In many countries, eye drops are sold to treat acute and chronic nonbacterial inflammation of the anterior part of the eyes (e.g., postoperative states). Diclofenac eye drops have also been used to manage pain for traumatic corneal abrasion.Diclofenac is often used to treat chronic pain associated with cancer, especially if inflammation is present. Use of diclofenac gel should not exceed 32 grams in a day.
Contraindications
Hypersensitivity against diclofenac
History of allergic reactions (bronchospasm, shock, rhinitis, urticaria) following the use of other NSAIDs such as aspirin
Third-trimester pregnancy
Active stomach and/or duodenal ulceration or gastrointestinal bleeding
Inflammatory bowel disease such as Crohns disease or ulcerative colitis
Severe congestive heart failure (NYHA III/IV)
Pain management in the setting of coronary artery bypass graft (CABG) surgery
Severe liver insufficiency (Child-Pugh Class C)
Severe chronic kidney disease (creatinine clearance <30 ml/min)
Caution in patients with pre-existing hepatic porphyria, as diclofenac may trigger attacks
Caution in patients with severe, active bleeding such as cerebral hemorrhage
NSAIDs in general should be avoided during dengue fever, as it induces (often severe) capillary leakage and subsequent heart failure.
Caution in patients with fluid retention or heart failure
Can lead to onset of new hypertension or worsening of pre-existing hypertension
Can cause serious skin adverse events such as exfoliative dermatitis, Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal
Adverse effects
Diclofenac consumption has been associated with significantly increased vascular and coronary risk in a study including coxib, diclofenac, ibuprofen and naproxen. Upper gastrointestinal complications were also reported. Major adverse cardiovascular events (MACE) were increased by about a third by diclofenac, chiefly due to an increase in major coronary events. Compared with placebo, of 1000 patients allocated to diclofenac for a year, three more had major vascular events, one of which was fatal. Vascular death was increased significantly by diclofenac.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.
Heart
In 2013, a study found major vascular events were increased by about a third by diclofenac, chiefly due to an increase in major coronary events. Compared with placebo, of 1000 people allocated to diclofenac for a year, three more had major vascular events, one of which was fatal. Vascular death was increased by diclofenac (1·65).Following the identification of increased risks of heart attacks with the selective COX-2 inhibitor rofecoxib in 2004, attention has focused on all the other members of the NSAIDs group, including diclofenac. Research results are mixed, with a meta-analysis of papers and reports up to April 2006 suggesting a relative increased rate of heart disease of 1.63 compared to nonusers. Professor Peter Weissberg, medical director of the British Heart Foundation said, "However, the increased risk is small, and many patients with chronic debilitating pain may well feel that this small risk is worth taking to relieve their symptoms". Only aspirin was found not to increase the risk of heart disease; however, this is known to have a higher rate of gastric ulceration than diclofenac. In Britain the Medicines and Healthcare products Regulatory Agency (MHRA) said in June 2013 that the drug should not be used by people with serious underlying heart conditions – people who had had heart failure, heart disease or a stroke were advised to stop using it completely. As of 15 January 2015, the MHRA announced that diclofenac will be reclassified as a prescription-only medicine (POM) due to the risk of cardiovascular adverse events.A subsequent large study of 74,838 Danish users of NSAIDs or coxibs found no additional cardiovascular risk from diclofenac use. A very large study of 1,028,437 Danish users of various NSAIDs or coxibs found the "Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death (odds ratio, 1.91; 95% confidence interval, 1.62 to 2.42; and odds ratio, 1.66; 95% confidence interval, 1.06 to 2.59, respectively), with a dose-dependent increase in risk."Diclofenac is similar in COX-2 selectivity to celecoxib.
Gastrointestinal
Gastrointestinal complaints are most often noted. The development of ulceration and/or bleeding requires immediate termination of treatment with diclofenac. Most patients receive a gastro-protective drug as prophylaxis during long-term treatment (misoprostol, ranitidine 150 mg at bedtime or omeprazole 20 mg at bedtime).
Liver
Liver damage occurs infrequently, and is usually reversible. Hepatitis may occur rarely without any warning symptoms and may be fatal. Patients with osteoarthritis more often develop symptomatic liver disease than patients with rheumatoid arthritis. Liver function should be monitored regularly during long-term treatment. If used for the short-term treatment of pain or fever, diclofenac has not been found more hepatotoxic than other NSAIDs.
As of December 2009, Endo, Novartis, and the US FDA notified healthcare professionals to add new warnings and precautions about the potential for elevation in liver function tests during treatment with all products containing diclofenac sodium.
Cases of drug-induced hepatotoxicity have been reported in the first month, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.
Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 week after initiating treatment with diclofenac.
Kidney
NSAIDs "are associated with adverse renal [kidney] effects caused by the reduction in synthesis of renal prostaglandins" in sensitive persons or animal species, and potentially during long-term use in nonsensitive persons if resistance to side effects decreases with age. However, this side effect cannot be avoided merely by using a COX-2 selective inhibitor because, "Both isoforms of COX, COX-1 and COX-2, are expressed in the kidney... Consequently, the same precautions regarding renal risk that are followed for nonselective NSAIDs should be used when selective COX-2 inhibitors are administered." However, diclofenac appears to have a different mechanism of renal toxicity.
Studies in Spain showed diclofenac caused acute kidney failure in vultures when they ate the carcasses of animals that had recently been treated with it. Drug-sensitive species and individual humans are initially assumed to lack genes expressing specific drug detoxification enzymes.
Mental health
Mental health side effects have been reported. These symptoms are rare, but exist in significant enough numbers to include as potential side effects. These include depression, anxiety, irritability, nightmares, and psychotic reactions.
Mechanism of action
As with most NSAIDs, the primary mechanism responsible for its anti-inflammatory, antipyretic, and analgesic action is thought to be inhibition of prostaglandin synthesis through COX-inhibition. Diclofenac inhibits COX-1 and COX-2 with relative equipotency.The main target in inhibition of prostaglandin synthesis appears to be the transiently expressed prostaglandin-endoperoxide synthase-2 (PGES-2) also known as cycloxygenase-2 (COX-2).
It also appears to exhibit bacteriostatic activity by inhibiting bacterial DNA synthesis.Diclofenac has a relatively high lipid solubility, making it one of the few NSAIDs that are able to enter the brain by crossing the blood-brain barrier. In the brain, too, it is thought to exert its effect through inhibition of COX-2. In addition, it may have effects inside the spinal cord.Diclofenac may be a unique member of the NSAIDs in other aspects. Some evidence indicates it inhibits the lipoxygenase pathways, thus reducing formation of the leukotrienes (also pro-inflammatory autacoids). It also may inhibit phospholipase A2 as part of its mechanism of action. These additional actions may explain its high potency – it is the most potent NSAID on a broad basis.Marked differences exist among NSAIDs in their selective inhibition of the two subtypes of cyclooxygenase, COX-1 and COX-2. Much pharmaceutical drug design has attempted to focus on selective COX-2 inhibition as a way to minimize the gastrointestinal side effects of NSAIDs such as aspirin. In practice, use of some COX-2 inhibitors with their adverse effects has led to massive numbers of patient family lawsuits alleging wrongful death by heart attack, yet other significantly COX-selective NSAIDs, such as diclofenac, have been well tolerated by most of the population.Besides the COX-inhibition, a number of other molecular targets of diclofenac possibly contributing to its pain-relieving actions have recently been identified. These include:
Blockage of voltage-dependent sodium channels (after activation of the channel, diclofenac inhibits its reactivation also known as phase inhibition)
Blockage of acid-sensing ion channels (ASICs)
Positive allosteric modulation of KCNQ- and BK-potassium channels (diclofenac opens these channels, leading to hyperpolarization of the cell membrane)The action of one single dose is much longer (6 to 8 h) than the very short 1.2–2 h half-life of the drug would indicate. This could be partly because it persists for over 11 hours in synovial fluids.
As a veterinary drug
Diclofenac is widely approved as a veterinary drug. It is used in the treatment of companion animals and livestock. In sheep, pigs, cattle and goats, it is used in the management of several bacterial diseases, including diarrhoea, enteritis, dysentery, foot rot and septicaemia. In some bird species, diclofenac causes accumulation of uric acid crystals in organs, especially kidneys, triggering acute renal necrosis and visceral gout. Vultures, among other carrion-eating birds, are known to scavenge deceased livestock. In South Asia in the 2000s, vulture populations were decimated by feeding on dead livestock that had been treated with diclofenac.
Society and culture
History
In the United States, 1% diclofenac gel was approved by the FDA in 2007. It was approved as a prescription drug and was indicated for the relief of the pain of osteoarthritis of joints responsive to topical treatment; in particular, it was prescribed for the joints in the hands, knees and feet. It has not been shown to work for strains, sprains, bruises or sports injuries. It was intended for the temporary relief of joint pain due to the most common type of arthritis, osteoarthritis. In February 2020, the gel became an over-the-counter drug and the FDA granted the approval of the nonprescription product to GlaxoSmithKline plc.
Formulations and trade names
The name "diclofenac" derives from its chemical name: 2-(2,6-dichloranilino) phenylacetic acid. Diclofenac was first synthesized by Alfred Sallmann and Rudolf Pfister and introduced as Voltaren by Ciba-Geigy (now Novartis) in 1973, then in 2015 it was bought by GlaxoSmithKline.Voltaren and Voltarol contain the sodium salt of diclofenac. In the United Kingdom, Voltarol can be supplied with either the sodium salt or the potassium salt, while Cataflam, sold in some other countries, is the potassium salt only. However, Voltarol Emulgel contains diclofenac diethylammonium, in which a 1.16% concentration is equivalent to a 1% concentration of the sodium salt. In 2016 Voltarol was one of the biggest selling branded over-the-counter medications sold in Great Britain, with sales of £39.3 million.On 14 January 2015, diclofenac oral preparations were reclassified as prescription-only medicines in the UK. The topical preparations are still available without prescription.Diclofenac formulations are available worldwide under many different trade names.
Ecological effects
Use of diclofenac for animals is controversial due to toxicity when eaten by scavenging birds that eat dead animals; the medication has been banned for veterinary use in several countries.Use of diclofenac in animals has been reported to have led to a sharp decline in the vulture population in the Indian subcontinent – a 95% decline by 2003 and a 99.9% decline by 2008. The mechanism is presumed to be renal failure; however, toxicity may be due to direct inhibition of uric acid secretion in vultures. Vultures eat the carcasses of livestock that have been administered veterinary diclofenac, and are poisoned by the accumulated chemical, as vultures do not have a particular enzyme to break down diclofenac. At a meeting of the National Wildlife Board in March 2005, the Government of India announced it intended to phase out the veterinary use of diclofenac. Meloxicam is a safer alternative to replace use of diclofenac. It is more expensive than diclofenac, but the cost is dropping as more pharmaceutical companies are beginning to manufacture it.Steppe eagles have the same vulnerability to diclofenac as vultures and may also fall victim to it. Diclofenac has been shown also to harm freshwater fish species such as rainbow trout. In contrast, New World vultures, such as the turkey vulture, can tolerate at least 100 times the level of diclofenac that is lethal to Gyps species."The loss of tens of millions of vultures over the last decade has had major ecological consequences across the Indian Subcontinent that pose a potential threat to human health. In many places, populations of feral dogs (Canis familiaris) have increased sharply from the disappearance of Gyps vultures as the main scavenger of wild and domestic ungulate carcasses. Associated with the rise in dog numbers is an increased risk of rabies" and casualties of almost 50,000 people. The Government of India cites this as one of the major consequences of a vulture species extinction. A major shift in the transfer of corpse pathogens from vultures to feral dogs and rats could lead to a disease pandemic, causing millions of deaths in a crowded country like India, whereas vultures digestive systems safely destroy many species of such pathogens. Vultures are long-lived and slow to breed. They start breeding only at the age of six and only 50% of young survive. Even if the government ban is fully implemented, it will take several years to revive the vulture population.The loss of vultures has had a social impact on the Indian Zoroastrian Parsi community, who traditionally use vultures to dispose of human corpses in Towers of Silence, but are now compelled to seek alternative methods of disposal.Despite the vulture crisis, diclofenac remains available in other countries including many in Europe. It was controversially approved for veterinary use in Spain in 2013 and continues to be available, despite Spain being home to around 90% of the European vulture population and an independent simulation showing that the drug could reduce the population of vultures by 1–8% annually. Spains medicine agency presented simulations suggesting that the number of deaths would be quite small. A paper published in 2021 identified the first authenticated death of a vulture from diclofenac in Spain, a Cinereous Vulture.
See also
Diclofenac etalhyaluronate, a sustained-release form of diclofenac
References
External links
"Diclofenac". Drug Information Portal. U.S. National Library of Medicine. |
Deflazacort | Deflazacort (trade name Calcort among others) is a glucocorticoid used as an anti-inflammatory and immunomodulatory agent.
It was patented in 1965 and approved for medical use in 1985. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication for Duchenne Muscular Dystrophy.
Medical uses
The manufacturer lists the following uses for deflazacort:
In the United States, deflazacort is approved for the treatment of duchenne muscular dystrophy in people over the age of two.
Adverse effects
Deflazacort carries the risks common to all corticosteroids, including immune suppression, decreased bone density, and endocrine insufficiency. In clinical trials, the most common side effects (>10% above placebo) were Cushings-like appearance, weight gain, and increased appetite.
Pharmacology
Mechanism of action
Deflazacort is an inactive prodrug which is metabolized rapidly to the active drug 21-desacetyldeflazacort.
Relative potency
Deflazacorts potency is around 70–90% that of prednisone. A 2017 review found its activity of 7.5 mg of deflazacort is approximately equivalent to 25 mg cortisone, 20 mg hydrocortisone, 5 mg of prednisolone or prednisone, 4 mg of methylprednisolone or triamcinolone, or 0.75 mg of betamethasone or dexamethasone. The review noted that the drug has a high therapeutic index, being used at initial oral doses ranging from 6 to 90 mg, and probably requires a 50% higher dose to induce the same demineralizing effect as prednisolone. Thus it has "a smaller impact on calcium metabolism than any other synthetic corticosteroid, and therefore shows a lower risk of growth rate retardation in children and of osteoporosis" in the elderly, and comparatively small effects on carbohydrate metabolism, sodium retention, and hypokalemia.
History
In January 2015, the FDA granted fast track status to Marathon Pharmaceuticals to pursue approval of deflazacort as a potential treatment for Duchenne muscular dystrophy, a rare, "progressive and fatal disease" that affects boys. Although deflazacort was approved by the FDA for use in treatment of Duchenne muscular dystrophy on February 9, 2017, Marathon CEO announced on February 13, 2017, that the launch of deflazacort (Emflaza) would be delayed amidst controversy over the steep price Marathon was asking for the drug in the United States - $89,000 per year, which is "roughly 70 times" more than it would cost overseas. Because deflazacort is an older drug which has been long-approved in some other countries, it is now available in many places as an inexpensive generic. For example, in Canada deflazacort can be purchased for around $1 per tablet.Deflazacort is sold in the United States under the brand name Emflaza after PTC Therapeutics, Inc. acquired all rights to Emflaza on March 16, 2017. Deflazacort is sold in the United Kingdom under the trade name Calcort; in Brazil as Cortax, Decortil, Defcort and Deflanil; in India as Moaid, Zenflav, Defolet, DFZ, Decotaz, and DefZot; in Bangladesh as Xalcort; in Panama as Zamen; Spain as Zamene; and in Honduras as Flezacor.The U.S. Food and Drug Administration approved deflazacort to treat people age five years and older with Duchenne muscular dystrophy (DMD), a rare genetic disorder that causes progressive muscle deterioration and weakness. Emflaza is a corticosteroid that works by decreasing inflammation and reducing the activity of the immune system. NDA 208684 was approved on February 9, 2017, as a Type 1- new molecular entity with orphan status.
References
External links
"Deflazacort". Drug Information Portal. U.S. National Library of Medicine. |
Plecanatide | Plecanatide, sold under the brand name Trulance, is a medication for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation. Plecanatide is an agonist of guanylate cyclase-C. Plecanatide increases intestinal transit and fluid through a buildup of cGMP.
Medical uses
As of January 2017, plecanatide is approved in the United States for the treatment of chronic idiopathic constipation in adults. The presence of this condition is determined using the Rome III diagnostic criteria for chronic constipation which requires that the patient meet stool frequency, stool consistency, incomplete evacuation, and straining requirements in addition to not being a likely candidate for irritable bowel syndrome. The symptoms should also have been present for at least three of the last six months to establish the chronic nature of the condition before treatment with plecanatide is indicated.Plecanatide has been shown to be safe and effective. It has shown to be at least equally as effective as its main competitor, linaclotide (brand name Linzess), but has been shown to have a lower rate of diarrhea as an adverse drug reaction.
Contraindications
Plecanatide has not been shown to be safe or effective in persons 6 years to 18 years of age. Use of plecanatide by persons under the age of 6 poses a serious dehydration risk and studies have demonstrated plecanatide can cause death in juvenile mice due to this dehydrating effect.Use of plecanatide is also contraindicated in persons who are suspected of having a mechanical gastrointestinal obstruction.
Pharmacology
Structure and function
Plecanatide is a 16 amino acid peptide with the amino acid sequence:
H-Asn1-Asp2-Glu3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-Leu16-OH
(one-letter sequence: NDECELCVNVACTGCL). Plecanatide is nearly structurally identical to human uroguanylin, apart from the substitution of Asp3 with Glu3. Disulfide bonds exist between Cys4 and Cys12, as well as Cys7 and Cys15.Plecanatide has two important motifs. The first being the acidic residues Asp2 and Glu3 which modulate the affinity for its receptor in response to environmental pH. Simulations predict the optimal activity of Plecanatide to occur at pH 5, making it suitable for targeting cells within the proximal intestine, which has a pH of between 5 and 6. The second is the ACTGC motif (residues Ala11 to Cys15) which is the region responsible for its binding to the receptor, guanylate cyclase-C.
Mechanism of action
Plecanatide works as a laxative by drawing water in to the gastrointestinal tract thereby softening stool and encouraging its natural passage.
Similar to its endogenous counterpart, plecanatide activates guanylate cyclase-C on endothelial cells within the gastrointestinal tract. The activation of guanylate cyclase-C catalyses the production of the second messenger guanosine 3’,5’-cyclic monophosphate (cGMP) which leads to the protein kinase A (PKA) and protein kinase G II (PKGII)-mediated phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is an anion channel and upon activation it will secrete negatively charged ions, particularly chloride (Cl−) and bicarbonate (HCO3−) in to the GI tract lumen. This disruption to the electrochemical gradient is in part rectified by the passive secretion of positively charged sodium ions in to the lumen and water follows by osmosis.Plecanatide is also known to have an anti-nociceptive effect in animal models, however the exact mechanism of action is not yet fully elucidated. It has been suggested that this may be in part to the anti-inflammatory action of guanylate cyclase-C by its inhibition of pro-inflammatory cytokines, or through the inhibition of associated sensory neurons.
Pharmacokinetics and metabolism
As plecanatide acts on receptors present on the apical side of endothelial cells lining the gastrointestinal tract it is able to impart its effect without ever entering circulation. As with most orally ingested peptides, plecanatide is degraded by intestinal enzymes, and so very little of the active drug enters systemic circulation. Minimal amounts of the drug are expected to be transported in to the body, and concentrations of plecanatide and its metabolites are undetectable in plasma following the recommended dosage of 3 mg. It has also been shown that dosages up to 48.6 mg produced no detectable concentration of plecanatide in human plasma at any time point after ingestion.
References
External links
"Plecanatide". Drug Information Portal. U.S. National Library of Medicine. |
Sodium phenylbutyrate | Sodium phenylbutyrate is a salt of an aromatic fatty acid, 4-phenylbutyrate (4-PBA) or 4-phenylbutyric acid. The compound is used to treat urea cycle disorders, because its metabolites offer an alternative pathway to the urea cycle to allow excretion of excess nitrogen.Sodium phenylbutyrate is also a histone deacetylase inhibitor and chemical chaperone, leading respectively to research into its use as an anti-cancer agent and in protein misfolding diseases such as cystic fibrosis.
Structure and properties
Sodium phenylbutyrate is a sodium salt of an aromatic fatty acid, made up of an aromatic ring and butyric acid. The chemical name for sodium phenylbutyrate is 4-phenylbutyric acid, sodium salt. It forms water-soluble off-white crystals.
Uses
Medical uses
Sodium phenylbutyrate is taken orally or by nasogastric intubation as a tablet or powder, and tastes very salty and bitter. It treats urea cycle disorders, genetic diseases in which nitrogen waste builds up in the blood plasma as ammonia glutamine (a state called hyperammonemia) due to deficiences in the enzymes carbamoyl phosphate synthetase I, ornithine transcarbamylase, or argininosuccinic acid synthetase. Uncontrolled, this causes intellectual impairment and early death. Sodium phenylbutyrate metabolites allows the kidneys to excrete excess nitrogen in place of urea, and coupled with dialysis, amino acid supplements and a protein-restricted diet, children born with urea cycle disorders can usually survive beyond 12 months. Patients may need treatment for all their life. The treatment was introduced by researchers in the 1990s, and approved by the U.S. Food and Drugs Administration (FDA) in April 1996.
Adverse effects
Nearly 1⁄4 of women may experience an adverse effect of amenorrhea or menstrual dysfunction. Appetite loss is seen is 4% of patients. Body odor due to metabolization of phenylbutyrate affects 3% of patients, and 3% experience unpleasant tastes. Gastrointestinal symptoms and mostly mild indications of neurotoxicity are also seen in less than 2% of patients, among several other reported adverse effects. Administration during pregnancy is not recommended because sodium phenylbutyrate treatment could mimic maternal phenylketonuria due to the production of phenylalanine, potentially causing fetal brain damage.
Research
Urea cycle disorders
Sodium phenylbutyrate administration was discovered to lead to an alternative nitrogen disposal pathway by Dr. Saul Brusilow, Mark Batshaw and colleagues at the Johns Hopkins School of Medicine in the early 1980s, due to some serendipitous discoveries. They had studied ketoacid therapy for another inborn error of metabolism, citrullinemia, in the late 1970s and they noticed that arginine treatment led to an increase of nitrogen in the urine and a drop in ammonia in the blood. The researchers spoke to Norman Radin about this finding, and he remembered a 1914 article on using sodium benzoate to reduce urea excretion. Another 1919 article had used sodium phenylacetate, and so the researchers treated 5 patients with hyperammonemia with benzoate and phenylacetate and published a report in Science. In 1982 and 1984, the researchers published on using benzoate and arginine for urea cycle disorders in the NEJM. Use of sodium phenylbutyrate was introduced in the early 1990s, as it lacks the odor of phenylacetate.
Chemical chaperone
In cystic fibrosis, a point mutation in the Cystic Fibrosis Transmembrane Conductance Regulator protein, ΔF508-CFTR, causes it to be unstable and misfold, hence trapped in the endoplasmic reticulum and unable to reach the cell membrane. This lack of CFTR in the cell membrane leads to disrupted chloride transport and the symptoms of cystic fibrosis. Sodium phenylbutyrate can act as a chemical chaperone, stabilising the mutant CFTR in the endoplasmic reticulum and allowing it to reach the cell surface.
Histone deacetylase inhibitor
Deriving from its activity as a histone deacetylase inhibitor, sodium phenylbutyrate is under investigation for use as a potential differentiation-inducing agent in malignant glioma and acute myeloid leukaemia, and also for the treatment of some sickle-cell disorders as an alternative to hydroxycarbamide due it inducing expression of fetal hemoglobin to replace missing adult hemoglobin. While small-scale investigation is proceeding, there is to date no published data to support the use of the compound in the clinical treatment of cancer, and it remains under limited investigation. Sodium phenylbutyrate is also being studied as a therapeutic option for the treatment of Huntingtons disease.
Other
Phenylbutyrate has been associated with longer lifespans in Drosophila.University of Colorado researchers Dr. Curt Freed and Wenbo Zhou demonstrated that phenylbutyrate stops the progression of Parkinsons disease in mice by turning on a gene called DJ-1 that can protect dopaminergic neurons in the midbrain from dying. As of July 2011 they plan on testing phenylbutyrate for the treatment of Parkinsons disease in humans.
Pharmacology
Phenylbutyrate is a prodrug. In the human body it is first converted to phenylbutyryl-CoA and then metabolized by mitochondrial beta-oxidation, mainly in the liver and kidneys, to the active form, phenylacetate. Phenylacetate conjugates with glutamine to phenylacetylglutamine, which is eliminated with the urine. It contains the same amount of nitrogen as urea, which makes it an alternative to urea for excreting nitrogen.A 5g tablet or powder of sodium phenylbutyrate taken by mouth can be detected in the blood within 15 minutes, and reaches peak concentration in the bloodstream within an hour. It is metabolized into phenylacetate within half an hour.
See also
Glycerol phenylbutyrate
References
External links
"Sodium phenylbutyrate". Drug Information Portal. U.S. National Library of Medicine. |
Bumetanide | Bumetanide, sold under the brand name Bumex among others, is a medication used to treat swelling and high blood pressure. This includes swelling as a result of heart failure, liver failure, or kidney problems. It may work for swelling when other medications have not. For high blood pressure it is not a preferred treatment. It is taken by mouth, or by injection into a vein or muscle. Effects generally begin within an hour and lasts for about six hours.Common side effects include dizziness, low blood pressure, low blood potassium, muscle cramps, and kidney problems. Other serious side effects may include hearing loss and low blood platelets. Blood tests are recommended regularly for those on treatment. Safety during pregnancy and breastfeeding is unclear. Bumetanide is a loop diuretic and works by decreasing the reabsorption of sodium by the kidneys.Bumetanide was patented in 1968 and came into medical use in 1972. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 241st most commonly prescribed medication in the United States, with more than one million prescriptions.
Uses
Medical uses
It is used to treat swelling and high blood pressure. This includes swelling as a result of heart failure, liver failure, or kidney problems. For high blood pressure it is not a preferred treatment. It is taken by mouth, or by injection into a vein or muscle.
Other uses
It 2008, ESPN reported that four NFL players were being suspended under the steroid policy as a result of taking bumetanide. It is sometimes used for weight loss because, as a diuretic, it removes water, but it also masks other drugs, including steroids, by diluting the contents of the users urine, yielding a lower concentration of filtered substances, which makes them less likely to be detected.
Bumetanide was an undisclosed active ingredient in the over-the-counter weight loss supplement StarCaps, which was removed from the market after its presence was discovered by the United States Food and Drug Administration.
Side effects
Common side effects include dizziness, low blood pressure, low blood potassium, muscle cramps, and kidney problems. Other serious side effects may include hearing loss and low blood platelets. A large observational study concluded that people with a sulfonamide antibiotic allergy may be allergic to sulfonamide non-antibiotics, such as bumetanide, but this is likely due to certain people being at an increased risk in general to developing allergic reactions rather than cross-reactivity between sulfonamide-containing drugs. In smaller studies, the lack of cross-reactivity between sulfonamide antibiotics and sulfonamide non-antibiotics has been demonstrated. Blood tests are recommended regularly for those on treatment. Safety during pregnancy and breastfeeding is unclear.
Mechanism of action
Bumetanide is a loop diuretic and works by decreasing the reabsorption of sodium by the kidneys.
The main difference between bumetanide and furosemide is in their bioavailability and potency. About 60% of furosemide is absorbed in the intestine, and there are substantial inter- and intraindividual differences in bioavailability (range 10-90%). About 80% of bumetanide is absorbed, and its absorption does not change when it is taken with food. It is said to be a more predictable diuretic, meaning that the predictable absorption is reflected in a more predictable effect. Bumetanide is 40 times more potent than furosemide for people with normal renal function.
Synthesis
Bumetanide is synthesized from 4-chlorobenzoic acid. In the first stage of synthesis, it undergoes sulfonylchlorination by chlorosulfonic acid, forming 4-chloro-3-chlorosulfonylbenzoic acid, which is further nitrated with nitric acid to 4-chloro-3-chlorosulfonyl-5-nitrobenzoic acid. Reacting this with ammonia gives 5-aminosulfonyl-4-chloro-3-nitrobenzoic acid, which when reacted with sodium phenolate is transformed into 5-amino-sulfonyl-3-nitro-5-phenoxybenzoic acid. Reduction of the nitro group in this product by hydrogen using a palladium on carbon catalyst gives 3-amino-5-aminosulfonyl-5-phenoxybenzoic acid. Finally, reacting this with butyl alcohol in the presence of sulfuric acid, followed by treatment with sodium hydroxide to hydrolyze the butyl ester, gives the desired bumetanide.
Research
In the brain, bumetanide blocks the NKCC1 cation-chloride co-transporter, and thus decreases internal chloride concentration in neurons. In turn, this concentration change makes the action of GABA more hyperpolarizing, which may be useful for treatment of neonatal seizures, which quite often are not responsive to traditional GABA-targeted treatment, such as barbiturates. Bumetanide is therefore under evaluation as a prospective antiepileptic drug.The drug has also been studied as a treatment for autism.
References
External links
"Bumetanide". Drug Information Portal. U.S. National Library of Medicine. |
Psoriasin | Psoriasin may refer to:
Coal tar, by-product of the production of coke and coal gas from coal.
S100A7, S100 calcium-binding protein A7. |
Amphetamine | Amphetamine (contracted from alpha-methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered in 1887 and exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.The first amphetamine pharmaceutical was Benzedrine, a brand which was used to treat a variety of conditions. Currently, pharmaceutical amphetamine is prescribed as racemic amphetamine, Adderall, dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine increases monoamine and excitatory neurotransmission in the brain, with its most pronounced effects targeting the norepinephrine and dopamine neurotransmitter systems.At therapeutic doses, amphetamine causes emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, and improved cognitive control. It induces physical effects such as improved reaction time, fatigue resistance, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown. Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses. Very high doses can result in psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses and carry a far greater risk of serious side effects.Amphetamine belongs to the phenethylamine class. It is also the parent compound of its own structural class, the substituted amphetamines, which includes prominent substances such as bupropion, cathinone, MDMA, and methamphetamine. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine and N-methylphenethylamine, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while N-methylphenethylamine is a positional isomer of amphetamine that differs only in the placement of the methyl group.
Uses
Medical
Amphetamine is used to treat attention deficit hyperactivity disorder (ADHD), narcolepsy (a sleep disorder), and obesity, and is sometimes prescribed off-label for its past medical indications, particularly for depression and chronic pain.
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.
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.
Contraindications
According to the International Programme on Chemical Safety (IPCS) and the United States Food and Drug Administration (USFDA), amphetamine is contraindicated in people with a history of drug abuse, cardiovascular disease, severe agitation, or severe anxiety. It is also contraindicated in individuals with advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension. These agencies indicate that people who have experienced allergic reactions to other stimulants or who are taking monoamine oxidase inhibitors (MAOIs) should not take amphetamine, although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented. These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression, hypertension, liver or kidney problems, mania, psychosis, Raynauds phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine. Evidence from human studies indicates that therapeutic amphetamine use does not cause developmental abnormalities in the fetus or newborns (i.e., it is not a human teratogen), but amphetamine abuse does pose risks to the fetus. Amphetamine has also been shown to pass into breast milk, so the IPCS and the USFDA advise mothers to avoid breastfeeding when using it. Due to the potential for reversible growth impairments, the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.
Adverse effects
The adverse side effects of amphetamine are many and varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of adverse effects. Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use. Recreational use of amphetamine generally involves much larger doses, which have a 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
An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care. The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine. Tolerant individuals have been known to take as much as 5 grams of amphetamine in a day, which is roughly 100 times the maximum daily therapeutic dose. Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma. In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an "amphetamine use disorder" resulted in an estimated 3,788 deaths worldwide (3,425–4,145 deaths, 95% confidence).
Toxicity
In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by dopamine terminal degeneration and reduced transporter and receptor function. There is no evidence that amphetamine is directly neurotoxic in humans. However, large doses of amphetamine may indirectly cause dopaminergic neurotoxicity as a result of hyperpyrexia, the excessive formation of reactive oxygen species, and increased autoxidation of dopamine. Animal models of neurotoxicity from high-dose amphetamine exposure indicate that the occurrence of hyperpyrexia (i.e., core body temperature ≥ 40 °C) is necessary for the development of amphetamine-induced neurotoxicity. Prolonged elevations of brain temperature above 40 °C likely promote the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting cellular protein function, and transiently increasing blood–brain barrier permeability.
Psychosis
An amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia. A Cochrane review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely. According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis. Psychosis rarely arises from therapeutic use.
Drug interactions
Many types of substances are known to interact with amphetamine, resulting in altered drug action or metabolism of amphetamine, the interacting substance, or both. Inhibitors of enzymes that metabolize amphetamine (e.g., CYP2D6 and FMO3) will prolong its elimination half-life, meaning that its effects will last longer. Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine); therefore, concurrent use of both is dangerous. Amphetamine modulates the activity of most psychoactive drugs. In particular, amphetamine may decrease the effects of sedatives and depressants and increase the effects of stimulants and antidepressants. Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively. Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD.In general, there is no significant interaction when consuming amphetamine with food, but the pH of gastrointestinal content and urine affects the absorption and excretion of amphetamine, respectively. Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite. Due to the effect pH has on absorption, amphetamine also interacts with gastric acid reducers such as proton pump inhibitors and H2 antihistamines, which increase gastrointestinal pH (i.e., make it less acidic).
Pharmacology
Pharmacodynamics
Amphetamine exerts its behavioral effects by altering the use of monoamines as neuronal signals in the brain, primarily in catecholamine neurons in the reward and executive function pathways of the brain. The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine because of its effects on monoamine transporters. The reinforcing and motivational salience-promoting effects of amphetamine are due mostly to enhanced dopaminergic activity in the mesolimbic pathway. The euphoric and locomotor-stimulating effects of amphetamine are dependent upon the magnitude and speed by which it increases synaptic dopamine and norepinephrine concentrations in the striatum.Amphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines. Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits monoamine transporter function. Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines. Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors. Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 co-localization in the associated monoamine neurons.In addition to the neuronal monoamine transporters, amphetamine also inhibits both vesicular monoamine transporters, VMAT1 and VMAT2, as well as SLC1A1, SLC22A3, and SLC22A5. SLC1A1 is excitatory amino acid transporter 3 (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter. Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression, a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro. The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gi/Go-coupled GPCR. Amphetamine also inhibits monoamine oxidases at very high doses, resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines. In humans, the only post-synaptic receptor at which amphetamine is known to bind is the 5-HT1A receptor, where it acts as an agonist with low micromolar affinity.The full profile of amphetamines short-term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine, serotonin, norepinephrine, epineph |
Amphetamine | rine, histamine, CART peptides, endogenous opioids, adrenocorticotropic hormone, corticosteroids, and glutamate, which it affects through interactions with CART, 5-HT1A, EAAT3, TAAR1, VMAT1, VMAT2, and possibly other biological targets. Amphetamine also activates seven human carbonic anhydrase enzymes, several of which are expressed in the human brain.Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine. Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.
Dopamine
In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft. Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly. As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter. Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation. Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces the reversal of dopamine transport through DAT (i.e., dopamine efflux). Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through an unidentified Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine efflux. Through direct activation of G protein-coupled inwardly-rectifying potassium channels, TAAR1 reduces the firing rate of dopamine neurons, preventing a hyper-dopaminergic state.Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2. Following amphetamine uptake at VMAT2, amphetamine induces the collapse of the vesicular pH gradient, which results in the release of dopamine molecules from synaptic vesicles into the cytosol via dopamine efflux through VMAT2. Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at DAT.
Norepinephrine
Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine. Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine. In other words, amphetamine induces TAAR1-mediated efflux and non-competitive reuptake inhibition at phosphorylated NET, competitive NET reuptake inhibition, and norepinephrine release from VMAT2.
Serotonin
Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine. Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1. Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor.
Other neurotransmitters, peptides, hormones, and enzymes
Acute amphetamine administration in humans increases endogenous opioid release in several brain structures in the reward system. Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase in the striatum following exposure to amphetamine. This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of EAAT3, a glutamate reuptake transporter, in dopamine neurons. Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through VMAT2. Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic–pituitary–adrenal axis.In December 2017, the first study assessing the interaction between amphetamine and human carbonic anhydrase enzymes was published; of the eleven carbonic anhydrase enzymes it examined, it found that amphetamine potently activates seven, four of which are highly expressed in the human brain, with low nanomolar through low micromolar activating effects. Based upon preclinical research, cerebral carbonic anhydrase activation has cognition-enhancing effects; but, based upon the clinical use of carbonic anhydrase inhibitors, carbonic anhydrase activation in other tissues may be associated with adverse effects, such as ocular activation exacerbating glaucoma.
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.
Lisdexamfetamine is a prodrug of dextroamphetamine. It is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract. Following absorption into the blood stream, lisdexamfetamine is completely converted by red blood cells to dextroamphetamine and the amino acid L-lysine by hydrolysis via undetermined aminopeptidase enzymes. This is the rate-limiting step in the bioactivation of lisdexamfetamine. The elimination half-life of lisdexamfetamine is generally less than 1 hour. Due to the necessary conversion of lisdexamfetamine into dextroamphetamine, levels of dextroamphetamine with lisdexamfetamine peak about one hour later than with an equivalent dose of immediate-release dextroamphetamine. Presumably due to its rate-limited activation by red blood cells, intravenous administration of lisdexamfetamine shows greatly delayed time to peak and reduced peak levels compared to intravenous administration of an equivalent dose of dextroamphetamine. The pharmacokinetics of lisdexamfetamine are similar regardless of whether it is administered orally, intranasally, or intravenously. Hence, in contrast to dextroamphetamine, parenteral use does not enhance the subjective effects of lisdexamfetamine. Because of its behavior as a prodrug and its pharmacokinetic differences, lisdexamfetamine has a longer duration of therapeutic effect than immediate-release dextroamphetamine and shows reduced misuse potential.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 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
The human metagenome (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individuals body) varies considerably between individuals. Since the total number of microbial and viral cells in the human body (over 100 trillion) greatly outnumbers human cells (tens of trillions), there is considerable potential for interactions between drugs and an individuals microbiome, including: drugs altering the composition of the human microbiome, drug metabolism by microbial enzymes modifying the drugs pharmacokinetic profile, and microbial drug metabolism affecting a drugs clinical efficacy and toxicity profile. The field that studies these interactions is known as pharmacomicrobiomics.Similar to most biomolecules and other orally administered xenobiotics (i.e., drugs), amphetamine is predicted to undergo promiscuous metabolism by human gastrointestinal microbiota (primarily bacteria) prior to absorption into the blood stream. The first amphetamine-metabolizing microbial enzyme, tyramine oxidase from a strain of E. coli commonly found in the human gut, was identified in 2019. This enzyme was found to metabolize amphetamine, tyramine, and phenethylamine with roughly the same binding affinity for all three compounds.
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.
Chemistry
Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula C9H13N. The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomers. This racemic mixture can be separated into its optical isomers: levoamphetamine and dextroamphetamine. At room temperature, the pure free base of amphetamine is a mobile, colorless, and volatile liquid with a characteristically strong amine odor, and acrid, burning taste. Frequently prepared solid salts of amphetamine include amphetamine adipate, aspartate, hydrochloride, phosphate, saccharate, sulfate, and tannate. Dextroamphetamine sulfate is the most common enantiopure salt. Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives. In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1-bi-2-naphthol.
Substituted derivatives
The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone"; specifically, this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with substituents. The class includes amphetamine itself, stimulants like methamphetamine, serotonergic empathogens like MDMA, and decongestants like ephedrine, among other subgroups.
Synthesis
Since the first preparation was reported in 1887, numerous synthetic routes to amphetamine have been developed. The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 1). In the first step, a reaction between phenylacetone and formamide, either using additional formic acid or formamide itself as a reducing agent, yields N-formylamphetamine. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, extracted with organic solvent, concentrated, and distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt.A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine. For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine. Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale. In addition, several enantioselective syntheses of amphetamine have been developed. In one example, optically pure (R)-1-phenyl-ethanamine is condensed with phenylacetone to yield a chiral Schiff base. In the key step, this intermediate is reduced by catalytic hydrogenation with a transfer of chirality to the carbon atom alpha to the amino group. Cleavage of the benzylic amine bond by hydrogenation yields optically pure dextroamphetamine.A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions. One example is the Friedel–Crafts alkylation of benzene by allyl chloride to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 2). Another example employs the Ritter reaction (method 3). In this route, allylbenzene is reacted acetonitrile in sulfuric acid to yield an organosulfate which in turn is treated with sodium hydroxide to give amphetamine via an acetamide intermediate. A third route starts with ethyl 3-oxobutanoate which through a double alkylation with methyl iodide followed by benzyl chloride can be converted into 2-methyl-3-phenyl-propanoic acid. This synthetic intermediate can be transformed into amphetamine using either a Hofmann or Curtius rearrangement (method 4).A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime, or other nitrogen-containing functional groups. In one such example, a Knoevenagel condensation of benzaldehyde with nitroethane yields phenyl-2-nitropropene. The double bond and nitro group of this intermediate is reduced using either catalytic hydrogenation or by treatment with lithium aluminium hydride (method 5). Another method is the reaction of phenylacetone with ammonia, producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride (method 6).
Detection in body fluids
Amphetamine is frequently measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics. Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs. Chromatographic methods specific for amphetamine are employed to prevent false positive results. Chiral separation techniques may be employed to help distinguish the source of the drug, whether prescription amphetamine, prescription amphetamine prodrugs, (e.g., selegiline), over-the-counter drug products that contain levomethamphetamine, or illicitly obtained substituted amphetamines. Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others. These compounds may produce positive results for amphetamine on drug tests. Amphetamine is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for 2–4 days.For the assays, a study noted that an enzyme multiplied immunoassay technique (EMIT) assay for amphetamine and methamphetamine may produce more false positives than liquid chromatography–tandem mass spectrometry. Gas chromatography–mass spectrometry (GC–MS) of amphetamine and methamphetamine with the derivatizing agent (S)-(−)-trifluoroacetylprolyl chloride allows for the detection of methamphetamine in urine. GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent Moshers acid chloride allows for the detection of both dextroamphetamine and dextromethamphetamine in urine. Hence, the latter method may be used on samples that test positive using other methods to help distinguish between the various sources of the drug.
History, society, and culture
Amphetamine-type stimulants were originally derived from the plant Ephedra, which contains the amphetamine-like stimulant ephedrine and had been used for its effects in China dating back an estimated 5,000 years. Ephedrine was isolated from Ephedra vulgaris in Japan in 1885 and was studied for its medicinal properties through the 1920s. The scarce amounts of ephedrine in the Ephedra plant led to investigations of synthetic analogues of ephedrine.Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine; its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties. Amphetamine had no medical use until late 1933, when Smith, Kline and French began selling it as an inhaler under the brand name Benzedrine as a decongestant. Benzedrine sulfate was introduced 3 years later and was used to treat a wide variety of medical conditions, including narcolepsy, obesity, low blood pressure, low libido, and chronic pain, among others. During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects. As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine. For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act. In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors, musicians, mathematicians, and athletes.Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries. Among European Union (EU) member states in 2018, 11.9 million adults of ages 15–64 have used amphetamine or methamphetamine at least once in their lives and 1.7 million have used either in the last year. During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states; the "street price" of illicit amphetamine within the EU ranged from €6–38 per gram during the same period. Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.
Legal status
As a result of the United Nations 1971 Convention on Psychotropic Substances, amphetamine became a schedule II controlled substance, as defined in the treaty, in all 183 state parties. Consequently, it is heavily regulated in most countries. Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use. In other nations, such as Canada (schedule I drug), the Netherlands (List I drug), the United States (schedule II drug), Australia (schedule 8), Thailand (category 1 narcotic), and United Kingdom (class B drug), amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.
Pharmaceutical products
Several currently marketed amphetamine formulations contain both enantiomers, including those marketed under the brand names Adderall, Adderall XR, Mydayis, Adzenys ER, Adzenys XR-ODT, Dyanavel XR, Evekeo, and Evekeo ODT. Of those, Evekeo (including Evekeo ODT) is the only product containing only racemic amphetamine (as amphetamine sulfate), and is therefore the only one whose active moiety can be accurately referred to simply as "amphetamine". Dextroamphetamine, marketed under the brand names Dexedrine and Zenzedi, is the only enantiopure amphetamine product currently available. A prodrug form of dextroamphetamine, lisdexamfetamine, is also available and is marketed under the brand name Vyvanse. As it is a prodrug, lisdexamfetamine is structurally different from dextroamphetamine, and is inactive until it metabolizes into dextroamphetamine. The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine. Levoamphetamine was previously available as Cydril. Many current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base. However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were introduced in 2015 and 2016, respectively. Some of the current brands and their generic equivalents are listed below.
Notes
Image legend
Reference notes
References
External links
"Amphetamine". Drug Information Portal. United States National Library of Medicine.
CID 5826 from PubChem – Dextroamphetamine
CID 32893 from PubChem – Levoamphetamine
Comparative Toxicogenomics Database entry: Amphetamine
Comparative Toxicogenomics Database entry: CARTPT |
Amédée Galzin | Amédée Galzin (1 May 1853, Parrinet, Aveyron – 14 February 1925, Parrinet) was a French veterinarian and mycologist.
In 1878 he obtained his degree from the veterinary college in Toulouse. From 1879 to 1905, he served as a military veterinarian, becoming a knight of the Legion of Honour in 1899.With Abbé Hubert Bourdot, he was co-author of a series of publications (11 parts, 1909 to 1925) involving Hymenomycetes native to France; all parts being published in the Bulletin de la Société Mycologique de France. With Bourdot, he also wrote Heterobasidiae nondum descriptae (Descriptions of a few jelly fungi).With Bourdot, he was the taxonomic authority of the fungi genus Oxyporus, as well as of numerous mycological species.
== References == |
Methohexital | Methohexital or methohexitone (marketed under the brand names Brevital and Brietal) is a drug which is a barbiturate derivative. It is classified as short-acting, and has a rapid onset of action. It is similar in its effects to sodium thiopental, a drug with which it competed in the market for anaesthetics.
Pharmacology
Methohexital binds to a distinct site which is associated with Cl− ionophores at GABAA receptors. This increases the length of time which the Cl− ionopores are open, thus causing an inhibitory effect.
Metabolism of methohexital is primarily hepatic via demethylation and oxidation. Side-chain oxidation is the primary means of metabolism involved in the termination of the drugs biological activity.
Indications
Methohexital is primarily used to induce anesthesia, and is generally provided as a sodium salt (i.e. methohexital sodium). It is only used in hospital or similar settings, under strict supervision. It has been commonly used to induce deep sedation or general anesthesia for surgery and dental procedures. Unlike many other barbiturates, methohexital actually lowers the seizure threshold, a property that makes it particularly useful when anesthesia is provided for an electroconvulsive therapy (ECT). Its rapid recovery rate with consciousness being gained within three to seven minutes after induction and full recovery within 30 minutes is a major advantage over other ECT barbiturates.
Synthesis
Methohexital can be synthesized in the classic manner of making barbituric acid derivatives, in particular by the reaction of malonic ester derivatives with derivatives of urea. The resulting allyl-(1-methyl-2-pentynyl) malonic ester is synthesized by subsequent alkylation of the malonic ester itself, beginning with 2-bromo-3-hexyne, which gives (1-methyl-2-pentynyl)malonic ester, and then by allylbromide. In the final step, reaction of the disubstituted malonic ester with N-methylurea gives methohexital.
References
External links
"Methohexital". Drug Information Portal. U.S. National Library of Medicine.
"Methohexital sodium". Drug Information Portal. U.S. National Library of Medicine. |
Trimethobenzamide | Trimethobenzamide (trade names Tebamide, Tigan) is an antiemetic used to prevent nausea and vomiting.
Mechanism of action
Trimethobenzamide is an antagonist of the D2 receptor. It is believed to affect the chemoreceptor trigger zone (CTZ) of the medulla oblongata to suppress nausea and vomiting.
Side effects
Possible side effects include drowsiness, dizziness, headache, muscle cramps, and blurred vision. More serious adverse effects include skin rash, tremors, parkinsonism, and jaundice.
Formulations
Trimethobenzamide is marketed under the brand names Tebamide and Tigan, manufactured by GlaxoSmithKline and King Pharmaceuticals, respectively. It is available as oral capsules and injectable formulations.
Trimethobenzamide was also available as a rectal suppository, but such formulations were banned by the U.S. Food and Drug Administration on April 6, 2007, due to unproven efficacy.
Synthesis
Alkylation of the sodium salt of p-hydroxybenzaldehyde (1) with 2-dimethylaminoethyl chloride affords the ether (2). Reductive amination of the aldehyde in the presence of ammonia gives diamine (3). Acylation of that product with 3,4,5-trimethoxybenzoyl chloride affords trimethobenzamide (4).
See also
Domperidone
Metoclopramide
References
External links
Tebamide
Tigan (manufacturers website) |
Denileukin diftitox | Denileukin diftitox (trade name Ontak) was an antineoplastic agent, an engineered protein combining interleukin-2 and diphtheria toxin. Denileukin diftitox could bind to interleukin-2 receptors and introduce the diphtheria toxin into cells that express those receptors, killing the cells. In some leukemias and lymphomas, malignant cells express these receptors, so denileukin diftitox can target these.
In 1999, Ontak was approved by the U.S. Food and Drug Administration (FDA) for treatment of Cutaneous T-cell lymphoma (CTCL).There is some evidence tying it to vision loss, and in 2006 the FDA added a black box warning to the drugs label.In 2014, marketing of Ontak was discontinued in the US.
References
External links
FDA Safety Alert |
Primaquine | Primaquine is a medication used to treat and prevent malaria and to treat Pneumocystis pneumonia. Specifically it is used for malaria due to Plasmodium vivax and Plasmodium ovale along with other medications and for prevention if other options cannot be used. It is an alternative treatment for Pneumocystis pneumonia together with clindamycin. It is taken by mouth.Common side effects include nausea, vomiting, and stomach cramps. Primaquine should not be given to people with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to the risk of red blood cell breakdown. It is often recommended that primaquine not be used during pregnancy. It may be used while breastfeeding if the baby is known not to have G6PD deficiency. The mechanisms of action is not entirely clear but is believed to involve effects on the malaria parasites DNA.Primaquine was first made in 1946. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication.
Medical uses
Malaria
Primaquine is primarily used to prevent relapse of malaria due to Plasmodium vivax and Plasmodium ovale. It eliminates hypnozoites, the dormant liver form of the parasite, after the organisms have been cleared from the bloodstream. If primaquine is not administered to patients with proven P. vivax or P. ovale infection, a very high likelihood of relapse exists for weeks or months (sometimes years). But it has been hypothesized that primaquine (and perhaps also the newer, related drug tafenoquine) might kill a proportion of non-circulating merozoites as well as hypnozoites, such as merozoites in bone marrow, thereby reducing the number of recrudescences (not only hypnozoite-mediated relapses) that take place. Clarity in this regard is expected to be forthcoming soon. Use of primaquine in combination with quinine or chloroquine each of which is very effective at clearing P. vivax from blood, improves outcomes; they appear to also potentiate the action of primaquine.As of 2016, the US Centers for Disease Control and Prevention recommends the use of primaquine for primary prophylaxis prior to travel to areas with a high incidence of P. vivax, and for terminal prophylaxis (anti-relapse therapy) after travel.A single dose of primaquine has rapid and potent ability to kill gametocytes (stage V) of P. falciparum and P. vivax in blood; it also kills asexual trophozoites of P. vivax in blood, but not of P. falciparum. Because of its action against gametocytes, the WHO recommends it for use in reducing transmission to control P. falciparum infections.
Pneumocystis pneumonia
Primaquine is also used in the treatment of Pneumocystis pneumonia (PCP), a fungal infection commonly occurring in people with AIDS and, more rarely, in those taking immunosuppressive drugs. To treat PCP effectively, it is usually combined with clindamycin.
Special populations
Primaquine has not been studied extensively in people 65 and older so it is not known if dosing should be adjusted for this population.Primaquine should not be administered to anyone with G6PD deficiency because a severe reaction can occur, resulting in hemolytic anemia. However, the WHO has recommended that a single dose of primaquine (0.25 mg/kg) is safe to give even in individuals with G6PD deficiency, for the purpose of preventing transmission of P. falciparum malaria.Primaquine is contraindicated in pregnancy, because the glucose-6-phosphate dehydrogenase status of the fetus would be unknown.Primaquine overdose can cause a dangerous reduction in various blood cell counts, and therefore should be avoided in people at risk for agranulocytosis, which include people with conditions such as rheumatoid arthritis and lupus erythematosus, and those taking concurrent medications that also decrease blood cell counts.Hemolytic reactions (moderate to severe) may occur in individuals with G6PD deficiency and in individuals with a family or personal history of favism. Areas of high prevalence of G6PD deficiency are Africa, Southern Europe, Mediterranean region, Middle East, South-East Asia, and Oceania. People from these regions have a greater tendency to develop hemolytic anemia (due to a congenital deficiency of erythrocytic G6PD) while receiving primaquine and related drugs.
Adverse reactions
Common side effects of primaquine administration include nausea, vomiting, and stomach cramps.In persons with cytochrome b5 reductase deficiency, primaquine causes methemoglobinemia, a condition in which the blood carries less oxygen that it does normally.Overdosing can reduce the number of function of various kinds of blood cells, including loss of red blood cells, methemoglobinemia, and loss of white blood cells.Persons with glucose-6-phosphate dehydrogenase deficiency (G6PD) may develop hemolytic anemia from primaquine.
Pharmacology
Mechanism of action
Primaquine is lethal to P. vivax and P. ovale in the liver stage, and also to P. vivax in the blood stage through its ability to do oxidative damage to the cell. However, the exact mechanism of action is not fully understood. Liver hypnozoites aside, primaquine can possibly eliminate P. vivax merozoites in bone marrow as a result of accumulation there of hydrogen peroxide.
Pharmacokinetics
Primaquine is well-absorbed in the gut and extensively distributed in the body without accumulating in red blood cells. Administration of primaquine with food or grapefruit juice increases its oral bioavailibity. In blood, about 20% of circulating primaquine is protein-bound, with preferential binding to the acute phase protein orosomucoid. With a half-life on the order of 6 hours, it is quickly metabolized by liver enzymes to carboxyprimaquine, which does not have anti-malarial activity. Renal excretion of the parent drug is less than 4%.
Chemistry
Primaquine is an analog of pamaquine which was the first drug of the 8-aminoquinoline class; tafenoquine is another such drug.
History
Primaquine was first made by Robert Elderfield of Columbia University in the 1940s as part of a coordinated effort led by the Office of Scientific Research and Development in World War II to develop anti-malarial drugs to protect and treat soldiers fighting in the Pacific theater.
Society and culture
It is on the World Health Organizations List of Essential Medicines.
Names
It is a generic drug and is available under many brand names worldwide, including Jasoprim, Malirid, Neo-Quipenyl, Pimaquin, Pmq, Primachina, Primacin, Primaquina, Primaquine, Primaquine diphosphate, Primaquine Phosphate, and Remaquin.
SN-13272
Research
Primaquine has been studied in animal models of Chagas disease and was about four times as effective as the standard of care, nifurtimox.A clinical trial in 2022 demonstrated the efficacy of higher-dose primaquine in preventing relapse of P. vivax malaria.
References
External links
"Primaquine". Drug Information Portal. U.S. National Library of Medicine. |
Axicabtagene ciloleucel | Axicabtagene ciloleucel, sold under the brand name Yescarta, is a medication used for the treatment for large B-cell lymphoma that has failed conventional treatment. T cells are removed from a person with lymphoma and genetically engineered to produce a specific T-cell receptor. The resulting chimeric antigen receptor T cells (CAR-Ts) that react to the cancer are then given back to the person to populate the bone marrow. Axicabtagene treatment carries a risk for cytokine release syndrome (CRS) and neurological toxicities.Due to CD19 being a pan-B cell marker, the T-cells that are engineered to target CD19 receptors on the cancerous B cells also influence normal B cells, except some plasma cells.
Side effects
Because treatment with axicabtagene carries a risk of cytokine release syndrome and neurological toxicities, the FDA has mandated that hospitals be certified for its use prior to treatment of any patients.
History
It was developed by California-based Kite Pharma.Axicabtagene ciloleucel was awarded U.S. Food and Drug Administration (FDA) breakthrough therapy designation on 18 October 2017, for diffuse large B-cell lymphoma, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma. It also received priority review and orphan drug designation.Based on the ZUMA-1 trial, Kite submitted a biologics license application for axicabtagene in March 2017, for the treatment of non-Hodgkin lymphoma.The FDA granted approval on 18 October 2017, for the second-line treatment of diffuse large B-cell lymphoma.On 1 April 2022, the FDA approved axicabtagene ciloleucel for adults with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or relapses within twelve months of first-line chemoimmunotherapy. It is not indicated for the treatment of patients with primary central nervous system lymphoma.Approval was based on ZUMA-7, a randomized, open-label, multicenter trial in adults with primary refractory LBCL or relapse within twelve months following completion of first-line therapy. Participants had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous hematopoietic stem cell transplantation (HSCT). A total of 359 participants were randomized 1:1 to receive a single infusion of axicabtagene ciloleucel following fludarabine and cyclophosphamide lymphodepleting chemotherapy or to receive second-line standard therapy, consisting of two or three cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT in participants who attained complete remission or partial remission.
References
External links
"Axicabtagene ciloleucel". Drug Information Portal. U.S. National Library of Medicine.
"Axicabtagene Ciloleucel". National Cancer Institute. 20 October 2017.
"Axicabtagene Ciloleucel". NCI Drug Dictionary. National Cancer Institute. |
Tavaborole | Tavaborole, sold under the brand name Kerydin, is a topical antifungal medication for the treatment of onychomycosis, a fungal infection of the nail and nail bed with a complete clearance rate of 6-7% and partial clearance rate of 23-24% in individuals whose “infection border does not reach the cuticle at the base of the large toenail.” Tavaborole was approved by the US FDA in July 2014. The medication inhibits an essential fungal enzyme, leucyl-tRNA synthetase, that is required for protein synthesis. The inhibition of protein synthesis leads to termination of cell growth and then cell death, eliminating the fungal infection.
Medical uses
Tavaborole is used in the treatment of onychomycosis. In clinical trials, tavaborole was more effective than the vehicle (ethyl acetate and propylene glycol) alone in curing onychomycosis. In two studies, fungal infection was eliminated using tavaborole in 6.5% of the cases vs. 0.5% using the vehicle alone, and 27.5% vs. 14.6% using the vehicle alone.
Side effects
Application site exfoliation, erythema (rash), and irritation are possible side effects, and may occur in less than 5% of individuals.
Pharmacology
Tavaborole acts as an inhibitor of fungal leucyl-tRNA synthetase.
Pharmacokinetics
Tavaborole, when prepared with a 1:1 mixture of ethyl acetate and propylene glycol, has the ability to fully penetrate through the human nail. In studies with cadaver fingernails, a 5% solution of tavaborole penetrated the nail an average of 524.7 mcg/cm2 after two weeks of daily use.Tavaborole is detectable in the blood at a level of 3.54 ng/mL after a single use of 0.2 mL of the 5% solution. Tavaborole has an elimination half-life of 28.5 hours, a maximum concentration of 5.17 ng/mL after two weeks of daily use, and takes 8 days to reach the maximum concentration.
Society and culture
Economics
Tavaborole began phase III clinical trials in December 2010 and was approved by the US FDA in July 2014.Originally developed by Anacor, it is now marketed in the United States by Novartis subsidiary Sandoz. Anacor was paid US$65 million and also entered into a profit sharing scheme for future sales. A 10 mL bottle of a 5% solution of tavaborole will cost the patient without insurance about $1,356.
See also
Crisaborole – a structurally related topical medication used for the treatment of mild-to-moderate atopic dermatitis (eczema)
References
External links
"Tavaborole". Drug Information Portal. U.S. National Library of Medicine. |
Glatiramer acetate | Glatiramer acetate (also known as Copolymer 1, Cop-1), sold under the brand name Copaxone among others, is an immunomodulator medication used to treat multiple sclerosis. Glatiramer acetate is approved in the United States to reduce the frequency of relapses, but not for reducing the progression of disability. Observational studies, but not randomized controlled trials, suggest that it may reduce progression of disability. While a conclusive diagnosis of multiple sclerosis requires a history of two or more episodes of symptoms and signs, glatiramer acetate is approved to treat a first episode anticipating a diagnosis. It is also used to treat relapsing-remitting multiple sclerosis. It is administered by subcutaneous injection.It is a mixture of random-sized peptides that are composed of the four amino acids found in myelin basic protein, namely glutamic acid, lysine, alanine, and tyrosine. Myelin basic protein is the antigen in the myelin sheaths of the neurons that stimulates an autoimmune reaction in people with MS, so the peptide may work as a decoy for the attacking immune cells.
History
Glatiramer acetate was originally discovered at the Weizmann Institute of Science. Three main clinical trials followed to demonstrate safety and efficacy: The first trial was performed in a single center, double-blind, placebo controlled trial and included 50 patients.
The second trial was a two-year, multi-center, randomized, double-blind, placebo controlled trial and involved 251 patients. The third trial was a double-blind MRI study involving participation of 239 patients.
Medical uses
Glatiramer acetate is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.A 2010 Cochrane review concluded that glatiramer acetate had partial efficacy in "relapse-related clinical outcomes" but no effect on progression of the disease. As a result, it is approved by the FDA for reducing the frequency of relapses, but not for reducing the progression of disability.A 15-year followup of the original trial compared patients who continued with glatiramer to patients who dropped out of the trial. Patients with glatiramer had reduced relapse rates, and decreased disability progression and transition to secondary progressive MS, compared to patients who did not continue glatiramer. However, the two groups were not necessarily comparable, as it was no longer a randomized trial. There were no long-term safety issues.
Adverse effects
Side effects may include a lump at the injection site (injection site reaction) in approximately 30% of users, and aches, fever, chills (flu-like symptoms) in approximately 10% of users. Side effect symptoms are generally mild in nature. A reaction that involves flushing, shortness of breath, anxiety and rapid heartbeat has been reported soon after injection in up to 5% of patients (usually after inadvertently injecting directly into a vein). These side effects subside within thirty minutes. Over time, a visible dent at a repeat-injection site can occur due to the local destruction of fat tissue, known as lipoatrophy, that may develop.
More serious side effects have been reported for glatiramer acetate, according to the FDAs prescribing label, these include serious side effects to the cardiovascular, digestive (including the liver), hematopoietic, lymphatic, musculoskeletal, nervous, respiratory, and urogenital systems as well as special senses (in particular the eyes). Metabolic and nutritional disorders have also been reported; however a link between glatiramer acetate and these adverse effects has not been established.It may also cause Jessner lymphocytic infiltrate.
Mechanism of action
Glatiramer acetate is a random polymer (average molecular mass 6.4 kD) composed of four amino acids found in myelin basic protein. The mechanism of action for glatiramer acetate is not fully elucidated. It is thought to act by modifying immune processes that are believed to be responsible for the pathogenesis of MS. Administration of glatiramer acetate shifts the population of T cells from proinflammatory Th1 T-cells to regulatory Th2 T-cells that suppress the inflammatory response. Given its resemblance to myelin basic protein, glatiramer acetate may act as a decoy, diverting an autoimmune response against myelin. This hypothesis is supported by findings of studies that have been carried out to explore the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a condition induced in several animal species through immunization against central nervous system derived material containing myelin and often used as an experimental animal model of MS. Studies in animals and in vitro systems suggest that upon its administration, glatiramer acetate-specific regulatory T cells (Tregs) are induced and activated in the periphery, inhibiting the inflammatory reaction to myelin basic protein.The integrity of the blood-brain barrier, however, is not appreciably affected by glatiramer acetate, at least not in the early stages of treatment. Glatiramer acetate has been shown in clinical trials to reduce the number and severity of multiple sclerosis exacerbations.
Society and culture
Marketing
Glatiramer acetate has been approved for marketing in numerous countries worldwide, including the United States, Israel, Canada and 24 European Union countries. Approval in the U.S. was obtained in 1997. Glatiramer acetate was approved for marketing in the U.K. in August 2000, and launched in December. This first approval in a major European market led to approval across the European Union under the mutual recognition procedure.
Iran is proceeding with domestic manufacture of glatiramer acetate.
Patent status
Novartis subsidiary Sandoz has marketed Glatopa since 2015, a generic version of the original Teva 20 mg formulation that requires daily injection.Teva developed a long-acting 40 mg formulation, marketed since 2015, which reduced required injections to three per week. In October 2017, the FDA approved a generic version, which is manufactured in India by Natco Pharma, and imported and sold by Dutch firm Mylan. In February 2018, Sandoz received FDA approval for their generic version. In parallel with the development and approval processes, the generic competitors have disputed Tevas newer patents, any of which if upheld, would prevent marketing of long-acting generics.While the patent on the chemical drug expired in 2015, Teva obtained new US patents covering pharmaceutical formulations for long-acting delivery. Litigation from industry competitors in 2016-2017 resulted in the new patents being judged invalid. In October 2018, the U.S. Court of Appeals for the Federal Circuit upheld the patent invalidation for obviousness. The case reflects the larger controversy over evergreening of generic drugs.
References
Further reading
"Glatiramer acetate". Drug Information Portal. U.S. National Library of Medicine. |
Thiamazole | Thiamazole, also known as methimazole, is a medication used to treat hyperthyroidism. This includes Graves disease, toxic multinodular goiter, and thyrotoxic crisis. It is taken by mouth. Full effects may take a few weeks to occur.Common side effects include itchiness, hair loss, nausea, muscle pain, swelling, and abdominal pain. Severe side effects may include low blood cell counts, liver failure, and vasculitis. Use is not recommended during the first trimester of pregnancy due to the risk of congenital anomalies, but it may be used in the second trimester or third trimester. It may be used during breastfeeding. Those who developed significant side effects may also have problems with propylthiouracil. Thiamazole is a thioamide and works by decreasing the production of thyroid hormones.Thiamazole was approved for medical use in the United States in 1950. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. It is also available in Europe and Asia. In 2019, it was the 194th most commonly prescribed medication in the United States, with more than 2 million prescriptions.
Medical uses
Thiamazole is a drug used to treat hyperthyroidism such as in Graves disease, a condition that occurs when the thyroid gland begins to produce an excess of thyroid hormone. The drug may also be taken before thyroid surgery to lower thyroid hormone levels and minimize the effects of thyroid manipulation. Additionally, thiamazole is used in the veterinary setting to treat hyperthyroidism in cats.
Adverse effects
It is important to monitor any symptoms of fever or sore throat while taking thiamazole; this could indicate the development of agranulocytosis, an uncommon but severe side effect resulting from a drop in the white blood cell count (to be specific, neutropenia, a deficiency of neutrophils). A complete blood count (CBC) with differential is performed to confirm the suspicion, in which case the drug is discontinued. Administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) may increase recovery.
Other known side effects include:
skin rash
itching
abnormal hair loss
upset stomach
vomiting
loss of taste
abnormal sensations (tingling, prickling, burning, tightness, and pulling)
swelling
joint and muscle pain
drowsiness
dizziness
decreased platelet count (thrombocytopenia)
aplasia cutis congenita (prenatal exposure)
thyroid gland enlargement (prenatal exposure)
choanal atresia (prenatal exposure during the first trimester of pregnancy)
acute pancreatitis
Interactions
Adverse effects may occur for individuals who:
Take anticoagulants (blood thinners) such as warfarin (Coumadin), diabetes medications, digoxin (Lanoxin), theophylline (Theobid, Theo-Dur), and vitamins
Have ever had any blood disease, such as decreased white blood cells (leukopenia), decreased platelets (thrombocytopenia) or aplastic anemia, or liver disease (hepatitis, jaundice)
Mechanism of action
Thiamazole inhibits the enzyme thyroperoxidase, which normally acts in thyroid hormone synthesis by oxidizing the anion iodide (I−) to iodine (I2), hypoiodous acid (HOI), and enzyme linked hypoiodate (EOI), facilitating iodines addition to tyrosine residues on the hormone precursor thyroglobulin, a necessary step in the synthesis of triiodothyronine (T3) and thyroxine (T4).
It does not inhibit the action of the sodium-dependent iodide transporter located on follicular cells basolateral membranes. Inhibition of this step requires competitive inhibitors such as perchlorate and thiocyanate.
A study has shown that it modulates secretion of CXCL10.
Chemical properties
The imidazole derivative thiamazole is a white to matte brown crystalline powder with a characteristic odour. The boiling point is 280 °C (decomposition). Thiamazole is soluble in water, ethanol and chloroform, but hardly soluble in ether. Galenic preparations are injectable solutions and tablets.
Thiamazole acts as a free radical scavenger for radicals such as the hydroxyl radical (•OH) radical. It is used as free radical scavenger in organic chemistry.
Veterinary uses
Thiamazole is also indicated in cats to treat hyperthyroidism.
References
External links
"Methimazole". Drug Information Portal. U.S. National Library of Medicine. |
Amitriptyline/chlordiazepoxide | Amitriptyline/chlordiazepoxide, sold under the brand names Limbitrol and Limbitrol DS, is a combination of amitriptyline (Elavil), a tricyclic antidepressant, and chlordiazepoxide (Librium), a benzodiazepine, which is approved for the treatment of moderate to severe depression associated with moderate to severe anxiety in the United States. It contains 12.5 to 25 mg amitriptyline and 5 to 10 mg chlordiazepoxide per tablet.
== References == |
Quinupristin/dalfopristin | Quinupristin/dalfopristin, or quinupristin-dalfopristin, (pronunciation: kwi NYOO pris tin / dal FOE pris tin) (trade name Synercid) is a combination of two antibiotics used to treat infections by staphylococci and by vancomycin-resistant Enterococcus faecium.
Quinupristin and dalfopristin are both streptogramin antibiotics, derived from pristinamycin. Quinupristin is derived from pristinamycin IA; dalfopristin from pristinamycin IIA. They are combined in a weight-to-weight ratio of 30% quinupristin to 70% dalfopristin.
Administration
Intravenous, usually 7.5 mg/kg every 8 hours (infections/life threatening VRSA); every 12 hours (skin infections).
No renal dosing adjustments, hepatic dosing adjustments are not defined, consider reducing dose.
Mechanism of action
Quinupristin and dalfopristin are protein synthesis inhibitors in a synergistic manner. While each of the two is only a bacteriostatic agent, the combination shows bactericidal activity.
Dalfopristin binds to the 23S portion of the 50S ribosomal subunit, and changes the conformation of it, enhancing the binding of quinupristin by a factor of about 100. In addition, it inhibits peptidyl transfer.
Quinupristin binds to a nearby site on the 50S ribosomal subunit and prevents elongation of the polypeptide, as well as causing incomplete chains to be released.
Pharmacokinetics
Clearance by the liver CYP450:3A4 inhibitor, half-life quinupristin 0.8 hours, dalfopristin 0.7 hours (with persistence of effects for 9–10 hours).
Excretion: Quinupristin: 85% feces, 15% urine; Dalfopristin: 81% feces, 19% urine
Side effects
Serious:
C.diff-associated diarrhea
superinfection
anaphylactoid reactions
angioedemaCommon:
Joint aches (arthralgia) or muscle aches (myalgia)
Nausea, diarrhea (C. diff associated) or vomiting
Rash or itching
Headache
Hyperbilirubinemia
Anemia
Thrombophlebitis
Drug interactions
The drug inhibits P450 and enhances the effects of terfenadine, astemizole, indinavir, midazolam, calcium channel blockers, warfarin, cisapride and ciclosporin.
References
== Further reading == |
Sotalol | Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. It is only recommended in those with significant abnormal heart rhythms due to potentially serious side effects. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or injection into a vein.Common side effects include a slow heart rate, chest pain, low blood pressure, feeling tired, dizziness, shortness of breath, problems seeing, vomiting, and swelling. Other serious side effects may include QT prolongation, heart failure, or bronchospasm. Sotalol is a non-selective beta-adrenergic receptor blocker which has both class II and class III antiarrhythmic properties.Sotalol was first described in 1964 and came into medical use in 1974. It is available as a generic medication. In 2017, it was the 267th most commonly prescribed medication in the United States, with more than one million prescriptions.
Medical uses
According to the U.S. Food and Drug Administration (FDA), sotalol can be validly used to maintain a normal heart rhythm in people with life-threatening ventricular arrhythmias (e.g., ventricular tachycardia), or very symptomatic atrial fibrillation or flutter. Due to the risk of serious side effects, the FDA states that sotalol should generally be reserved for people whose ventricular arrhythmias are life-threatening, or whose fibrillation/flutter cannot be resolved using the Valsalva maneuver or another simple method.
Contraindications
According to the FDA, sotalol should not be used in people with a waking heart rate lower than 50 beats per minute. It should not be used in people with sick sinus syndrome, long QT syndrome, cardiogenic shock, uncontrolled heart failure, asthma or a related bronchospastic condition, or people with serum potassium below 4 meq/L. It should only be used in people with a second and third degree AV block if a functioning pacemaker is present.Since sotalol is removed from the body through the kidneys, it should not be used in people with a creatinine clearance rate below 40 mL/min. It is also excreted in breast milk, so mothers should not breastfeed while taking sotalol.Since sotalol prolongs the QT interval, the FDA recommends against using it in conjunction with other medications that prolong the QT interval. Studies have found serious side effects to be more common in individuals also taking digoxin, possibly because of pre-existing heart failure in those people. As with other beta blockers, it may interact with calcium channel blockers, catecholamine-depleting drugs, insulin or antidiabetic drugs, beta2-adrenergic agonists, and clonidine.Some evidence suggests that sotalol should be avoided in the setting of heart failure with a reduced ejection fraction (resulting in the heart squeezing little blood out into the circulation with each pump) due to an increased risk of death.
Adverse effects
Over 10% of oral sotalol users experience fatigue, dizziness, lightheadedness, headache, weakness, nausea, shortness of breath, bradycardia (slow heart rate), a sensation of the heart beating too hard, fast, or irregularly, or chest pain. Higher doses of sotalol increase the risk for all of these possible side effects.In rare cases, the QT prolongation caused by sotalol can lead to the development of life-threatening torsade de pointes (TdP) polymorphic ventricular tachycardia. Across several clinical trials, 0.6% of oral sotalol patients with supraventricular abnormal heart rhythms (such as atrial fibrillation) developed TdP. For patients who had a history of sustained ventricular tachycardia (abnormal rhythm lasting more than 30 seconds), 4% developed TdP. Risk increases with dosage, female sex, or having a history of an enlarged heart or congestive heart failure. The incidence of TdP for sustained ventricular tachycardia patients was 0% with an 80 mg daily dose, 0.5% at 160 mg, 1.6% at 320 mg, 4.4% at 480 mg, 3.7% at 640 mg, and 5.8% at doses greater than 640 mg. Due to this risk, the U.S. Food and Drug Administration requires affected individuals to be hospitalized for at least three days in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring upon starting or restarting sotalol.
Mechanisms of action
Beta-blocker action
Sotalol non-selectively binds to both β1- and β2-adrenergic receptors preventing activation of the receptors by their stimulatory ligand (catecholamines). Without the binding of this ligand to the receptor, the G-protein complex associated with the receptor cannot activate production of cyclic AMP, which is responsible for turning on calcium inflow channels. A decrease in activation of calcium channels will therefore result in a decrease in intracellular calcium. In heart cells, calcium is important in generating electrical signals for heart muscle contraction, as well as generating force for this contraction. In consideration of these important properties of calcium, two conclusions can be drawn. First, with less calcium in the cell, there is a decrease in electrical signals for contraction, thus allowing time for the hearts natural pacemaker to rectify arrhythmic contractions. Secondly, lower calcium means a decrease in strength and rate of the contractions, which can be helpful in treatment of abnormally fast heart rates.
Type III antiarrhythmic action
Sotalol also acts on potassium channels and causes a delay in relaxation of the ventricles. By blocking these potassium channels, sotalol inhibits efflux of K+ ions, which results in an increase in the time before another electrical signal can be generated in ventricular myocytes. This increase in the period before a new signal for contraction is generated, helps to correct arrhythmias by reducing the potential for premature or abnormal contraction of the ventricles but also prolongs the frequency of ventricular contraction to help treat tachycardia.
History
Sotalol was first synthesized in 1960 by A. A. Larsen of Mead-Johnson Pharmaceutical. It was originally recognized for its blood pressure lowering effects and its ability to reduce the symptoms of angina. It was made available in the United Kingdom and France in 1974, Germany in 1975, and Sweden in 1979. It became widely used in the 1980s. In the 1980s, its antiarrhythmic properties were discovered. The United States approved the drug in 1992.
Brand names
Trade names for Sotalol include Betapace and Betapace AF (Berlex Laboratories), Sotalex and Sotacor (Bristol-Myers Squibb), and Sotylize (Arbor Pharmaceuticals).
References
External links
"Sotalol". Drug Information Portal. U.S. National Library of Medicine. |
Deoxycholic acid | Deoxycholic acid is a bile acid. Deoxycholic acid is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria. The two primary bile acids secreted by the liver are cholic acid and chenodeoxycholic acid. Bacteria metabolize chenodeoxycholic acid into the secondary bile acid lithocholic acid, and they metabolize cholic acid into deoxycholic acid. There are additional secondary bile acids, such as ursodeoxycholic acid. Deoxycholic acid is soluble in alcohol and acetic acid. When pure, it comes in a white to off-white crystalline powder form.
Deoxycholic acid is available as a generic medication in the United States as of April 2021, sold under the brand name Kybella among others.
Applications
Deoxycholic acid has been used since its discovery in various fields of human medicine. In the human body deoxycholic acid is used in the emulsification of fats for absorption in the intestine. It has, in some countries (including Switzerland) been licensed as an emulsifier in food industry, but it is no longer common. Outside the body it is used in experimental basis of cholagogues and is also in use to prevent and dissolve gallstones.In research deoxycholic acid is used as a mild detergent for the isolation of membrane associated proteins. The critical micelle concentration for deoxycholic acid is approximately 2.4–4 mM.Sodium deoxycholate, the sodium salt of deoxycholic acid, is often used as a biological detergent to lyse cells and solubilise cellular and membrane components. Sodium deoxycholate mixed with phosphatidylcholine, is used in mesotherapy injections to produce lipolysis, and has been used as an alternative to surgical excision in the treatment of lipomas.Deoxycholates and bile acid derivatives in general are actively being studied as structures for incorporation in nanotechnology. They also have found application in microlithography as photoresistant components.In the United States, deoxycholic acid, under the brand name Kybella, is approved by the Food and Drug Administration for reducing moderate-to-severe fat below the chin. When injected into submental fat, deoxycholic acid helps destroy fat cells. Kybella is produced by Kythera Biopharmaceuticals.
Research in immunology
Its function as a detergent and isolating agent for membrane proteins also suits it for production of outer membrane protein (OMP) vaccines such as MenB, a Norwegian vaccine developed in the early 1990s. The MeNZB vaccine was produced using the same method.Deoxycholic acid binds and activates the membrane enzyme NAPE-PLD, which catalyzes the release of the endogenous cannabinoid anandamide and other N-acylethanolamines. These bioactive signaling molecules play important roles in several physiological pathways including stress and pain response, appetite, and lifespan.Some publications point towards the effect of deoxycholic acid as an immunostimulant of the innate immune system, activating its main actors, the macrophages. According to these publications, a sufficient amount of deoxycholic acid in the human body would correspond with a good immune reaction of the non-specific immune system. Clinical studies conducted in the 1970s and 1980s confirm the expectation that deoxycholic acid is involved in the natural healing processes of local inflammations, different types of herpes, and possibly cancer.
Research in cancer
Deoxycholate and other secondary bile acids cause DNA damage. Secondary bile acids increase intracellular production of reactive oxygen and reactive nitrogen species resulting in increased oxidative stress and DNA damage. As shown in the figure below, deoxycholate added to the diet of mice increased the level of 8-oxo-dG, an oxidative DNA damage, in the colonic epithelium of mice. When the level of deoxycholate-induced DNA damage is high, DNA repair enzymes that ordinarily reverse DNA damage may not be able to keep up.DNA damage has frequently been proposed as a major cause of cancer. DNA damage can give rise to cancer by causing mutations.When deoxycholate was added to the food of mice so that their feces contained deoxycholate at about the same level present in feces of human on a high fat diet, 45% to 56% of the mice developed colon cancer over the next 10 months, while none of the mice on a diet without deoxycholate developed cancer. Thus, exposure of the colon to deoxycholate may cause cancer in mice. However, this same study reported that, when chlorogenic acid was added to the diet alongside deoxycholate, only 18% of the mice developed colon cancer. Chlorogenic acid is a component of common foods and beverages; coffee contains an average of 53.8 mg chlorogenic acid per 100 ml. Therefore, to consume the level of chlorogenic acid used in the study, a human on a "standard" 2000-calorie daily diet (416 g/d; 250g carbs, 100g protein, 66g fat) would need to consume roughly 55 mL of coffee each day, or just under 2 fluid ounces.
In humans, higher levels of colonic deoxycholate are associated with higher frequencies of colon cancer. As an example, the fecal deoxycholate concentrations in African Americans (who eat a relatively high fat diet) is more than five times higher than fecal deoxycholate of Native Africans in South Africa (who eat a low fat diet). Male African Americans have a high incidence of colon cancer of 72 per 100,000, while Native Africans in South Africa have a low incidence rate of colon cancer of less than 1 per 100,000, a more than 72-fold difference in rates of colon cancer.
A prospective human study investigating the relationship between microbial metabolites and cancer found a strong correlation between circulating deoxycholic acid and colorectal cancer risk in women.
Factors affecting deoxycholate levels
A number of factors, including diet, obesity, and exercise, affect the level of deoxycholate in the human colon. When humans were switched from their usual diet to a meat, egg and cheese based diet for five days, deoxycholate in their feces increased by factors of 2 to 10 fold. Rats fed diets with 30% beef tallow (high fat) had almost 2-fold more deoxycholate in their feces than rats fed 5% beef tallow (low fat). In the same study, adding the further dietary elements of curcumin or caffeic acid to the rats high fat (30% beef tallow) diet reduced the deoxycholate in their feces to levels comparable to levels seen in the rats on a low fat diet. Curcumin is a component of the spice turmeric, and caffeic acid is a component high in some fruits and spices. Caffeic acid is also a digestive break-down product of chlorogenic acid, high in coffee and some fruits and vegetables.In addition to fats, the type or amount of protein in the diet may also affect bile acid levels. Switching from a diet with protein provided by casein to a diet with protein provided by salmon protein hydrolysate led to as much as a 6-fold increase in levels of bile acids in the blood plasma of rats. In humans, adding high protein to a high fat diet raised the level of deoxycholate in the plasma by almost 50%.Obesity has been linked to cancer, and this link is in part through deoxycholate. In obese people, the relative proportion of Firmicutes (Gram-positive bacteria) in gut microbiota is increased resulting in greater conversion of the non-genotoxic primary bile acid, cholic acid, to carcinogenic deoxycholate.Exercise decreases deoxycholate in the colon. Humans whose level of physical activity placed them in the top third had a 17% decrease in fecal bile acid concentration compared to those whose level of physical activity placed them in the lowest third. Rats provided with an exercise wheel had a lower ratio of secondary bile acids to primary bile acids than sedentary rats in their feces. There is a positive association of exercise and physical activity with cancer prevention, tolerance to cancer-directed therapies (radiation and chemotherapy), reduction in recurrence, and improvement in survival.
References
External links
"Deoxycholic acid". Drug Information Portal. U.S. National Library of Medicine. |
Leena | Leena is a feminine given name. It is a variant spelling of Lina and Lena.
It is a direct Quranic Arabic name, meaning "young palm tree", or figuratively "tender, young, delicate".
In Persian, it means "light", "a ray of sunlight" or "beautiful girl". In Kurdish, it means cascade falls (تئاڤگەی بچوک).
Notable people with the name include:
Leena (model) (born 1990), Japanese fashion model
Leena Alam, Afghan film actress
Leena Khamis (born 1986), Australian football player of Assyrian-Iraqi descent
Leena Chandavarkar (born 1950), Indian Bollywood actress
Leena Dhingra, British Asian actress
Leena Gade (born c. 1975), British race engineer
Leena Günther (born 1991), German sprint athlete
Leena Harkimo (born 1963), Finnish politician and business executive
Leena Häkinen (1928–1990), Finnish stage, film and television actress
Leena Jumani, Indian actress and model
Leena Kapoor (born 1994), Indian model and actress
Leena Krohn (born 1947), Finnish author
Leena La Bianca (born 1963), Italian American pornographic actress
Leena Lander (born 1955), Finnish author
Leena Lehtolainen (born 1964), Finnish crime novelist
Leena Luhtanen (born 1941), Finnish politician, member of the cabinet
Leena Luostarinen (1949–2013), Finnish painter
Leena Manimekalai, Indian filmmaker, poet and actor
Leena Mohanty, Indian Odissi dancer
Leena Nair (born 1969), Indian businesswoman
Leena Peisa (born 1979), Finnish keyboard player
Leena Peltonen-Palotie (1952–2010), Finnish geneticist
Leena Pietilä (1925–2014), Finnish figure skater
Leena Puotiniemi (born 1976), Finnish long-distance runner
Leena Puranen (born 1986), Finnish football forward
Leena Rauhala (born 1942), Finnish politician, member of the Parliament of Finland
Leena Salmenkylä (born 1958), Finnish orienteering competitor
Leena Silvennoinen (born 1958), Finnish orienteering competitor
Leena Tiwari, Indian politician, member of 17th Legislative Assembly of Mariyahu, Uttar Pradesh
Leena Yadav (born 1971), Indian filmmaker and producer
Fictional characters
Leena (Warehouse 13), from Warehouse 13
A character in Chrono Cross
Media
Leena (film), a Maldivian thriller film
"Leena", a song by Caravan Palace on the 2019 album Chronologic
See also
Lena (name) |
Recombinant human parathyroid hormone | Recombinant human parathyroid hormone, sold under the brand names Preotact and Natpara, is an artificially manufactured form of the parathyroid hormone used to treat hypoparathyroidism. Recombinant human parathyroid hormone is used in the treatment of osteoporosis in postmenopausal women at high risk of osteoporotic fractures. A significant reduction in the incidence of vertebral fractures has been demonstrated.The most common side effects include sensations of tingling, tickling, pricking, or burning of the skin (paraesthesia); low blood calcium; headache; high blood calcium; and nausea.
Medical uses
Natpara is indicated as an adjunct to calcium and vitamin D to control hypocalcemia in people with hypoparathyroidism.Preotact was approved by the European Medicines Agency for the treatment of osteoporosis in postmenopausal women at high risk of fractures, but the marketing authorisation has been withdrawn at the manufacturers request.
Administration
The recommended dose is 100 micrograms of Preotact administered once-daily as a subcutaneous injection into the abdomen, during 18 months (data support treatment up to 24 months). The injections are given using a specially designed injection device (Preotact(TM)Pen). The PreotactPen is specifically designed to allow osteoporosis patients to administer the injections, despite challenges of vision impairment and limited strength of hands and digits tributable to high age. Patients should receive supplemental calcium and vitamin D during treatment with parathyroid hormone.
Following treatment with Preotact, patients can be treated with a bisphosphonate to further increase bone mineral density
Contraindications for use
Parathyroid hormone treatment should not be initiated in patients:
with hypersensitivity to PTH or excipients
who have received radiation therapy to the skeleton
with pre-existing hypercalcemia and other disturbances in the metabolism of phosphate or calcium
with metabolic bone diseases other than primary osteoporosis (including hyperparathyroidism and Pagets disease
with unexplained elevations of bone-specific alkaline phosphatase
with severe chronic kidney disease
with severe liver impairment
Interactions
Parathyroid hormone is a natural peptide that is not metabolised in the liver. It is not protein bound and has a low volume of distribution, therefore no specific drug-drug interactions are suspected. From the knowledge of the mechanism of action, combined use of Preotact and cardiac glycosides may predispose patients to digitalis toxicity if hypercalcemia develops.
Undesirable effects
Hypercalcemia and/or hypercalciuria reflect the known pharmacodynamic actions of parathyroid hormone in the gastrointestinal tract, the kidney and the skeleton, and is therefore an expected undesirable effect. Nausea is another commonly reported adverse reaction to the use of parathyroid hormone.
Pharmacodynamic properties
Mechanism of action
Preotact contains recombinant human parathyroid hormone which is identical to the full-length native 84-amino acid polypeptide.
Physiological actions of parathyroid hormone include stimulation of bone formation by direct effects on bone forming cells (osteoblasts) indirectly increasing the intestinal absorption of calcium and increasing the tubular reabsorption of calcium and excretion of phosphate by the kidney.
Pharmacodynamic effects
The skeletal effects of parathyroid hormone depend upon the pattern of systemic exposure. Transient elevations in parathyroid hormone levels after subcutaneous injection of Preotact stimulates new bone formation on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity.
Effects on serum calcium concentrations
Parathyroid hormone is the principal regulator of serum calcium hemostasis. In response to subcutaneous doses of Preotact (100 micrograms), serum total calcium levels increase gradually and reach peak concentration at approximately 6 to 8 hours after dosing. In general, serum calcium levels return to normal within 24 hours.
Clinical efficacy
In an 18-month double-blind, placebo controlled study, the effects of Preotact on the fracture incidence in 2532 women with postmenopausal osteoporosis was studied. Approximately 19% of patients had a prevalent vertebral fracture at baseline and the mean lumbar T-score of -3.0 in both active and placebo arm.
Compared to the placebo group, there was a 61% relative risk reduction of a new vertebral fracture at month 18 for the women in the Preotact group.
To prevent one or more new vertebral fractures, 48 women had to be treated for a median of 18 months for the total population. For patients who were already fractured, the number needed to treat was 21.
Effect on bone mineral density
In the same study mentioned above, Preotact increased bone mineral density in the lumbar spine after 18 months treatment by 6.5% compared with a reduction by 0.3% in the placebo group. The difference was statistically significant. The increase of bone mineral density in the hip was also statistically significant compared to placebo, but only around 1.0% at study endpoint. Continued treatment up to 24 months lead to a continued increase in bone mineral density.
Pharmacokinetics
Absorption
Subcutaneous administration of parathyroid hormone into the abdomen produces a rapid increase in plasma parathyroid hormone levels which reach peak at 1 to 2 hours after dosing. The mean half-life is approximately 1.5 hours. The absolute bioavailability of 100 micrograms of Preotact after subcutaneous administration in the abdomen is 55%.
Distribution
The volume of distribution at steady-state following intravenous administration is approximately 5.4 liters. Intersubject variability is about 40%.
Biotransformation
Parathyroid hormone is efficiently removed from the blood by a receptor-mediated process in the liver and is broken down into smaller peptide fragments. The fragments derived from the amino-terminus are further degraded within the cell while the fragments derived from the carboxy-terminus are released back into the blood and cleared by the kidney. These carboxy-terminal fragments are thought to play a role in the regulation of parathyroid hormone activity. Under normal physiological conditions full-length parathyroid hormone H constitutes only 5-30% of the circulating forms of the molecule, while 70-95% is present as carboxy-terminal fragments. Following administration of Preotact, carboxy-terminal fragments make up about 60-90% of the circulating forms of the molecule. Intersubject variability in systemic clearance is about 15%.
Elimination
Parathyroid hormone is metabolised in the liver and to a lesser extent in the kidney. It is not excreted from the body in its intact form. Circulating carboxy-terminal fragments are filtered by the kidney, but are subsequently broken down into even smaller fragments during tubular reuptake. No studies have so far been performed in patients with severe hepatic impairment. The pharmacokinetics of parathyroid hormone in patients with severe chronic kidney disease (creatinine clearance of less than 30 ml/min) has not been investigated either.
Pharmaceutical particulars
Preotact is delivered in a two chamber, glass ampoule. One chamber contains the active substance in the form of a white powder (with excipients: mannitol, citric acid monohydrate, NaCl, NaOH, HCl). And the other contains the solvent; water for injection. The powder is mixed with the solvent when the ampoule is inserted into the injection device.
Storage and shelf-life
The mixed solution is stable for 28 days when stored between 2 and 8 °C. During this 28-day period the mixed solution may be stored for up to 7 days at room temperature, allowing the patient the freedom to travel. Unmixed ampoules have a shelf-life of 30 months. The products should not be frozen and should be protected from light.
See also
Teriparatide, another parathyroid hormone
References
External links
"Parathyroid hormone". Drug Information Portal. U.S. National Library of Medicine. |
Glipizide | Glipizide, sold under the brand name Glucotrol among others, is an anti-diabetic medication of the sulfonylurea class used to treat type 2 diabetes. It is used together with a diabetic diet and exercise. It is not indicated for use by itself in type 1 diabetes. It is taken by mouth. Effects generally begin within half an hour and can last for up to a day.Common side effects include nausea, diarrhea, low blood sugar, and headache. Other side effects include sleepiness, skin rash, and shakiness. The dose may need to be adjusted in those with liver or kidney disease. Use during pregnancy or breastfeeding is not recommended. It works by stimulating the pancreas to release insulin and increases tissue sensitivity to insulin.Glipizide was approved for medical use in the United States in 1984. It is available as a generic medication. In 2020, it was the 49th most commonly prescribed medication in the United States, with more than 13 million prescriptions.
Mechanism of action
Glipizide sensitizes the beta cells of pancreatic islets of Langerhans insulin response, meaning that more insulin is released in response to glucose than would be without glipizide ingestion. Glipizide acts by partially blocking potassium channels among beta cells of pancreatic islets of Langerhans. By blocking potassium channels, the cell depolarizes, which results in the opening of voltage-gated calcium channels. The resulting calcium influx encourages insulin release from beta cells.
History
It was patented in 1969 and approved for medical use in 1971. Glipizide was approved for medical use in the United States in 1984.
References
External links
"Glipizide". Drug Information Portal. U.S. National Library of Medicine. |
Itraconazole | Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mouth or intravenously.Common side effects include nausea, diarrhea, abdominal pain, rash, and headache. Severe side effects may include liver problems, heart failure, Stevens–Johnson syndrome and allergic reactions including anaphylaxis. It is unclear if use during pregnancy or breastfeeding is safe. It is in the triazole family of medications. It stops fungal growth by affecting the cell membrane or affecting their metabolism.Itraconazole was patented in 1978 and approved for medical use in the United States in 1992. It is on the World Health Organizations List of Essential Medicines.Recent research works suggest itraconazole (ITZ) could also be used in the treatment of cancer by inhibiting the hedgehog pathway in a similar way to sonidegib.
Medical uses
Itraconazole has a broader spectrum of activity than fluconazole (but not as broad as voriconazole or posaconazole). In particular, it is active against Aspergillus, which fluconazole is not. It is also licensed for use in blastomycosis, sporotrichosis, histoplasmosis, and onychomycosis. Itraconazole is over 99% protein-bound and has virtually no penetration into cerebrospinal fluid. Therefore, it should not be used to treat meningitis or other central nervous system infections. According to the Johns Hopkins Abx Guide, it has "negligible CSF penetration, however treatment has been successful for cryptococcal and coccidioidal meningitis".It is also prescribed for systemic infections, such as aspergillosis, candidiasis, and cryptococcosis, where other antifungal drugs are inappropriate or ineffective.
In the past decade, itraconazole has been explored as an anticancer agent for patients with basal cell carcinoma, non-small cell lung cancer, and prostate cancer. For example, in a phase II study involving men with advanced prostate cancer, high-dose itraconazole (600 mg/day) was associated with significant PSA responses and a delay in tumor progression. Itraconazole also showed activity in a phase II trial in men with non-small cell lung cancer when it was combined with the chemotherapy agent, pemetrexed. A recent review has also highlights its use topically and orally in conjunction with other chemotherapeutic agents for advanced and metastatic basal cell carcinomas that cannot be treated surgically.
Available forms
Itraconazole is produced as blue 22 mm (0.87 in) capsules with tiny 1.5 mm (0.059 in) blue pellets inside. Each capsule contains 100 mg and is usually taken twice a day at twelve-hour intervals. The Sporanox brand of itraconazole has been developed and marketed by Janssen Pharmaceutica, a subsidiary of Johnson & Johnson. The three-layer structure of these blue capsules is complex because itraconazole is insoluble and is sensitive to pH. The complicated procedure not only requires a specialized machine to create it, but also the method used has manufacturing problems. Also, the pill is quite large, making it difficult for many patients to swallow. Parts of the processes of creating Sporanox were discovered by the Korean Patent Laid-open No. 10-2001-2590. The tiny blue pellets contained in the capsule are manufactured in Beerse, Belgium.The oral solution is better absorbed. The cyclodextrin contained in the oral solution can cause an osmotic diarrhea, and if this is a problem, then half the dose can be given as oral solution and half as capsule to reduce the amount of cyclodextrin given. "Sporanox" itraconazole capsules should always be taken with food, as this improves absorption, however the manufacturers of "Lozanoc" assert that it may be taken "without regard to meals". Itraconazole oral solution should be taken an hour before food, or two hours after food (and likewise if a combination of capsules and oral solution are used). Itraconazole may be taken with orange juice or cola, as absorption is also improved by acid. Absorption of itraconazole is impaired when taken with an antacid, H2 blocker or proton pump inhibitor.
Side effects
Itraconazole is a relatively well-tolerated drug (although not as well tolerated as fluconazole or voriconazole) and the range of adverse effects it produces is similar to the other azole antifungals:
elevated alanine aminotransferase levels are found in 4% of people taking itraconazole
"small but real risk" of developing congestive heart failure
liver failure, sometimes fatalThe cyclodextrin used to make the syrup preparation can cause diarrhea. Side effects that may indicate a greater problem include:
Interactions
The following drugs should not be taken with itraconazole:
Pharmacology
Pharmacodynamics
The mechanism of action of itraconazole is the same as the other azole antifungals: it inhibits the fungal-mediated synthesis of ergosterol, via inhibition of lanosterol 14α-demethylase. Because of its ability to inhibit cytochrome P450 3A4 CC-3, caution should be used when considering interactions with other medications.Itraconazole is pharmacologically distinct from other azole antifungal agents in that it is the only inhibitor in this class that has been shown to inhibit both the hedgehog signaling pathway and angiogenesis. These distinct activities are unrelated to inhibition of the cytochrome P450 lanosterol 14 alpha-demethylase and the exact molecular targets responsible remain unidentified. Functionally, the antiangiogenic activity of itraconazole has been shown to be linked to inhibition of glycosylation, VEGFR2 phosphorylation, trafficking, and cholesterol biosynthesis pathways. Evidence suggests the structural determinants for inhibition of hedgehog signaling by itraconazole are recognizably different from those associated with antiangiogenic activity.
Pharmacokinetics
Itraconazole, like cyclosporine, quinidine, and clarithromycin, can inhibit P-glycoprotein, causing drug interactions by reducing elimination and increasing absorption of organic cation drugs. With conventional itraconazole preparations serum levels can vary greatly between patients, often resulting in serum concentrations lower than the therapeutic index. It has therefore been conventionally advised that patients take itraconazole after a fatty meal rather than prior to eating.A product (Lozanoc) licensed through the European union decentralised procedure has increased bioavailability, decreased sensitivity to co ingestion of food, and hence decreased variability of serum levels.
Chemistry
The itraconazole molecule has three chiral carbons. The two chiral centers in the dioxolane ring are fixed in relation to one another, and the triazolomethylene and aryloxymethylene dioxolane-ring substituents are always cis to each other. The clinical formulation is a 1:1:1:1 mixture of four stereoisomers (two enantiomeric pairs).
History
Itraconazole was approved for medical use in the United States in 1992.It was designated an orphan drug by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
References
External links
Media related to Itraconazole at Wikimedia Commons
"Itraconazole". Drug Information Portal. U.S. National Library of Medicine. |
Hormonal intrauterine device | A hormonal intrauterine device (IUD), also known as a intrauterine system (IUS) with progestogen and sold under the brand name Mirena among others, is an intrauterine device that releases a progestogenic hormonal agent such as levonorgestrel into the uterus. It is used for birth control, heavy menstrual periods, and to prevent excessive build of the lining of the uterus in those on estrogen replacement therapy. It is one of the most effective forms of birth control with a one-year failure rate around 0.2%. The device is placed in the uterus and lasts three to seven years. Fertility often returns quickly following removal.Side effects include irregular periods, benign ovarian cysts, pelvic pain, and depression. Rarely uterine perforation may occur. Use is not recommended during pregnancy but is safe with breastfeeding. The IUD with progestogen is a type of long-acting reversible birth control. It works by thickening the mucus at the opening of the cervix, stopping the buildup of the lining of the uterus, and occasionally preventing ovulation.The IUD with levonorgestrel was first approved for medical use in 1990 in Finland and in the United States in 2000. It is on the World Health Organizations List of Essential Medicines.
Medical uses
The hormonal IUD is an extremely effective method of birth control, and a 2021 study demonstrated that it may be used for emergency contraception. In addition to birth control, the hormonal IUD is used for prevention and treatment of:
Heavy menstrual periods
Endometriosis and chronic pelvic pain
Adenomyosis and dysmenorrhea
Anemia
Endometrial hyperplasia (especially in pre-menopausal women who wish to maintain fertility in the treatment of endometrial hyperplasia)
In some cases, use of a hormonal IUD may prevent a need for a hysterectomy.Advantages:
Considered one of the most effective forms of reversible birth control
Can be used while breastfeeding (see also nursing mothers)
No preparations needed before sex, though routine checking of the device strings by patient and physician is advised to ensure proper placement remains intact
90% of users who wish to become pregnant do so within 24 months of removal.
May experience lighter periods (some women stop having periods completely, see also amenorrhea)
Effective for up to three to seven years (depending on the IUD)Disadvantages:
Irregular periods and spotting between periods often occurs after insertion This usually improves after three to six months.
Moderate to severe discomfort may be experienced during insertion procedure, including uterine cramping and back pain.
Other potential adverse effects and risks
Effectiveness
After insertion, Mirena is effective at preventing pregnancy for up to seven years. Kyleena is approved for five years and Skyla is approved for three years.The hormonal IUD is a long-acting reversible contraceptive, and is considered one of the most effective forms of birth control. The first year failure rate for the hormonal IUD is 0.1-0.2% and the five-year failure rate is 0.7-0.9%. These rates are comparable to tubal sterilization, but unlike sterilization the effects of the hormonal IUD are reversible.
The hormonal IUD is considered to be more effective than other common forms of reversible contraception, such as the birth control pill, because it requires little action by the user after insertion. The effectiveness of other forms of birth control is mitigated (decreased) by the users themselves. If medication regimens for contraception are not followed precisely, the method becomes less effective. IUDs require no daily, weekly, or monthly regimen, so their typical use failure rate is therefore the same as their perfect use failure rate.In women with bicornuate uterus and in need of contraception, two IUDs are generally applied (one in each horn) due to lack of evidence of efficacy with only one IUD. Evidence is lacking regarding progestogen IUD usage for menorrhagia in bicornuate uterus, but a case report showed good effect with a single IUD for this purpose.
Breastfeeding
Progestogen-only contraceptives such as an IUD are not believed to affect milk supply or infant growth. However, a study in the Mirena application for FDA approval found a lower continuation of breastfeeding at 75 days in hormonal IUD users (44%) versus copper IUD users (79%).When using Mirena, about 0.1% of the maternal dose of levonorgestrel can be transferred via milk to the
nursed infant.
A six-year study of breastfed infants whose mothers used a levonorgestrel-only method of birth control found the infants had increased risk of respiratory infections and eye infections, though a lower risk of neurological conditions, compared to infants whose mothers used a copper IUD. No longer-term studies have been performed to assess the long-term effects on infants of levonorgestrel in breast milk.
There are conflicting recommendations about use of Mirena while breastfeeding. The U.S. CDC does not recommend any hormonal method as a first choice of contraceptive for nursing mothers, although progestin-only methods, such as Mirena, may be used with close follow-up or when the benefits outweigh the risks. The World Health Organization recommends against immediate postpartum insertion, citing increased expulsion rates. It also reports concerns about potential effects on the infants liver and brain development in the first six weeks postpartum. However, it recommends offering Mirena as a contraceptive option beginning at six weeks postpartum even to nursing women. Planned Parenthood offers Mirena as a contraceptive option for breastfeeding women beginning at four weeks postpartum.
Contraindications
A hormonal IUD should not be used by women who:
Are, or think they may be, pregnant
Have abnormal vaginal bleeding that has not been explained (controversial)
Have untreated cervical or uterine cancer
Have, or may have, breast cancer
Have abnormalities of the cervix or uterus (controversial)
Have had pelvic inflammatory disease within the past three months
Have had an STI such as chlamydia or gonorrhea within the past three months
Have liver disease or tumor
Have an allergy to levonorgestrel or any of the inactive ingredients included in the deviceInsertion of an IUD is acceptable after a dilation and evacuation (D&E) abortion (second-trimester abortion), but may be associated with a higher expulsion rate. To reduce the risk of infection, insertion of an IUD is not recommended for women that have had a medical abortion but have not yet had an ultrasound to confirm that the abortion was complete, or that have not yet had their first menstruation following the medical abortion.A full list of contraindications can be found in the WHO Medical Eligibility Criteria for Contraceptive Use and the CDC United States Medical Eligibility Criteria for Contraceptive Use.
Side effects
Irregular menstrual pattern: irregular bleeding and spotting is common in the first three to six months of use. After that time periods become shorter and lighter, and 20% of women stop having periods after one year of use. The average user reports 16 days of bleeding or spotting in the first month of use, but this diminishes to about four days at 12 months.
Cramping and pain: many women feel discomfort or pain during and immediately after insertion. Some women may have cramping for the first 1–2 weeks after insertion.
Expulsion: Sometimes the IUD can slip out of the uterus. This is termed expulsion. Around 5% of IUD users experience expulsion. If this happens a woman is not protected from pregnancy. Expulsion is more common in younger women, women who have not had children, and when an IUD is inserted immediately after childbirth or abortion.
Perforation: Very rarely, the IUD can be pushed through the wall of the uterus during insertion. Risk of perforation is mostly determined by the skill of the practitioner performing the insertion. For experienced medical practitioners, the risk of perforation is one per 1,000 insertions or less. With postpartum insertions, perforation of the uterus is more likely to occur when uterine involution is incomplete; involution usually completes by 4–6 weeks postpartum. Special considerations apply to women who plan to breastfeed. If perforation does occur it can damage the internal organs, and in some cases surgery is needed to remove the IUD.
Pregnancy complications: Although the risk of pregnancy with an IUD is very small, if one does occur there is an increased risk of serious problems. These include ectopic pregnancy, infection, miscarriage, and early labor and delivery. As many as half the pregnancies that occur in Mirena users may be ectopic. The incidence rate of ectopic pregnancies is approximately one per 1000 users per year. Immediate removal of the IUD is recommended in the case of pregnancy. No pattern of birth defects was found in the 35 babies for whom birth outcomes were available at the time of FDA approval.
Infection: The insertion of the IUD does have a small risk of pelvic inflammatory disease (PID). Concurrent infection with gonorrhea or chlamydia at the time of insertion increases the risk of pelvic inflammatory disease. If PID does occur, it will most likely happen within 21 days of insertion. The device itself does not increase the risk of infection.
Ovarian cysts: Enlarged follicles (ovarian cysts) have been diagnosed in about 12% of the subjects using a hormonal IUD in studies that use ultrasound to look for cysts, even if asymptomatic. In studies that only evaluate symptomatic cysts, only 4.5% of women complain of any ovarian cysts over 5 or more years of use, and only 0.3% require IUD removal for ovarian cysts. Thus, any issues with ovarian cysts are not of a clinically relevant nature. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases the enlarged follicles disappear spontaneously after two to three months. Surgical intervention is not usually required.
Mental health changes including: nervousness, depressed mood, mood swings
Weight gain
Headache, migraine
Nausea
Acne
Excessive hairiness
Lower abdominal or back pain
Decreased libido
Itching, redness or swelling of the vagina
Vaginal discharge
Breast pain, tenderness
Edema
Abdominal distension
Cervicitis
Bacterial vaginosis
May affect glucose tolerance
May experience a change in vision or contact lens tolerance
May deplete vitamin B1 which can affect energy, mood, and nervous system functioning
A "lost coil" occurs when the thread cannot be felt by a woman on routine checking and is not seen on speculum examination. Various thread collector devices or simple forceps may then be used to try to grasp the device through the cervix. In the rare cases when this is unsuccessful, an ultrasound scan may be arranged to check the position of the coil and exclude its perforation through into the abdominal cavity or its unrecognised previous expulsion.
Cancer
According to a 1999 evaluation of the studies performed on progestin-only birth control by the International Agency for Research on Cancer, there is some evidence that progestin-only birth control reduces the risk of endometrial cancer. The IARC in 1999 concluded that there is no evidence progestin-only birth control increases the risk of any cancer, though the available studies were too small to be definitively conclusive.Progesterone is a hormone in the endometrium that counteracts estrogen driven growth. Very low levels of progesterone will cause estrogen to act more, leading to endometrial hyperplasia and adenocarcinoma. These effects can be minimized if treated with progestin, but not in very many cases.
Estrogen and progesterone have an antagonistic relationship. Estrogen promotes the growing of endometrial lining, while progesterone limits it. In the case of endometrial cancer, progesterone can negatively regulate estrogen driven growth. Tumors formed are correlated with insufficient progesterone and excess estrogen. In patients with endometrial cancer who use progestin releasing IUDs concluded mixed results.
A 2020 meta-analysis by Livia Conz et al. estimated that users of levonorgestrel-releasing systems had an increased breast cancer risk in general (with an odds ratio of 1.16) and higher risk for those over age 50 (odds ratio 1.52), and suggested balancing this risk against the known benefits of long-term use. Researchers cautioned against causal interpretation from this study, citing confounding effects, methodological concerns and a 2020 meta-analysis of randomized controlled trials which showed no increased risk.
Bone density
No evidence has been identified to suggest Mirena affects bone mineral density (BMD). Two small studies, limited to studying BMD in the forearm, show no decrease in BMD. One of the studies showed at seven years of use, similar BMD at the midshaft of the ulna and at the distal radius as nonusers matched by age and BMI. In addition, BMD measurements were similar to the expected values for women in the same age group as the participants. The authors of the study said their results were predictable, since it is well established that the main factor responsible for bone loss in women is hypoestrogenism, and, in agreement with previous reports, they found estradiol levels in Mirena users to be normal.
Composition and hormonal release
The hormonal IUD is a small T-shaped piece of plastic, which contains levonorgestrel, a type of progestin. The cylinder of the device is coated with a membrane that regulates the release of the drug. Bayer markets Skyla as Jaydess in the United Kingdom. Jaydess releases six micrograms per day and lasts for three years. In comparison, oral contraceptives can contain 150 micrograms of levonorgestrel. The hormonal IUD releases the levonorgestrel directly into the uterus, as such its effects are mostly paracrine rather than systemic. Most of the drug stays inside the uterus, and only a small amount is absorbed into the rest of the body.
Insertion and removal
The hormonal IUD is inserted in a similar procedure to the nonhormonal copper IUD, and can only be inserted by a qualified medical practitioner. Before insertion, a pelvic exam is performed to examine the shape and position of the uterus. A current STI at the time of insertion can increase the risk of pelvic infection. However, routine screening for gonorrhea and chlamydia prior to insertion is not recommended. If a person needs screening and there is no evidence of infection on examination or has been previously screened, insertion of the IUD does not need to be delayed.
Insertion
During the insertion, the vagina is held open with a speculum, the same device used during a pap smear. A grasping instrument is used to steady the cervix, the length of the uterus is measured for proper insertion with a uterine sound for decreasing chance of uterine perforation with the IUD, and the IUD is placed using a narrow tube through the opening of the cervix into the uterus. A short length of monofilament plastic/nylon string hangs down from the cervix into the vagina. The string allows physicians and patients to check to ensure the IUD is still in place and enables easy removal of the device. Mild to moderate cramping can occur during the procedure, which generally takes five minutes or less. Insertion can be performed immediately postpartum and post-abortion if no infection has occurred.Misoprostol is not effective in reducing pain in IUD insertion.
Removal
Removal of the device should also be performed by a qualified medical practitioner. After removal, fertility will return to previous levels relatively quickly. One study found that the majority of participants returned to fertility within three months.
Mechanisms of action
Levonorgestrel is a progestogen, i.e. a progesterone receptor agonist. The hormonal IUDs primary mechanism of action is to prevent fertilization. The levonorgestrel intrauterine system has several contraceptive effects, although thickening of the cervical mucus appears to be the primary effect. Other effects include making the inside of the uterus become fatal to sperm and thinning of the endometrial lining, but this is not the usual function.Ovulation is not inhibited in all cases.Numerous studies have demonstrated that IUDs primarily prevent fertilization, not implantation. In one experiment involving tubal flushing, fertilized eggs were found in half of women not using contraception, but no fertilized eggs were found in women using IUDs. IUDs also decrease the risk of ectopic pregnancy, which further implies that IUDs prevent fertilization.
History
Hormonal IUDs were developed in the 1970s following the development of the copper IUD in the 1960s and 1970s. Dr. Antonio Scommenga, working at the Michael Reese Hospital in Chicago, discovered that administering progesterone inside the uterus could have contraceptive benefits. With knowledge of Scommegnas work, a Finnish doctor, Jouni Valter Tapani Luukkainen, created the T-shaped IUD that released progesterone, marketed as the Progestasert System in 1976. This IUD had a short, 1-year lifespan and never achieved widespread popularity. Following this relative lack of success, Dr. Luukkainen replaced the progesterone with the hormone levonorgestrel to be released over a five-year period, creating what is now Mirena.The Mirena IUD was studied for safety and efficacy in two clinical trials in Finland and Sweden involving 1,169 women who were all between 18 and 35 years of age at the beginning of the trials. The trials included predominantly Caucasian women who had been previously pregnant with no history of ectopic pregnancy or pelvic inflammatory disease within the previous year. Over 70% of the participants had previously used IUDs.In 2013 Skyla, a lower dose levonorgestrel IUD effective for up to three years, was approved by the FDA. Skyla has a different bleeding pattern than Mirena, with only 6% of women in clinical trials becoming amenorrheic (compared to approximately 20% with Mirena).
The city of Finland, Turku, is currently the only production site for the Mirena contraceptive family.
Controversies
In 2009, Bayer, the maker of Mirena, was issued an FDA Warning Letter by the United States Food and Drug Administration for overstating the efficacy, minimizing the risks of use, and making "false or misleading presentations" about the device. From 2000 to 2013, the federal agency received over 70,072 complaints about the device and related adverse effects. As of April 2014, over 1,200 lawsuits have been filed in the United States.
References
External links
FDA (2000). "Medical review" (PDF scanned image). Food and Drug Administration. - on Berlex Laboratories Mirena application
Physician Fact Sheet (2008 U.S. version)
Physician Fact Sheet (2013 U.K. version)
Mirena drug description/side effects
Video showing the insertion procedure for a Mirena IUD |
Baclofen | Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity such as from a spinal cord injury or multiple sclerosis. It may also be used for hiccups and muscle spasms near the end of life. It is taken by mouth or by delivery into the spinal canal.Common side effects include sleepiness, weakness, and dizziness. Serious side effects may occur if baclofen is rapidly stopped including seizures and rhabdomyolysis. Use in pregnancy is of unclear safety while use during breastfeeding is probably safe. It is believed to work by decreasing levels of certain neurotransmitters.Baclofen was approved for medical use in the United States in 1977. It is available as a generic medication. In 2019, it was the 125th most commonly prescribed medication in the United States, with more than 5 million prescriptions.
Medical uses
Baclofen is primarily used for the treatment of spastic movement disorders, especially in instances of spinal cord injury, cerebral palsy, and multiple sclerosis. Its use in people with stroke or Parkinsons disease is not recommended. Baclofen has also been used for the treatment of alcohol use disorder but evidence as of a systematic review conducted in 2018 shows that the evidence of its use as a first line intervention remains uncertain.
Adverse Drug Reactions
Adverse effects include drowsiness, dizziness, weakness, fatigue, headache, trouble sleeping, nausea and vomiting, urinary retention, or constipation.
Withdrawal syndrome
Discontinuation of baclofen can be associated with a withdrawal syndrome which resembles benzodiazepine withdrawal and alcohol withdrawal. Withdrawal symptoms are more likely if baclofen is administered intrathecally or for long periods of time (more than a couple of months) and can occur from low or high doses. The severity of baclofen withdrawal depends on the rate at which it is discontinued. Thus to minimise withdrawal symptoms, the dose should be tapered down slowly when discontinuing baclofen therapy. Abrupt withdrawal is more likely to result in severe withdrawal symptoms. Acute withdrawal symptoms can be eased or completely reversed by re-initiating therapy with baclofen.Withdrawal symptoms may include auditory hallucinations, visual hallucinations, tactile hallucinations, delusions, confusion, agitation, delirium, disorientation, fluctuation of consciousness, insomnia, dizziness, nausea, inattention, memory impairments, perceptual disturbances, itching, anxiety, depersonalization, hypertonia, hyperthermia (higher than normal temperature without infection), formal thought disorder, psychosis, mania, mood disturbances, restlessness, and behavioral disturbances, tachycardia, seizures, tremors, autonomic dysfunction, hyperpyrexia (fever), extreme muscle rigidity resembling neuroleptic malignant syndrome and rebound spasticity.
Abuse
Baclofen, at standard dosing, does not appear to possess addictive properties, and has not been associated with any degree of drug craving. Euphoria is however listed as a common to very common side-effect of baclofen in the BNF 75 There are very few cases of abuse of baclofen for reasons other than attempted suicide. In contrast to baclofen, another GABAB receptor agonist, γ-hydroxybutyric acid (GHB), has been associated with euphoria, abuse, and addiction. These effects are likely mediated not by activation of the GABAB receptor, but rather by activation of the GHB receptor. Baclofen possesses both sedative and anxiolytic properties.
Overdose
Reports of overdose indicate that baclofen may cause symptoms including vomiting, general weakness, sedation, respiratory insufficiency, seizures, unusual pupil size, dizziness, headaches, itching, hypothermia, bradycardia, hypertension, hyporeflexia and coma sometimes mimicking brain death.
Pharmacology
Chemically, baclofen is a derivative of the neurotransmitter γ-aminobutyric acid (GABA). It is believed to work by activating (or agonizing) GABA receptors, specifically the GABAB receptors. Its beneficial effects in spasticity result from its actions in the brain and spinal cord.
Pharmacodynamics
Baclofen produces its effects by activating the GABAB receptor, similar to the drug phenibut which also activates this receptor and shares some of its effects. Baclofen is postulated to block mono-and-polysynaptic reflexes by acting as an inhibitory ligand, inhibiting the release of excitatory neurotransmitters. However, baclofen does not have significant affinity for the GHB receptor, and has no known abuse potential. The modulation of the GABAB receptor is what produces baclofens range of therapeutic properties.
Similarly to phenibut (β-phenyl-GABA), as well as pregabalin (β-isobutyl-GABA), which are close analogues of baclofen, baclofen (β-(4-chlorophenyl)-GABA) has been found to block α2δ subunit-containing voltage-gated calcium channels (VGCCs). However, it is weaker relative to phenibut in this action (Ki = 23 and 39 μM for R- and S-phenibut and 156 μM for baclofen). Moreover, baclofen is in the range of 100-fold more potent by weight as an agonist of the GABAB receptor in comparison to phenibut, and in accordance, is used at far lower relative dosages. As such, the actions of baclofen on α2δ subunit-containing VGCCs are likely not clinically relevant.
Pharmacokinetics
The drug is rapidly absorbed after oral administration and is widely distributed throughout the body. Biotransformation is low: the drug is predominantly excreted unchanged by the kidneys. The half-life of baclofen is roughly 2–4 hours; it therefore needs to be administered frequently throughout the day to control spasticity appropriately.
Chemistry
Baclofen is a white (or off-white) mostly odorless crystalline powder, with a molecular weight of 213.66 g/mol. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform.
History
Historically, baclofen was designed as a drug for treating epilepsy. It was first made at Ciba-Geigy, by the Swiss chemist Heinrich Keberle, in 1962. Its effect on epilepsy was disappointing, but it was found that in certain people, spasticity decreased.
Currently, baclofen continues to be given by mouth, with variable effects. In severely affected children, the oral dose is so high that side-effects appear, and the treatment loses its benefit. How and when baclofen came to be used in the spinal sac (intrathecally) remains unclear, but as of 2012, this has become an established method of treating spasticity in many conditions.In his 2008 book, Le Dernier Verre (translated literally as The Last Glass or The End of my Addiction), French-American cardiologist Olivier Ameisen described how he treated his alcoholism with baclofen. Inspired by this book, an anonymous donor gave $750,000 to the University of Amsterdam in the Netherlands to initiate a clinical trial of high-dose baclofen, which Ameisen had called for since 2004. The trial concluded, "In summary, the current study did not find evidence of a positive effect of either low or high doses of baclofen in AD patients. However, we cannot exclude the possibility that baclofen is an effective medication for the treatment of severe, heavy drinking AD patients not responding to or not accepting routine psychosocial interventions."
Society and culture
Routes of administration
Baclofen can be administered transdermally as part of a pain-relieving and muscle-relaxing topical cream mix at a compounding pharmacy, orally or intrathecally (directly into the cerebral spinal fluid) using a pump implanted under the skin.
Intrathecal pumps offer much lower doses of baclofen because they are designed to deliver the medication directly to the spinal fluid rather than going through the digestive and blood system first. They are often preferred in spasticity patients such as those with spastic diplegia, as very little of the oral dose actually reaches the spinal fluid. Besides those with spasticity, intrathecal administration is also used in patients with multiple sclerosis who have severe painful spasms which are not controllable by oral baclofen. With pump administration, a test dose is first injected into the spinal fluid to assess the effect, and if successful in relieving spasticity, a chronic intrathecal catheter is inserted from the spine through the abdomen and attached to the pump which is implanted under the abdomens skin, usually by the ribcage. The pump is computer-controlled for automatic dosage and its reservoir can be replenished by percutaneous injection. The pump also has to be replaced every five years or so when the battery is changed.
Other names
Synonyms include chlorophenibut. Brand names include Beklo, Baclodol, Flexibac, Gablofen, Kemstro, Liofen, Lioresal, Lyflex, Clofen, Muslofen, Bacloren, Baklofen, Sclerofen, Pacifen and others.
Research
Baclofen is being studied for the treatment of alcoholism. Evidence as of 2019 is not conclusive enough to recommend its use for this purpose. In 2014, the French drug agency ANSM issued a 3-year temporary recommendation allowing the use of baclofen in alcoholism. In 2018, baclofen received a Marketing Authorization for use in alcoholism treatment from the agency if all other treatments are not effective.It is being studied along with naltrexone and sorbitol for Charcot-Marie-Tooth disease (CMT), a hereditary disease that causes peripheral neuropathy. It is also being studied for cocaine addiction. Baclofen and other muscle relaxants are being studied for potential use for persistent hiccups.From 2014 to 2017 baclofen misuse, toxicity and use in suicide attempts among adults in the US increased.
References
External links
"Baclofen". Drug Information Portal. U.S. National Library of Medicine. |
Sucroferric oxyhydroxide | Sucroferric oxyhydroxide, sold under the brand name Velphoro, is a non-calcium, iron-based phosphate binder used for the control of serum phosphorus levels in adults with chronic kidney disease (CKD) on haemodialysis (HD) or peritoneal dialysis (PD). It is used in form of chewable tablets.Sucroferric oxyhydroxide is also known as a mixture of polynuclear iron(III)-oxyhydroxide, sucrose and starches.The most common side effects include diarrhea and discolored feces, which may become less frequent with continued treatment.It was approved for medical use in the United States in November 2013, and in the European Union in August 2014.
Medical uses
Sucroferric oxyhydroxide is approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the control of serum phosphorus levels in patients with chronic kidney disease (CKD) on dialysis.
Adverse effects
The most frequently reported adverse drug reactions reported from trials were diarrhoea and discoloured faeces. The vast majority of gastrointestinal adverse events occurred early during treatment and abated with time under continued dosing.
Interactions
Drug-interaction studies and post hoc analyses of Phase III studies showed no clinically relevant interaction of sucroferric oxyhydroxide with the systemic exposures to losartan, furosemide, omeprazole, digoxin, and warfarin, the lipid-lowering effects of statins, and oral vitamin D receptor agonists. According to the European label (Summary of Product Characteristics), medicinal products that are known to interact with iron (e.g. doxycycline) or have the potential to interact with Velphoro should be administered at least one hour before or two hours after Velphoro. This allows sucroferric oxyhydroxide to bind phosphate as intended and be excreted without coming into contact with medications in the gut that it might interact with. According to the US prescribing information, Velphoro should not be prescribed with oral levothyroxine. The combination of sucroferric oxyhydroxide and levothyroxine is contraindicated because sucroferric oxyhydroxide contains iron, which may cause levothyroxine to become insoluble in the gut, thereby preventing the intestinal absorption of levothyroxine.
Hyperphosphatemia
In a healthy person, normal serum phosphate levels are maintained by the regulation of dietary absorption, bone formation and resorption, equilibration with intracellular stores, and renal excretion. When kidney function is impaired, phosphate excretion declines. Without specific treatment, hyperphosphataemia occurs almost universally, despite dietary phosphate restriction and conventional dialysis treatment. In patients on dialysis, hyperphosphataemia is an independent risk factor for fractures, cardiovascular disease and mortality. Abnormalities in phosphate metabolism such as hyperphosphatemia are included in the definition of the new chronic kidney disease–mineral and bone disorder (CKD-MBD).
Structure and mechanism of action
Sucroferric oxyhydroxide comprises a polynuclear iron(III)-oxyhydroxide core that is stabilised with a carbohydrate shell composed of sucrose and starch. The carbohydrate shell stabilises the iron(III)-oxyhydroxide core to preserve the phosphate adsorption capacity.
Dietary phosphate binds strongly to sucroferric oxyhydroxide in the gastrointestinal (GI) tract. The bound phosphate is eliminated in the faeces and thereby prevented from absorption into the blood. As a consequence of the decreased dietary phosphate absorption, serum phosphorus concentrations are reduced.
Chewability
The chewability of sucroferric oxyhydroxide compares
well with that of Calcimagon, a calcium containing tablet used as a standard for very good chewability. Tablets of sucroferric oxyhydroxide easily disintegrated in artificial saliva.
Effectiveness and phosphate binding
Clinical Phase III studies showed that sucroferric oxyhydroxide achieves and maintains phosphate levels in compliance with the KDOQI guidelines. The reduction in serum phosphate levels of sucroferric oxyhydroxide-treated patients was non-inferior to that in sevelamer-treated patients. The required daily pill burden was lower with sucroferric oxyhydroxide.Sucroferric oxyhydroxide binds phosphate under empty and full stomach conditions and across the physiologically relevant pH range of the GI tract.In a retrospective, real-world study, hyperphosphatemic peritoneal dialysis patients who were prescribed to switch to sucroferric oxyhydroxide from sevelamer, lanthanum carbonate, or calcium acetate had significant reductions in serum phosphorus levels, along with a 53% decrease in the prescribed daily pill burden.
References
External links
"Succharated ferric oxide". Drug Information Portal. U.S. National Library of Medicine. |
Viloxazine | Viloxazine, sold under the brand name Qelbree and formerly as Vivalan among others, is a noradrenergic medication which is used in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. It was marketed for almost 30 years as an antidepressant for the treatment of depression before being discontinued and subsequently repurposed as a treatment for ADHD. Viloxazine is taken by mouth. It was used as an antidepressant in an immediate-release form and is used in ADHD in an extended-release form.Side effects of viloxazine include insomnia, headache, somnolence, fatigue, nausea, vomiting, decreased appetite, dry mouth, constipation, irritability, increased heart rate, and increased blood pressure. Rarely, the medication may cause suicidal thoughts and behaviors. It can also activate mania or hypomania in people with bipolar disorder. Viloxazine acts as a selective norepinephrine reuptake inhibitor (NRI). The immediate-release form has an elimination half-life of 2.5 hours while the half-life of the extended-release form is 7 hours.Viloxazine was first described by 1972 and was marketed as an antidepressant in Europe in 1974. It was not marketed in the United States at this time. The medication was discontinued in 2002 due to commercial reasons. However, it was repurposed for the treatment of ADHD and was reintroduced, in the United States, in April 2021. Viloxazine is a non-stimulant medication; it has no known misuse liability and is not a controlled substance.
Medical uses
Attention deficit hyperactivity disorder
Viloxazine is indicated to treat attention deficit hyperactivity disorder (ADHD) in children age 6 to 12 years, adolescents age 13 to 17 years, and adults.In a phase 3 regulatory randomized controlled trial of viloxazine for ADHD in adults, scores on the Attention-Deficit/Hyperactivity Disorder Investigator Symptom Rating Scale (AISRS) with viloxazine therapy decreased from 38.5 points at baseline to 23.0 points following treatment (–40%) and with placebo decreased from 37.6 points at baseline to 25.9 points (–31%). This gave a placebo-subtracted score difference (drug minus placebo), or improvement in scores attributable to the effects of viloxazine, of –3.7 points (–9%).
Depression
Viloxazine was previously marketed as an antidepressant for the treatment of major depressive disorder. It was considered to be effective in mild to moderate as well as severe depression with or without co-morbid symptoms. The typical dose range for depression was 100 to 400 mg per day in divided doses administered generally two to three times per day.
Available forms
Viloxazine is available for ADHD in the form of 100, 150, and 200 mg extended-release capsules. These capsules can be opened and sprinkled into food for easier administration.
Side effects
Side effects included nausea, vomiting, insomnia, loss of appetite, increased erythrocyte sedimentation, EKG and EEG anomalies, epigastric pain, diarrhea, constipation, vertigo, orthostatic hypotension, edema of the lower extremities, dysarthria, tremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, seizure, (there were three cases worldwide, and most animal studies [and clinical trials that included epilepsy patients] indicated the presence of anticonvulsant properties, so was not completely contraindicated in epilepsy) and increased libido.
Interactions
Viloxazine increased plasma levels of phenytoin by an average of 37%. It also was known to significantly increase plasma levels of theophylline and decrease its clearance from the body, sometimes resulting in accidental overdose of theophylline.
Pharmacology
Pharmacodynamics
Viloxazine acts as a selective norepinephrine reuptake inhibitor and this is believed to be responsible for its therapeutic effectiveness in the treatment of conditions like ADHD and depression. The affinities (KD) of viloxazine at the human monoamine transporters are 155 to 630 nM for the norepinephrine transporter (NET), 17,300 nM for the serotonin transporter (SERT), and >100,000 nM for the dopamine transporter (DAT). Viloxazine has negligible affinity for a variety of assessed receptors, including the serotonin 5-HT1A and 5-HT2A receptors, the dopamine D2 receptor, the α1- and α2-adrenergic receptors, the histamine H1 receptor, and the muscarinic acetylcholine receptors (all >10,000 nM).More recent research has found that the pharmacodynamics of viloxazine may be more complex than previously assumed. In 2020, viloxazine was reported to have significant affinity for the serotonin 5-HT2B and 5-HT2C receptors (Ki = 3,900 nM and 6,400 nM) and to act as an antagonist and agonist of these receptors, respectively. It also showed weak antagonistic activity at the serotonin 5-HT7 receptor and the α1B- and β2-adrenergic receptors. These actions, although relatively weak, might be involved in its effects and possibly its therapeutic effectiveness in the treatment of ADHD.
Pharmacokinetics
Absorption
The bioavailability of extended-release viloxazine relative to an instant-release formulation was about 88%. Peak and AUC levels of extended-release viloxazine are proportional over a dosage range of 100 to 400 mg once daily. The time to peak levels is 5 hours with a range of 3 to 9 hours after a single 200 mg dose. A high-fat meal modestly decreases levels of viloxazine and delays the time to peak by about 2 hours. Steady-state levels of viloxazine are released after 2 days of once-daily administration and no accumulation occurs. Levels of viloxazine are approximately 40 to 50% higher in children age 6 to 11 years compared to children age 12 to 17 years.
Distribution
The plasma protein binding of viloxazine is 76 to 82% over a concentration range of 0.5 to 10 μg/mL.
Metabolism
The metabolism of viloxazine is primarily via the cytochrome P450 enzyme CYP2D6 and the UDP-glucuronosyltransferases UGT1A9 and UGT2B15. The major metabolite of viloxazine is 5-hydroxyviloxazine glucuronide. Viloxazine levels are slightly higher in CYP2D6 poor metabolizers relative to CYP2D6 extensive metabolizers.
Elimination
The elimination of viloxazine is mainly renal. Approximately 90% of the dose is excreted in urine within 24 hours and less than 1% of the dose is recovered in feces.The elimination half-life of instant-release viloxazine is 2 to 5 hours (2–3 hours in the most reliable studies) and the half-life of extended-release viloxazine is 7.02 ± 4.74 hours.
Chemistry
Viloxazine is a racemic compound with two stereoisomers, the (S)-(–)-isomer being five times as pharmacologically active as the (R)-(+)-isomer.
History
Viloxazine was discovered by scientists at Imperial Chemical Industries when they recognized that some beta blockers inhibited serotonin reuptake inhibitor activity in the brain at high doses. To improve the ability of their compounds to cross the blood brain barrier, they changed the ethanolamine side chain of beta blockers to a morpholine ring, leading to the synthesis of viloxazine.: 610 : 9 It was first described in the scientific literature as early as 1972.The medication was first marketed in 1974. Viloxazine was not approved for medical use by the FDA. In 1984, the FDA granted the medication an orphan designation for treatment of cataplexy and narcolepsy with the tentative brand name Catatrol. For unknown reasons however, it was never approved or introduced for these uses in the United States. Viloxazine was withdrawn from markets worldwide in 2002 for commercial reasons unrelated to efficacy or safety.As of 2015, Supernus Pharmaceuticals was developing extended release formulations of viloxazine as a treatment for ADHD and major depressive disorder under the names SPN-809 and SPN-812. Viloxazine was approved for the treatment of ADHD in the United States in April 2021.
Research
Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bedwetting) in children, both of those times versus imipramine. By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM without really improving daytime somnolence. In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy.Viloxazine has also been studied for the treatment of alcoholism, with some success.While viloxazine may have been effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia.
References
External links
"Viloxazine". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03247530 for "Evaluation of SPN-812 ER Low Dose in Children With ADHD" at ClinicalTrials.gov
Clinical trial number NCT03247543 for "Evaluation of SPN-812 ER High Dose in Children With ADHD" at ClinicalTrials.gov |
Lomustine | Lomustine (INN); abbreviated as CCNU; original brand name CeeNU, now marketed as Gleostine) is an alkylating nitrosourea compound used in chemotherapy. It is closely related to semustine and is in the same family as streptozotocin. It is a highly lipid-soluble drug, thus it crosses the blood-brain barrier. This property makes it ideal for treating brain tumors, which is its primary use, although it is also used to treat Hodgkin lymphoma as a second-line option. Lomustine has a long time to nadir (the time when white blood cells reach their lowest number).
Unlike carmustine, lomustine is administered orally. It is a bifunctional alkylating agent, alkylates both DNA and RNA, has the ability to created interstrand cross-links (ICLs) in DNA. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. Lomustine is cell-cycle nonspecific.
It has also been used in veterinary practice as a treatment for mast cell tumors in dogs.
Price increase
In the U.S., the patent for lomustine has expired, but only one company manufactures it. In 2013, Bristol-Myers Squibb Co. sold its CeeNU brand of lomustine to CordenPharma, a subsidiary of International Chemical Investors S.E., which markets it as Gleostine through NextSource Biotechnology. In 2013, BMS charged $50 a capsule. In 2018, NextSource charged $768 a capsule. Some doctors said the price increase made it unaffordable, and one doctor called it "price gouging."
References
External links
CeeNu (lomustine) Capsules data sheet published by the FDA
Lomustine at the US National Library of Medicine Medical Subject Headings (MeSH)
Diseases Database (DDB): 29525 |
Bupivacaine | Bupivacaine, marketed under the brand name Marcaine among others, is a medication used to decrease feeling in a specific area. In nerve blocks, it is injected around a nerve that supplies the area, or into the spinal canals epidural space. It is available mixed with a small amount of epinephrine to increase the duration of its action. It typically begins working within 15 minutes and lasts for 2 to 8 hours.Possible side effects include sleepiness, muscle twitching, ringing in the ears, changes in vision, low blood pressure, and an irregular heart rate. Concerns exist that injecting it into a joint can cause problems with the cartilage. Concentrated bupivacaine is not recommended for epidural freezing. Epidural freezing may also increase the length of labor. It is a local anaesthetic of the amide group.Bupivacaine was discovered in 1957. It is on the World Health Organizations List of Essential Medicines. Bupivacaine is available as a generic medication. An implantable formulation of bupivacaine (Xaracoll) was approved for medical use in the United States in August 2020.
Medical uses
Bupivacaine is indicated for local infiltration, peripheral nerve block, sympathetic nerve block, and epidural and caudal blocks. It is sometimes used in combination with epinephrine to prevent systemic absorption and extend the duration of action. The 0.75% (most concentrated) formulation is used in retrobulbar block. It is the most commonly used local anesthetic in epidural anesthesia during labor, as well as in postoperative pain management. Liposomal formulations of bupivacaine (brand name EXPAREL) have shown to be more effective in providing pain relief than plain solutions of bupivacaine.The fixed-dose combination of bupivacaine with Type I collagen (brand name Xaracoll) is indicated for acute postsurgical analgesia (pain relief) for up to 24 hours in adults following open inguinal hernia repair.Bupivacaine (Posimir) is indicated in adults for administration into the subacromial space under direct arthroscopic visualization to produce post-surgical analgesia for up to 72 hours following arthroscopic subacromial decompression.
Contraindications
Bupivacaine is contraindicated in patients with known hypersensitivity reactions to bupivacaine or amino-amide anesthetics. It is also contraindicated in obstetrical paracervical blocks and intravenous regional anaesthesia (Bier block) because of potential risk of tourniquet failure and systemic absorption of the drug and subsequent cardiac arrest. The 0.75% formulation is contraindicated in epidural anesthesia during labor because of the association with refractory cardiac arrest.
Adverse effects
Compared to other local anaesthetics, bupivacaine is markedly cardiotoxic. However, adverse drug reactions are rare when it is administered correctly. Most reactions are caused by accelerated absorption from the injection site, unintentional intravascular injection, or slow metabolic degradation. However, allergic reactions can rarely occur.Clinically significant adverse events result from systemic absorption of bupivacaine and primarily involve the central nervous and cardiovascular systems. Effects on the central nervous system typically occur at lower blood plasma concentrations. Initially, cortical inhibitory pathways are selectively inhibited, causing symptoms of neuronal excitation. At higher plasma concentrations, both inhibitory and excitatory pathways are inhibited, causing central nervous system depression and potentially coma. Higher plasma concentrations also lead to cardiovascular effects, though cardiovascular collapse may also occur with low concentrations. Adverse effects on the central nervous system may indicate impending cardiotoxicity and should be carefully monitored.
Central nervous system: circumoral numbness, facial tingling, vertigo, tinnitus, restlessness, anxiety, dizziness, seizure, coma
Cardiovascular: hypotension, arrhythmia, bradycardia, heart block, cardiac arrestToxicity can also occur in the setting of subarachnoid injection during high spinal anesthesia. These effects include: paresthesia, paralysis, apnea, hypoventilation, fecal incontinence, and urinary incontinence. Additionally, bupivacaine can cause chondrolysis after continuous infusion into a joint space.Bupivacaine has caused several deaths when the epidural anaesthetic has been administered intravenously accidentally.
Treatment of overdose
Animal evidence indicates intralipid, a commonly available intravenous lipid emulsion, can be effective in treating severe cardiotoxicity secondary to local anaesthetic overdose, and human case reports of successful use in this way. Plans to publicize this treatment more widely have been published.
Pregnancy and lactation
Bupivacaine crosses the placenta and is a pregnancy category C drug. However, it is approved for use at term in obstetrical anesthesia. Bupivacaine is excreted in breast milk. Risks of stopping breast feeding versus stopping bupivacaine should be discussed with the patient.
Postarthroscopic glenohumeral chondrolysis
Bupivacaine is toxic to cartilage and its intra-articular infusions may lead to postarthroscopic glenohumeral chondrolysis.
Pharmacology
Pharmacodynamics
Bupivacaine binds to the intracellular portion of voltage-gated sodium channels and blocks sodium influx into nerve cells, which prevents depolarization. Without depolarization, no initiation or conduction of a pain signal can occur.
Pharmacokinetics
The rate of systemic absorption of bupivacaine and other local anesthetics is dependent upon the dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the preparation.
Onset of action (route and dose-dependent): 1-17 min
Duration of action (route and dose-dependent): 2-9 hr
Half life: neonates, 8.1 hr, adults: 2.7 hr
Time to peak plasma concentration (for peripheral, epidural, or caudal block): 30-45 min
Protein binding: about 95%
Metabolism: hepatic
Excretion: renal (6% unchanged)
Chemical structure
Like lidocaine, bupivacaine is an amino-amide anesthetic; the aromatic head and the hydrocarbon chain are linked by an amide bond rather than an ester as in earlier local anesthetics. As a result, the amino-amide anesthetics are more stable and less likely to cause allergic reactions. Unlike lidocaine, the terminal amino portion of bupivacaine (as well as mepivacaine, ropivacaine, and levobupivacaine) is contained within a piperidine ring; these agents are known as pipecholyl xylidines.
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 the medicinal product Exparel, intended for the treatment of post-operative pain. The applicant for this medicinal product is Pacira Ireland Limited. Exparel liposomal was approved for medical use in the European Union in November 2020.
Economics
Bupivacaine is available as a generic medication.
Research
Levobupivacaine is the (S)-(–)-enantiomer of bupivacaine, with a longer duration of action, producing less vasodilation. Durect Corporation is developing a biodegradable, controlled-release drug delivery system for after surgery. It has currently completed a phase-III clinical trial.
See also
Bupivacaine/meloxicam
References
External links
"Bupivacaine". Drug Information Portal. U.S. National Library of Medicine. |
Spinosad | Spinosad is an insecticide based on chemical compounds found in the bacterial species Saccharopolyspora spinosa. The genus Saccharopolyspora was discovered in 1985 in isolates from crushed sugarcane. The bacteria produce yellowish-pink aerial hyphae, with bead-like chains of spores enclosed in a characteristic hairy sheath. This genus is defined as aerobic, Gram-positive, nonacid-fast actinomycetes with fragmenting substrate mycelium. S. spinosa was isolated from soil collected inside a nonoperational sugar mill rum still in the Virgin Islands. Spinosad is a mixture of chemical compounds in the spinosyn family that has a generalized structure consisting of a unique tetracyclic ring system attached to an amino sugar (D-forosamine) and a neutral sugar (tri-Ο-methyl-L-rhamnose). Spinosad is relatively nonpolar and not easily dissolved in water.Spinosad is a novel mode-of-action insecticide derived from a family of natural products obtained by fermentation of S. spinosa. Spinosyns occur in over 20 natural forms, and over 200 synthetic forms (spinosoids) have been produced in the lab. Spinosad contains a mix of two spinosoids, spinosyn A, the major component, and spinosyn D (the minor component), in a roughly 17:3 ratio.
Mode of action
Spinosad is highly active, by both contact and ingestion, in numerous insect species. Its overall protective effect varies with insect species and life stage. It affects certain species only in the adult stage, but can affect other species at more than one life stage. The species subject to very high rates of mortality as larvae, but not as adults, may gradually be controlled through sustained larval mortality. The mode of action of spinosoid insecticides is by a neural mechanism. The spinosyns and spinosoids have a novel mode of action, primarily targeting binding sites on nicotinic acetylcholine receptors (nAChRs) of the insect nervous system that are distinct from those at which other insecticides have their activity. Spinosoid binding leads to disruption of acetylcholine neurotransmission. Spinosad also has secondary effects as a γ-amino-butyric acid (GABA) neurotransmitter agonist. It kills insects by hyperexcitation of the insect nervous system. Spinosad so far has proven not to cause cross-resistance to any other known insecticide.
Use
Spinosad has been used around the world for the control of a variety of insect pests, including Lepidoptera, Diptera, Thysanoptera, Coleoptera, Orthoptera, and Hymenoptera, and many others. It was first registered as a pesticide in the United States for use on crops in 1997. Its labeled use rate is set at 1 ppm (1 mg a.i./kg of grain) and its maximum residue limit (MRL) or tolerance is set at 1.5 ppm. Spinosads widespread commercial launch was deferred, awaiting final MRL or tolerance approvals in a few remaining grain-importing countries. It is considered a natural product, thus is approved for use in organic agriculture by numerous nations. Two other uses for spinosad are for pets and humans. Spinosad has recently been used in oral preparations (as Comfortis) to treat C. felis, the cat flea, in canines and felines; the optimal dose set for canines is reported to be 30 mg/kg.Spinosad is sold under the trade names, Comfortis, Trifexis, and Natroba. Trifexis also includes milbemycin oxime. Comfortis and Trifexis brands treat adult fleas on pets; the latter also prevents heartworm disease. Natroba is sold for treatment of human head lice. Spinosad is also commonly used to kill thrips.
Spinosyn A
Spinosyn A does not appear to interact directly with known insecticidal-relevant target sites, but rather acts via a novel mechanism. Spinosyn A resembles a GABA antagonist and is comparable to the effect of avermectin on insect neurons. Spinosyn A is highly active against neonate larvae of the tobacco budworm, Heliothis virescens, and is slightly more biologically active than spinosyn D. In general, spinosyns possessing a methyl group at C6 (spinosyn D-related analogs) tend to be more active and less affected by changes in the rest of the molecule. Spinosyn A is slow to penetrate to the internal fluids of larvae; it is also poorly metabolized once it enters the insect. The apparent lack of spinosyn A metabolism may contribute to its high level of activity, and may compensate for the slow rate of penetration.
Resistance
Spinosad resistance has been found in Musca domestica by Liu & Yue 2000, in Plutella xylostella by Sayyed et al 2004, in Bactrocera dorsalis by Hsu & Feng 2006, in Frankliniella occidentalis by Bielza et al 2007, and in Cydia pomonella by Reyes et al 2007; see Insecticide Resistance Action Committees Arthropod Pesticide Resistance Database for continued updates.
Safety and ecotoxicology
Spinosad has high efficacy, a broad insect pest spectrum, low mammalian toxicity, and a good environmental profile, a unique feature of the insecticide compared to others currently used for the protection of grain products. It is regarded as natural product-based, and approved for use in organic agriculture by numerous national and international certifications. Spinosad residues are highly stable on grains stored in bins, with protection ranging from 6 months to 2 years.Ecotoxicology parameters have been reported for spinosad, and are:
in rat (Rattus norvegicus (Bergenhout, 1769)), acute oral: LD50 >5000 mg/kg (nontoxic)
in rat (R. norvegicus), acute dermal: LD50 >2000 mg/kg (nontoxic)
in California quail (Callipepla californica (Shaw, 1798)), oral toxicity: LD50 >2000 mg/kg (nontoxic)
in duck (Anas platyrhynchos domestica (Linnaeus, 1758)), dietary toxicity: LC50 >5000 mg/kg (nontoxic)
in rainbow trout (Oncorhynchus mykiss (Walbaum, 1792)), LC50-96h = 30.0 mg/L (slightly toxic)
in Honeybee (Apis mellifera (Linnaeus, 1758)), LD50 = 0.0025 mg/bee (highly toxic if directly sprayed on and of dried residues).Chronic exposure studies failed to induce tumor formation in rats and mice; mice given up to 51 mg/kg/day for 18 months resulted in no tumor formation. Similarly, administration of 25 mg/kg/day to rats for 24 months did not result in tumor formation.
Further reading
The non‐target impact of spinosyns on beneficial arthropods
Spinosad toxicity to pollinators and associated risk
References
External links
"Spinosad". Drug Information Portal. U.S. National Library of Medicine.
Monograph |
Influenza vaccine | Influenza vaccines, also known as flu shots, are vaccines that protect against infection by influenza viruses. New versions of the vaccines are developed twice a year, as the influenza virus rapidly changes. While their effectiveness varies from year to year, most provide modest to high protection against influenza. The United States Centers for Disease Control and Prevention (CDC) estimates that vaccination against influenza reduces sickness, medical visits, hospitalizations, and deaths. Immunized workers who do catch the flu return to work half a day sooner on average. Vaccine effectiveness in those over 65 years old remains uncertain due to a lack of high-quality research. Vaccinating children may protect those around them.Vaccination against influenza began in the 1930s, with large-scale availability in the United States beginning in 1945. It is on the World Health Organizations List of Essential Medicines.The World Health Organization (WHO) and the CDC recommend yearly vaccination for nearly all people over the age of six months, especially those at high risk. The European Centre for Disease Prevention and Control (ECDC) also recommends yearly vaccination of high risk groups. These groups include pregnant women, the elderly, children between six months and five years of age, and those with certain health problems.The vaccines are generally safe; fever occurs in five to ten percent of children vaccinated, and temporary muscle pains or feelings of tiredness may occur. In certain years, the vaccine was linked to an increase in Guillain–Barré syndrome among older people at a rate of about one case per million doses. Although most influenza vaccines are produced using egg proteins, they are still recommended as safe for people who have severe egg allergies, as no increased risk of allergic reaction to the egg-based vaccines has been shown for people with egg allergies. Vaccines produced using other technologies, notably recombinant vaccines and those based on cell culture rather than egg protein, started to become available from 2012 in the US, and later in Europe and Australia. Influenza vaccines are not recommended in those who have had a severe allergy to previous versions of the vaccine itself. The vaccine comes in inactive and weakened viral forms. The live, weakened vaccine is generally not recommended in pregnant women, children less than two years old, adults older than 50, or people with a weakened immune system. Depending on the type they can be injected into a muscle, sprayed into the nose, or injected into the middle layer of the skin (intradermal). The intradermal vaccine was not available during the 2018–2019 and 2019–2020 influenza seasons.
History
Vaccines are used in both humans and nonhumans. Human vaccine is meant unless specifically identified as a veterinary, poultry or livestock vaccine.
Origins and development
In the worldwide Spanish flu pandemic of 1918, "Pharmacists tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and serums (chiefly against what we now call Hemophilus influenzae – a name derived from the fact that it was originally considered the etiological agent – and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success."In 1931, viral growth in embryonated hens eggs was reported by Ernest William Goodpasture and colleagues at Vanderbilt University. The work was extended to growth of influenza virus by several workers, including Thomas Francis, Jonas Salk, Wilson Smith and Macfarlane Burnet, leading to the first experimental influenza vaccines. In the 1940s, the US military developed the first approved inactivated vaccines for influenza, which were used in the Second World War. Hens eggs continued to be used to produce virus used in influenza vaccines, but manufacturers made improvements in the purity of the virus by developing improved processes to remove egg proteins and to reduce systemic reactivity of the vaccine. In 2012, the US Food and Drug Administration (FDA) approved influenza vaccines made by growing virus in cell cultures and influenza vaccines made from recombinant proteins have been approved, with plant-based influenza vaccines being tested in clinical trials.
Acceptance
The egg-based technology for producing influenza vaccine was created in the 1950s. In the US swine flu scare of 1976, President Gerald Ford was confronted with a potential swine flu pandemic. The vaccination program was rushed, yet plagued by delays and public relations problems. Meanwhile, maximum military containment efforts succeeded unexpectedly in confining the new strain to the single army base where it had originated. On that base, a number of soldiers fell severely ill, but only one died. The program was canceled after about 24% of the population had received vaccinations. An excess in deaths of 25 over normal annual levels as well as 400 excess hospitalizations, both from Guillain–Barré syndrome, were estimated to have occurred from the vaccination program itself, demonstrating that the vaccine itself is not free of risks. The result can be cited to support lingering doubts about vaccination as well as to counter ungrounded claims about the safety of vaccination. In the end, however, even the maligned 1976 vaccine may have saved lives. A 2010 study found a significantly enhanced immune response against the 2009 pandemic H1N1 in study participants who had received vaccination against the swine flu in 1976.
Quadrivalent vaccines for seasonal flu
A quadrivalent flu vaccine administered by nasal mist was approved by the FDA in March 2012. Fluarix Quadrivalent was approved by the FDA in December 2012.In 2014, the Canadian National Advisory Committee on Immunization (NACI) published a review of quadrivalent influenza vaccines.Starting with the 2018–2019 influenza season most of the regular-dose egg-based flu shots and all the recombinant and cell-grown flu vaccines in the United States are quadrivalent. In the 2019–2020 influenza season all regular-dose flu shots and all recombinant influenza vaccine in the United States are quadrivalent.In November 2019, the FDA approved Fluzone High-Dose Quadrivalent for use in the United States starting with the 2020–2021 influenza season.In February 2020, the FDA approved Fluad Quadrivalent for use in the United States. In July 2020, the FDA approved both Fluad and Fluad Quadrivalent for use in the United States for the 2020–2021 influenza season.
Medical uses
The U.S Centers for Disease Control and Prevention (CDC) recommends the flu vaccine as the best way to protect people against the flu and prevent its spread. The flu vaccine can also reduce the severity of the flu if a person contracts a strain that the vaccine did not contain. It takes about two weeks following vaccination for protective antibodies to form.A 2012 meta-analysis found that flu vaccination was effective 67 percent of the time; the populations that benefited the most were HIV-positive adults aged 18 to 55 (76 percent), healthy adults aged 18 to 46 (approximately 70 percent), and healthy children aged six months to 24 months (66 percent). The influenza vaccine also appears to protect against myocardial infarction with a benefit of 15–45%.
Effectiveness
A vaccine is assessed by its efficacy – the extent to which it reduces risk of disease under controlled conditions – and its effectiveness – the observed reduction in risk after the vaccine is put into use. In the case of influenza, effectiveness is expected to be lower than the efficacy because it is measured using the rates of influenza-like illness, which is not always caused by influenza. Studies on the effectiveness of flu vaccines in the real world are difficult; vaccines may be imperfectly matched, virus prevalence varies widely between years, and influenza is often confused with other influenza-like illnesses. However, in most years (16 of the 19 years before 2007), the flu vaccine strains have been a good match for the circulating strains, and even a mismatched vaccine can often provide cross-protection. The virus rapidly changes due to antigenic drift, a slight mutation in the virus that causes a new strain to arise.The effectiveness of seasonal flu vaccines varies significantly, with an estimated average efficacy of 50–60% against symptomatic disease, depending on vaccine strain, age, prior immunity, and immune function, so vaccinated people can still contract influenza. The effectiveness of flu vaccines is considered to be suboptimal, particularly among the elderly, but vaccination is still beneficial in reducing the mortality rate and hospitalization rate due to influenza as well as duration of hospitalization. Vaccination of school-age children has shown to provide indirect protection for other age groups. LAIVs are recommended for children based on superior efficacy, especially for children under 6, and greater immunity against non-vaccine strains when compared to inactivated vaccines.From 2012 to 2015 in New Zealand, vaccine effectiveness against admission to an intensive care unit was 82%. Effectiveness against hospitalized influenza illness in the 2019–2020 United States flu season was 41% overall and 54% in people aged 65 years or older. One review found 31% effectiveness against death among adults.Repeated annual influenza vaccination generally offer consistent year-on-year protection against influenza. There is, however, suggestive evidence that repeated vaccinations may cause a reduction in vaccine effectiveness for certain influenza subtypes; this has no relevance to current recommendations for yearly vaccinations but might influence future vaccination policy. As of 2019, the CDC recommends a yearly vaccine as most studies demonstrate overall effectiveness of annual influenza vaccination.There is not enough evidence to establish significant differences in the effectiveness of different influenza vaccine types, but there are high-dose or adjuvanted products that induce a stronger immune response in the elderly.
Children
In April 2002, the Advisory Committee on Immunization Practices (ACIP) encouraged that children 6 to 23 months of age be vaccinated annually against influenza. In 2010, ACIP recommended annual influenza vaccination for those 6 months of age and older. Currently the CDC recommends that everyone except infants under the age of six months should receive the seasonal influenza vaccine. Vaccination campaigns usually focus special attention on people who are at high risk of serious complications if they catch the flu, such as pregnant women, children under 59 months, the elderly, and people with chronic illnesses or weakened immune systems, as well as those to whom they are exposed, such as health care workers.As the death rate is also high among infants who catch influenza, the CDC and the WHO recommend that household contacts and caregivers of infants be vaccinated to reduce the risk of passing an influenza infection to the infant.In children, the vaccine appears to decrease the risk of influenza and possibly influenza-like illness. In children under the age of two data are limited. During the 2017–18 flu season, the CDC director indicated that 85 percent of the children who died "likely will not have been vaccinated".In the United States, as of January 2019, the CDC recommend that children aged six through 35 months may receive either 0.25 milliliters or 0.5 milliliters per dose of Fluzone Quadrivalent. There is no preference for one or the other dose volume of Fluzone Quadrivalent for that age group. All persons 36 months of age and older should receive 0.5 milliliters per dose of Fluzone Quadrivalent. As of October 2018, Afluria Quadrivalent is licensed for children six months of age and older in the United States. Children six months through 35 months of age should receive 0.25 milliliters for each dose of Afluria Quadrivalent. All persons 36 months of age and older should receive 0.5 milliliters per dose of Afluria Quadrivalent. As of February 2018, Afluria Tetra is licensed for adults and children five years of age and older in Canada.In 2014, the Canadian National Advisory Committee on Immunization (NACI) published a review of influenza vaccination in healthy 5–18-year-olds, and in 2015, published a review of the use of pediatric Fluad in children 6–72 months of age. In one study, conducted in a tertiary referral center, the rate of influenza vaccination in children was only 31%. Higher rates were found among immuno-suppressed pediatric patients (46%), and in patients with inflammatory bowel disease (50%).
Adults
In unvaccinated adults, 16% get symptoms similar to the flu, while about 10% of vaccinated adults do. Vaccination decreased confirmed cases of influenza from about 2.4% to 1.1%. No effect on hospitalization was found.In working adults, a review by the Cochrane Collaboration found that vaccination resulted in a modest decrease in both influenza symptoms and working days lost, without affecting transmission or influenza-related complications. In healthy working adults, influenza vaccines can provide moderate protection against virologically confirmed influenza, though such protection is greatly reduced or absent in some seasons.In health care workers, a 2006 review found a net benefit. Of the eighteen studies in this review, only two also assessed the relationship of patient mortality relative to staff influenza vaccine uptake; both found that higher rates of health care worker vaccination correlated with reduced patient deaths. A 2014 review found benefits to patients when health care workers were immunized, as supported by moderate evidence based in part on the observed reduction in all-cause deaths in patients whose health care workers were given immunization compared with comparison patients where the workers were not offered vaccine.
Elderly
Evidence for an effect in adults over 65 is unclear. Systematic reviews examining both randomized controlled and case–control studies found a lack of high-quality evidence. Reviews of case–control studies found effects against laboratory-confirmed influenza, pneumonia, and death among the community-dwelling elderly.The group most vulnerable to non-pandemic flu, the elderly, benefits least from the vaccine. There are multiple reasons behind this steep decline in vaccine efficacy, the most common of which are the declining immunological function and frailty associated with advanced age. In a non-pandemic year, a person in the United States aged 50–64 is nearly ten times more likely to die an influenza-associated death than a younger person, and a person over 65 is more than ten times more likely to die an influenza-associated death than the 50–64 age group.There is a high-dose flu vaccine specifically formulated to provide a stronger immune response. Available evidence indicates that vaccinating the elderly with the high-dose vaccine leads to a stronger immune response against influenza than the regular-dose vaccine.A flu vaccine containing an adjuvant was approved by the US Food and Drug Administration (FDA) in November 2015, for use by adults aged 65 years of age and older. The vaccine is marketed as Fluad in the US and was first available in the 2016–2017 flu season. The vaccine contains the MF59C.1 adjuvant which is an oil-in-water emulsion of squalene oil. It is the first adjuvanted seasonal flu vaccine marketed in the United States. It is not clear if there is a significant benefit for the elderly to use a flu vaccine containing the MF59C.1 adjuvant. Per Advisory Committee on Immunization Practices guidelines, Fluad can be used as an alternative to other influenza vaccines approved for people 65 years and older.Vaccinating health care workers who work with elderly people is recommended in many countries, with the goal of reducing influenza outbreaks in this vulnerable population. While there is no conclusive evidence from randomized clinical trials that vaccinating health care workers helps protect elderly people from influenza, there is tentative evidence of benefit.Fluad Quad was approved for use in Australia in September 2019, Fluad Quadrivalent was approved for use in the United States in February 2020, and Fluad Tetra was approved for use in the European Union in May 2020.
Pregnancy
As well as protecting mother and child from the effects of an influenza infection, the immunization of pregnant women tends to increase their chances of experiencing a successful full-term pregnancy.The trivalent inactivated influenza vaccine is protective in pregnant women infected with HIV.
Safety
Side effects
Common side effects of vaccination include local injection-site reactions and cold-like symptoms. Fever, malaise, and myalgia are less common. Flu vaccines are contraindicated for people who have experienced a severe allergic reaction in response to a flu vaccine or to any component of the vaccine. LAIVs are not given to children or adolescents with severe immunodeficiency or to those who are using salicylate treatments because of the risk of developing Reye syndrome. LAIVs are also not recommended for children under the age of 2, pregnant women, and adults with immunosuppression. Inactivated flu vaccines cannot cause influenza and are regarded as safe during pregnancy.While side effects of the flu vaccine may occur, they are usually minor, including soreness, redness, and swelling around the point of injection, headache, fever, nausea or fatigue. Side effects of a nasal spray vaccine may include runny nose, wheezing, sore throat, cough, or vomiting.In some people, a flu vaccine may cause serious side effects, including an allergic reaction, but this is rare. Furthermore, the common side effects and risks are mild and temporary when compared to the risks and severe health effects of the annual influenza epidemic.
Guillain–Barré syndrome
Although Guillain–Barré syndrome had been feared as a complication of vaccination, the CDC states that most studies on modern influenza vaccines have seen no link with Guillain–Barré. Infection with influenza virus itself increases both the risk of death (up to one in ten thousand) and the risk of developing Guillain–Barré syndrome to a far higher level than the highest level of suspected vaccine involvement (approximately ten times higher by 2009 estimates).Although one review gives an incidence of about one case of Guillain–Barré per million vaccinations, a large study in China, covering close to a hundred million doses of vaccine against the 2009 H1N1 "swine" flu found only eleven cases of Guillain–Barré syndrome, (0.1 per million doses) total incidence in persons vaccinated, actually lower than the normal rate of the disease in China, and no other notable side effects.
Egg allergy
Although most influenza vaccines are produced using egg-based techniques, influenza vaccines are nonetheless still recommended for people with egg allergies, even if severe. Studies examining the safety of influenza vaccines in people with severe egg allergies found that anaphylaxis was very rare, occurring in 1.3 cases per million doses given.Monitoring for symptoms from vaccination is recommended in those with more severe symptoms. A study of nearly 800 children with egg allergy, including over 250 with previous anaphylactic reactions, had zero systemic allergic reactions when given the live attenuated flu vaccine.
Other
Several studies have identified an increased incidence of narcolepsy among recipients of the pandemic H1N1 influenza AS03-adjuvanted vaccine; efforts to identify a mechanism for this suggest that narcolepsy is autoimmune, and that the AS03-adjuvanted H1N1 vaccine may mimic hypocretin, serving as a trigger.Some injection-based flu vaccines intended for adults in the United States contain thiomersal (also known as thimerosal), a mercury-based preservative. Despite some controversy in the media, the World Health Organizations Global Advisory Committee on Vaccine Safety has concluded that there is no evidence of toxicity from thiomersal in vaccines and no reason on grounds of safety to change to more-expensive single-dose administration.
Types
Flu vaccines are available either as:
a trivalent or quadrivalent intramuscular injection (IIV3, IIV4, or RIV4, that is, TIV or QIV), which contains the inactivated form of the virus
a nasal spray of live attenuated influenza vaccine (LAIV, Q/LAIV), which contains the live but attenuated (weakened) form of the virus.TIV or QIV induce protection after injection (typically intramuscular, though subcutaneous and intradermal routes can also be protective) based on an immune response to the antigens present on the inactivated virus, while cold-adapted LAIV works by establishing infection in the nasal passages.
Recommendations
Various public health organizations, including the World Health Organization (WHO), recommend that yearly influenza vaccination be routinely offered, particularly to people at risk of complications of influenza and those individuals who live with or care for high-risk individuals, including:
people aged 50 years of age or older
people with chronic lung diseases, including asthma
people with chronic heart diseases
people with chronic liver diseases
people with chronic kidney diseases
people who have had their spleen removed or whose spleen is not working properly
people who are immunocompromised
residents of nursing homes and other long-term care facilities
health care workers (both to prevent sickness and to prevent spread to their patients)
women who are or will be pregnant during the influenza season
children and adolescents (aged 6 months through 18 years) who are receiving aspirin- or salicylate-containing medications and who might be at risk for experiencing Reye syndrome after influenza virus infection
American Indians/Alaska Natives
people who are extremely obese (body mass index ≥40 for adults)The flu vaccine is contraindicated for those under six months of age and those with severe, life-threatening allergies to flu vaccine or any ingredient in the vaccine.
World Health Organization
As of 2016, the World Health Organization (WHO) recommends seasonal influenza vaccination for:First priority:
Pregnant womenSecond priority (in no particular order):
Children aged 6–59 months
Elderly
Individuals with specific chronic medical conditions
Health-care workers
Canada
The National Advisory Committee on Immunization (NACI), the group that advises the Public Health Agency of Canada, recommends that everyone over six months of age be encouraged to receive annual influenza vaccination, and that children between the age of six months and 24 months, and their household contacts, should be considered a high priority for the flu vaccine.
Particularly:
People at high risk of influenza-related complications or hospitalization, including people who are morbidly obese, healthy pregnant women, children aged 6–59 months, the elderly, aboriginals, and people with one of an itemized list of chronic health conditions
People capable of transmitting influenza to those at high risk, including household contacts and health care workers
People who provide essential community services
Certain poultry workersLive attenuated influenza vaccine (LAIV) was not available in Canada for the 2019–2020 season.
European Union
The European Centre for Disease Prevention and Control (ECDC) recommends vaccinating the elderly as a priority, with a secondary priority people with chronic medical conditions and health care workers.The influenza vaccination strategy is generally that of protecting vulnerable people, rather than limiting influenza circulation or eliminating human influenza sickness. This is in contrast with the high herd immunity strategies for other infectious diseases such as polio and measles. This is also due in part to the financial and logistics burden associated with the need of an annual injection.
United States
In the United States routine influenza vaccination is recommended for all persons aged six months and over. It takes up to two weeks after vaccination for sufficient antibodies to develop in the body. The CDC recommends vaccination before the end of October, although it considers getting a vaccine in December or even later to be still beneficial.According to the CDC, the live attenuated virus (LAIV4) (which comes in the form of the nasal spray in the US) should be avoided by some groups.Within its blanket recommendation for general vaccination in the United States, the CDC, which began recommending the influenza vaccine to health care workers in 1981, emphasizes to clinicians the special urgency of vaccination for members of certain vulnerable groups, and their caregivers:
Vaccination is especially important for people at higher risk of serious influenza complications or people who live with or care for people at higher risk for serious complications. In 2009, a new high-dose formulation of the standard influenza vaccine was approved. The Fluzone High Dose is specifically for people 65 and older; the difference is that it has four times the antigen dose of the standard Fluzone.The US government requires hospitals to report worker vaccination rates. Some US states and hundreds of US hospitals require health care workers to either get vaccinations or wear masks during flu season. These requirements occasionally engender union lawsuits on narrow collective bargaining grounds, but proponents note that courts have generally endorsed forced vaccination laws affecting the general population during disease outbreaks.Vaccination against influenza is especially considered important for members of high-risk groups who would be likely to have complications from influenza, for example pregnant women and children and teenagers from six months to 18 years of age who are receiving aspirin- or salicylate-containing medications and who might be at risk for experiencing Reye syndrome after influenza virus infection;
In raising the upper age limit to 18 years, the aim is to reduce both the time children and parents lose from visits to pediatricians and missing school and the need for antibiotics for complications
An added benefit expected from the vaccination of children is a reduction in the number of influenza cases among parents and other household members, and of possible spread to the general community.The CDC indicated that live attenuated influenza vaccine (LAIV), also called the nasal spray vaccine, was not recommended for the 2016–2017 flu season in the United States.Furthermore, the CDC recommends that health care personnel who care for severely immunocompromised persons receive injections (TIV or QIV) rather than LAIV.
United Kingdom
Dr Jenny Harries maintained winter 2021–2022 in the UK will be "uncertain" since flu and COVID-19 will be circulating together for the first time. She urged eligible people to get COVID-19 and flu vaccines. She maintains flu vaccination is important every year. People need to know that flu can be fatal as many people do not know this.
Australia
The Australian Government recommends seasonal flu vaccination for everyone over the age of six months. Australia uses inactivated vaccines. Until 2021, the egg-based vaccine has been the only one available (and continues to be the only free one), but from March 2021 a new cell-based vaccine is available for those who wish to pay for it, and it is expected that this one will become the standard by 2026.
The standard flu vaccine is free for the following people:
children aged six months to five years;
people aged 65 years and over;
Aboriginal and Torres Strait Islander people aged six months and over;
pregnant women; and
anyone over six months of age with medical conditions such as severe asthma, lung disease or heart disease, low immunity or diabetes that can lead to complications from influenza.
Uptake
At risk groups
Uptake of flu vaccination, both seasonally and during pandemics, is often low. Systematic reviews of pandemic flu vaccination uptake have identified several personal factors that may influence uptake, including gender (higher uptake in men), ethnicity (higher in people from ethnic minorities) and having a chronic illness. Beliefs in the safety and effectiveness of the vaccine are also important.A number of measures have been found to be useful to increase rates of vaccination in those over sixty including: patient reminders using leaflets and letters, postcard reminders, client outreach programs, vaccine home visits, group vaccinations, free vaccinations, physician payment, physician reminders and encouraging physician competition.
Health care workers
Frontline health care workers are often recommended to get seasonal and any pandemic flu vaccination. For example, in the UK all health care workers involved in patient care are recommended to receive the seasonal flu vaccine, and were also recommended to be vaccinated against the H1N1/09 (later renamed A(H1N1)pdm09) swine flu virus during the 2009 pandemic. However, uptake is often low. During the 2009 pandemic, low uptake by healthcare workers was seen in countries including the UK, Italy, Greece, and Hong Kong.In a 2010 survey of United States health care workers, 63.5% reported that they received the flu vaccine during the 2010–11 season, an increase from 61.9% reported the previous season. US Health professionals with direct patient contact had higher vaccination uptake, such as physicians and dentists (84.2%) and nurse practitioners (82.6%).The main reason to vaccinate health care workers is to prevent staff from spreading flu to their patients and to reduce staff absence at a time of high service demand, but the reasons health care workers state for their decisions to accept or decline vaccination may more often be to do with perceived personal benefits.In Victoria (Australia) public hospitals, rates of health care worker vaccination in 2005 ranged from 34% for non-clinical staff to 42% for laboratory staff. One of the reasons for rejecting vaccines was concern over adverse reactions; in one study, 31 |
Influenza vaccine | % of resident physicians at a teaching hospital incorrectly believed Australian vaccines could cause influenza.
Manufacturing
Research continues into the idea of a "universal" influenza vaccine that would not require tailoring to a particular strain, but would be effective against a broad variety of influenza viruses. No vaccine candidates had been announced by November 2007, but as of 2021, there are several universal vaccines candidates, in pre-clinical development and in clinical trials.In a 2007 report, the global capacity of approximately 826 million seasonal influenza vaccine doses (inactivated and live) was double the production of 413 million doses. In an aggressive scenario of producing pandemic influenza vaccines by 2013, only 2.8 billion courses could be produced in a six-month time frame. If all high- and upper-middle-income countries sought vaccines for their entire populations in a pandemic, nearly two billion courses would be required. If China pursued this goal as well, more than three billion courses would be required to serve these populations. Vaccine research and development is ongoing to identify novel vaccine approaches that could produce much greater quantities of vaccine at a price that is affordable to the global population.
Egg-based
Most flu vaccines are grown by vaccine manufacturers in fertilized chicken eggs. In the Northern hemisphere, the manufacturing process begins following the announcement (typically in February) of the WHO recommended strains for the winter flu season. Three strains (representing an H1N1, an H3N2, and a B strain) of flu are selected and chicken eggs are inoculated separately. These monovalent harvests are then combined to make the trivalent vaccine.
As of November 2007, both the conventional injection and the nasal spray are manufactured using chicken eggs. The European Union also approved Optaflu, a vaccine produced by Novartis using vats of animal cells. This technique is expected to be more scalable and avoid problems with eggs, such as allergic reactions and incompatibility with strains that affect avians like chickens.Influenza vaccines are produced in pathogen-free eggs that are eleven or twelve days old. The top of the egg is disinfected by wiping it with alcohol and then the egg is candled to identify a non-veinous area in the allantoic cavity where a small hole is poked to serve as a pressure release. A second hole is made at the top of the egg, where the influenza virus is injected in the allantoic cavity, past the chorioallantoic membrane. The two holes are then sealed with melted paraffin and the inoculated eggs are incubated for 48 hours at 37 degrees Celsius. During incubation time, the virus replicates and newly replicated viruses are released into the allantoic fluidAfter the 48-hour incubation period, the top of the egg is cracked and the ten milliliters of allantoic fluid is removed, from which about fifteen micrograms of the flu vaccine can be obtained. At this point, the viruses have been weakened or killed and the viral antigen is purified and placed inside vials, syringes, or nasal sprayers. Done on a large-scale, this method is used to produce the flu vaccine for the human population.
Other methods of manufacture
Methods of vaccine generation that bypass the need for eggs include the construction of influenza virus-like particles (VLP). VLP resemble viruses, but there is no need for inactivation, as they do not include viral coding elements, but merely present antigens in a similar manner to a virion. Some methods of producing VLP include cultures of Spodoptera frugiperda Sf9 insect cells and plant-based vaccine production (e.g., production in Nicotiana benthamiana). There is evidence that some VLPs elicit antibodies that recognize a broader panel of antigenically distinct viral isolates compared to other vaccines in the hemagglutination-inhibition assay (HIA).A gene-based DNA vaccine, used to prime the immune system after boosting with an inactivated H5N1 vaccine, underwent clinical trials in 2011.On November 20, 2012, Novartis received FDA approval for the first cell-culture vaccine. In 2013, the recombinant influenza vaccine, Flublok, was approved for use in the United States.On September 17, 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 Supemtek, a quadrivalent influenza vaccine (recombinant, prepared in cell culture). The applicant for this medicinal product is Sanofi Pasteur. Supemtek was approved for medical use in the European Union in November 2020.Australia authorised its first and cell-based vaccine in March 2021, based on an "eternal cell line" of a dog kidney. Because of the way it is produced, it produces better-matched vaccine (to the flu strains).
Vaccine manufacturing countries
According to the WHO, as of 2019, countries where influenza vaccine is produced include:
In addition, Kazakhstan, Serbia and Thailand had facilities in final stages of establishing production.
Cost-effectiveness
The cost-effectiveness of seasonal influenza vaccination has been widely evaluated for different groups and in different settings. In the elderly (over 65), the majority of published studies have found that vaccination is cost saving, with the cost savings associated with influenza vaccination (e.g. prevented health care visits) outweighing the cost of vaccination. In older adults (aged 50–64 years), several published studies have found that influenza vaccination is likely to be cost-effective, however the results of these studies were often found to be dependent on key assumptions used in the economic evaluations. The uncertainty in influenza cost-effectiveness models can partially be explained by the complexities involved in estimating the disease burden, as well as the seasonal variability in the circulating strains and the match of the vaccine. In healthy working adults (aged 18–49 years), a 2012 review found that vaccination was generally not cost-saving, with the suitability for funding being dependent on the willingness to pay to obtain the associated health benefits. In children, the majority of studies have found that influenza vaccination was cost-effective, however many of the studies included (indirect) productivity gains, which may not be given the same weight in all settings. Several studies have attempted to predict the cost-effectiveness of interventions (including prepandemic vaccination) to help protect against a future pandemic, however estimating the cost-effectiveness has been complicated by uncertainty as to the severity of a potential future pandemic and the efficacy of measures against it.
Research
Influenza research includes molecular virology, molecular evolution, pathogenesis, host immune responses, genomics, and epidemiology. These help in developing influenza countermeasures such as vaccines, therapies and diagnostic tools. Improved influenza countermeasures require basic research on how viruses enter cells, replicate, mutate, evolve into new strains and induce an immune response. The Influenza Genome Sequencing Project is creating a library of influenza sequences that will help researchers understanding of what makes one strain more lethal than another, what genetic determinants most affect immunogenicity, and how the virus evolves over time. Solutions to limitations in current vaccine methods are being researched.
A different approach uses Internet content to estimate the impact of an influenza vaccination campaign. More specifically, researchers have used data from Twitter and Microsofts Bing search engine, and proposed a statistical framework which, after a series of operations, maps this information to estimates of the influenza-like illness reduction percentage in areas where vaccinations have been performed. The method has been used to quantify the impact of two flu vaccination programmes in England (2013/14 and 2014/15), where school-age children were administered a live attenuated influenza vaccine (LAIV). Notably, the impact estimates were in accordance with estimations from Public Health England based on traditional syndromic surveillance endpoints.
Rapid response to pandemic flu
The rapid development, production, and distribution of pandemic influenza vaccines could potentially save millions of lives during an influenza pandemic. Due to the short time frame between identification of a pandemic strain and need for vaccination, researchers are looking at novel technologies for vaccine production that could provide better "real-time" access and be produced more affordably, thereby increasing access for people living in low- and moderate-income countries, where an influenza pandemic may likely originate, such as live attenuated (egg-based or cell-based) technology and recombinant technologies (proteins and virus-like particles). As of July 2009, more than seventy known clinical trials have been completed or are ongoing for pandemic influenza vaccines. In September 2009, the FDA approved four vaccines against the 2009 H1N1 influenza virus (the 2009 pandemic strain), and expected the initial vaccine lots to be available within the following month.In January 2020, the US Food and Drug Administration (FDA) approved Audenz as a vaccine for the H5N1 flu virus. Audenz is a vaccine indicated for active immunization for the prevention of disease caused by the influenza A virus H5N1 subtype contained in the vaccine. Audenz is approved for use in persons six months of age and older at increased risk of exposure to the influenza A virus H5N1 subtype contained in the vaccine.
Universal flu vaccines
A "universal vaccine" that would not have to be designed and made for each flu season in each hemisphere would stabilize the supply, avoid error in predicting the seasons variants, and protect against escape of the circulating strains by mutation. Such a vaccine has been the subject of research for decades.One approach is to use broadly neutralizing antibodies that, unlike the annual seasonal vaccines used over the first decades of the 21st century that provoke the body to generate an immune response, instead provide a component of the immune response itself. The first neutralizing antibodies were identified in 1993, via experimentation. It was found that the flu neutralizing antibodies bound to the stalk of the Hemagglutinin protein. Antibodies that could bind to the head of those proteins were identified. The highly conserved M2 proton channel was proposed as a potential target for broadly neutralizing antibodies.The challenges for researchers are to identify single antibodies that could neutralize many subtypes of the virus, so that they could be useful in any season, and that target conserved domains that are resistant to antigenic drift.Another approach is to take the conserved domains identified from these projects, and to deliver groups of these antigens to provoke an immune response; various approaches with different antigens, presented different ways (as fusion proteins, mounted on virus-like particles, on non-pathogenic viruses, as DNA, and others), are under development.Efforts have also been undertaken to develop universal vaccines that specifically activate a T-cell response, based on clinical data showing that people with a strong, early T-cell response have better outcomes when infected with influenza and because T-cells respond to conserved epitopes. The challenge for developers is that these epitopes are on internal protein domains that are only mildly immunogenic.Along with the rest of the vaccine field, people working on universal vaccines have experimented with vaccine adjuvants to improve the ability of their vaccines to create a sufficiently powerful and enduring immune response.
Oral influenza vaccine
As of 2019, an oral flu vaccine was in clinical research. The oral vaccine candidate is based on an adenovirus type 5 vector modified to remove genes needed for replication, with an added gene that expresses a small double-stranded RNA hairpin molecule as an adjuvant. In 2020, a Phase II human trial of the pill form of the vaccine showed that it was well tolerated and provided similar immunity to a licensed injectable vaccine.
COVID-19
An influenza vaccine and a COVID-19 vaccine may be given safely at the same time. Preliminary research indicates that influenza vaccination does not prevent COVID-19, but may reduce the incidence and severity of COVID-19 infection.
Criticism
Tom Jefferson, who has led Cochrane Collaboration reviews of flu vaccines, has called clinical evidence concerning flu vaccines "rubbish" and has therefore declared them to be ineffective; he has called for placebo-controlled randomized clinical trials, which most in the field hold as unethical. His views on the efficacy of flu vaccines are rejected by medical institutions including the CDC and the National Institutes of Health, and by key figures in the field like Anthony Fauci.Michael Osterholm, who led the Center for Infectious Disease Research and Policy 2012 review on flu vaccines, recommended getting the vaccine but criticized its promotion, saying, "We have overpromoted and overhyped this vaccine... it does not protect as promoted. Its all a sales job: its all public relations."
Veterinary use
Veterinary influenza vaccination aims to achieve the following four objectives:
Protection from clinical disease
Protection from infection with virulent virus
Protection from virus excretion
Serological differentiation of infected from vaccinated animals (so-called DIVA principle).
Horses
Horses with horse flu can run a fever, have a dry hacking cough, have a runny nose, and become depressed and reluctant to eat or drink for several days but usually recover in two to three weeks. "Vaccination schedules generally require a primary course of two doses, 3–6 weeks apart, followed by boosters at 6–12 month intervals. It is generally recognized that in many cases such schedules may not maintain protective levels of antibody and more frequent administration is advised in high-risk situations."It is a common requirement at shows in the United Kingdom that horses be vaccinated against equine flu and a vaccination card must be produced; the International Federation for Equestrian Sports (FEI) requires vaccination every six months.
Poultry
Poultry vaccines for bird flu are made inexpensively and are not filtered and purified like human vaccines to remove bits of bacteria or other viruses. They usually contain whole virus, not just hemagglutinin as in most human flu vaccines. Another difference between human and poultry vaccines is that poultry vaccines are adjuvated with mineral oil, which induces a strong immune reaction but can cause inflammation and abscesses. "Chicken vaccinators who have accidentally jabbed themselves have developed painful swollen fingers or even lost thumbs, doctors said. Effectiveness may also be limited. Chicken vaccines are often only vaguely similar to circulating flu strains – some contain an H5N2 strain isolated in Mexico years ago. With a chicken, if you use a vaccine thats only 85 percent related, youll get protection, Dr. Cardona said. In humans, you can get a single point mutation, and a vaccine thats 99.99 percent related wont protect you. And they are weaker [than human vaccines]. Chickens are smaller and you only need to protect them for six weeks, because thats how long they live till you eat them, said Dr. John J. Treanor, a vaccine expert at the University of Rochester. Human seasonal flu vaccines contain about 45 micrograms of antigen, while an experimental A(H5N1) vaccine contains 180. Chicken vaccines may contain less than one microgram. You have to be careful about extrapolating data from poultry to humans, warned Dr. David E. Swayne, director of the agriculture departments Southeast Poultry Research Laboratory. Birds are more closely related to dinosaurs."Researchers, led by Nicholas Savill of the University of Edinburgh in Scotland, used mathematical models to simulate the spread of H5N1 and concluded that "at least 95 percent of birds need to be protected to prevent the virus spreading silently. In practice, it is difficult to protect more than 90 percent of a flock; protection levels achieved by a vaccine are usually much lower than this." The Food and Agriculture Organization of the United Nations has issued recommendations on the prevention and control of avian influenza in poultry, including the use of vaccination.A filtered and purified Influenza A vaccine for humans is being developed and many countries have recommended it be stockpiled so if an Avian influenza pandemic starts jumping to humans, the vaccine can quickly be administered to avoid loss of life. Avian influenza is sometimes called avian flu, and commonly bird flu.
Pigs
Swine influenza vaccines are extensively used in pig farming in Europe and North America. Most swine flu vaccines include an H1N1 and an H3N2 strain.
Swine influenza has been recognized as a major problem since the outbreak in 1976. Evolution of the virus has resulted in inconsistent responses to traditional vaccines. Standard commercial swine flu vaccines are effective in controlling the problem when the virus strains match enough to have significant cross-protection. Customised (autogenous) vaccines made from the specific viruses isolated, are made and used in the more difficult cases. The vaccine manufacturer Novartis claims that the H3N2 strain (first identified in 1998) has brought major losses to pig farmers. Abortion storms are a common sign and sows stop eating for a few days and run a high fever. The mortality rate can be as high as fifteen percent.
Dogs
In 2004, influenza A virus subtype H3N8 was discovered to cause canine influenza. Because of the lack of previous exposure to this virus, dogs have no natural immunity to this virus. However, a vaccine was found in 2004.
Annual reformulation
Each year, three strains are chosen for selection in that years flu vaccination by the WHO Global Influenza Surveillance and Response System. The chosen strains are the H1N1, H3N2, and Type-B strains thought most likely to cause significant human suffering in the coming season. Starting with the 2012–2013 Northern Hemisphere influenza season (coincident with the approval of quadrivalent influenza vaccines), the WHO has also recommended a 2nd B-strain for use in quadrivalent vaccines. The World Health Organization (WHO) coordinates the contents of the vaccine each year to contain the most likely strains of the virus to attack the next year.
"The WHO Global Influenza Surveillance Network was established in 1952 [renamed "Global Influenza Surveillance and Response System" in 2011]. The network comprises four WHO Collaborating Centres (WHO CCs) and 112 institutions in 83 countries, which are recognized by WHO as WHO National Influenza Centres (NICs). These NICs collect specimens in their country, perform primary virus isolation and preliminary antigenic characterization. They ship newly isolated strains to WHO CCs for high level antigenic and genetic analysis, the result of which forms the basis for WHO recommendations on the composition of influenza vaccine for the Northern and Southern Hemisphere each year."The Global Influenza Surveillance and Response Systems selection of viruses for the vaccine manufacturing process is based on its best estimate of which strains will predominate the next year, amounting in the end to well-informed but fallible guesswork.Formal WHO recommendations were first issued in 1973. Beginning in 1999 there have been two recommendations per year: one for the northern hemisphere and the other for the southern hemisphere.Historical annual reformulations of the influenza vaccine are listed in a separate article. Recent WHO seasonal influenza vaccine composition recommendations:
2020–2021 northern hemisphere
The composition of virus vaccines for use in the 2020–2021 Northern Hemisphere influenza season recommended by the World Health Organization on February 28, 2020, is:for egg-based:
an A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus
an A/Hong Kong/2671/2019 (H3N2)-like virus
a B/Washington/02/2019 (B/Victoria lineage)-like virus
a B/Phuket/3073/2013 (B/Yamagata lineage)-like virusfor cell- or recombinant-based:
an A/Hawaii/70/2019 (H1N1)pdm09-like virus
an A/Hong Kong/45/2019 (H3N2)-like virus
a B/Washington/02/2019 (B/Victoria lineage)-like virus
a B/Phuket/3073/2013 (B/Yamagata lineage)-like virusThe WHO recommends that trivalent vaccines use as their influenza B virus a B/Washington/02/2019 (B/Victoria lineage)-like virus.
United StatesThe Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the Food and Drug Administration (FDA) recommended that the quadrivalent formulation of egg-based influenza vaccines for the US 2020–2021 influenza season contain the following:
an A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus;
an A/HongKong/2671/2019 (H3N2)-like virus;
a B/Washington/02/2019-like virus (B/Victoria lineage);
a B/Phuket/3073/2013-like virus (B/Yamagata lineage).The committee recommended that the quadrivalent formulation of cell- or recombinant-based influenza vaccines for the US 2020–2021 influenza season contain the following:
an A/Hawaii/70/2019 (H1N1)pdm09-like virus;
an A/HongKong/45/2019 (H3N2)-like virus;
a B/Washington/02/2019-like virus (B/Victoria lineage);
a B/Phuket/3073/2013-like virus (B/Yamagata lineage)For trivalent influenza vaccines for use in the US for the 2020–2021 influenza season, depending on the manufacturing method of the vaccine, the committee recommended that the A(H1N1)pdm09, A(H3N2) and B/Victoria lineage viruses recommended above for the quadrivalent vaccines be used.
European UnionThe composition of virus vaccines for use in the European Union for the 2020–2021 Northern Hemisphere influenza season recommended by the European Medicines Agency on April 1, 2020, was:Egg-based or live attenuated trivalent vaccines should contain:
an A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus;
an A/Hong Kong/2671/2019 (H3N2)-like virus;
a B/Washington/02/2019 (B/Victoria lineage)-like virus.Cell-based trivalent vaccines should contain:
an A/Hawaii/70/2019 (H1N1)pdm09-like virus;
an A/Hong Kong/45/2019 (H3N2)-like virus;
a B/Washington/02/2019 (B/Victoria lineage)-like virus.A B/Phuket/3073/2013-like virus is recommended in addition to the strains mentioned above for the quadrivalent vaccines.
2021 southern hemisphere
The composition of vaccines for use in the 2021 Southern Hemisphere influenza season influenza season recommended by the World Health Organization in September 2020:For egg-based (trivalent):
an A/Victoria/2570/2019 (H1N1)pdm09-like virus;
an A/Hong Kong/2671/2019 (H3N2)-like virus; and
a B/Washington/02/2019 (B/Victoria lineage)-like virus.For cell- or recombinant-based (trivalent):
an A/Wisconsin/588/2019 (H1N1)pdm09-like virus;
an A/Hong Kong/45/2019 (H3N2)-like virus; and
a B/Washington/02/2019 (B/Victoria lineage)-like virus.The quadrivalent version should contain, in addition to the above:
a B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.In Australia, the standard vaccine under the National Immunisation Program for 2021 is the quadrivalent one.
2021–2022 northern hemisphere
The composition of virus vaccines for use in the 2021–2022 Northern Hemisphere influenza season is
European UnionThe composition of virus vaccines for use in the European Union for the 2021–2022 Northern Hemisphere influenza season recommended by the European Medicines Agency on March 30, 2021, is:Egg-based or live attenuated trivalent vaccines should contain:
an A/Victoria/2570/2019 (H1N1)pdm09-like virus;
an A/Cambodia/e0826360/2020 (H3N2)-like virus;
a B/Washington/02/2019 (B/Victoria lineage)-like virus.Cell-based trivalent vaccines should contain:
an A/Wisconsin/588/2019 (H1N1)pdm09-like virus;
an A/Cambodia/e0826360/2020 (H3N2)-like virus;
a B/Washington/02/2019 (B/Victoria lineage)-like virus.A B/Phuket/3073/2013-like virus is recommended in addition to the strains mentioned above for the quadrivalent vaccines.
United StatesThe FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) recommended that the quadrivalent formulation of egg-based influenza vaccines for the US 2021-2022 influenza season contain the following:
an A/Victoria/2570/2019 (H1N1) pdm09-like virus;
an A/Cambodia/e0826360/2020 (H3N2)-like virus;
a B/Washington/02/2019- like virus (B/Victoria lineage);
a B/Phuket/3073/2013-like virus (B/Yamagata lineage).The committee recommended that the quadrivalent formulation of cell- or recombinant based influenza vaccines for the US 2021-2022 influenza season contain the following:
an A/Wisconsin/588/2019 (H1N1) pdm09-like virus;
an A/Cambodia/e0826360/2020 (H3N2)-like virus;
a B/Washington/02/2019- like virus (B/Victoria lineage);
a B/Phuket/3073/2013-like virus (B/Yamagata lineage).For trivalent influenza vaccines for use in the US for the 2021-2022 influenza season, depending on the manufacturing method of the vaccine, the committee recommended that the A(H1N1) pdm09, A(H3N2) and B/Washington/02/2019-like virus (B/Victoria lineage) viruses recommended above for the quadrivalent vaccines be used.
2022 southern hemisphere
The composition of vaccines for use in the 2022 Southern Hemisphere influenza season influenza season recommended by the World Health Organization in September 2021:Egg-based vaccines:
A/Victoria/2570/2019 (H1N1)pdm09-like virus;
A/Darwin/9/2021 (H3N2)-like virus;
B/Austria/1359417/2021 (B/Victoria lineage)-like virus; and
B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.Cell- or recombinant-based vaccines:
A/Wisconsin/588/2019 (H1N1)pdm09-like virus;
A/Darwin/6/2021 (H3N2)-like virus;
B/Austria/1359417/2021 (B/Victoria lineage)-like virus; and
B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.It is recommended that trivalent influenza vaccines for use in the 2022 southern hemisphere influenza season contain the following:
Egg-based vaccines:
A/Victoria/2570/2019 (H1N1)pdm09-like virus;
A/Darwin/9/2021 (H3N2)-like virus; and
B/Austria/1359417/2021 (B/Victoria lineage)-like virus.Cell- or Recombinant-based vaccines:
A/Wisconsin/588/2019 (H1N1)pdm09-like virus;
A/Darwin/6/2021 (H3N2)-like virus; and
B/Austria/1359417/2021 (B/Victoria lineage)-like virus
2022–2023 northern hemisphere
The composition of virus vaccines for use in the 2022–2023 Northern Hemisphere influenza season is
European UnionThe composition of virus vaccines for use in the European Union for the 2022–2023 Northern Hemisphere influenza season recommended by the European Medicines Agency on March 29, 2022, is:Quadrivalent egg-based or live attenuated vaccines should contain:
an A/Victoria/2570/2019 (H1N1)pdm09-like virus;
an A/Darwin/ |
Influenza vaccine | 9/2021 (H3N2)-like virus;
a B/Austria/1359417/2021 (B/Victoria lineage)-like virus; and
a B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.Quadrivalent cell-culture or recombinant-based vaccines should contain:
an A/Wisconsin/588/2019 (H1N1)pdm09-like virus;
an A/Darwin/6/2021 (H3N2)-like virus;
a B/Austria/1359417/2021 (B/Victoria lineage)-like virus; and
a B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.United StatesThe FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) recommended that the quadrivalent formulation of egg-based influenza vaccines for the U.S. 2022-2023 influenza season contain the following:
an A/Victoria/2570/2019 (H1N1)pdm09-like virus;
an A/Darwin/9/2021 (H3N2)-like virus;
a B/Austria/1359417/2021-like virus (B/Victoria lineage); and
a B/Phuket/3073/2013-like virus (B/Yamagata lineage).The committee recommended that the quadrivalent formulation of cell- or recombinant-based influenza vaccines for the US 2022–2023 influenza season contain the following:
an A/Wisconsin/588/2019 (H1N1)pdm09-like virus;
an A/Darwin/6/2021 (H3N2)-like virus;
a B/Austria/1359417/2021-like virus (B/Victoria lineage); and
a B/Phuket/3073/2013-like virus (B/Yamagata lineage).For trivalent influenza vaccines for use in the US for the 2022–2023 influenza season, depending on the manufacturing method of the vaccine, the committee recommended that the A(H1N1)pdm09, A(H3N2) and B/Austria/1359417/2021-like virus (B/Victoria lineage) viruses recommended above for the quadrivalent vaccines be used.
Notes
See also
H5N1 vaccine
Seasonal influenza vaccine brands
Universal influenza vaccine
References
Further reading
World Health Organization (October 2017). The immunological basis for immunization series: module 23: influenza vaccines. World Health Organization (WHO). hdl:10665/259211. ISBN 978-9241513050.
Ramsay M (ed.). "Chapter 19: Influenza". Immunisation against infectious disease. Public Health England.
Hamborsky J, Kroger A, Wolfe S, eds. (2015). "Chapter 12: Influenza". Epidemiology and Prevention of Vaccine-Preventable Diseases (13th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC). ISBN 978-0990449119.
Budd A, Blanton L, Grohskopf L, Campbell A, Dugan V, Wentworth DE, et al. (March 29, 2019). "Chapter 6: Influenza". In Roush SW, Baldy LM, Hall MA (eds.). Manual for the surveillance of vaccine-preventable diseases. Atlanta GA: U.S. Centers for Disease Control and Prevention (CDC).
National Advisory Committee on Immunization (May 2020). "Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2020–2021" (PDF). Public Health Agency of Canada. Cat.: HP37-25F-PDF; Pub.: 200003. Lay summary. {{cite web}}: Cite uses deprecated parameter |lay-url= (help)
National Advisory Committee on Immunization (NACI) (May 2018). NACI literature review on the comparative effectiveness and immunogenicity of subunit and split virus inactivated influenza vaccines in adults 65 years of age and older (PDF). Government of Canada. ISBN 9780660264387. Cat.: HP40-213/2018E-PDF; Pub.: 180039. Lay summary. {{cite book}}: Cite uses deprecated parameter |lay-url= (help)
Rajaram S, Wojcik R, Moore C, Ortiz de Lejarazu R, de Lusignan S, Montomoli E, et al. (August 2020). "The impact of candidate influenza virus and egg-based manufacture on vaccine effectiveness: Literature review and expert consensus". Vaccine. 38 (38): 6047–6056. doi:10.1016/j.vaccine.2020.06.021. PMID 32600916.
External links
Inactivated Influenza Vaccine Information Statement, US Centers for Disease Control and Prevention (CDC)
Live, Intranasal Influenza Vaccine Information Statement, US Centers for Disease Control and Prevention (CDC)
Seasonal Influenza (Flu) Vaccination and Preventable Disease, US Centers for Disease Control and Prevention (CDC)
Misconceptions about Seasonal Flu and Flu Vaccines, US Centers for Disease Control and Prevention (CDC)
"Influenza Vaccine". Drug Information Portal. U.S. National Library of Medicine.
Influenza Vaccines at the US National Library of Medicine Medical Subject Headings (MeSH) |
Aminophylline | Aminophylline is a compound of the bronchodilator theophylline with ethylenediamine in 2:1 ratio. The ethylenediamine improves solubility, and the aminophylline is usually found as a dihydrate.Aminophylline is less potent and shorter-acting than theophylline. Its most common use is in the treatment of airway obstruction from asthma or COPD. Aminophylline is a nonselective adenosine receptor antagonist and phosphodiesterase inhibitor.
Medical uses
Intravenous aminophylline can be used for acute exacerbation of symptoms and reversible airway obstruction in asthma and other chronic lung disease such as COPD, emphysema and chronic bronchitis. It is used as an adjunct to inhaled beta-2 selective agonists and systemically administered corticosteroids.Aminophylline is used to reverse regadenoson, dipyridamole or adenosine based infusions during nuclear cardiology stress testing. Aminophylline has also been reported to be effective in preventing slow heart rates during complex cardiovascular interventions [Atherectomy of the right coronary artery]. It is also used in the treatment of heart block due to acute inferior myocardial infarction. It can also cause cardiac arrest.
Aminophylline has shown some promise as a bodyfat reducer when used as a topical cream. Aminophylline is also a treatment option for anaphylactic shock.While it has been suggested for use in cardiac arrest evidence does not support a benefit.
Side effects
Aminophylline can lead to theophylline toxicity. Aminophylline has been found to decrease the sedative effects of propofol and decrease topiramate antiseizure action.
Properties
It is more soluble in water than theophylline. White or slightly yellowish granules or powder, having a slight ammoniacal odor and a bitter taste. Upon exposure to air, it gradually loses ethylenediamine and absorbs carbon dioxide with the liberation of free theophylline. Its solutions are alkaline. 1 g dissolves in 25 mL of water to give a clear solution; 1 g dissolved in 5 mL of water crystallizes upon standing, but redissolves when a small amount of ethylenediamine is added. Insoluble in alcohol and in ether.
Pharmacology
Like other methylated xanthine derivatives, aminophylline is both a
competitive nonselective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNF-alpha and leukotriene synthesis, and reduces inflammation and innate immunity and
nonselective adenosine receptor antagonist.Aminophylline causes bronchodilation, diuresis†, central nervous system and cardiac stimulation, and gastric acid secretion by blocking phosphodiesterase which increases tissue concentrations of cyclic adenosine monophosphate (cAMP) which in turn promotes catecholamine stimulation of lipolysis, glycogenolysis, and gluconeogenesis, and induces release of epinephrine from adrenal medulla cells.†Note that diuresis is caused by an increase in cAMP which acts in the CNS to inhibit the release of antidiuretic hormone (arginine-vasopressin).
Adenosine is an endogenous extracellular messenger that can regulate myocardial oxygen needs. It acts through cellular surface receptors which effect intracellular signalling pathways to increase coronary artery blood flow, slow heart rate, block atrioventricular node conduction, suppress cardiac automaticity, and decrease β-adrenergic effects on contractility. Adenosine also antagonizes chronotropic and ionotropic effects of circulating catecholamines. Overall, adenosine decreases the heart’s rate and force of contraction, which increases blood supply to the cardiac muscle. Given specific circumstances this mechanism (which is intended to protect the heart) may cause atropine-resistant refractory bradyasystole. Adenosines effects are concentration-dependent. Adenosine’s receptors are competitively antagonized by methylxanthines such as aminophylline. Aminophylline competitively antagonizes the cardiac actions of adenosine at the cell surface receptors. Thus, it increases heart rate and contractility.
Brand names
Euphyllin
Phyllocontin
Truphylline
Minomal R 175 mg tab
Minomal R 350 mg tab
Minomal SR 600 mg tab
References
External links
"Aminophylline". Drug Information Portal. U.S. National Library of Medicine. |
Cladribine | Cladribine, sold under the brand name Leustatin, among others, is a medication used to treat hairy cell leukemia (leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia.Cladribine, sold under the brand name Mavenclad, is indicated for the treatment of adult patients with highly active forms of relapsing-remitting multiple sclerosis.Cladribine (2-chloro-2-deoxyadenosine [2-CdA]) is a purine analogue that selectively targets and suppresses lymphocytes implicated in the underlying pathogenesis of multiple sclerosis and B-cell leukaemia. Chemically, it mimics the nucleoside adenosine. However, unlike adenosine, it is relatively resistant to breakdown by the enzyme adenosine deaminase, which causes it to accumulate in targeted cells and interfere with the cells ability to process DNA.Cladribine is taken up by cells via transporter proteins. Once inside a cell, cladribine undergoes phosphorylation by the enzyme deoxycytidine kinase (DCK) to produce mononucleotide 2-chlorodeoxyadenosine 5’monophosphate (2-CdAMP), which is subsequently phosphorylated to the triphosphorylated active compound 2-chlorodeoxyadenosine 5’triphosphate (2-CdATP). Activated cladribine is incorporated into cellular DNA, which triggers apoptosis. Accumulation of cladribine into cells is dependent on the ratio of 2-CdATP and 5-nucleotidase (5’-NT), which breaks down and inactivates the compound. This ratio differs between cell types, with high levels in T and B lymphocytes, resulting in selective targeting of these cells. In contrast, CdATP:5NT is relatively low in other cell types, thus sparing numerous non-haematological cells.
Medical uses
Cladribine is used as a first- and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukaemia, and is administered by intravenous or subcutaneous infusion. Some investigators have used the parenteral formulation orally to treat patients with hairy cell leukemia. About 37–51% of oral cladribine is bioavailable orally. It is used, often in combination with other cytotoxic agents, to treat various kinds of histiocytosis, including Erdheim–Chester disease and Langerhans cell histiocytosis.Following EMA approval of cladribine tablets for the treatment of adult patients with highly active relapsing-remitting multiple sclerosis in 2017, as of July 2020, cladribine tablets have gained marketing authorisation in over 75 countries. In 2019, cladribine tablets were approved by the FDA for the treatment of relapsing forms of multiple sclerosis, to include relapsing-remitting disease and active secondary progressive disease, in adult patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of multiple sclerosis.Cladribine may cause foetal harm when administered to a pregnant woman and is listed by the FDA as pregnancy category D; safety and efficacy in children has not been established.
Mechanism of action
As a purine analogue, cladribine (2-chloro-2-deoxyadenosine [2-CdA]) is taken up into rapidly proliferating cells, including B and T lymphocytes, to be incorporated into DNA synthesis. Chemically, it mimics nucleoside adenosine; however, unlike adenosine, cladribine has a chlorine molecule at position 2, which renders it partially resistant to breakdown by adenosine deaminase. This causes it to accumulate in cells and interfere with the targeted cells ability to process DNA.Cladribine is taken up by specific nucleoside transporter proteins. Once inside a cell, cladribine undergoes phosphorylation by the enzyme deoxycytidine kinase (DCK) to produce mononucleotide 2-chlorodeoxyadenosine 5’monophosphate (2-CdAMP), which is subsequently phosphorylated to the triphosphorylated active compound, 2-chlorodeoxyadenosine 5’triphosphate (2-CdATP).Activated cladribine is incorporated into the DNA synthesis pathway, where it disrupts DNA repair and synthesis, resulting in an accumulation of DNA strand breaks This is followed by the activation of transcription factor p53, the release of cytochrome c from mitochondria and eventual programmed cell death (apoptosis). This process occurs over approximately 2 months, with a peak level of cell depletion 4–8 weeks after treatment.Another family of enzymes, the 5-nucleotidase (5-NT) family, is also capable of dephosphorylating cladribine, making it inactive. The most important subtypes of this group appear to be cytosolic 5-NT, c-5NCT1A and c-NT1B, which are cytosolically active and specific for purine analogues.Accumulation of cladribine into cells is dependent on the ratio of 2-CdATP and 5-NT. This ratio differs between cell types, with high levels in T and B lymphocytes, making them particularly susceptible to cell death. The cells with the highest ratios are B cells, especially germinal centre and naïve B cells. This helps to explain which B cells are more vulnerable to cladribine-mediated apoptosis. DCK is the rate-limiting enzyme for conversion of the cladribine prodrug into its active triphosphate form, leading to the selective depletion of dividing and non-dividing T and B lymphocytes. In contrast, the CdATP:5-NT ratio is relatively low in other cell types, thus sparing numerous non-hematologic cells.In multiple sclerosis, cladribines effectiveness may be due to depletion of B cells, in particular memory B cells. In the pivotal phase 3 clinical trial of oral cladribine in multiple sclerosis, CLARITY, cladribine selectively depleted 80% of peripheral B cells, compared to only 40–45% of CD4+ T cells and 15‒30% CD8+ T cells. More recently, cladribine has been shown to induce long term, selective suppression of certain subtypes of B cells, especially memory B cells.Although cladribine is selective for B cells, the long-term suppression of memory B cells, which may contribute to its effect in multiple sclerosis, is not explained by gene or protein expression. Instead, cladribine appears to deplete the entire B cell department, but while naïve B cells rapidly move from lymphoid organs, the memory B cell pool repopulates slowly from the bone marrow. Both hairy cell leukemia and B-cell chronic lymphocytic leukaemia are types of B cell blood cancers.
History in hairy cell leukemia
Ernest Beutler and Dennis A. Carson had studied adenosine deaminase deficiency and recognised that because the lack of adenosine deaminase led to the destruction of B cell lymphocytes, a drug designed to inhibit adenosine deaminase might be useful in lymphomas. Carson then synthesised cladribine, and through clinical research at Scripps starting in the 1980s, Beutler tested it as intravenous infusion and found it was especially useful to treat hairy cell leukemia. No pharmaceutical companies were interested in selling the drug because hairy cell leukemia was an orphan disease, so Beutlers lab synthesised and packaged it and supplied it to the hospital pharmacy; the laboratory also developed a test to monitor blood levels. This was the first treatment that led to prolonged remission of hairy cell leukemia, which was previously untreatable.: 14–15 In February 1991, Scripps began a collaboration with Johnson & Johnson to bring intravenous cladribine to market, and by December of that year, Johnson & Johnson had filed a new drug application; cladribine was approved by the FDA in 1993 for hairy cell leukemia as an orphan drug, and was approved in Europe later that year.: 2 The subcutaneous formulation was developed in Switzerland in the early 1990s and it was commercialised by Lipomed GmbH in the 2000s.: 2
Safety profile of cladribine in hairy cell leukemia
Injectable cladribine suppresses the bodys ability to make new lymphocytes, natural killer cells, and neutrophils (called myelosuppression); data from hairy cell leukemia studies showed that about 70% of people taking the drug developed dangerously low levels of white blood cells and about 30% developed infections and some of those progressed to septic shock; about 40% of people taking the drug had fewer red blood cells and became severely anaemic; and about 10% of people had too few platelets. At the dosage used to treat hairy cell leukemia in two clinical trials, 16% of people had rashes and 22% had nausea, the nausea generally did not lead to vomiting.
History in multiple sclerosis
In the mid-1990s, Beutler, in collaboration with Jack Sipe, a neurologist at Scripps Institute, ran several clinical trials exploring the utility of cladribine in multiple sclerosis, based on the drugs immunosuppressive effects. Sipes insight into multiple sclerosis, and Beutlers interest in multiple sclerosis due to his sister having the disease, initiated a very productive collaboration. Ortho-Clinical, a subsidiary of Johnson & Johnson, filed a new drug application for cladribine for multiple sclerosis in 1997 but withdrew it in the late 1990s after discussion with the FDA proved that more clinical data would be needed.Ivax acquired the rights for oral administration of cladribine to treat multiple sclerosis from Scripps in 2000, and partnered with Serono in 2002. Ivax was acquired by Teva in 2006, and Merck KGaA acquired control of Seronos drug business in 2006.An oral formulation of the drug with cyclodextrin was developed: 16 by Ivax and Serono, and then Merck KGaA conducted clinical trials. Merck KGaA submitted an application to the European Medicines Agency in 2009, which was rejected in 2010, and an appeal was denied in 2011.: 4–5 Likewise Merck KGaAs new drug application with the FDA rejected in 2011.The ratio of benefit to harm was not clear to regulators, and further studies were requested to address concerns related to severe lymphopenia and cancer cases observed during pivotal trials.: 54–55 Clinical studies of multiple sclerosis were still ongoing at the time of the rejections, and Merck KGaA committed to completing them. A meta-analysis of data from clinical trials comparing the risk of cancer and other disease-modifying therapies showed that cladribine tablets did not increase the risk of cancer at the doses used in the initial clinical trials.Based on the supporting data from the completed clinical trials that confirmed no increased risk of cancer, Merck announced it would again seek regulatory approval. In 2016, the EMA accepted its application for review. On June 22, 2017, the EMAs Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the treatment of relapsing forms of multiple sclerosis.Cladribine tablets were later approved in Europe, in August 2017, for highly active relapsing-remitting multiple sclerosis, and has since been approved by the FDA for the treatment of relapsing-remitting and secondary progressive multiple sclerosis in the US.
Use in multiple sclerosis
As per the EU label, cladribine tablets are indicated for the treatment of adult patients with highly active relapsing multiple sclerosis as defined by clinical or imaging features: (i) patients with a relapse in the previous year and at least one T1 Gd+ lesion or 9 or more T2 lesions, while on another disease-modifying therapies or (ii) patients with two or more relapses in the previous year, whether on disease-modifying treatment or not.Two main approaches to multiple sclerosis treatment maintenance therapy are used – immunomodulation and immunosuppression and alternatively, immune reconstitution therapy. Classified as the latter, cladribine tablets are administered intermittently as a short treatment course without continuous immunosuppression. In contrast to maintenance therapies, clinical efficacy extends beyond the dosing period.Cladribine tablets are administered as 2 courses separated by 1 year (a maximum of 20 days of treatment). The recommended cumulative dose is 3.5 mg/kg weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (1 or 2 tablets) as a single daily dose based on body weight.Before initiating treatment with cladribine tablets, blood tests, MRI and infection screening must be performed. Due to an increased risk of herpes zoster with cladribine tablets, patients who are antibody-negative for varicella zoster virus are recommended to be vaccinated before starting treatment. Treatment should not be initiated within 4 to 6 weeks of receiving a live or attenuated live vaccine because of a risk of active infection. Vaccination with live or attenuated live vaccines should also be avoided during and after treatment, but can be considered when lymphocyte counts have recovered to ≥1000 cells/mm3.Following completion of the two treatment courses, no further treatment or additional monitoring is required.The use of cladribine tablets is contraindicated in pregnant women, and women of childbearing potential must use effective contraception to prevent pregnancy during treatment and 6 months after receiving the last dose.
Efficacy of cladribine tablets in multiple sclerosis
Clinical trial results have shown that cladribine tablets can be an effective treatment for highly active, relapsing forms of multiple sclerosis, with significant clinical benefits in relapse rate, disability progression, and radiological measures. Compared with placebo, patients who received cladribine tablets (3.5 mg/kg) in the CLARITY study had a 58% reduction in annualized relapse rate and 47% of patients showed no evidence of disease activity at 2 years. Clinical improvements can be observed at Week 24 of treatment, and benefits may be sustained up to 4 years, beyond the 2-year dosing period and recovery of total lymphocytes. Post-hoc analyses of clinical trial data showed that 89% of patients remained free from disability progression two years after treatment.Further analyses of a subgroup of patients in the CLARITY study who had very active multiple sclerosis showed a 67% reduction in relapse rates and an 82% reduction in disability progression in those treated with cladribine tablets. Similarly, clinical improvements were seen in lesion burden on MRI scans in this population.Studies evaluating the treatment effects of cladribine tablets across a spectrum of baseline demographics and disease characteristics showed that the relative risk of relapse was significantly reduced compared with placebo, irrespective of previous treatment experience.Furthermore, treatment with cladribine tablets has been shown to significantly reduce the rate of brain atrophy in patients with highly active relapsing-remitting multiple sclerosis. This reduction correlated with a reduced risk in disability progression in a retrospective analysis.In clinical trials, higher cumulative doses of cladribine tablets did not result in further improvement in efficacy nor did additional courses after the 2-year treatment period, but was associated with a higher incidence of Grade 3 and Grade 4 lymphopenia.
Safety profile of cladribine tablets in multiple sclerosis
Cladribine tablets target the cells of the adaptive immune system with minimal impact on innate immune cells. Although the exact mechanism by which cladribine exerts its therapeutic effect is not fully elucidated, it is proposed to have a transient effect on B and T lymphocyte depletion, interrupting the cascade of immune events central to multiple sclerosis. As a result, a reduction in lymphocyte count (lymphopenia) may be reported following treatment. In clinical trials, lymphocyte levels above Grade 0 (≥1000 cells/mm3) and Grade 1 (<1000–800 cells/mm3) were maintained in most patients, with levels continuing to improve after the 2-year dosing period. Less than 1% of patients developed Grade 4 lymphopenia (<200 cells/mm3). It is important that patients with lymphocyte counts below 500 cells/mm3 should be actively monitored for signs suggestive of infection and that anti-infective treatments are given to at-risk patients.Despite the initial reduction in lymphocyte counts following treatment, studies showed the overall risk of infection in patients receiving cladribine tablets was comparable to those who received placebo, except for herpes zoster infection. Due to this increased risk, it is recommended that patients are screened for varicella zoster virus and antibody-negative patients are vaccinated prior to receiving treatment. In an analysis of post-approval data, as of 2020, no new infection safety signals were observed in over 18,000 patients.Progressive multifocal leukoencephalopathy has been reported in patients with hairy cell leukemia treated with parenteral cladribine. However, in up to 10 years of follow-up of patients receiving cladribine tablets for multiple sclerosis, no cases of progressive multifocal leukoencephalopathy have been observed; baseline MRI must be performed prior to initiating treatment.In clinical trials, malignancies were observed more frequently in patients treated with cladribine tablets compared with patients who received placebo. Compared with a matched reference population from the Global Cancer Observatory database, cladribine tablets had no increased risk of malignancy in long-term real-world evidence data.
Research directions
Cladribine has been studied as part of a multidrug chemotherapy regimen for drug-resistant T-cell prolymphocytic leukaemia.
References
External links
"Cladribine". Drug Information Portal. U.S. National Library of Medicine. |
Imipenem/cilastatin | Imipenem/cilastatin, sold under the brand name Primaxin among others, is an antibiotic useful for the treatment of a number of bacterial infections. It is made from a combination of imipenem and cilastatin. Specifically it is used for pneumonia, sepsis, endocarditis, joint infections, intra-abdominal infections, and urinary tract infections. It is given by injection into a vein or muscle.Common side effects include nausea, diarrhea, and pain at the site of injection. Other side effects may include Clostridium difficile diarrhea and allergic reactions including anaphylaxis. It is unclear if use during pregnancy is safe for the baby. Imipenem is in the carbapenem family of medications and works by interfering with the bacterias cell wall. Cilastatin blocks the activity of dehydropeptidase I which prevents the breakdown of imipenem.Imipenem/cilastatin was first sold in 1987. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Imipenem/cilastatin is used for lower respiratory tract infections, urinary tract infections, intra-abdominal infections, gynecologic infections, bacterial sepsis, bone and joint infections, skin and skin structure infections, endocarditis and polymicrobic infections.It is a broad-spectrum beta-lactam containing equal quantities of imipenem and cilastatin.
Side effects
Common side effects for both forms are:
Upset stomach
Vomiting
Stomach painMajor side effects requiring medical attention:
Diarrhea
Rash
Fever
Facial swelling
Difficulty breathing
Unusual bleeding
SeizuresThis medicine is passed through breast milk, so its use during pregnancy or breastfeeding should only be done when clearly needed. Primaxin is cleared from the body by the kidneys, so it is important to tell ones doctor about any other drugs being taken that are also cleared through the kidneys (such as other antibiotics), especially for older patients, as kidney function declines with age.Patients who are allergic to penicillin, cephalosporins, and related drugs may react to imipenem.
It is important tell ones doctor or pharmacist ones medical history, especially of brain disorders (e.g., seizures, head injury, tumor), kidney disease, liver disease, and stomach/intestinal diseases (e.g., colitis).
Hepatotoxicity
In large clinical trials, imipenem was associated with transient and asymptomatic elevations in serum aminotransferase levels in about 6% of patients given the drug for five to 14 days. More serious hepatic injury from imipenem/cilastatin is rare, but jaundice and liver test abnormalities have been reported in 0.1% of patients in prospective trials of the agent. Several instances of cholestatic jaundice arising during or shortly after therapy have been reported with imipenem-cilastatin and other carbapenems. The latency to onset has been within one to three weeks, and the pattern of enzyme elevations is usually cholestatic. Immunoallergic features can occur, but autoantibodies are rare. The course is usually self-limiting, but at least one case of vanishing bile duct syndrome related to the carbapenems has been reported. Imipenem and other carbapenems have not been linked to cases of acute liver failure.
Mechanism of liver injury
The cause of the mild, transient serum enzyme elevations during imipenem-cilastatin therapy is not known. The cholestatic hepatitis attributed to imipenem-cilastatin and the carbapenems is probably immunoallergic and resembles the rare, clinically apparent liver injury that has been linked to penicillins and cephalosporins.
Outcome and management
The liver injury due to the carbapenems is usually mild and self-limited. Rarely, the carbapenems can cause a clinically apparent acute cholestatic hepatitis that is usually self-limiting and not requiring therapy or intervention. In patients with vanishing bile duct syndrome, corticosteroids are often used but have not been shown to be beneficial and are best avoided. Some patients may benefit from symptomatic therapy of the pruritus associated with cholestasis using antihistamines, ursodiol, or cholestyramine. Little information is available on possible cross-sensitivity to liver injury among the different betalactam antibiotics, but patients with clinically apparent liver injury due to imipenem should probably avoid the other carbapenems.
Interactions
valproic acid (Depakene, Stavzor)
ganciclovir (Cytovene)
probenecid (Benemid)
penicillin antibiotics such as amoxicillin (Amoxil, Augmentin), ampicillin (Omnipen, Principen), dicloxacillin (Dycill, Dynapen), oxacillin (Bactocill), or penicillin (Beepen-VK, Ledercillin VK, Pen-V, Pen-Vee K, Pfizerpen, V-Cillin K, Veetids, and others); or
cephalosporin antibiotics such as cefaclor (Ceclor), cefuroxime (Ceftin), cefadroxil (Duricef), cephalexin (Keflex), and others.
Mechanism of action
Imipenem/cilastatin has the ability to kill a wide variety of bacteria. Imipenem is the active antibiotic agent and works by interfering with their ability to form cell walls, so the bacteria break up and die.
Imipenem is rapidly degraded by the renal enzyme dehydropeptidase if administered alone (making it less effective); the metabolites can cause kidney damage.
Imipenem is a broad-spectrum betalactam antibiotic used for severe bacterial infections caused by susceptible organisms. Because imipenem is rapidly inactivated by renal dehydropeptidase I, it is given in combination with cilastatin, a DHP-I inhibitor which increases half-life and tissue penetration of imipenem. Imipenem/cilastatin, like other carbapenems, binds to bacterial penicillin-binding proteins and interferes with bacterial cell wall integrity and synthesis. It has activity against many aerobic and anaerobic Gram-positive and Gram-negative organisms, including Staphylococcus aureus, Streptococcus pyogenes, S. agalactiae, S. viridans- group streptococci, Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis and Peptostreptococcus species. Imipenem/cilastatin was approved for use in the United States in 1985. Imipenem/cilastatin is indicated for the treatment of severe or complicated skin, tissue, joint, respiratory tract, intra-abdominal, urinary tract and urogenital infections, but not meningitis (as it does not pass through the blood brain barrier), endocarditis, and sepsis due to susceptible organisms. Its use is generally restricted to severe infections largely in hospitalized patients. The recommended dosage is 250 mg to 1 gram given intravenously every 6 to 8 hours or in intramuscular doses of no more than 1.5 gm daily, usually for five to 14 days. It is commercially available as Primaxin as 250-mg or 500-mg infusion bottles for IV use or 500-mg or 750-mg vials of lyophilized powder for IM injection. The most common side effects of imipenem are diarrhea, nausea, vomiting, skin rash, pruritus, and injection-site reactions.
Pharmacology
Mechanism of action
Imipenem inhibits bacterial cell-wall synthesis by binding to penicillin-binding proteins; cilastatin prevents renal metabolism of imipenem.
Bioavailability
Intramuscular injection:
imipenem: 60–75%
cilastatin: 95–100%
Distribution
The drug is distributed rapidly and widely to most tissues and fluids, including sputum, pleural fluid, peritoneal fluid, interstitial fluid, bile, aqueous humor, reproductive organs, and bone; highest concentrations occur in pleural fluid, interstitial fluid, peritoneal fluid, and reproductive organs; low concentrations occur in CSF; it crosses the placenta, and enters breast milk
Protein binding
imipenem: 13–21%
cilastatin, 40%
Metabolism
Imipenem is metabolized in the kidney by dehydropeptidase 1; activity is blocked by cilastatin.
Elimination
Half-life (both drugs): 60 min; prolonged with renal impairment.
Excretion (both drugs): Urine (~70% as unchanged drug)
Availability and description
Primaxin IV is a combination of imipenem, cilastatin sodium, and sodium bicarbonate which is added as a buffer.
Primaxin IM lacks the sodium bicarbonate buffer.
See also
Imipenem/cilastatin/relebactam
References
External links
"Cilastatin mixture with Imipenem". Drug Information Portal. U.S. National Library of Medicine. |
Alpha-1 antitrypsin | Alpha-1 antitrypsin or α1-antitrypsin (A1AT, α1AT, A1A, or AAT) is a protein belonging to the serpin superfamily. It is encoded in humans by the SERPINA1 gene. A protease inhibitor, it is also known as alpha1–proteinase inhibitor (A1PI) or alpha1-antiproteinase (A1AP) because it inhibits various proteases (not just trypsin). In older biomedical literature it was sometimes called serum trypsin inhibitor (STI, dated terminology), because its capability as a trypsin inhibitor was a salient feature of its early study. As a type of enzyme inhibitor, it protects tissues from enzymes of inflammatory cells, especially neutrophil elastase, and has a reference range in blood of 0.9–2.3 g/L (in the US the reference range is expressed as mg/dL or micromoles), but the concentration can rise manyfold upon acute inflammation.When the blood contains inadequate amounts of A1AT or functionally defective A1AT (such as in alpha-1 antitrypsin deficiency), neutrophil elastase is excessively free to break down elastin, degrading the elasticity of the lungs, which results in respiratory complications, such as chronic obstructive pulmonary disease, in adults. Normally, A1AT leaves its site of origin, the liver, and joins the systemic circulation; defective A1AT can fail to do so, building up in the liver, which results in cirrhosis in either adults or children.
In addition to binding to neutrophil elastase released by inflammatory cells, A1AT also binds to elastase localized on the cell surface in which case elastase does not act as an enzyme, but instead acts to signal cells to undergo locomotion. Besides liver cells, A1PI is produced in bone marrow, by lymphocytic and monocytic cells in lymphoid tissue, and by the Paneth cells of the gut.Inactivation of A1AT by enzymes other than elastase due to inflammation/infection causes the migration of T cells to halt precisely at the site where the pathologic insult exists. This suggests a role for α1PI not only in locomotion of lymphocytes through tissue, but as a consequence of infection, a primary role as a sentinel in immune vigilance.A1AT is both an endogenous protease inhibitor and an exogenous one used as medication. The pharmaceutical form is purified from human donor blood and is sold under the nonproprietary name alpha1–proteinase inhibitor (human) and under various trade names (including Aralast NP, Glassia, Prolastin, Prolastin-C, and Zemaira). Recombinant versions are also available but are currently used in medical research more than as medication.
Function
A1AT is a 52-kDa serpin and, in medicine, it is considered the most prominent serpin; the terms α1-antitrypsin and protease inhibitor (Pi) are often used interchangeably.
Most serpins inactivate enzymes by binding to them covalently. These enzymes are released locally in relatively low concentrations where they are immediately cleared by proteins such as A1AT. In the acute phase reaction, a further elevation is required to "limit" the damage caused by activated neutrophil granulocytes and their enzyme elastase, which breaks down the connective tissue fiber elastin.
Besides limiting elastase activity to limit tissue degradation, A1PI also acts to induce locomotion of lymphocytes through tissue including immature T cells through the thymus where immature T cells mature to become immunocompetent T cells that are released into tissue to elevate immune responsiveness.Like all serine protease inhibitors, A1AT has a characteristic secondary structure of beta sheets and alpha helices. Mutations in these areas can lead to non-functional proteins that can polymerise and accumulate in the liver (infantile hepatic cirrhosis).
Role in disease
Disorders of this protein include alpha-1 antitrypsin deficiency, an autosomal co-dominant hereditary disorder in which a deficiency of alpha-1 antitrypsin leads to a chronic uninhibited tissue breakdown. This causes the degradation especially of lung tissue and eventually leads to characteristic manifestations of pulmonary emphysema. Evidence has shown that cigarette smoke can result in oxidation of methionine 358 of α1-antitrypsin (382 in the pre-processed form containing the 24 amino acid signal peptide), a residue essential for binding elastase; this is thought to be one of the primary mechanisms by which cigarette smoking (or second-hand smoke) can lead to emphysema. Because A1AT is expressed in the liver, certain mutations in the gene encoding the protein can cause misfolding and impaired secretion, which can lead to liver cirrhosis.
An extremely rare form of Pi, termed PiPittsburgh, functions as an antithrombin (a related serpin), due to a mutation (Met358Arg). One person with this mutation has been reported to have died of a bleeding diathesis.A liver biopsy will show abundant PAS-positive globules within periportal hepatocytes.
Patients with rheumatoid arthritis (RA) have been found to make autoantibodies toward the carbamylated form of A1AT in the synovial fluid. This suggests that A1AT may play an anti-inflammatory or tissue-protecting role outside the lungs. These antibodies are associated with a more severe disease course, can be observed years before disease onset, and may predict the development of RA in arthralgia patients. Consequently, carbamylated A1AT is currently being developed as an antigenic biomarker for RA.
Nomenclature
The protein was initially named "antitrypsin" because of its ability to bind and irreversibly inactivate the enzyme trypsin in vitro covalently. Trypsin, a type of peptidase, is a digestive enzyme active in the duodenum and elsewhere.
The term alpha-1 refers to the proteins behavior on protein electrophoresis. On electrophoresis, the protein component of the blood is separated by electric current. There are several clusters, the first being albumin, the second being the alpha, the third beta and the fourth gamma (immunoglobulins). The non-albumin proteins are referred to as globulins.
The alpha region can be further divided into two sub-regions, termed "1" and "2". Alpha-1 antitrypsin is the main protein of the alpha-globulin 1 region.
Another name used is alpha-1 proteinase inhibitor (α1-PI).
Genetics
The gene is located on the long arm of chromosome 14 (14q32.1).
Over 100 different variants of α1-antitrypsin have been described in various populations. North-Western Europeans are most at risk for carrying one of the most common mutant forms of A1AT, the Z mutation (Glu342Lys on M1A, rs28929474).
Biochemical properties
A1AT is a single-chain glycoprotein consisting of 394 amino acids in the mature form and exhibits many glycoforms. The three N-linked glycosylations sites are mainly equipped with so-called diantennary N-glycans. However, one particular site shows a considerable amount of heterogeneity since tri- and even tetraantennary N-glycans can be attached to the Asparagine 107 (UniProtKB amino acid nomenclature). These glycans carry different amounts of negatively charged sialic acids; this causes the heterogeneity observed on normal A1AT when analysed by isoelectric focusing. Also, the fucosylated triantennary N-glycans were shown to have the fucose as part of a so-called Sialyl Lewis x epitope, which could confer this protein particular protein-cell recognition properties. The single cysteine residue of A1AT in position 256 (UniProtKB nomenclature) is found to be covalently linked to a free single cysteine by a disulfide bridge.
Analysis
The level of A1AT in serum is most often determined by adding an antibody that binds to A1AT, then using turbidimetry to measure how much A1AT is present. Other detection methods include the use of enzyme-linked-immuno-sorbent-assays and radial immunodiffusion.
Different analytical methods are used to determine A1AT phenotype. As protein electrophoresis is imprecise, the A1AT phenotype is analysed by isoelectric focusing (IEF) in the pH range 4.5-5.5, where the protein migrates in a gel according to its isoelectric point or charge in a pH gradient.
Normal A1AT is termed M, as it migrates toward the center of such an IEF gel. Other variants are less functional and are termed A-L and N-Z, dependent on whether they run proximal or distal to the M band. The presence of deviant bands on IEF can signify the presence of alpha-1 antitrypsin deficiency. Since the number of identified mutations has exceeded the number of letters in the alphabet, subscripts have been added to most recent discoveries in this area, as in the Pittsburgh mutation described above.
As every person has two copies of the A1AT gene, a heterozygote with two different copies of the gene may have two different bands showing on electrofocusing, although heterozygote with one null mutant that abolishes expression of the gene will only show one band.
In blood test results, the IEF results are notated as in PiMM, where Pi stands for protease inhibitor and "MM" is the banding pattern of that patient.
Alpha-1 antitrypsin levels in the blood depend on the genotype. Some mutant forms fail to fold properly and are, thus, targeted for destruction in the proteasome, whereas others have a tendency to polymerise, being retained in the endoplasmic reticulum. The serum levels of some of the common genotypes are:
PiMM: 100% (normal)
PiMS: 80% of normal serum level of A1AT
PiSS: 60% of normal serum level of A1AT
PiMZ: 60% of normal serum level of A1AT
PiSZ: 40% of normal serum level of A1AT
PiZZ: 10-15% (severe alpha-1 antitrypsin deficiency)
PiZ is caused by a glutamate to lysine mutation at position 342 (366 in pre-processed form)
PiS is caused by a glutamate to valine mutation at position 264 (288 in pre-processed form)Other rarer forms have been described; in all, there are over 80 variants.
Medical uses
Alpha-1 antitrypsin concentrates are prepared from the blood plasma of blood donors. The US Food and Drug Administration (FDA) has approved the use of four alpha-1 antitrypsin products derived from a human plasma: Prolastin, Zemaira, Glassia, and Aralast. These products for intravenous augmentation A1AT therapy can cost up to $100,000 per year per patient. They are administered intravenously at a dose of 60 mg/kg once a week; higher doses do not provided additional benefit although they can be used in anticipation of an interruption of weekly administration, such as for a vacation.Alpha1-proteinase inhibitor (Respreeza) was approved for medical use in the European Union in August 2015. It is indicated for maintenance treatment, to slow the progression of emphysema in adults with documented severe alpha1-proteinase inhibitor deficiency (e.g., genotypes PiZZ, PiZ (null), Pi (null, null), PiSZ). People are to be under optimal pharmacologic and non-pharmacologic treatment and show evidence of progressive lung disease (e.g. lower forced expiratory volume per second (FEV1) predicted, impaired walking capacity or increased number of exacerbations) as evaluated by a healthcare professional experienced in the treatment of alpha1-proteinase inhibitor deficiency.The most common side effects include dizziness, headache, dyspnoea (shortness of breath) and nausea. Allergic reactions have been observed during treatment, some of which were severe.Aerosolized-augmented A1AT therapy is under study. This involves inhaling purified human A1AT into the lungs and trapping the A1AT into the lower respiratory tract. However, inhaled A1AT may not reach the elastin fibers in the lung where elastase injury occurs. Further study is currently underway. Recombinant alpha-1 antitrypsin is not yet available for use as a medication but is under development.
History
Axelsson and Laurell first investigated the possibility of allelic variants of A1AT leading to disease in 1965.
See also
Alpha 1-antichymotrypsin, another serpin that is analogous for protecting the body from excessive effects of its own inflammatory proteases
References
Further reading
External links
"Alpha 1-Antitrypsin". Drug Information Portal. U.S. National Library of Medicine.
The MEROPS online database for peptidases and their inhibitors: I04.001
Proteopedia: Alpha-1-antitrypsin
Human SERPINA1 genome location and SERPINA1 gene details page in the UCSC Genome Browser. |
Streptomycin | Streptomycin is an antibiotic medication used to treat a number of bacterial infections, including tuberculosis, Mycobacterium avium complex, endocarditis, brucellosis, Burkholderia infection, plague, tularemia, and rat bite fever. For active tuberculosis it is often given together with isoniazid, rifampicin, and pyrazinamide. It is administered by injection into a vein or muscle.Common side effects include vertigo, vomiting, numbness of the face, fever, and rash. Use during pregnancy may result in permanent deafness in the developing baby. Use appears to be safe while breastfeeding. It is not recommended in people with myasthenia gravis or other neuromuscular disorders. Streptomycin is an aminoglycoside. It works by blocking the ability of 30S ribosomal subunits to make proteins, which results in bacterial death.Albert Schatz first isolated streptomycin in 1943 from Streptomyces griseus. It is on the World Health Organizations List of Essential Medicines. The World Health Organization classifies it as critically important for human medicine.
Uses
Medication
Infective endocarditis: An infection of the endocardium caused by enterococcus; used when the organism is not sensitive to gentamicin
Tuberculosis: Used in combination with other antibiotics. For active tuberculosis it is often given together with isoniazid, rifampicin, and pyrazinamide. It is not the first-line treatment, except in medically under-served populations where the cost of more expensive treatments is prohibitive. It may be useful in cases where resistance to other drugs is identified.
Plague (Yersinia pestis): Has historically been used as the first-line treatment. However streptomycin is approved for this purpose only by the US Food and Drug Administration.
In veterinary medicine, streptomycin is the first-line antibiotic for use against gram negative bacteria in large animals (horses, cattle, sheep, etc.). It is commonly combined with procaine penicillin for intramuscular injection.
Tularemia infections have been treated mostly with streptomycin.Streptomycin is traditionally given intramuscularly, and in many nations is only licensed to be administered intramuscularly, though in some regions the drug may also be administered intravenously.
Pesticide
Streptomycin also is used as a pesticide, to combat the growth of bacteria beyond human applications. Streptomycin controls bacterial diseases of certain fruit, vegetables, seed, and ornamental crops. A major use is in the control of fireblight on apple and pear trees. As in medical applications, extensive use can be associated with the development of resistant strains. Streptomycin could potentially be used to control cyanobacterial blooms in ornamental ponds and aquaria. While some antibacterial antibiotics are inhibitory to certain eukaryotes, this seems not to be the case for streptomycin, especially in the case of anti-fungal activity.
Cell culture
Streptomycin, in combination with penicillin, is used in a standard antibiotic cocktail to prevent bacterial infection in cell culture.
Protein purification
When purifying protein from a biological extract, streptomycin sulfate is sometimes added as a means of removing nucleic acids. Since it binds to ribosomes and precipitates out of solution, it serves as a method for removing rRNA, mRNA, and even DNA if the extract is from a prokaryote.
Side effects
The most concerning side effects, as with other aminoglycosides, are kidney toxicity and ear toxicity. Transient or permanent deafness may result. The vestibular portion of cranial nerve VIII (the vestibulocochlear nerve) can be affected, resulting in tinnitus, vertigo, ataxia, kidney toxicity, and can potentially interfere with diagnosis of kidney malfunction.Common side effects include vertigo, vomiting, numbness of the face, fever, and rash. Fever and rashes may result from persistent use.Use is not recommended during pregnancy. Congenital deafness has been reported in children whose mothers received streptomycin during pregnancy. Use appears to be okay while breastfeeding.It is not recommended in people with myasthenia gravis.
Mechanism of action
Streptomycin functions as a protein synthesis inhibitor. It binds to the small 16S rRNA of the 30S ribosomal subunit irreversibly, interfering with the binding of formyl-methionyl-tRNA to the 30S subunit. This causes codon misreading, inhibition of protein synthesis, and ultimately death of the cell through mechanisms that are not well understood. Speculation indicates that the binding of the molecule to the 30S subunit interferes with 30S subunit association with the mRNA strand. This results in an unstable ribosomal-mRNA complex, leading to premature stopping of protein synthesis, leading to cell death. As human and bacteria both have ribosomes, streptomycin has significant side effects in humans. At low concentrations, however, streptomycin inhibits only bacterial growth.Streptomycin is an antibiotic that inhibits both Gram-positive and Gram-negative bacteria, and is therefore a useful broad-spectrum antibiotic.
History
Streptomycin was first isolated on October 19, 1943, by Albert Schatz, a PhD student in the laboratory of Selman Abraham Waksman at Rutgers University in a research project funded by Merck and Co. Waksman and his laboratory staff discovered several antibiotics, including actinomycin, clavacin, streptothricin, streptomycin, grisein, neomycin, fradicin, candicidin, and candidin. Of these, streptomycin and neomycin found extensive application in the treatment of numerous infectious diseases. Streptomycin was the first antibiotic cure for tuberculosis (TB). In 1952 Waksman was the recipient of the Nobel Prize in Physiology or Medicine in recognition "for his discovery of streptomycin, the first antibiotic active against tuberculosis". Waksman was later accused of playing down the role of Schatz who did the work under his supervision, claiming that Elizabeth Bugie had a more important role in its development. Schatz sued both Dr. Waksman and the Rutgers Research and Endowment Foundation, wanting to be given credited as co-discover and receive the royalties for the streptomycin. By the end of the settlement, Waksman would receive a 10% royalty, while Schatz got 3% and compensation for his missed royalties. The rest of the lab shared the remaining 7% of the royalties, in which Bugie received 0.2%.Bugie was pursuing a masters degree in Waksmans lab at Rutgers University at this time. Prior to this, she received her bachelors degree in microbiology at New Jersey College for Women. Although Bugie was considered to be the second author on the Proceedings of the Society for Experimental Biology paper, she was not listed on the patent submission. Bugies contributions to Wakemans lab were great. In addition to her work on streptomycin, she also helped develop other antimicrobial substances, had two peer-reviewed publications, and researched the use of antimicrobals against plant pathogens, among several other important contributions to the scientific field, particularly in regard to microbiology.
The Rutgers team reported streptomycin in the medical literature in January 1944. Within months they began working with William Feldman and H. Corwin Hinshaw of the Mayo Clinic with hopes of starting a human clinical trial of streptomycin in tuberculosis.: 209–241 The difficulty at first was even producing enough streptomycin to do a trial, because the research laboratory methods of creating small batches had not yet been translated to commercial large-batch production. They managed to do an animal study in a few guinea pigs with just 10 grams of the scarce drug, demonstrating survival.: 209–241 This was just enough evidence to get Merck & Co. to divert some resources from the young penicillin production program to start work toward streptomycin production.: 209–241 At the end of World War II, the United States Army experimented with streptomycin to treat life-threatening infections at a military hospital in Battle Creek, Michigan. The first person who was treated with streptomycin did not survive; the second person survived but became blind as a side effect of the treatment. In March 1946, the third person—Robert J. Dole, later Majority Leader of the United States Senate and presidential nominee—experienced a rapid and robust recovery.The first randomized trial of streptomycin against pulmonary tuberculosis was carried out in 1946 through 1948 by the MRC Tuberculosis Research Unit under the chairmanship of Geoffrey Marshall (1887–1982). The trial was neither double-blind nor placebo-controlled. It is widely accepted to have been the first randomized curative trial.Results showed efficacy against TB, albeit with minor toxicity and acquired bacterial resistance to the drug.
New Jersey
Because streptomycin was isolated from a microbe discovered on New Jersey soil, and because of its activity against tuberculosis and Gram negative organisms, and in recognition of both the microbe and the antibiotic in the history of New Jersey, S. griseus was nominated as the Official New Jersey state microbe. The draft legislation was submitted by Senator Sam Thompson (R-12) in May 2017 as bill S3190 and Assemblywoman Annette Quijano (D-20) in June 2017 as bill A31900. The bill was passed on 2018-01-08 The bill designates Streptomyces griseus as New Jersey State Microbe (New Jersey Senate Bill 3190 (2017). Passed in January 2018.
See also
Philip DArcy Hart – The British medical researcher and pioneer in tuberculosis treatment in the early twentieth century.
References
Further reading
External links
"Streptomycin". Drug Information Portal. U.S. National Library of Medicine. |
Atogepant | Atogepant, sold under the brand name Qulipta, is a medication used to treat migraines. It is a gepant, an orally active calcitonin gene-related peptide receptor (CGRPR) antagonist.It was approved for medical use in the United States in September 2021.
Medical uses
Atogepant is indicated for the preventive treatment of episodic migraine in adults.
Research
A study found that atogepant reduced the number of migraine days over twelve weeks.
References
External links
"Atogepant". Drug Information Portal. U.S. National Library of Medicine. |
Luspatercept | Luspatercept, sold under the brand name Reblozyl, is a medication used for the treatment of anemia in beta thalassemia and myelodysplastic syndromes.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
Medical uses
Luspatercept is indicated for the treatment of adults with transfusion-dependent anemia due to very low, low and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy.Luspatercept is indicated for the treatment of adults with transfusion-dependent anaemia associated with beta thalassaemia.
Side effects
Possible adverse effects include temporary bone pain, joint pains (arthralgias), dizziness, elevated blood pressure (hypertension) and elevated uric acid levels (hyperuricemia). There was also an increased risk of thrombosis (blood clots) in patients who have risk factors for thrombosis who are taking luspatercept.
Structure and mechanism
Luspatercept is a recombinant fusion protein derived from human activin receptor type IIb (ActRIIb) linked to a protein derived from immunoglobulin G. It binds TGF (transforming growth factor beta) superfamily ligands to reduce SMAD signaling. The reduction in SMAD signaling leads to enhanced erythroid maturation.
History
Phase III trials evaluated the efficacy of luspatercept for the treatment of anemia in the hematological disorders beta thalassemia and myelodysplastic syndromes.It was developed by Acceleron Pharma in collaboration with Celgene.The U.S. Food and Drug Administration (FDA) granted approval for luspatercept–aamt in November 2019, for the treatment of anemia (lack of red blood cells) in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions. Luspatercept was approved for medical use in the European Union in June 2020.The U.S. Food and Drug Administration (FDA) awarded orphan drug status in 2013, and fast track designation in 2015.
Research
Luspatercept is being evaluated for use in adults with non-transfusion dependent beta thalassemia.
References
External links
"Luspatercept". Drug Information Portal. U.S. National Library of Medicine. |
Micafungin | Micafungin, sold under the brand name Mycamine, is an echinochandin antifungal medication used to treat and prevent invasive fungal infections including candidemia, abscesses, and esophageal candidiasis. It inhibits the production of beta-1,3-glucan, an essential component of fungal cell walls that is not found in mammals. Micafungin is administered intravenously. It received final approval from the U.S. Food and Drug Administration (FDA) in March 2005, and gained approval in the European Union in April 2008.
It is on the World Health Organizations List of Essential Medicines.
Indications
Micafungin is indicated for the treatment of candidemia, acute disseminated candidiasis, Candida peritonitis, abscesses and esophageal candidiasis. Since January 23, 2008, micafungin has been approved for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation (HSCT).
Micafungin works by way of concentration-dependent inhibition of 1,3-beta-D-glucan synthase resulting in reduced formation of 1,3-beta-D-glucan, which is an essential polysaccharide comprising one-third of the majority of Candida spp. cell walls. This decreased glucan production leads to osmotic instability and thus cellular lysis.
Dosage
The metabolism of micafungin occurs hepatically via acryp sulfatase followed by secondary metabolism by a transferase. Precautions should be taken with regards to dosing, as micafungin weakly inhibits CYP3A4.
Dosage forms
Micafungin is a natural antifungal product derived from other fungi as a defense mechanism for competition of nutrients, etc. To be specific, micafungin is derived from FR901379, and is produced by Coleophoma empetri.
References
Further reading
External links
"Micafungin". Drug Information Portal. U.S. National Library of Medicine. |
Cefuroxime axetil | Cefuroxime axetil, sold under the brand name Ceftin among others, is a second generation oral cephalosporin antibiotic.
It is an acetoxyethyl ester prodrug of cefuroxime which is effective orally. The activity depends on in vivo hydrolysis and release of cefuroxime tablets.
It was patented in 1976 and approved for medical use in 1987.
Medical uses
Second generation cephalosporins are more effective in treating Gram-negative bacilli compared to first generation cephalosporins, which have a greater coverage for Gram-positive cocci. Also, it has been reported that cefuroxime is resistant to hydrolysis by β-lactamases produced by Gram-negative bacteria.Some medical uses are:
Upper respiratory tract infections.
Lower respiratory tract infections.
Urinary tract infections.
Skin and soft tissue infections.
Gonorrhoea.
Early Lyme disease.
Bacterial susceptibility
Cefuroxime axetil treats infections against methicillin, oxacillin and penicillin-sensitive bacterial strains. Cefuroxime axetil does not work against enterococci. Gram-positive aerobic microorganisms
Staphylococcus aureus (Methicillin-sensitive only)
Staphylococcus epidermis
Streptococcus pneumoniae (Penicillin-sensitive only)Gram-negative aerobic microorganisms
Haemophilus influenzae
Moraxella catarrhalis
Neisseria gonorrhoeae
Escherichia coli
Proteus mirabilis
Klebsiella pneumoniae (variable activity)
Mechanism of action
Cefuroxime axetil is a second generation cephalosporin that, like penicillins antibiotics, contains a β-lactam ring structure. Cephalosporins works as a bactericidal antibiotic; that by binding to penicillin-binding proteins (PBPs), inhibit the last step of the bacterial cell wall synthesis. Once the β-lactam ring binds to PBPs, cross-linking between peptidoglycan units is inhibited.
Pharmacokinetics
Absorption: Once consumed, cefuroxime axetil is converted to the active compound cefuroxime by esterases of mucosal cells in the gastrointestinal tract. Cefuroxime is then released for systematic circulation. If cefuroxime axetil is given with food, absorption values can increase by 52% compared to fasting patients.Distribution: It has been reported that after cefuroxime axetil administration, it can be found in tonsil tissue, sinus tissue, bronchial tissue and middle ear effusion.Elimination: After cefuroxime production, the body is unable to metabolize the drug, and is eliminated unchanged in the urine.
History
It was discovered by Glaxo (now GlaxoSmithKline) and introduced in 1987. It was approved by FDA on December 28, 1987. It is available by GSK as Ceftin in US and Ceftum in India.
See also
Cefuroxime
== References == |
Methotrexate | Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leukemia, lung cancer, lymphoma, gestational trophoblastic disease, and osteosarcoma. Types of autoimmune diseases it is used for include psoriasis, rheumatoid arthritis, and Crohns disease. It can be given by mouth or by injection.Common side effects include nausea, feeling tired, fever, increased risk of infection, low white blood cell counts, and breakdown of the skin inside the mouth. Other side effects may include liver disease, lung disease, lymphoma, and severe skin rashes. People on long-term treatment should be regularly checked for side effects. It is not safe during breastfeeding. In those with kidney problems, lower doses may be needed. It acts by blocking the bodys use of folic acid.Methotrexate was first made in 1947 and initially was used to treat cancer, as it was less toxic than the then current treatments. In 1956 it provided the first cures of a metastatic cancer. It is on the World Health Organizations List of Essential Medicines. Methotrexate is available as a generic medication. In 2019, it was the 111th most commonly prescribed medication in the United States, with more than 5 million prescriptions.
Medical uses
Chemotherapy
Methotrexate was originally developed and continues to be used for chemotherapy, either alone or in combination with other agents. It is effective for the treatment of a number of cancers, including breast, head and neck, leukemia, lymphoma, lung, osteosarcoma, bladder, and trophoblastic neoplasms.
Autoimmune disorders
It is used as a disease-modifying treatment for some autoimmune diseases, including rheumatoid arthritis, juvenile dermatomyositis, psoriasis, psoriatic arthritis, lupus, sarcoidosis, Crohns disease, eczema and many forms of vasculitis. Although originally designed as a chemotherapy drug (using high doses), in low doses methotrexate is a generally safe and well-tolerated drug in the treatment of certain autoimmune diseases. Because of its effectiveness, low-dose methotrexate is first-line therapy for the treatment of rheumatoid arthritis. Weekly doses are beneficial for 12 to 52 weeks duration therapy, although discontinuation rates are as high as 16% due to adverse effects. Although methotrexate for autoimmune diseases is taken in lower doses than it is for cancer, side effects such as hair loss, nausea, headaches, and skin pigmentation are still common. Use of low doses of methotrexate together with NSAIDs such as aspirin or analgesics such as paracetamol is relatively safe in people being treated for rheumatoid arthritis, if adequate monitoring is done.Studies and reviews have found that most rheumatoid arthritis patients treated with methotrexate for up to one year had less pain, functioned better, had fewer swollen and tender joints, and had less disease activity overall as reported by themselves and their doctors. X-rays also showed that the progress of the disease slowed or stopped in many people receiving methotrexate, with the progression being completely halted in about 30% of those receiving the drug. Those individuals with rheumatoid arthritis treated with methotrexate have been found to have a lower risk of cardiovascular events such as myocardial infarctions (heart attacks) and strokes.Results of a systematic review exploring the comparative effectiveness of treatments of early rheumatoid arthritis can be improved with combination therapy of tumor necrosis factor (TNF) or non-TNF biologics with methotrexate alone.Likewise, a 2016 study found the use of methotrexate, in combination with anti-TNF agents, has been shown to be effective for the treatment of ulcerative colitis.Methotrexate has also been used for multiple sclerosis and is used occasionally in systemic lupus erythematosus, with tentative evidence to support such use.
During pregnancy
Methotrexate is an abortifacient and it is used to treat ectopic pregnancies, provided the fallopian tube has not ruptured. Methotrexate with dilation and curettage is used to treat molar pregnancy. Rarely, it is used in combination with mifepristone to abort uterine pregnancies.
Administration
Methotrexate can be given by mouth or by injection (intramuscular, intravenous, subcutaneous, or intrathecal). Doses are usually taken weekly, not daily, to limit toxicity. Routine monitoring of the complete blood count, liver function tests, and creatinine are recommended. Measurements of creatinine are recommended at least every two months.
Adverse effects
The most common adverse effects include: hepatotoxicity (liver damage), ulcerative stomatitis, leukopenia and thus predisposition to infection, nausea, abdominal pain, fatigue, fever, dizziness, acute pneumonitis, rarely pulmonary fibrosis, and kidney failure. Methotrexate is teratogenic and hence is not advised for either the prospective father to take it before or for the mother to take it before or during pregnancy (pregnancy category X) and for a period after birth. Methotrexate can also cause mucositis.Central nervous system reactions to methotrexate have been reported, especially when given via the intrathecal route (directly into the cerebrospinal fluid), which include myelopathies and leukoencephalopathies. It has a variety of cutaneous side effects, particularly when administered in high doses.Another little understood but serious possible adverse effect of methotrexate is neurological damage and memory loss. Neurotoxicity may result from the drug crossing the blood–brain barrier and damaging neurons in the cerebral cortex. People with cancer who receive the medication often nickname these effects "chemo brain" or "chemo fog".
Drug interactions
Penicillins may decrease the elimination of methotrexate, so increase the risk of toxicity. While they may be used together, increased monitoring is recommended. The aminoglycosides, neomycin and paromomycin, have been found to reduce gastrointestinal (GI) absorption of methotrexate. Probenecid inhibits methotrexate excretion, which increases the risk of methotrexate toxicity. Likewise, retinoids and trimethoprim have been known to interact with methotrexate to produce additive hepatotoxicity and haematotoxicity, respectively. Other immunosuppressants like cyclosporins may potentiate methotrexates haematologic effects, hence potentially leading to toxicity. NSAIDs have also been found to fatally interact with methotrexate in numerous case reports. Nitrous oxide potentiating the haematological toxicity of methotrexate has also been documented. Proton-pump inhibitors such as omeprazole and the anticonvulsant valproate have been found to increase the plasma concentrations of methotrexate, as have nephrotoxic agents such as cisplatin, the GI drug colestyramine, and dantrolene.
Mechanism of action
Methotrexate is an antimetabolite of the antifolate type. It is thought to affect cancer and rheumatoid arthritis by two different pathways. For cancer, methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about 1000-fold that of folate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. Also, folate is essential for purine and pyrimidine base biosynthesis, so synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.For the treatment of rheumatoid arthritis, inhibition of DHFR is not thought to be the main mechanism, but rather multiple mechanisms appear to be involved, including the inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine; inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells; selective down-regulation of B cells; increasing CD95 sensitivity of activated T cells; and inhibition of methyltransferase activity, leading to deactivation of enzyme activity relevant to immune system function. Another mechanism of MTX is the inhibition of the binding of interleukin 1-beta to its cell surface receptor.
History
In 1947, a team of researchers led by Sidney Farber showed aminopterin, a chemical analogue of folic acid developed by Yellapragada Subbarao of Lederle, could induce remission in children with acute lymphoblastic leukemia. The development of folic acid analogues had been prompted by the discovery that the administration of folic acid worsened leukemia, and that a diet deficient in folic acid could, conversely, produce improvement; the mechanism of action behind these effects was still unknown at the time. Other analogues of folic acid were in development, and by 1950, methotrexate (then known as amethopterin) was being proposed as a treatment for leukemia. Animal studies published in 1956 showed the therapeutic index of methotrexate was better than that of aminopterin, and clinical use of aminopterin was thus abandoned in favor of methotrexate.
In 1951, Jane C. Wright demonstrated the use of methotrexate in solid tumors, showing remission in breast cancer. Wrights group was the first to demonstrate use of the drug in solid tumors, as opposed to leukemias, which are a cancer of the marrow. Min Chiu Li and his collaborators then demonstrated complete remission in women with choriocarcinoma and chorioadenoma in 1956, and in 1960 Wright et al. produced remissions in mycosis fungoides.
Research
In 2018, a photoactivated version of methotrexate (phototrexate) has been developed and proposed to be useful in localized, target-specific chemotherapy of psoriasis and cancer.
References
43. Peymanfar, Yaser, Yu-Wen Su, and Cory J. Xian. 2022. "Notch2 Blockade Mitigates Methotrexate Chemotherapy-Induced Bone Loss and Marrow Adiposity" Cells 11, no. 9: 1521. https://doi.org/10.3390/cells11091521
External links
"Methotrexate". Drug Information Portal. U.S. National Library of Medicine.
National Rheumatoid Arthritis Society (NRAS) article on Methotrexate
Methotrexate Injection MedlinePlus article from NIH |
Aldara | Aldara may refer to:
Former name of Alvanq, a community or municipality in Armenia
Àldara, Sardinian name of Ardara, Sardinia, a comune or municipality
Imiquimod or Aldara, a prescription medication that acts as an immune response modifier
See also
Aldara Park, Gauteng, a suburb of Johannesburg, South Africa |
Potassium bicarbonate | Potassium bicarbonate (IUPAC name: potassium hydrogencarbonate, also known as potassium acid carbonate) is the inorganic compound with the chemical formula KHCO3. It is a white solid.
Production and reactivity
It is manufactured by treating an aqueous solution of potassium carbonate with carbon dioxide:
K2CO3 + CO2 + H2O → 2 KHCO3Decomposition of the bicarbonate occurs between 100 and 120 °C (212 and 248 °F):
2 KHCO3 → K2CO3 + CO2 + H2OThis reaction is employed to prepare high purity potassium carbonate.
Uses
Food and drink
This compound is a source of carbon dioxide for leavening in baking. It can substitute for baking soda (sodium bicarbonate) for those with a low-sodium diet, and it is an ingredient in low-sodium baking powders.As an inexpensive, nontoxic base, it is widely used in diverse application to regulate pH or as a reagent. Examples include as buffering agent in medications, an additive in winemaking.
Potassium bicarbonate is often found added to club soda to improve taste, and to soften the effect of effervescence.
Fire extinguishers
Potassium bicarbonate is used as a fire suppression agent ("BC dry chemical") in some dry chemical fire extinguishers, as the principal component of the Purple-K dry chemical, and in some applications of condensed aerosol fire suppression. It is the only dry chemical fire suppression agent recognized by the U.S. National Fire Protection Association for firefighting at airport crash rescue sites. It is about twice as effective in fire suppression as sodium bicarbonate.
Agriculture
Potassium bicarbonate has widespread use in crops, especially for neutralizing acidic soil.Potassium bicarbonate is an effective fungicide against powdery mildew and apple scab, allowed for use in organic farming.
Potassium bicarbonate is a contact killer for Spanish moss when mixed 1/4 cup per gallon.
History
The word saleratus, from Latin sal æratus meaning "aerated salt", first used in the nineteenth century, refers to both potassium bicarbonate and sodium bicarbonate.
References
External links
Potassium Bicarbonate Handbook
OMRI Potassium Bicarbonate
Safety Data sheet - potassium bicarbonate
"Saleratus" . New International Encyclopedia. 1905. |
Levobunolol | Levobunolol (trade names AKBeta, Betagan, Vistagan, among others) is a non-selective beta blocker. It is used topically in the form of eye drops to manage ocular hypertension (high pressure in the eye) and open-angle glaucoma.
Contraindications
Like other beta blockers, levobunolol is contraindicated in patients with airway diseases such as asthma and severe chronic obstructive pulmonary disease (COPD), as well as heart problems such as sinus bradycardia, second- or third-degree atrioventricular block, sick sinus syndrome, and cardiogenic shock. Combination with MAO-A inhibitors is also contraindicated because it could cause a dangerous rise in blood pressure.Levobunolol is not useful for the treatment of closed-angle glaucoma.
Side effects
The most common side effect is eye irritation felt as stinging or burning, which occurs in up to a third of patients. Blepharoconjunctivitis occurs in up to 5% of patients. Rarer adverse effects include keratitis, edema and increased lacrimation. Allergies are rare, but seem to be more common than under the related drug timolol.If the substance reaches the nasal mucosa via the tear duct, it can be absorbed into the bloodstream and cause systemic side effects. These include orthostatic hypotension (low blood pressure) and other effects on the heart and circulatory system, breathing problems in people with asthma, and skin symptoms such as itching and aggravation of psoriasis.
Interactions
Even in the form of eye drops, levebunolol may cause hypotension when combined with alpha blockers, calcium channel blockers, tricyclic antidepressants, and other drugs that lower blood pressure. It can also cause severe hypertension (high blood pressure) when combined with sympathomimetic drugs or MAO-A inhibitors, bradycardia (low heart rate) when combined with antiarrhythmics or mefloquine, and hypoglycemia (low blood sugar) when combined with antidiabetic drugs such as insulin.
Pharmacology
Mechanism of action
Levobunolol is a non-cardioselective beta blocker, that is, it blocks beta-1 receptors as well as beta-2 receptors. The latter type dominates in the ciliary body, where it controls aqueous humour production. Blocking this type of receptor reduces aqueous humour production, lowering intraocular pressure. The substance has no relevant membrane stabilizing effect or intrinsic sympathomimetic activity. Like other beta blockers, and unlike the anti-glaucoma medication pilocarpine, levobunolol has no effect on accommodation and pupil size.
Pharmacokinetics
The substance quickly penetrates the cornea and reaches the aqueous humour. It is reduced to dihydrolevobunolol, which is equally active, in the eyes tissues. The drug starts to lower intraocular pressure within an hour, reaches its maximum effect after two to six hours, and remains effective for up to 16 hours. It has an elimination half-life of six hours and is mainly excreted via the kidney.
Chemistry
Levobunolol is the pure L-enantiomer of bunolol and has more than 60 times the pharmacological activity of D-bunolol. It is used as the hydrochloride, which melts at 209 to 211 °C (408 to 412 °F) and is soluble in water and methanol and slightly soluble in ethanol.
References
Ishibashi T, Yokoi N, Kinoshita S (2003). "Comparison of the effects of topical levobunolol and timolol solution on the human ocular surface". Cornea. 22 (8): 709–15. doi:10.1097/00003226-200311000-00001. PMID 14576520. S2CID 25444383.
Ogasawara H, Yoshida A, Fujio N, Konno S, Ishiko S (1999). "[Effect of topical levobunolol on retinal, optic nerve head, and choroidal circulation in normal volunteers]". Nippon Ganka Gakkai Zasshi. 103 (7): 544–50. PMID 10443129.
Leung M, Grunwald J (1997). "Short-term effects of topical levobunolol on the human retinal circulation". Eye. 11 (3): 371–6. doi:10.1038/eye.1997.78. PMID 9373479. |
Conjugated estrogens/medroxyprogesterone acetate | Conjugated estrogens/medroxyprogesterone acetate (CEs/MPA), sold under the brand names Prempro and Premphase, is a combination product of conjugated estrogens (Premarin), an estrogen, and medroxyprogesterone acetate (Provera), a progestogen, which is used in menopausal hormone therapy for the treatment of menopausal symptoms.In 2017, it was the 294th most commonly prescribed medication in the United States, with more than one million prescriptions.
See also
Estradiol/medroxyprogesterone acetate
Estradiol cypionate/medroxyprogesterone acetate
List of combined sex-hormonal preparations
References
External links
"Estrogens mixture with medroxyprogesterone acetate". Drug Information Portal. U.S. National Library of Medicine. |
Meningococcal vaccine | Meningococcal vaccine refers to any vaccine used to prevent infection by Neisseria meningitidis. Different versions are effective against some or all of the following types of meningococcus: A, B, C, W-135, and Y. The vaccines are between 85 and 100% effective for at least two years. They result in a decrease in meningitis and sepsis among populations where they are widely used. They are given either by injection into a muscle or just under the skin.The World Health Organization recommends that countries with a moderate or high rate of disease or with frequent outbreaks should routinely vaccinate. In countries with a low risk of disease, they recommend that high risk groups should be immunized. In the African meningitis belt efforts to immunize all people between the ages of one and thirty with the meningococcal A conjugate vaccine are ongoing. In Canada and the United States the vaccines effective against four types of meningococcus (A, C, W, and Y) are recommended routinely for teenagers and others who are at high risk. Saudi Arabia requires vaccination with the quadrivalent vaccine for international travellers to Mecca for Hajj.Meningococcal vaccines are generally safe. Some people develop pain and redness at the injection site. Use in pregnancy appears to be safe. Severe allergic reactions occur in less than one in a million doses.The first meningococcal vaccine became available in the 1970s. It is on the World Health Organizations List of Essential Medicines.Inspired by the response to the 1997 outbreak in Nigeria, the WHO, Médecins Sans Frontières, and other groups created the International Coordinating Group on Vaccine Provision for Epidemic Meningitis Control, which manages global response strategy. ICGs have since been created for other epidemic diseases.
Types
Neisseria meningitidis has 13 clinically significant serogroups, classified according to the antigenic structure of their polysaccharide capsule. Six serogroups, A, B, C, Y, W-135, and X, are responsible for virtually all cases of the disease in humans.
Quadrivalent (Serogroups A, C, W-135, and Y)
There are three vaccines available in the United States to prevent meningococcal disease, all quadrivalent in nature, targeting serogroups A, C, W-135, and Y:
three conjugate vaccines (MCV-4), Menactra, Menveo and MenQuadfi. The pure polysaccharide vaccine Menomune, MPSV4, was discontinued in the United States in 2017.Menveo and MenQuadfi are approved for medical use in the European Union.
Menactra and Menveo
The first meningococcal conjugate vaccine (MCV-4), Menactra, was licensed in the U.S. in 2005 by Sanofi Pasteur; Menveo was licensed in 2010 by Novartis. Both MCV-4 vaccines have been approved by the Food and Drug Administration (FDA) for people 2 through 55 years of age. Menactra received FDA approval for use in children as young as 9 months in April 2011 while Menveo received FDA approval for use in children as young as two months in August 2013. The Centers for Disease Control and Prevention (CDC) has not made recommendations for or against its use in children less than two years.
MenQuadFi
MenQuadFi, manufactured by Sanofi Pasteur, was approved by the US Food and Drug Administration (FDA) on April 23, 2020, for use in individuals 2 years of age and older.
Menomune
Meningococcal polysaccharide vaccine (MPSV-4), Menomune, has been available since the 1970s. It may be used if MCV-4 is not available, and is the only meningococcal vaccine licensed for people older than 55. Information about who should receive the meningococcal vaccine is available from the CDC.
Nimenrix
Nimenrix (developed by GlaxoSmithKline and later acquired by Pfizer), is a quadrivalent conjugate vaccine against serogroups A, C, W-135, and Y. In April 2012 Nimenrix was approved as the first quadrivalent vaccine against invasive meningococcal disease to be administered as a single dose in those over the age of one year, by the European Medicines Agency. In 2016, they approved the vaccine in infants six weeks of age and older, and it has been approved in other countries including Canada and Australia, among others. It is not licensed in the United States.
Mencevax
Mencevax (GlaxoSmithKline) and NmVac4-A/C/Y/W-135 (JN-International Medical Corporation) are used worldwide, but have not been licensed in the United States.
Limitations
The duration of immunity mediated by Menomune (MPSV-4) is three years or less in children aged under five because it does not generate memory T cells. Attempting to overcome this problem by repeated immunization results in a diminished, not increased, antibody response, so boosters are not recommended with this vaccine. As with all polysaccharide vaccines, Menomune does not produce mucosal immunity, so people can still become colonised with virulent strains of meningococcus, and no herd immunity can develop. For this reason, Menomune is suitable for travellers requiring short-term protection, but not for national public health prevention programs.
Menveo and Menactra contain the same antigens as Menomune, but the antigens are conjugated to a diphtheria toxoid polysaccharide–protein complex, resulting in anticipated enhanced duration of protection, increased immunity with booster vaccinations, and effective herd immunity.
Endurance
A study published in March 2006, comparing the two kinds of vaccines found that 76% of subjects still had passive protection three years after receiving MCV-4 (63% protective compared with controls), but only 49% had passive protection after receiving MPSV-4 (31% protective compared with controls). As of 2010, there remains limited evidence that any of the current conjugate vaccines offer continued protection beyond three years; studies are ongoing to determine the actual duration of immunity, and the subsequent requirement of booster vaccinations. The CDC offers recommendations regarding who they feel should get booster vaccinations.
Bivalent (Serogroups C and Y)
On 14 June 2012, the FDA approved a combination vaccine against two types of meningococcal disease and Hib disease for infants and children 6 weeks to 18 months old. The vaccine, Menhibrix, prevents disease caused by Neisseria meningitidis serogroups C and Y and Haemophilus influenzae type b. This was the first meningococcal vaccine that could be given to infants as young as six weeks old.
Serogroup A
A vaccine called MenAfriVac has been developed through a program called the Meningitis Vaccine Project and has the potential to prevent outbreaks of group A meningitis, which is common in sub-Saharan Africa.
Serogroup B
Vaccines against serotype B meningococcal disease have proved difficult to produce, and require a different approach from vaccines against other serotypes. Whereas effective polysaccharide vaccines have been produced against types A, C, W-135, and Y, the capsular polysaccharide on the type B bacterium is too similar to human neural adhesion molecules to be a useful target.A number of "serogroup B" vaccines have been produced. Strictly speaking, these are not "serogroup B" vaccines, as they do not aim to produce antibodies to the group B antigen: it would be more accurate to describe them as serogroup independent vaccines, as they employ different antigenic components of the organism; indeed, some of the antigens are common to different Neisseria species.A vaccine for serogroup B was developed in Cuba in response to a large outbreak of meningitis B during the 1980s. This vaccine was based on artificially produced outer membrane vesicles of the bacterium. The VA-MENGOC-BC vaccine proved safe and effective in randomized double-blind studies, but it was granted a licence only for research purposes in the United States as political differences limited cooperation between the two countries.Due to a similarly high prevalence of B-serotype meningitis in Norway between 1974 and 1988, Norwegian health authorities developed a vaccine specifically designed for Norwegian children and young adolescents. Clinical trials were discontinued after the vaccine was shown to cover only slightly more than 50% of all cases. Furthermore, lawsuits for damages were filed against the State of Norway by persons affected by serious adverse reactions. Information that the health authorities obtained during the vaccine development were subsequently passed on to Chiron (now GlaxoSmithKline), who developed a similar vaccine, MeNZB, for New Zealand.A MenB vaccine was approved for use in Europe in January 2013. Following a positive recommendation from the European Unions Committee for Medicinal Products for Human Use, Bexsero, produced by Novartis, received a licence from the European Commission. However, deployment in individual EU member countries still depends on decisions by national governments. In July 2013, the United Kingdoms Joint Committee on Vaccination and Immunisation (JCVI) issued an interim position statement recommending against adoption of Bexsero as part of a routine meningococcal B immunisation program, on the grounds of cost-effectiveness. This decision was reverted in favor of Bexsero vaccination in March 2014. In March 2015 the UK government announced that they had reached agreement with GlaxoSmithKline who had taken over Novartis vaccines business, and that Bexsero would be introduced into the UK routine immunization schedule later in 2015.In November 2013, in response to an outbreak of B-serotype meningitis on the campus of Princeton University, the acting head of the Centers for Disease Control and Prevention (CDC) meningitis and vaccine preventable diseases branch told NBC News that they had authorized emergency importation of Bexsero to stop the outbreak. Bexsero was subsequently approved by the FDA in February 2015 for use in individuals 10 through 25 years of age. In October 2014, Trumenba, a serogroup B vaccine produced by Pfizer, was approved by the FDA for use in individuals 10 through 25 years of age.
Serogroup X
The occurrence of serogroup X has been reported in North America, Europe, Australia, and West Africa. There is no vaccine to protect against serogroup X N. meningitidis disease.
Side effects
Common side effects include pain and redness around the site of injection (up to 50% of recipients). A small percentage of people develop a mild fever. A small proportion of people develop a severe allergic reaction. In 2016 Health Canada warned of an increased risk of anemia or hemolysis in people treated with eculizumab (Soliris). The highest risk was when individuals "received a dose of Soliris within 2 weeks after being vaccinated with Bexsero".Despite initial concerns about Guillain-Barré syndrome, subsequent studies in 2012 have shown no increased risk of GBS after meningococcal conjugate vaccination.
Travel requirements
Travellers who wish to enter or leave certain countries or territories must be vaccinated against meningococcal meningitis, preferably 10–14 days before crossing the border, and be able to present a vaccination record/certificate at the border checks.: 21–24 Countries with required meningococcal vaccination for travellers include The Gambia, Indonesia, Lebanon, Libya, the Philippines and, most importantly and extensively, Saudi Arabia for Muslims visiting or working in Mecca during the Hajj or Umrah pilgrimages. For some countries in African meningitis belt, vaccinations prior to entry are not required, but highly recommended.: 21–24
References
Further reading
Conterno LO, Silva Filho CR, Rüggeberg JU, Heath PT (2006). Conterno LO (ed.). "Conjugate vaccines for preventing meningococcal C meningitis and septicaemia". Cochrane Database Syst Rev. 3 (3): CD001834. doi:10.1002/14651858.CD001834.pub2. PMID 16855979.
Patel M, Lee CK (2005). Patel M (ed.). "Polysaccharide vaccines for preventing serogroup A meningococcal meningitis". Cochrane Database Syst Rev (1): CD001093. doi:10.1002/14651858.CD001093.pub2. PMID 15674874.
External links
"Meningococcal ACWY Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 10 August 2021.
"Meningococcal B Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 17 August 2021.
"Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine". U.S. Food and Drug Administration (FDA). 17 April 2019.
"Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined". U.S. Food and Drug Administration (FDA). 25 April 2019.
"Menveo". U.S. Food and Drug Administration (FDA). 28 July 2020.
"Bexsero". U.S. Food and Drug Administration (FDA). 18 November 2019.
"Trumenba". U.S. Food and Drug Administration (FDA). 18 November 2019.
"Meningococcal Vaccine". Drug Information Portal. U.S. National Library of Medicine.
Meningococcal Vaccines at the US National Library of Medicine Medical Subject Headings (MeSH) |
Vancomycin | Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant Staphylococcus aureus. Blood levels may be measured to determine the correct dose. Vancomycin is also taken by mouth as a treatment for severe Clostridium difficile colitis. When taken by mouth it is poorly absorbed.Common side effects include pain in the area of injection and allergic reactions. Occasionally, hearing loss, low blood pressure, or bone marrow suppression occur. Safety in pregnancy is not clear, but no evidence of harm has been found, and it is likely safe for use when breastfeeding. It is a type of glycopeptide antibiotic and works by blocking the construction of a cell wall.Vancomycin was approved for medical use in the United States in 1958. It is on the World Health Organizations List of Essential Medicines. The World Health Organization classifies vancomycin as critically important for human medicine. It is available as a generic medication. Vancomycin is made by the soil bacterium Amycolatopsis orientalis.
Medical uses
Vancomycin is indicated for the treatment of serious, life-threatening infections by Gram-positive bacteria unresponsive to other antibiotics.
The increasing emergence of vancomycin-resistant enterococci has resulted in the development of guidelines for use by the Centers for Disease Control Hospital Infection Control Practices Advisory Committee. These guidelines restrict use of vancomycin to these indications:
Treatment of serious infections caused by susceptible organisms resistant to penicillins (methicillin-resistant S. aureus (MRSA) and multidrug-resistant S. epidermidis (MRSE)) or in individuals with serious allergy to penicillins
Treatment of pseudomembranous colitis caused by C. difficile; in particular, in cases of relapse or where the infection is unresponsive to metronidazole treatment (for this indication, vancomycin is given orally, rather than by its typical intravenous route)
For treatment of infections caused by Gram-positive microorganisms in patients with serious allergies to beta-lactam antimicrobials.
Antibacterial prophylaxis for endocarditis following certain procedures in penicillin-hypersensitive individuals at high risk
Surgical prophylaxis for major procedures involving implantation of prostheses in institutions with a high rate of MRSA or MRSE
Early in treatment as an empiric antibiotic for possible MRSA infection while waiting for culture identification of the infecting organism
Halting the progression of primary sclerosing cholangitis and preventing symptoms; vancomycin does not cure the patient and success is limited
Treatment of endophthalmitis by intravitreal injection for gram-positive bacteria coverage. It use to prevent the condition, however, is not recommended due to the risk of side effects.
Spectrum of susceptibility
Vancomycin is considered a last resort medication for the treatment of sepsis and lower respiratory tract, skin, and bone infections caused by Gram-positive bacteria. The minimum inhibitory concentration susceptibility data for a few medically significant bacteria are:
S. aureus: 0.25 μg/mL to 4.0 μg/mL
S. aureus (methicillin resistant or MRSA): 1 μg/mL to 138 μg/mL
S. epidermidis: ≤0.12 μg/mL to 6.25 μg/mL
Side effects
Serum vancomycin levels may be monitored in an effort to reduce side effects, although the value of such monitoring has been questioned. Peak and trough levels are usually monitored, and for research purposes, the area under the concentration curve is also sometimes used. Toxicity is best monitored by looking at trough values.Common adverse drug reactions (≥1% of patients) associated with IV vancomycin include: local pain, which may be severe, and thrombophlebitis.
Damage to the kidneys (nephrotoxicity) and to the hearing (ototoxicity) were side effects of the early impure versions of vancomycin, and these were prominent in the clinical trials conducted in the mid-1950s. Later trials using purer forms of vancomycin found nephrotoxicity is an infrequent adverse effect (0.1% to 1% of patients), but this is accentuated in the presence of aminoglycosides.Rare adverse effects (<0.1% of patients) include: anaphylaxis, toxic epidermal necrolysis, erythema multiforme, red man syndrome, superinfection, thrombocytopenia, neutropenia, leukopenia, tinnitus, dizziness and/or ototoxicity, and DRESS syndrome.Vancomycin can induce platelet-reactive antibodies in the patient, leading to severe thrombocytopenia and bleeding with florid petechial hemorrhages, ecchymoses, and wet purpura.Vancomycin has traditionally been considered a nephrotoxic and ototoxic drug, based on observations by early investigators of elevated serum levels in renally impaired patients who had experienced ototoxicity, and subsequently through case reports in the medical literature. However, as the use of vancomycin increased with the spread of MRSA beginning in the 1970s, the previously reported rates of toxicity were recognized as not being observed. This was attributed to the removal of the impurities present in the earlier formulation of the drug, although those impurities were not specifically tested for toxicity.
Nephrotoxicity
Subsequent reviews of accumulated case reports of vancomycin-related nephrotoxicity found many of the patients had also received other known nephrotoxins, in particular, aminoglycosides. Most of the rest had other confounding factors, or insufficient data regarding the possibility of such, that prohibited the clear association of vancomycin with the observed kidney dysfunction.
In 1994, the use of vancomycin monotherapy was clearly documented in only three of 82 available cases in the literature. Prospective and retrospective studies attempting to evaluate the incidence of vancomycin-related nephrotoxicity have largely been methodologically flawed and have produced variable results. The most methodologically sound investigations indicate the actual incidence of vancomycin-induced nephrotoxicity is around 5% to 7%. To put this into context, similar rates of kidney dysfunction have been reported for cefamandole and benzylpenicillin, two reputedly non-nephrotoxic antibiotics.
In addition, evidence to relate nephrotoxicity to vancomycin serum levels is inconsistent. Some studies have indicated an increased rate of nephrotoxicity when trough levels exceed 10 µg/mL, but others have not reproduced these results. Nephrotoxicity has also been observed with concentrations within the "therapeutic" range, as well. In essence, the reputation of vancomycin as a nephrotoxin is overstated, and it has not been demonstrated that maintaining vancomycin serum levels within certain ranges will prevent its nephrotoxic effects, when they do occur.
Ototoxicity
Attempts to establish rates of vancomycin-induced ototoxicity are even more difficult due to the scarcity of quality evidence. The current consensus is that clearly related cases of vancomycin ototoxicity are rare. The association between vancomycin serum levels and ototoxicity is also uncertain. While cases of ototoxicity have been reported in patients whose vancomycin serum level exceeded 80 µg/mL, cases have been reported in patients with therapeutic levels, as well. Thus, whether therapeutic drug monitoring of vancomycin for the purpose of maintaining "therapeutic" levels will prevent ototoxicity also remains unproven.
Interactions with other nephrotoxins
Another area of controversy and uncertainty concerns the question of whether, and if so, to what extent, vancomycin increases the toxicity of other nephrotoxins. Clinical studies have yielded variable results, but animal models indicate some increased nephrotoxic effect probably occurs when vancomycin is added to nephrotoxins such as aminoglycosides. However, a dose- or serum level-effect relationship has not been established.
Dosing considerations
The recommended parenteral dosage in adults is 500 mg iv every 6 hours or 1000 mg every 12 hours, with modification to achieve a therapeutic range as needed. The recommended oral dosage in the treatment of antibiotic induced pseudomembranous enterocolitis is 125 to 500 mg every 6 hours for 7 to 10 days.
Intravenous vs oral administration
Vancomycin must be given intravenously (IV) for systemic therapy, since it is not absorbed from the intestine. It is a large hydrophilic molecule that partitions poorly across the gastrointestinal mucosa. Due to short half-life, it is often injected twice daily.The only approved indication for oral vancomycin therapy is in the treatment of pseudomembranous colitis, where it must be given orally to reach the site of infection in the colon. Following oral administration, the fecal concentration of vancomycin is around 500 µg/mL (sensitive strains of C. difficile have a mean inhibitory concentration of ≤2 µg/mL)
Inhaled vancomycin has also been used (off-label), via nebulizer, for treatment of various infections of the upper and lower respiratory tract.
There is an ongoing debate as to whether vancomycin should be given through a central or peripheral line. According to a 2014 review, midline catheters are a safe option for administration.
Vancomycin Flushing Reaction (aka "Red man syndrome")
Vancomycin is recommended to be administered in a dilute solution slowly, over at least 60 min (maximum rate of 10 mg/min for doses >500 mg) due to the high incidence of pain and thrombophlebitis and to avoid an infusion reaction known as vancomycin flushing reaction. This phenomenon has been often clinically referred to as "red man syndrome". The reaction usually appears within 4 to 10 min after the commencement or soon after the completion of an infusion and is characterized by flushing and/or an erythematous rash that affects the face, neck, and upper torso, attributed due to release of histamine from the mast cells. These findings are due to interaction of vancomycin with MRGPRX2, a GPCR mediating IgE-independent mast cell degranulation. Less frequently, hypotension and angioedema may also occur. Symptoms may be treated or prevented with antihistamines, including diphenhydramine, and are less likely to occur with slow infusion.
Therapeutic drug monitoring
Plasma level monitoring of vancomycin is necessary due to the drugs biexponential distribution, intermediate hydrophilicity, and potential for ototoxicity and nephrotoxicity, especially in populations with poor renal function and/or increased propensity to bacterial infection. Vancomycin activity is considered to be time-dependent; that is, antimicrobial activity depends on the duration that the serum drug concentration exceeds the minimum inhibitory concentration of the target organism. Thus, peak serum levels have not been shown to correlate with efficacy or toxicity; indeed, concentration monitoring is unnecessary in most cases. Circumstances in which therapeutic drug monitoring is warranted include: patients receiving concomitant aminoglycoside therapy, patients with (potentially) altered pharmacokinetic parameters, patients on haemodialysis, patients administered high-dose or prolonged treatment, and patients with impaired renal function. In such cases, trough concentrations are measured.Target ranges for serum vancomycin concentrations have changed over the years. Early authors suggested peak levels of 30 to 40 mg/L and trough levels of 5 to 10 mg/L,
but current recommendations are that peak levels need not be measured and that trough levels of 10 to 15 mg/L or 15 to 20 mg/L, depending on the nature of the infection and the specific needs of the patient, may be appropriate. Using measured vancomycin concentrations to calculate doses optimizes therapy in patients with augmented renal clearance.
Biosynthesis
Vancomycin is made by the soil bacterium Amycolatopsis orientalis.
Vancomycin biosynthesis occurs primarily via three nonribosomal protein syntheses (NRPSs) VpsA, VpsB, and VpsC. The enzymes determine the amino acid sequence during its assembly through its 7 modules. Before vancomycin is assembled through NRPS, the non-proteinogenic amino acids are first synthesized. L-tyrosine is modified to become the β-hydroxytyrosine (β-HT) and 4-hydroxyphenylglycine (4-Hpg) residues. 3,5 dihydroxyphenylglycine ring (3,5-DPG) is derived from acetate.
Nonribosomal peptide synthesis occurs through distinct modules that can load and extend the protein by one amino acid per module through the amide bond formation at the contact sites of the activating domains. Each module typically consists of an adenylation (A) domain, a peptidyl carrier protein (PCP) domain, and a condensation (C) domain. In the A domain, the specific amino acid is activated by converting into an aminoacyl adenylate enzyme complex attached to a 4phosphopantetheine cofactor by thioesterification The complex is then transferred to the PCP domain with the expulsion of AMP. The PCP domain uses the attached 4-phosphopantethein prosthetic group to load the growing peptide chain and their precursors. The organization of the modules necessary to biosynthesize Vancomycin is shown in Figure 1. In the biosynthesis of Vancomycin, additional modification domains are present, such as the epimerization (E) domain, which isomerizes the amino acid from one stereochemistry to another, and a thioesterase domain (TE) is used as a catalyst for cyclization and releases of the molecule via a thioesterase scission.
A set of NRPS enzymes (peptide synthase VpsA, VpsB, and VpsC) are responsible for assembling the heptapeptide. (Figure 2). VpsA codes for modules 1, 2, and 3. VpsB codes for modules 4, 5, and 6, and VpsC codes for module 7. The vancomycin aglycone contains 4 D-amino acids, although the NRPSs only contain 3 epimerization domains. The origin of D-Leu at residue 1 is not known. The three peptide syntheses are located at the start of the region of the bacterial genome linked with antibiotic biosynthesis, and span 27 kb.β-hydroxytyrosine (β-HT) is synthesized prior to incorporation into the heptapeptide backbone. L-tyrosine is activated and loaded on the NRPS VpsD, hydroxylated by OxyD, and released by the thioesterase Vhp. The timing of the chlorination by halogenase VhaA during biosynthesis is currently undetermined, but is proposed to occur before the complete assembly of the heptapeptide.After the linear heptapeptide molecule is synthesized, vancomycin has to undergo further modifications, such as oxidative cross-linking and glycosylation, in trans by distinct enzymes, referred to as tailoring enzymes, to become biologically active (Figure 3). To convert the linear heptapeptide to cross-linked, glycosylated vancomycin, six enzymes, are required. The enzymes OxyA, OxyB, OxyC, and OxyD are cytochrome P450 enzymes. OxyB catalyzes oxidative cross-linking between residues 4 and 6, OxyA between residues 2 and 4, and OxyC between residues 5 and 7. This cross-linking occurs while the heptapeptide is covalently bound to the PCP domain of the 7th NRPS module. These P450s are recruited by the X domain present in the 7th NRPS module, which is unique to glycopeptide antibiotic biosynthesis. The cross-linked heptapeptide is then released by the action of the TE domain, and methyltransferase Vmt then N-methylates the terminal leucine residue. GtfE then joins D-glucose to the phenolic oxygen of residue 4, followed by the addition of vancosamine catalyzed by GtfD.
Some of the glycosyltransferases capable of glycosylating vancomycin and related nonribosomal peptides display notable permissivity and have been employed for generating libraries of differentially glycosylated analogs through a process known as glycorandomization.
Total synthesis
Both the vancomycin aglycone and the complete vancomycin molecule have been targets successfully reached by total synthesis. The target was first achieved by David Evans in October 1998, KC Nicolaou in December 1998, Dale Boger in 1999, and has recently been more selectively synthesized again by Dale Boger in 2020.
Pharmacology and chemistry
Vancomycin is a branched tricyclic glycosylated nonribosomal peptide produced by the Actinomycetota species Amycolatopsis orientalis (formerly designated Nocardia orientalis).
Vancomycin exhibits atropisomerism — it has multiple chemically distinct rotamers owing to the rotational restriction of some of the bonds. The form present in the drug is the thermodynamically more stable conformer.
Mechanism of action
Vancomycin acts by inhibiting proper cell wall synthesis in Gram-positive bacteria. Due to the different mechanism by which Gram-negative bacteria produce their cell walls and the various factors related to entering the outer membrane of Gram-negative organisms, vancomycin is not active against them (except some nongonococcal species of Neisseria).
The large hydrophilic molecule is able to form hydrogen bond interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides. Under normal circumstances, this is a five-point interaction. This binding of vancomycin to the D-Ala-D-Ala prevents cell wall synthesis of the long polymers of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) that form the backbone strands of the bacterial cell wall, and it prevents the backbone polymers that do manage to form from cross-linking with each other.
Plant tissue culture
Vancomycin is one of the few antibiotics used in plant tissue culture to eliminate Gram-positive bacterial infection. It has relatively low toxicity to plants.
Antibiotic resistance
Intrinsic resistance
A few Gram-positive bacteria are intrinsically resistant to vancomycin: Leuconostoc and Pediococcus species, but these organisms rarely cause diseases in humans. Most Lactobacillus species are also intrinsically resistant to vancomycin, with the exception of L. acidophilus and L. delbrueckii, which are sensitive. Other Gram-positive bacteria with intrinsic resistance to vancomycin include Erysipelothrix rhusiopathiae, Weissella confusa, and Clostridium innocuum.Most Gram-negative bacteria are intrinsically resistant to vancomycin because their outer membranes are impermeable to large glycopeptide molecules (with the exception of some non-gonococcal Neisseria species).
Acquired resistance
Evolution of microbial resistance to vancomycin is a growing problem, in particular, within healthcare facilities such as hospitals. While newer alternatives to vancomycin exist, such as linezolid (2000) and daptomycin (2003), the widespread use of vancomycin makes resistance to the drug a significant worry, especially for individual patients if resistant infections are not quickly identified and the patient continues the ineffective treatment. Vancomycin-resistant Enterococcus emerged in 1986. Vancomycin resistance evolved in more common pathogenic organisms during the 1990s and 2000s, including vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA). Agricultural use of avoparcin, another similar glycopeptide antibiotic, may have contributed to the evolution of vancomycin-resistant organisms.One mechanism of resistance to vancomycin involves the alteration to the terminal amino acid residues of the NAM/NAG-peptide subunits, under normal conditions, D-alanyl-D-alanine, to which vancomycin binds. The D-alanyl-D-lactate variation results in the loss of one hydrogen-bonding interaction (4, as opposed to 5 for D-alanyl-D-alanine) possible between vancomycin and the peptide. This loss of just one point of interaction results in a 1000-fold decrease in affinity. The D-alanyl-D-serine variation causes a six-fold loss of affinity between vancomycin and the peptide, likely due to steric hindrance.In enterococci, this modification appears to be due to the expression of an enzyme that alters the terminal residue. Three main resistance variants have been characterised to date among resistant Enterococcus faecium and E. faecalis populations:
VanA - enterococcal resistance to vancomycin and teicoplanin; inducible on exposure to these agents
VanB - lower-level enterococcal resistance; inducible by vancomycin, but strains may remain susceptible to teicoplanin
VanC - least clinically important; enterococci resistant only to vancomycin; constitutive resistanceVariant of vancomycin has been tested that binds to the resistant D-lactic acid variation in vancomycin-resistant bacterial cell walls, and also binds well to the original target (vancomycin-susceptible bacteria).
"Re-gained" vancomycin
In 2020 a team at the University Hospital Heidelberg (Germany) re-gained the antibacterial power of vancomycin by modifying the molecule with a cationic oligopeptide. The oligopeptide consists of six arginin units in Position VN. In comparison to the unmodified vancomycin the activity against vancomycin-resistant bacteria could be enhanced by a factor of 1 000. This pharmacon is still in preclinical development. Therefore, a potential approval will take several more years.
History
Vancomycin was first isolated in 1953 by Edmund Kornfeld (working at Eli Lilly) from a soil sample collected from the interior jungles of Borneo by a missionary, Rev. William M. Bouw (1918-2006). The organism that produced it was eventually named Amycolatopsis orientalis. The original indication for vancomycin was for the treatment of penicillin-resistant Staphylococcus aureus.The compound was initially called compound 05865, but was eventually given the generic name vancomycin, derived from the term "vanquish". One advantage that was quickly apparent was that staphylococci did not develop significant resistance, despite serial passage in culture media containing vancomycin. The rapid development of penicillin resistance by staphylococci led to its being fast-tracked for approval by the Food and Drug Administration. In 1958, Eli Lilly first marketed vancomycin hydrochloride under the trade name Vancocin.Vancomycin never became the first-line treatment for S. aureus for several reasons:
It possesses poor oral bioavailability, so must be given intravenously for most infections.
β-Lactamase-resistant semisynthetic penicillins such as methicillin (and its successors, nafcillin and cloxacillin) were subsequently developed, which have better activity against non-MRSA staphylococci.
Early trials used early, impure forms of the drug ("Mississippi mud"), which were found to be toxic to the inner ear and to the kidneys; these findings led to vancomycins being relegated to the position of a drug of last resort.In 2004, Eli Lilly licensed Vancocin to ViroPharma in the U.S., Flynn Pharma in the UK, and Aspen Pharmacare in Australia. The patent had expired in the early 1980s, and the FDA authorized the sale of several generic versions in the US, including from manufacturers Bioniche Pharma, Baxter Healthcare, Sandoz, Akorn-Strides, and Hospira.
References
External links
"Vancomycin". Drug Information Portal. U.S. National Library of Medicine.
"Vancomycin hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Floxuridine | Floxuridine (also 5-fluorodeoxyuridine) is an oncology drug that belongs to the class known as antimetabolites. Specifically, floxuridine is a pyrimidine analog, classified as a deoxyuridine. The drug is usually administered via an artery, and most often used in the treatment of colorectal cancer. The quality of life and survival rates of individuals that receive continuous hepatic artery infusion of floxuridine for colorectal cancer metastases is significantly higher than control groups. Floxuridine can also be prescribed for the treatment of kidney and stomach cancers. In vitro uses of floxuridine include 5-minute treatments of fluorouracil, floxuridine, and mitomycin to increase cell proliferation in Tenons capsule fibroblasts.
Biosynthesis
Immobilized Aeromonas salmonicida ATCC 27013, when exposed to thymidine and 5-fluorouracil in phosphate buffer at room temperature for one hour, can synthesize floxuridine and thymine.
Pharmacology
Floxuridine primarily works by stopping the growth of newly born cells. The drug essentially stops DNA from forming in new and rapidly developing cells, which is a sign of a cancerous cell. Therefore, the floxuridine kills the cancerous cells. For colorectal cancer and hepatic metastases, an average adult should be given an intra-arterial dosage of 0.1–0.6 mg/kg/day as a continuous infusion, continued until intolerable toxicity is reached (white blood cell count < 3,500/mm3 or platelet count < 100,000/mm3).
Lethal dosages for other species are below. LD50 is the lethal dose at which half of organisms exposed to the drug die.
Pharmacodynamics
Floxuridine is a pyrimidine analog that acts as an inhibitor of the S-phase of cell division. This selectively kills rapidly dividing cells. Antimetabolites masquerade as pyrimidine-like molecules which prevents normal pyrimidines from being incorporated into DNA during the S phase of the cell cycle. Fluorouracil (the end-product of catabolism of floxuridine) blocks an enzyme which converts cytosine nucleosides into the deoxy derivative. In addition, DNA synthesis is further inhibited because fluorouracil blocks the incorporation of the thymidine nucleotide into the DNA strand.
Mechanism of action
Floxuridine is rapidly catabolized to 5-fluorouracil, which is the active form of the drug. The primary effect is interference with DNA synthesis and to a lesser extent, inhibition of RNA formation through the drugs incorporation into RNA, thus leading to the production of fraudulent RNA. Fluorouracil also inhibits uracil riboside phosphorylase, which prevents the utilization of preformed uracil in RNA synthesis. As well, the monophosphate of floxuridine, 5-fluoro-2-deoxyuridine-5-phosphate (FUDR-MP) inhibits the enzyme thymidylate synthetase. This leads to the inhibition of methylation of deoxyuridylic acid to thymidylic acid, thus interfering with DNA synthesis.
Route of elimination
The drug is excreted intact and as urea, fluorouracil, α-fluoro-β-ureidopropionic acid, dihydrofluorouracil, α-fluoro-β-guanidopropionic acid, and α-fluoro-β-alanine in the urine; it is also expired as respiratory carbon dioxide.
Side effects
Side effects include:
Common (30% of patients)
Low blood counts. Your white and red blood cells and platelets may temporarily decrease. This can put you at increased risk for infection, anemia and/or bleeding.
Mouth sores
Diarrhea (may be severe)
Less common (10–29% of patients)
Poor appetite
Nausea and vomiting
Hair loss
Elevated liver enzymes (temporary increase in alkaline phosphatase, lactate dehydrogenase, transaminase, and bilirubin). This is seen more with the intra-arterial infusion directly into the liver.
Hand-foot syndrome (Palmar-plantar erythrodysesthesia or PPE) -skin rash, swelling, redness, pain and/or peeling of the skin on the palms of hands and soles of feet
Stomach ulcers (This is seen more with the intra-arterial infusion).
Contact your health provider immediately
Fever of 100.4 °F (38 °C) or higher, chills (possible signs of infection).
Contact your health provider
Diarrhea (2 episodes in a 24-hour period)
Nausea (interferes with ability to eat and unrelieved with prescribed medication)
Vomiting (vomiting more than 4–5 times in a 24-hour period)
Mouth sores (painful redness, swelling or ulcers)
Unusual bleeding or bruising
Black or tarry stools, or blood in your stools
Blood in the urine
Yellowing of the skin or eyes
Tingling or burning, redness, swelling of the palms of the hands or soles of feet
Other
Fertility for both men and women may be affected by floxuridine.
Use in research
Apart from its use in chemotherapy, floxuridine is also used in aging research employing a C. elegans model, namely to stop growth and to prevent reproduction. The latter is brought about by treatment of larvae close to maturity with low doses of floxuridine that, even though allowing normal maturation, causes reproducing individuals to lay eggs that are unable to hatch. This limits the population to a single generation allowing quantification of aging processes and measurement of longevity. It has, however, been indicated that floxuridin exposure by itself increases life expectancy potentially leading to flawed data in respective studies.
History
Floxuridine first gained FDA approval in December 1970 under the brand name FUDR. The drug was initially marketed by Roche, which also did a lot of the initial work on 5-fluorouracil. The National Cancer Institute was an early developer of the drug. Roche sold its FUDR product line in 2001 to F H Faulding, which became Mayne Pharma.
Alternative names
Synonyms for floxuridine include:
== References == |
Isocarboxazid | Isocarboxazid (Marplan, Marplon, Enerzer) is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class used as an antidepressant. Along with phenelzine and tranylcypromine, it is one of only three classical MAOIs still available for clinical use in the treatment of psychiatric disorders in the United States, though it is not as commonly employed in comparison to the others.Isocarboxazid is primarily used to treat mood and anxiety disorders. It has also been investigated in the treatment of schizophrenia, Parkinsons disease and other dementia-related disorders. Isocarboxazid, as well as other MAOIs, increase the levels of the monoamine neurotransmitters serotonin, dopamine, and norepinephrine in the brain.Classical MAOIs, including isocarboxazid, are used only rarely due to prominent food and drug interactions and have been largely superseded by newer antidepressants such as the selective serotonin reuptake inhibitors (SSRIs). The cause of the interactions is because MAOIs inhibit the metabolism of dietary amines (e.g., tyramine) and the monoamine neurotransmitters. In combination with other drugs that increase the levels of the monoamine neurotransmitters such as the SSRIs, or with certain foods high in dietary amines such as aged cheeses, MAOIs can produce dangerous elevations of monoamine neurotransmitters resulting in potentially life-threatening syndromes such as hypertensive crisis and serotonin syndrome.
See also
Hydrazine (antidepressant)
== References == |
Pemirolast | Pemirolast (INN) is a mast cell stabilizer used as an anti-allergic drug therapy. It is marketed under the tradenames Alegysal and Alamast.
Clinical trials studying treatments for allergic conjunctivitis have found that an ophthalmic solution containing levocabastine with pemirolast potassium may be more effective in alleviating symptoms than levocabastine alone.It has also been studied for the treatment of asthma.
Pemirolast has appeared as a possible candidate for SARS-CoV-2 (COVID-19) spike protein disruption and interference. Such results were ascertained by molecular dynamics calculations executed on the Summit supercomputer. By simulating compounds with FDA or similar regulatory approval, the authors found 4 interfacial molecules that could potentially disrupt the SARS-CoV-2 interface with ACE-2 receptors, suggesting that such small molecules could mitigate SARS-CoV-2 infection. The 4 candidate interfacial molecules included pemirolast, isoniazid pyruvate, nitrofurantoin, and eriodictyol.
References
Tinkelman DG, Berkowitz RB (February 1991). "A pilot study of pemirolast in patients with seasonal allergic rhinitis". Ann Allergy. 66 (2): 162–5. PMID 1994787.
Kawashima T, Iwamoto I, Nakagawa N, Tomioka H, Yoshida S (1994). "Inhibitory effect of pemirolast, a novel antiallergic drug, on leukotriene C4 and granule protein release from human eosinophils". Int. Arch. Allergy Immunol. 103 (4): 405–9. doi:10.1159/000236662. PMID 8130655.
Abelson MB, Berdy GJ, Mundorf T, Amdahl LD, Graves AL (October 2002). "Pemirolast potassium 0.1% ophthalmic solution is an effective treatment for allergic conjunctivitis: a pooled analysis of two prospective, randomized, double-masked, placebo-controlled, phase III studies". J Ocul Pharmacol Ther. 18 (5): 475–88. doi:10.1089/10807680260362759. PMID 12419098.
Kemp JP, Bernstein IL, Bierman CW, et al. (June 1992). "Pemirolast, a new oral nonbronchodilator drug for chronic asthma". Ann Allergy. 68 (6): 488–91. PMID 1610024.
External links
"Pemirolast Potassium". Drug Information Portal. U.S. National Library of Medicine. |
Levetiracetam | Levetiracetam, sold under the brand name Keppra among others, is a medication used to treat epilepsy. It is used for partial-onset, myoclonic, or tonic–clonic seizures and is taken either by mouth as an immediate or extended release formulation or by injection into a vein.Common side effects of levetiracetam include sleepiness, dizziness, feeling tired, and aggression. Severe side effects may include psychosis, suicide, and allergic reactions such as Stevens–Johnson syndrome or anaphylaxis. It is unclear if levetiracetam is safe for use during pregnancy and breastfeeding. Levetiracetam is the S-enantiomer of etiracetam. Its mechanism of action is not yet clear.Levetiracetam was approved for medical use in the United States in 1999 and is available as a generic medication. In 2019, it was the 97th most commonly prescribed medication in the United States, with more than 7 million prescriptions.
Medical uses
Focal epilepsy
Levetiracetam is effective as single-drug treatment for newly diagnosed focal epilepsy in adults. It reduces focal seizures by 50% or more as an add-on medication.
Partial-complex epilepsy
Levetiracetam is effective as add-on treatment for partial (focal) epilepsy.
Generalized epilepsy
Levetiracetam is effective for treatment of generalized tonic-clonic epilepsy. It has been approved in the United States as add-on treatment for myoclonic, and tonic-clonic seizures. Levetiracetam has been approved in the European Union as a monotherapy treatment for epilepsy in the case of partial seizures or as an adjunctive therapy for partial, myoclonic, and tonic-clonic seizures.Levetiracetam is sometimes used off label to treat status epilepticus.
Prevention of seizures
Based on low-quality evidence, levetiracetam is about as effective as phenytoin for prevention of early seizures after traumatic brain injury. It may be effective for prevention of seizures associated with subarachnoid hemorrhages.
Other
Levetiracetam has not been found to be useful for treatment of neuropathic pain, nor for treatment of essential tremors. Levetiracetam has not been found to be useful for treating autism, but is an effective treatment for partial, myoclonic, or tonic-clonic seizures associated with autism spectrum disorder.
Special groups
Studies in female pregnant rats have shown minor fetal skeletal abnormalities when given maximum recommended human doses of levetiracetam orally throughout pregnancy and lactation.Studies were conducted to look for increased adverse effects in the elderly population as compared to younger patients. One such study published in Epilepsy Research showed no significant increase in incidence of adverse symptoms experienced by young or elderly patients with central nervous system (CNS) disorders.Levetiracetam may be safely used with caution in children over the age of four. However, it has not been determined whether it can be safely given to children under the age of four.
Adverse effects
The most common adverse effects of levetiracetam treatment include CNS effects such as somnolence, decreased energy, headache, dizziness, mood swings and coordination difficulties. These adverse effects are most pronounced in the first month of therapy. About 4% of patients dropped out of pre-approval clinical trials due to these side effects.About 13% of people taking levetiracetam experience adverse neuropsychiatric symptoms, which are usually mild. These include agitation, hostility, apathy, anxiety, emotional lability, and depression. Serious psychiatric adverse side effects that are reversed by drug discontinuation occur in about 1%. These include hallucinations, suicidal thoughts, or psychosis. These occurred mostly within the first month of therapy, but they could develop at any time during treatment.Although rare, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which appears as a painful spreading rash with redness and blistering and/or peeling skin, have been reported in patients treated with levetiracetam. The incidence of SJS following exposure to anti-epileptics such as levetiracetam is about 1 in 3,000.Levetiracetam should not be used in people who have previously shown hypersensitivity to levetiracetam or any of the inactive ingredients in the tablet or oral solution. Such hypersensitivity reactions include, but are not limited to, unexplained rash with redness or blistered skin, difficulty breathing, and tightness in the chest or airways.In a study, the incidence of decreased bone mineral density of patients on levetiracetam was significantly higher than those for other epileptic medications.
Suicide
Levetiracetam, along with other anti-epileptic drugs, can increase the risk of suicidal behavior or thoughts. People taking levetiracetam should be monitored closely for signs of worsening depression, suicidal thoughts or tendencies, or any altered emotional or behavioral states.
Kidney and liver
Kidney impairment decreases the rate of elimination of levetiracetam from the body. Individuals with reduced kidney function may require dose adjustments. Kidney function can be estimated from the rate of creatinine clearance.Dose adjustment of levetiracetam is not necessary in liver impairment.
Drug interactions
No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications. The pharmacokinetic profile of levetiracetam is not influenced by phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, lamotrigine, gabapentin, digoxin, ethinylestradiol, or warfarin.
Mechanism of action
The exact mechanism by which levetiracetam acts to treat epilepsy is unknown. Levetiracetam does not exhibit pharmacologic actions similar to that of classical anticonvulsants. It does not inhibit voltage-dependent Na+ channels, does not affect GABAergic transmission, and does not bind to GABAergic or glutamatergic receptors. However, the drug binds to SV2A, a synaptic vesicle glycoprotein, and inhibits presynaptic calcium channels, reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses.
Pharmacokinetics
Absorption
The absorption of levetiracetam tablets and oral solution is rapid and essentially complete. The bioavailability of levetiracetam is close to 100 percent, and the effect of food on absorption is minor.
Distribution
The volume of distribution of levetiracetam is similar to total body water. Levetiracetam modestly binds to plasma proteins (less than 10%).
Metabolism
Levetiracetam does not undergo extensive metabolism, and the metabolites formed are not active and do not exert pharmacological activity. Metabolism of levetiracetam is not by liver cytochrome P450 enzymes, but through other metabolic pathways such as hydrolysis and hydroxylation.
Excretion
In persons with normal kidney function, levetiracetam is eliminated from the body primarily by the kidneys with about 66 percent of the original drug passed unchanged into urine. The plasma half-life of levetiracetam in adults is about 6 to 8 hours although the mean CSF half life of approx. 24 hours better reflects levels at site of action.
Analogues
Brivaracetam, a chemical analogue to levetiracetam, is a racetam derivative with similar properties.
Society and culture
Levetiracetam is available as regular and extended release oral formulations and as intravenous formulations.The immediate release tablet has been available as a generic in the United States since 2008, and in the UK since 2011. The patent for the extended release tablet will expire in 2028.The branded version Keppra is manufactured by UCB Pharmaceuticals Inc.In 2015, Aprecias 3D-printed orally disintegrating tablet form of the drug was approved by the FDA, under the trade name Spritam. Some have said that the drug has been improved by 3D printing, as the formula used now has improved disintegration properties.
Legal status
Australia
Levetiracetam is a Schedule 4 substance in Australia under the Poisons Standard (February 2020). A Schedule 4 substance is classified as "Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription."
Japan
Under Japanese law, levetiracetam and other racetams cannot be brought into the country except for personal use by a traveler for whom it has been prescribed. Travelers who plan to bring more than a months worth must apply for an import certificate, known as a Yakkan Shoumei (薬監証明, yakkan shōmei).
Research
Levetiracetam is being looked at in psychiatric and neurologic conditions such as Tourette syndrome, and anxiety disorder. However, its most serious adverse effects are behavioral, and its benefit-risk ratio in these conditions is not well understood.Levetiracetam is being tested as a drug to reduce hyperactivity in the hippocampus in Alzheimers disease.Additionally, Levetiracetam has been experimentally shown to reduce Levodopa-induced dyskinesia, a type of movement disorder, or dyskinesia associated with the use of Levodopa, a medication used to treat Parkinsons disease.
References
External links
"Levetiracetam". Drug Information Portal. U.S. National Library of Medicine. |
Vestronidase alfa | Vestronidase alfa, sold under brand name Mepsevii, is a drug for the treatment of Sly syndrome. It is a recombinant form of the human enzyme beta-glucuronidase. It was approved in the United States in November 2017, to treat children and adults with an inherited metabolic condition called mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome. MPS VII is an extremely rare, progressive condition that affects most tissues and organs.The most common side effects after treatment with vestronidase alfa include infusion site reactions, diarrhea, rash (urticaria) and anaphylaxis (sudden, severe allergic reaction).The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. It was approved for use in the European Union in August 2018.
Medical uses
Mepsevii is indicated for the treatment of non-neurological manifestations of Mucopolysaccharidosis VII (MPS VII; Sly syndrome).
History
The safety and efficacy of vestronidase alfa were established in a clinical trial and expanded access protocols enrolling a total of 23 participants ranging from five months to 25 years of age. Participants received treatment with vestronidase alfa at doses up to 4 mg/kg once every two weeks for up to 164 weeks. Efficacy was primarily assessed via the six-minute walk test in ten participants who could perform the test. After 24 weeks of treatment, the mean difference in distance walked relative to placebo was 18 meters. Additional follow-up for up to 120 weeks suggested continued improvement in three participants and stabilization in the others. Two participants in the vestronidase alfa development program experienced marked improvement in pulmonary function. Overall, the results observed would not have been anticipated in the absence of treatment. The effect of vestronidase alfa on the central nervous system manifestations of MPS VII has not been determined.The FDA approved vestronidase alfa-vjbk based primarily on evidence from one clinical trial (NCT02230566) of 12 participants with mucopolysaccharidosis VII. The trial was conducted at four sites in the United States.The benefit and side effects of vestronidase alfa were based primarily on one trial. Participants were randomly assigned to four groups. Three groups of participants received placebo treatment before starting vestronidase alfa treatment and one group received vestronidase alfa only. vestronidase alfa or placebo were given once every two weeks as intravenous (IV) infusions. Neither participants nor healthcare providers knew which treatment was given until after the trial was competed.The benefit of 24 weeks of vestronidase alfa treatment was primarily evaluated by the 6-minute walking test (6MWT) and compared to placebo treatment in ten participants who could perform the test. The 6MWT measured the distance a patient could walk on a flat surface in 6 minutes. An additional follow-up using 6MWT was done for up to 120 weeks.The application for vestronidase alfa was granted fast track designation, orphan drug designation, and a rare pediatric disease priority review voucher. This was the twelfth rare pediatric disease priority review voucher issued.The U.S. Food and Drug Administration (FDA) granted approval of Mepsevii to Ultragenyx Pharmaceutical, Inc, and required the manufacturer to conduct a post-marketing study to evaluate the long-term safety of the product.
References
External links
"Vestronidase alfa". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02230566 for "A Phase 3 Study of UX003 Recombinant Human Betaglucuronidase (rhGUS) Enzyme Replacement Therapy in Patients With Mucopolysaccharidosis Type 7 (MPS 7)" at ClinicalTrials.gov |
Ganciclovir | Ganciclovir, sold under the brand name Cytovene among others, is an antiviral medication used to treat cytomegalovirus (CMV) infections.
Ganciclovir was patented in 1980 and approved for medical use in 1988.
Medical use
Ganciclovir is indicated for:
Sight-threatening CMV retinitis in severely immunocompromised people
CMV pneumonitis in bone marrow transplant recipients
Prevention of CMV disease in bone marrow and solid organ transplant recipients
Confirmed CMV retinitis in people with AIDS (intravitreal implant)It is also used for acute CMV colitis in HIV/AIDS and CMV pneumonitis in immunosuppressed patients.Ganciclovir has also been used with some success in treating Human herpesvirus 6 infections.Ganciclovir has also been found to be an effective treatment for herpes simplex virus epithelial keratitis.
Adverse effects
Ganciclovir is commonly associated with a range of serious haematological adverse effects. Common adverse drug reactions (≥1% of patients) include: granulocytopenia, neutropenia, anaemia, thrombocytopenia, fever, nausea, vomiting, dyspepsia, diarrhea, abdominal pain, flatulence, anorexia, raised liver enzymes, headache, confusion, hallucination, seizures, pain and phlebitis at injection site (due to high pH), sweating, rash, itch, increased serum creatinine and blood urea concentrations.
Toxicity
Ganciclovir is considered a potential human carcinogen, teratogen, and mutagen. It is also considered likely to cause inhibition of spermatogenesis. Thus, it is used judiciously and handled as a cytotoxic drug in the clinical setting.
Mechanism of action
Ganciclovir is a synthetic analogue of 2′-deoxy-guanosine. It is first phosphorylated to ganciclovir monophosphate by a viral kinase encoded by the cytomegalovirus (CMV) gene UL97 during infection. Subsequently, cellular kinases catalyze the formation of ganciclovir diphosphate and ganciclovir triphosphate, which is present in 10-fold greater concentrations in CMV or herpes simplex virus (HSV)-infected cells than uninfected cells.
Ganciclovir triphosphate is a competitive inhibitor of deoxyguanosine triphosphate (dGTP) incorporation into DNA and preferentially inhibits viral DNA polymerases more than cellular DNA polymerases. In addition, ganciclovir triphosphate serves as a poor substrate for chain elongation, thereby disrupting viral DNA synthesis by a second route.
Pharmacokinetics
Absorption of the oral form is very limited—about 5% fasting, about 8% with food. It achieves a concentration in the central nervous system of about 50% of the plasma level. About 90% of plasma ganciclovir is eliminated unchanged in the urine, with a half-life of 2–6 hours, depending on renal function (elimination takes over 24 hours in end-stage renal disease).
Administration
Acute infections are treated in two phases:
induction phase, 5 mg per kilogram intravenously every 12 hours for 14–21 days, the intravenous dose given as a 1-hour infusion
maintenance phase, 5 mg per kg intravenously every dayStable disease is treated with 1000 mg orally three times daily. Similar dosing is used to prevent disease in high-risk patients, such as those infected with human immunodeficiency virus (HIV) or those with organ transplants.
Ganciclovir is also available in slow-release formulations for insertion into the vitreous humour of the eye, as treatment for CMV retinitis (associated with HIV infection).
A topical ophthalmic gel preparation of ganciclovir was recently approved for the treatment of acute herpes simplex keratitis.
See also
Valganciclovir, the prodrug of ganciclovir
References
Further reading
External links
"Ganciclovir". Drug Information Portal. U.S. National Library of Medicine.
"Ganciclovir sodium". Drug Information Portal. U.S. National Library of Medicine. |
Trimipramine | Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression. It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively. The drug is described as an atypical or "second-generation" TCA because, unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor. Similarly to other TCAs however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.
Medical uses
Trimipramines primary use in medicine is in the treatment of major depressive disorder, especially where sedation is helpful due to its prominent sedative effects. The drug is also an effective anxiolytic, and can be used in the treatment of anxiety. In addition to depression and anxiety, trimipramine is effective in the treatment of insomnia, and unlike most other hypnotics, does not alter the normal sleep architecture. In particular, it does not suppress REM sleep, and dreams are said to "brighten" during treatment. Trimipramine also has some weak antipsychotic effects with a profile of activity described as similar to that of clozapine, and may be useful in the treatment of psychotic symptoms such as in delusional depression or schizophrenia.A major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found that trimipramine had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4 weeks of 0.55 (95% CI –0.11 to 1.21). The certainty of evidence was rated as very low, and no data were available for longer-term treatment (3 months). For comparison, the other sedating antihistamines assessed, doxepin and doxylamine, had effect sizes (SMD) at 4 weeks of 0.30 (95% CI –0.05 to 0.64) (very low certainty evidence) and 0.47 (95% CI 0.06 to 0.89) (moderate certainty evidence), respectively.The effective dosage of trimipramine in depression is 150 to 300 mg/day. Doses of trimipramine used for insomnia range from 25 to 200 mg/day. However, it has been advised that doses be kept as low as possible, and a low dose of 25 mg/day has been recommended.
Contraindications
Contraindications include:
Recent myocardial infarction
Any degree of heart block or other cardiac arrhythmias
Mania
Severe liver disease
During breastfeeding
Hypersensitivity to trimipramine or to any of the excipients
Side effects
The side effects of trimipramine have been said to be similar to those of other tertiary amine TCAs, with a preponderance of anticholinergic and sedative effects. However, trimipramine has also been said to be associated with a different side effect profile compared to other TCAs and in general with fewer side effects, chiefly due to its lack of norepinephrine reuptake inhibition and relatively lower anticholinergic effects (although it is still a potent anticholinergic). Somnolence is the most common side effect of the drug. Dry mouth is the most common anticholinergic side effect, but others like constipation, urinary retention, and blurred vision are also present.It is described as being associated with minimal or no orthostatic hypotension, at least in comparison to clomipramine, in spite of its potent and comparable activity as an alpha-1 blocker. However, it has also been said to have a rate of orthostatic hypotension similar to that of other TCAs. Trimipramine is said to be less epileptogenic than other TCAs, although seizures have still been reported in association with it. It is also less cardiotoxic than other TCAs and cardiotoxicity is said to be minimal, with a "very favorable profile".Heavy exposure to any tricyclic antidepressants was associated with an elevated rate ratio for breast cancer 11–15 years later. However, on tests done on Drosophila melanogaster, nongenotoxic TCAs (amitriptyline, maprotiline, nortriptyline, and protriptyline), and genotoxic TCAs (amoxapine, clomipramine, desipramine, doxepin, imipramine, and trimipramine) were identified.
List of side effects
Common adverse effects include:
Adverse effects with an unknown incidence includes:
Confusion
Nausea
Vomiting
Extrapyramidal side effects (e.g. parkinsonism, dystonia, etc.)
Tinnitus
Paraesthesia
ECG changes
Increased liver function testsRare adverse effects include:
Seizures
Syndrome of inappropriate secretion of antidiuretic hormone
Blood dyscrasias including:
Agranulocytosis
Thrombocytopenia
Eosinophilia
Leukopenia
Myocardial infarction
Heart block
QTc interval prolongation
Sudden cardiac death
Depression worsening
Suicidal ideation
Overdose
Compared to other TCAs, trimipramine is relatively safe in overdose, although it is more dangerous than the selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) but less dangerous than bupropion in cases of overdose.
Interactions
Trimipramine should not be given with sympathomimetic agents such as epinephrine (adrenaline), ephedrine, isoprenaline, norepinephrine (noradrenaline), phenylephrine and phenylpropanolamine.
Barbiturates may increase the rate of metabolism. Trimipramine should be administered with care in patients receiving therapy for hyperthyrodism.
Pharmacology
Pharmacodynamics
The mechanism of action of trimipramine in terms of its antidepressant effects differs from that of other TCAs and is not fully clear. The mechanism of action of its anxiolytic effects is similarly unclear. Trimipramine is a very weak reuptake inhibitor of serotonin, norepinephrine, and dopamine (see below), and unlike most other TCAs, has been claimed to be devoid of clinically significant monoamine reuptake inhibition. The effects of the drug are thought to be mainly due to receptor antagonism as follows:
Very strong: H1
Strong: 5-HT2A, α1-adrenergic
Moderate: D2, mACh
Weak: 5-HT2C, D1, α2-adrenergicIn spite of its atypical nature and different profile of activity, trimipramine has been shown in head-to-head clinical studies to possess equivalent effectiveness to other antidepressants, including but not limited to other TCAs (e.g., amitriptyline, imipramine, doxepin, amineptine), tetracyclic antidepressants (TeCAs) (e.g., maprotiline), monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, isocarboxazid), and selective serotonin reuptake inhibitors (e.g., fluoxetine). In addition, trimipramine has been found to possess greater anxiolytic effects than other TCAs such as amitriptyline and doxepin in head-to-head comparisons. Indeed, its prominent anxiolytic effects have been said to distinguish it from most other TCAs. The atypicality of trimipramine in relation to its lack of monoamine reuptake inhibition is described as challenging the monoamine hypothesis of depression.The major metabolite of trimipramine, desmethyltrimipramine, is considered to possess pharmacological activity similar to that of other demethylated tertiary amine TCA variants.
Monoamine reuptake inhibition
Studies have generally found only very weak inhibition of serotonin and norepinephrine reuptake with trimipramine, and the drug has been described by various authors as devoid of monoamine reuptake inhibition. Richelson & Pfenning (1984) found a relatively high Ki for the NET of 510 nM in rat brain synaptosomes and Tatsumi et al. (1997) found a relatively high KD of 149 nM for the SERT in human HEK293 cells, but other authors and a more recent study with an improved design have not had the same findings. In the most recent study, by Haenisch et al. (2011), the researchers suggested that the discrepant findings from the Tatsumi et al. study were due to methodological differences, in particular the use of radioligand binding in isolated membranes (KD) to study interactions as opposed to actual functional reuptake inhibition (IC50).
Trimipramine is extensively metabolized, so its metabolites may contribute to its pharmacology, including potentially to monoamine reuptake inhibition. In what was the only study to date to have assessed the activity profiles of the metabolites of trimipramine, Haenisch et al. (2011) assayed desmethyltrimipramine, 2-hydroxytrimipramine, and trimipramine-N-oxide in addition to trimipramine and found that these metabolites showed IC50 values for the SERT, NET, and DAT similar to those of trimipramine (see table to the right). Like other secondary amine TCAs, desmethyltrimipramine was slightly more potent than trimipramine in its norepinephrine reuptake inhibition but less potent in its inhibition of serotonin reuptake. However, desmethyltrimipramine still showed only very weak inhibition of the NET.Therapeutic concentrations of trimipramine are between 0.5 and 1.2 μM (150–350 ng/mL) and hence significant monoamine reuptake inhibition would not be expected with it or its metabolites. However, these concentrations are nearly 2-fold higher if the active metabolites of trimipramine are also considered, and studies of other TCAs have found that they cross the blood–brain barrier and accumulate in the brain to levels of up to 10-fold those in the periphery. As such, trimipramine and its metabolites might at least partially inhibit reuptake of serotonin and/or norepinephrine, though not of dopamine, at therapeutic concentrations, and this could be hypothesized to contribute at least in part to its antidepressant effects. This is relevant as Haenisch et al. has stated that these are the only actions known at present which could explain or at least contribute to the antidepressant effects of trimipramine. That said, blockade of the 5-HT2A, 5-HT2C, and α2-adrenergic receptors, as with mirtazapine, has also been implicated in antidepressant effects.In any case, there is also clinical and animal evidence that trimipramine does not inhibit the reuptake of monoamines. Unlike other TCAs, it does not downregulate β3-adrenergic receptors, which is likely the reason that it does not cause orthostatic hypotension. It can be safely combined with MAOIs apparently without risk of serotonin syndrome or hypertensive crisis. Indeed, in rabbits, whereas hyperpyrexia (a symptom of serotonin syndrome) occurs with imipramine and an MAOI and to a lesser extent with amitriptyline and an MAOI, it does not occur at all with trimipramine and an MAOI, likely due to trimipramines lack of serotonin reuptake inhibition.
Antihistamine activity
Trimipramine is a very potent antihistamine; it has the third highest affinity for the H1 receptor (Ki = 0.27 nM) after mirtazapine (Ki = 0.14 nM) and doxepin (Ki = 0.24 nM) among the TCAs and tetracyclic antidepressants (TeCAs). The TeCA mianserin (Ki = 0.40) and the TCA amitriptyline (Ki = 1.0) are also very potent H1 receptor antagonists, whereas other TCAs and TeCAs are less potent. These TCAs and TeCAs, including trimipramine, are far more potent than the standard antihistamine diphenhydramine (approximately 800 times for doxepin and 250 times for trimipramine), and are among the most potent antihistamines available.Trimipramine is also an antagonist of the H2 receptor with lower potency and has been found to be effective in the treatment of duodenal ulcers.
As a hypnotic
Blockade of the H1 receptor is responsible for the sedative effects of trimipramine and other TCAs and their effectiveness in the treatment of insomnia.Most antidepressants suppress REM sleep, in parallel with their alleviation of depressive symptoms (although suppression of REM sleep is not required for antidepressant effects). This includes TCAs (e.g., amitriptyline, nortriptyline), TeCAs (e.g., mianserin, maprotiline), MAOIs (e.g., clorgiline, pargyline), and SSRIs (e.g., fluoxetine, zimelidine, indalpine). Trimipramine is unique in that it is an exception and produces antidepressant effects without compromising or otherwise affecting REM sleep. Even long-term treatment with trimipramine for up to 2 years has not been found to suppress REM sleep. In addition, trimipramine has been found to decrease nocturnal cortisol levels to normal and to normalize cortisol response in depressed patients; hence, it normalizes the hypothalamic–pituitary–adrenal axis, whereas imipramine and other antidepressants tend to increase nocturnal cortisol secretion.In clinical studies, trimipramine has been found in doses of 50 to 200 mg/day to significantly increase sleep efficiency and total sleep time and to decrease waking time for up to 3 weeks in patients with insomnia. It also improved subjectively perceived sleep quality and well-being during daytime. Monitoring of patients upon discontinuation of trimipramine found that it did not cause rebound insomnia or worsening of sleep quality in subjective evaluations of sleep, although objective measurements found total sleep time below baseline in a subset of patients during trimipramine withdrawal.
Antidopaminergic activity
Trimipramine is a weak but significant antagonist of the dopamine D1 and D2 receptors, and also binds to the D4 receptor (Ki = 275 nM). Its affinities for various monoamine receptors including the D2 and 5-HT2A receptors closely resemble those of the atypical antipsychotic clozapine. In accordance, high doses of trimipramine have been found to have antipsychotic effects in schizophrenic patients, notably without causing extrapyramidal symptoms, and trimipramine has recently been found to be effective in reducing psychotic symptoms in patients with delusional depression. The lack of extrapyramidal symptoms with trimipramine may be related to its affinity for the D4 receptor, these both being properties it shares with clozapine. Unlike other TCAs, but reminiscent of antipsychotics, trimipramine has been found to markedly increase plasma prolactin levels (a marker of D2 receptor antagonism) at a dose of 75 mg/day and to increase nocturnal prolactin secretion at doses of 75 and 200 mg/day. These findings are suggestive of important antidopaminergic actions of trimipramine.Unlike various other TCAs, trimipramine shows marked antagonism of presynaptic dopamine autoreceptors, potentially resulting in increased dopaminergic neurotransmission. This effect has also been observed with low-potency tricyclic antipsychotics like thioridazine and chlorprothixene. Notably, these two antipsychotics have been claimed many times to also possess antidepressant effects. As such, blockade of inhibitory dopamine autoreceptors and hence facilitation of dopaminergic signaling could be involved in the antidepressant effects of trimipramine. However, other authors have attributed the claimed antidepressant effects of antipsychotics like the two previously mentioned to α2-adrenergic receptor antagonism, although trimipramine specifically has only weak affinity for this receptor. Aside from antidepressant effects, low doses of antipsychotics have been found to increase REM sleep, and so dopamine autoreceptor antagonism could be involved in the unique effects of trimipramine in terms of REM sleep and sleep architecture.
Pharmacokinetics
The time to peak concentrations following a dose is 2 to 4 hours. The typical antidepressant therapeutic range of trimipramine concentrations is 150 to 300 ng/mL. The terminal half-life of trimipramine has been variously reported to be as little as 8 hours (in plasma) and as long as 24 hours. In any case, the terminal half-life of trimipramine is described as shorter than that of other TCAs, which makes it ideal for use in the treatment of insomnia.Trimipramine is a racemic compound with two enantiomers.[1] CYP2C19 is responsible for the demethylation of (D)- and (L)-trimipramine to (D)- (L)-desmethyltrimipramine, respectively, and CYP2D6 is responsible for the 2-hydroxylation of (D)- and (L)-desmethyltrimipramine to (D)- and (L)-2-hydroxydesmethyltrimipramine, respectively. CYP2D6 also metabolizes (L)-trimipramine into (L)-2-hydroxytrimipramine.
Chemistry
Trimipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include imipramine, desipramine, and clomipramine. Trimipramine is a derivative of imipramine with a methyl group added to its side chain and is also known as 2-methylimipramine or β-methylimipramine. The tri- prefix in its name may allude to the fact that its side chain features three methyl groups. Trimipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desmethyltrimipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), and doxepin. The chemical name of trimipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine and its free base form has a chemical formula of C20H26N2 with a molecular weight of 294.434 g/mol. The drug is used commercially as the maleate salt. The CAS Registry Number of the free base is 739-71-9 and of the maleate is 521-78-8.
History
Trimipramine was developed by Rhône-Poulenc. It was patented in 1959 and first appeared in the literature in 1961. The drug was first introduced for medical use in 1966, in Europe. It was not introduced in the United States until later in 1979 or 1980.
Society and culture
Generic names
Trimipramine is the generic name of the drug and its INN, USAN, BAN, and DCF, while trimipramine maleate is its USAN, USP, BANM, and JAN. Its generic name in Latin is trimipraminum, in German is trimipramin, and in Spanish is trimipramina.
Brand names
Trimipramine is marketed throughout the world mainly under the brand name Surmontil. Other notable brand names of trimipramine have included Herphonal, Rhotrimine, Sapilent, Stangyl, and Tydamine.
Availability
Trimipramine is no longer marketed in Australia, though it was previously.
== References == |
Imipenem/cilastatin/relebactam | Imipenem/cilastatin/relebactam, sold under the brand name Recarbrio, is a fixed-dose combination medication used as an antibiotic. In 2019, it was approved for use in the United States for the treatment of complicated urinary tract and complicated intra-abdominal infections. It is administered via intravenous injection.The most common adverse reactions include nausea, diarrhea, headache, fever and increased liver enzymes.The most common adverse reactions observed in people treated for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) include increased aspartate/alanine aminotransferases (increased liver enzymes), anemia, diarrhea, hypokalemia (low potassium), and hyponatremia (low sodium).
Medical uses
In the United States imipenem/cilastatin/relebactam is indicated for the treatment of people with complicated urinary tract infections and complicated intra-abdominal infections who have limited or no alternative treatment options. It is also indicated to treat HABP/VABP in adults 18 years of age and older.In the European Union it is indicated for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options.
History
The application for imipenem/cilastatin/relebactam was granted Qualified Infectious Disease Product (QIDP), fast track, and priority review designations by the U.S. Food and Drug Administration (FDA). The FDA granted the approval of Recarbrio to Merck & Co., Inc.The determination of efficacy of imipenem/cilastatin/relebactam was supported in part by the findings of the efficacy and safety of imipenem-cilastatin for the treatment of complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI). The contribution of relebactam to imipenem/cilastatin/relebactam was assessed based on data from in vitro studies and animal models of infection. The safety of imipenem/cilastatin/relebactam, administered via injection, was studied in two trials (Trial 1/NCT01505634, Trial 2/NCT01506271), one each for cUTI and cIAI. The cUTI trial included 298 adult participants with 99 treated with the proposed dose of imipenem/cilastatin/relebactam. The cIAI trial included 347 participants with 117 treated with the proposed dose of imipenem/cilastatin/relebactam.Trial 1 enrolled adult participants hospitalized with cUTI. Trial 2 enrolled adult participants hospitalized with cIAI that required surgery or drainage. In both trials, participants were assigned to either imipenem/cilastatin with varying doses of relebactam or imipenem/cilastatin with placebo intravenously, every 6 hours for 4 to 14 days. Neither the participants nor the investigators knew which treatment was being given until after the trial was completed. The trials were conducted in Europe, South America, the United States, Asia Pacific, Africa, and Mexico.It was approved for use in the European Union in February 2020.In June 2020, imipenem/cilastatin/relebactam was approved for the indication to treat hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in adults 18 years of age and older.The safety and efficacy of imipenem/cilastatin/relebactam for the treatment of HABP/VABP were evaluated in a randomized, controlled clinical trial of 535 hospitalized adults with HABP/VABP due to Gram-negative bacteria (a type of bacteria) in which 266 participants were treated with imipenem/cilastatin/relebactam and 269 participants were treated with piperacillin-tazobactam, another antibacterial drug. Overall, 16% of participants who received imipenem/cilastatin/relebactam and 21% of participants who received piperacillin-tazobactam died through day 28 of the study.
See also
Imipenem/cilastatin
References
External links
"Imipenem". Drug Information Portal. U.S. National Library of Medicine.
"Cilastatin". Drug Information Portal. U.S. National Library of Medicine.
"Relebactam". Drug Information Portal. U.S. National Library of Medicine. |
Donepezil | Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimers type. It appears to result in a small benefit in mental function and ability to function. Use, however, has not been shown to change the progression of the disease. Treatment should be stopped if no benefit is seen. It is taken by mouth or via a transdermal patch.Common side effects include nausea, trouble sleeping, aggression, diarrhea, feeling tired, and muscle cramps. Serious side effects may include abnormal heart rhythms, urinary incontinence, and seizures. Donepezil is a centrally acting reversible acetylcholinesterase inhibitor and structurally unrelated to other anticholinesterase agents.Donepezil was approved for medical use in the United States in 1996. It is available as a generic medication. In 2019, it was the 120th most commonly prescribed medication in the United States, with more than 5 million prescriptions.
Medical uses
Alzheimers disease
There is no evidence that donepezil or other similar agents alter the course or progression of Alzheimers disease. Six-to-twelve-month controlled studies have shown modest benefits in cognition or behavior. The UK National Institute for Clinical Excellence (NICE) recommends donepezil as an option in the management of mild to moderate Alzheimers disease. The person should, however, be reviewed frequently and if there is no significant benefit it should be stopped. In 2006, the U.S. Food and Drug Administration (FDA) also approved donepezil for treatment of mild, moderate and severe dementia in Alzheimers disease.
Other
Lewy body dementia: Some studies have shown benefits of donepezil for the treatment of cognitive and behavioral symptoms in Lewy body dementia.
Traumatic brain injury: Some research suggests an improvement in memory dysfunction in patients with traumatic brain injury with donepezil use.
Vascular dementia: Studies have shown that donepezil may improve cognition in patients with vascular dementia but not overall global functioning.
Dementia associated with Parkinson disease: Some evidence suggests that donepezil can improve cognition, executive function, and global status in Parkinson disease dementia.
Adverse effects
In clinical trials the most common adverse events leading to discontinuation were nausea, diarrhea, and vomiting. Other side effects included difficulty sleeping, muscle cramps and loss of appetite. Most side effects were observed in patients taking the 23 mg dose compared to 10 mg or lower doses. Side effects are mild and transient in most patients, lasting up to three weeks and usually improved even with continued use.Donepezil, like other cholinesterase inhibitors, can cause nightmares due to enhanced activation of the visual association cortex during REM sleep. Dosing donepezil in the morning can reduce the frequency of nightmares.
Precautions
Donepezil should be used with caution in people with heart disease, cardiac conduction disturbances, chronic obstructive pulmonary disease, asthma, severe cardiac arrhythmia and sick sinus syndrome.People with peptic ulcer disease or taking NSAIDs should use with caution because increased risk of gastrointestinal bleeding was noted. Slow heart beat and fainting in people with heart problems were also seen. These symptoms may appear more frequent when initiating treatment or increasing the donepezil dose. Although occurrence of seizures is rare, people who have a predisposition to seizures should be treated with caution.If daily donepezil has suspended for 7 days or less, restarting at the same dose is recommended, while if the suspension lasts longer than 7 days, retitrate from 5 mg daily is suggested.
Mechanism of action
Donepezil binds and reversibly inactivates the cholinesterases, thus inhibiting hydrolysis of acetylcholine. This increases acetylcholine concentrations at cholinergic synapses.The precise mechanism of action of donepezil in patients with Alzheimers disease is not fully understood. Certainly, Alzheimers disease involves a substantial loss of the elements of the cholinergic system and it is generally accepted that the symptoms of Alzheimers disease are related to this cholinergic deficit, particularly in the cerebral cortex and other areas of the brain.In addition to its actions as an acetylcholinesterase inhibitor, donepezil has been found to act as a potent agonist of the σ1 receptor (Ki = 14.6 nM), and has been shown to produce specific antiamnestic effects in animals mainly via this action.Some noncholinergic mechanisms have also been proposed. Donepezil upregulates the nicotinic receptors in the cortical neurons, adding to neuroprotective property. It inhibits voltage-activated sodium currents reversibly and delays rectifier potassium currents and fast transient potassium currents, although this action is unlikely to contribute to clinical effects.
Synergy
Donepezil was claimed to act synergistically with an agent called FK962 [283167-06-6] & FK960 [133920-70-4]. {potential activation of somatostatinergic neurotransmission}
Stereochemistry
Donepezil medications are racemates.
History
Research leading to the development of donepezil began in 1983, at Eisai, and in 1996, Eisai received approval from the United States Food and Drug Administration (FDA) for donepezil under the brand Aricept, which it co-marketed with Pfizer. The team at Eisai was led by Hachiro Sugimoto.As of 2011, Aricept was the worlds best-selling Alzheimers disease treatment. The first generic donepezil became available in November 2010, with the US FDA approval of a formulation prepared by Ranbaxy Labs.
Research
Donepezil has been tested in other cognitive disorders, including Lewy body dementia, and vascular dementia, but it is not currently approved for these indications. Donepezil has also been found to improve sleep apnea in people with Alzheimers. It also improves gait in people with mild Alzheimers.Donepezil has also been studied in people with mild cognitive impairment, schizophrenia, attention deficit disorder, post-coronary artery bypass surgery cognitive impairment, cognitive impairment associated with multiple sclerosis, CADASIL syndrome, and Down syndrome. A three-year National Institutes of Health trial in people with mild cognitive impairment reported donepezil was superior to placebo in delaying rate of progression to dementia during the initial 18 months of the study, but this was not sustained at 36 months. In a secondary analysis, a subgroup of individuals with the apolipoprotein E4 genotype showed sustained benefits with donepezil throughout the study. At this time, though, donepezil is not indicated for prevention of dementia.
ADHD
The addition of donepezil with existing ADHD medications has shown mixed results. In those with Tourette syndrome and ADHD, donepezil may reduce tics while it had no effect on ADHDs symptoms.
Pervasive developmental disorder
Donepezil along with other cholinesterase inhibitors is suggested as having potential for trouble behaviors, irritability, hyperactivity, and difficulty in social communication which are typically seen in those with pervasive developmental disorder, pervasive developmental disorder not otherwise specified, or autism spectrum disorder.
References
Further reading
Brenner, George D.; George M. Brenner (2000). Pharmacology. Philadelphia: W. B. Saunders. ISBN 978-0-7216-7757-6.
Louise Welbanks (2000). Compendium of Pharmaceuticals and Specialities (25th ed.). Canadian Pharmacists Association. ISBN 978-0-919115-76-7.
External links
"Donepezil". Drug Information Portal. U.S. National Library of Medicine.
"Donepezil hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Apraclonidine | Apraclonidine (INN), also known under the brand name Iopidine, is a sympathomimetic used in glaucoma therapy. It is an α2 adrenergic receptor agonist and a weak α1 adrenergic receptor agonist.Topical apraclonidine is administered at a concentration of 1% for the prevention and treatment of post-surgical intraocular pressure (IOP) elevation and 0.5% for short-term adjunctive therapy in patients on maximally tolerated medical therapy who require additional reduction of IOP. One drop is usually added one hour prior to laser eye surgery and another drop is given after the procedure is complete.
Clinical uses
Apraclonidine is indicated for the short-term adjunctive treatment of glaucoma for patients on maximally tolerated medical therapy who require additional reduction of IOP. These patients, who are treated with apraclonidine to delay surgery, should have frequent follow-up examinations and treatment should be discontinued if the intraocular pressure rises significantly.
Apraclonidine may be useful in the diagnosis of Horners syndrome. In Horners syndrome, the sympathetic innervation to the pupillary dilator muscle is lost. The affected pupil is thus miotic and the pupillary dilator responds to denervation by increasing α1 receptors. Apraclonidine is useful in this case due to its weak α1-adrenergic properties. When applied to the denervated (and thus hyper-sensitive) pupillary dilator muscle, a super-normal dilatory response is generated in which the pupil dilates to a degree greater than that which would be seen in a non-denervated muscle. This causes the reversal of anisocoria that is characteristic of Horners.
Topical apraclonidine can also decrease IOP in glaucoma patients by increasing trabecular outflow, in a similar way to clonidine, but without the cardiovascular side effects. Apraclonidine has been compared with other treatments such as brimonidine and pilocarpine in preventing IOP spikes after laser trabeculoplasty. The results did not show significant differences in the reduction of IOP for apraclonidine, when compared to brimonidine or pilocarpine.
References
Further reading
Chen P, Chen J, Lu D, Chen Y, Hsiao C (2006). "Comparing efficacies of 0.5% apraclonidine with 4% cocaine in the diagnosis of horner syndrome in pediatric patients". J Ocul Pharmacol Ther. 22 (3): 182–7. doi:10.1089/jop.2006.22.182. PMID 16808679.
Aslanides l; Tsiklis N; Ozkilic E; Coskunseven E; Pallikaris l; Jankov M (2006). "The effect of topical apraclonidine on subconjunctival hemorrhage and flap adherence in LASIK patients". J Refract Surg. 22 (6): 585–8. doi:10.3928/1081-597X-20060601-11. PMID 16805122.
Koc F, Kansu T, Kavuncu S, Firat E (2006). "Topical apraclonidine testing discloses pupillary sympathetic denervation in diabetic patients". J Neuroophthalmol. 26 (1): 25–9. doi:10.1097/01.wno.0000204648.79744.71. PMID 16518162. S2CID 45290834.
Garibaldi D, Hindman H, Grant M, Iliff N, Merbs S (2006). "Effect of 0.5% apraclonidine on ptosis in Horner syndrome". Ophthal Plast Reconstr Surg. 22 (1): 53–5. doi:10.1097/01.iop.0000196322.05586.6a. PMID 16418668.
Onal S, Gozum N, Gucukoglu A (2005). "Effect of apraclonidine versus dorzolamide on intraocular pressure after phacoemulsification". Ophthalmic Surg Lasers Imaging. 36 (6): 457–62. doi:10.3928/1542-8877-20051101-05. PMID 16355950.
External links
Iopidine prescribing information (from the FDA website) |
Thiotepa | Thiotepa (INN), sold under the brand name Tepadina, is a medication used to treat cancer.Thiotepa is an organophosphorus compound with the formula (C2H4N)3PS. It is an analog of N,N′,N′′-triethylenephosphoramide (TEPA), which contains tetrahedral phosphorus and is structurally akin to phosphate. It is manufactured by heating aziridine with thiophosphoryl chloride.
Medical uses
Thiotepa is indicated for use in combination with other chemotherapy agents to treat cancer. This can be with or without total body irradiation (TBI), as a conditioning treatment prior to allogeneic or autologous hematopoietic progenitor cell transplantation (HPCT) in hematological diseases in adults and children. These diseases include Hodgkins disease and leukaemia. Thiotepa is also used with high-dose chemotherapy with HPCT support to treat certain solid tumors in adult and children.Thiotepa is used in the palliation of many neoplastic diseases. The best results are found in the treatment of adenocarcinoma of the breast, adenocarcinoma of the ovary, papillary thyroid cancer and bladder cancer. Thiotepa is used to control intracavitary effusions caused by serosal neoplastic deposits.
Intravesical use
Thiotepa is used as intravesical chemotherapy in bladder cancer.It may be used prophylactically to prevent seeding of tumor cells at cystoscopic biopsy; as an adjunctive agent at the time of biopsy; or as a therapeutic agent to prevent recurrence after cystoscopic resection of bladder tumor (transurethral resection of bladder tumor, TURBT). Efficacy in tumor control may reach 55%. The main toxicity of this therapy is bone marrow suppression due to systemic absorption of the drug.
Side effects
The main side effect of thiotepa is bone marrow suppression resulting in leukopenia, thrombocytopenia and anemia. Liver and lung toxicity may also occur.
History
Thiotepa was developed by the American Cyanamid company in the early 1950s and reported to media outlets in 1953. In 1959, thiotepa was registered with the Food and Drug Administration (FDA) as a drug therapy for several solid cancers.On January 29, 2007, the European Medicines Agency (EMA) designated thiotepa as an orphan drug. On April 2, 2007, the United States FDA designated thiotepa as a conditioning treatment for use prior to hematopoietic stem cell transplantation. Adienne Pharma & Biotech (Italy), the owner of thiotepa (Tepadina) applied for these designations.
References
External links
"Thiotepa". Drug Information Portal. U.S. National Library of Medicine. |
Migalastat | Migalastat, sold under the brand name Galafold, is a medication for the treatment of Fabry disease, a rare genetic disorder. It was developed by Amicus Therapeutics. The US Food and Drug Administration (FDA) granted it orphan drug status in 2004, and the European Commission followed in 2006. The European Medicines Agencys Committee for Medicinal Products for Human Use (CHMP) granted the drug a marketing approval under the name Galafold in May 2016.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
Medical uses
Migalastat is used for the long-term treatment of Fabry disease in adults and adolescents aged 16 or older with an amenable mutation of the enzyme alpha-galactosidase A (α-GalA). An "amenable" mutation is one that leads to misfolding of the enzyme, but otherwise would not significantly impair its function.Based on an in vitro test, Amicus Therapeutics has published a list of 269 amenable and nearly 600 non-amenable mutations. About 35 to 50% of people with Fabry have an amenable mutation.
Adverse effects
The most common side effect in clinical trials was headache (in about 10% of people who take it). Less common side effects (between 1 and 10% of people) included unspecific symptoms such as dizziness, fatigue, and nausea, but also depression. Possible rare side effects could not be assessed because of the low number of subjects in the clinical trials in which adverse effects were measured.
Interactions
When combined with intravenous agalsidase alfa or beta, which are recombinant versions of the enzyme α-GalA, migalastat increases tissue concentrations of functional α-GalA compared to agalsidase given alone up to fivefold.Migalastat is not intended to be combined with agalsidase.Migalastat does not inhibit or induce cytochrome P450 liver enzymes or transporter proteins and is therefore expected to have a low potential for interactions with other drugs.
Pharmacology
Mechanism of action
Fabry disease is a genetic disorder caused by various mutations of the enzyme α-GalA, which is responsible for breaking down the sphingolipid globotriaosylceramide (Gb3), among other glycolipids and glycoproteins. Some of these mutations result in misfolding of α-GalA, which subsequently fails protein quality control in the endoplasmic reticulum and is decomposed. Lack of functional α-GalA leads to accumulation of Gb3 in blood vessels and other tissues, with a wide range of symptoms including kidney, heart, and skin problems.Migalastat is a potent, orally available inhibitor of α-GalA (IC50: 4 μM). When binding to faulty α-GalA, it shifts the folding behaviour towards the proper conformation, resulting in a functional enzyme provided the mutation is amenable. Molecules with this type of mechanism are called pharmacological chaperones.When the enzyme reaches its destination, the lysosome, migalastat dissociates because of the low pH and the relative abundance of Gb3 and other substrates, leaving α-GalA free to fulfill its function. Depending on the mutation, the EC50 is between 0.8 μM and over 1 mM in cellular models.
Pharmacokinetics
Migalastat is almost completely absorbed from the gut; taking the drug together with food decreases its absorption by about 40%. Total bioavailability is about 75% when taken without food. The substance is not bound to blood plasma proteins.Only a small fraction of a migalastat dose is metabolized, mainly to three dehydrogenated O-glucuronides (4% of the dose) and a number of unspecified metabolites (10%). The drug is mainly eliminated via the urine (77%) and to a smaller extent via the faeces (20%). Practically all of the metabolites are excreted in the urine. Elimination half-life is three to five hours after a single dose.
Chemistry
Migalastat is used in form of the hydrochloride, which is a white crystalline solid and is soluble in water.: 11 The molecule has four asymmetric carbon atoms with the same stereochemistry as the sugar D-galactose, but is missing the first hydroxyl group. It has a nitrogen atom in the ring instead of an oxygen, which makes it an iminosugar.The structure is formally derived from nojirimycin.
History
Migalastat was isolated as a fermentation product of the bacterium Streptomyces lydicus (strain PA-5726) in 1988 and called 1-deoxygalactonojirimycin. In 2004, it was designated orphan drug status by the US FDA for the treatment of Fabry disease, and in 2006 the European CHMP did likewise.
The sponsorship for the drug was transferred several times over the following years: from Amicus Therapeutics to Shire Pharmaceuticals in 2008, back to Amicus in 2010, to Glaxo in 2011, and again to Amicus in 2014.Two phase III clinical trials with a total of about 110 subjects were conducted between 2009 and 2015, one double-blind comparing the drug to placebo, and one comparing it to recombinant α-GalA without blinding. Migalastat stabilised heart and kidney function over the 30-months period of these trials.In September 2015, Amicus announced that it would submit a new drug application (NDA) for accelerated approval of migalastat to the FDA by the end of 2015. The CHMP recommended approval in April 2016, but the FDA rejected the application in November for having insufficient data in November 2016. The drug was approved in the European Union in May 2016. Germany was the first country where migalastat was launched. After Scott Gottlieb became FDA commissioner in 2017, the CEO of Amicus began lobbying him directly for the FDA to accept the NDA and in February 2018 the FDA accepted it and promised a response by August 2018.
See also
Miglustat, a drug for the treatment of Gaucher disease, with a similar structure
1-Deoxynojirimycin, a stereoisomer of migalastat
References
External links
"Migalastat". Drug Information Portal. U.S. National Library of Medicine. |
Camila | Camila is the Portuguese and Spanish form of the given name Camilla and may refer to:
Film and television
Camila (TV series), a Mexican telenovela from 1998
Camila (film), a 1984 Argentine film by María Luisa Bemberg
Music
Camila (band), Mexican band
Camila (album), Camila Cabellos debut studio album released 2018
"Camila, Camila", a song by Brazilian rock band Nenhum de Nós
Other uses
Camila (Pontus), a town of ancient Pontus, in Anatolia
Camila Martins Pereira (born 1994), Brazilian footballer known by the mononym Camila
Camila, brand name of a progestogen-only pill containing norethisterone (norethindrone)
See also
Camilla (disambiguation)
Camilla (born 1947), Queen consort of Charles III of the United Kingdom |
Tacrolimus | Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After allogeneic organ transplant, the risk of organ rejection is moderate. To lower the risk of organ rejection, tacrolimus is given. The drug can also be sold as a topical medication in the treatment of T-cell-mediated diseases such as eczema and psoriasis. For example, it is prescribed for severe refractory uveitis after a bone marrow transplant, exacerbations of minimal change disease, Kimuras disease, and vitiligo. It can be used to treat dry eye syndrome in cats and dogs.Tacrolimus inhibits calcineurin, which is involved in the production of interleukin-2, a molecule that promotes the development and proliferation of T cells, as part of the bodys learned (or adaptive) immune response.
Chemically, it is a macrolide lactone that was first discovered in 1987, from the fermentation broth of a Japanese soil sample that contained the bacterium Streptomyces tsukubensis.
It is on the World Health Organizations List of Essential Medicines.
Medical uses
Organ transplantation
It has similar immunosuppressive properties to ciclosporin, but is much more potent. Immunosuppression with tacrolimus was associated with a significantly lower rate of acute rejection compared with ciclosporin-based immunosuppression (30.7% vs 46.4%) in one study. Clinical outcome is better with tacrolimus than with ciclosporin during the first year of liver transplantation. Long-term outcome has not been improved to the same extent. Tacrolimus is normally prescribed as part of a post-transplant cocktail including steroids, mycophenolate, and IL-2 receptor inhibitors such as basiliximab. Dosages are titrated to target blood levels at specific times after medication administration.
Skin
As an ointment, tacrolimus is used in the treatment of eczema, in particular atopic dermatitis. It suppresses inflammation in a similar way to steroids, and is equally as effective as a mid-potency steroid. An important advantage of tacrolimus is that, unlike steroids, it does not cause skin thinning (atrophy), or other steroid related side effects.It is applied on the active lesions until they heal off, but may also be used continuously in low doses (twice a week), and applied to the thinner skin over the face and eyelids. Clinical trials of up to one year have been conducted. Recently it has also been used to treat segmental vitiligo in children, especially in areas on the face.
Eyes
Tacrolimus solution, as drops, is sometimes prescribed by veterinarians for keratoconjunctivitis, and other dry eye maladies, in the eyes of domestic cats, dogs, and horses. It has been studied for use in human eyes.
Contraindications and precautions
Contraindications and precautions include:
Hepatic disease
Immunosuppression
Infants
Infection
Neoplastic disease, such as:
Skin cancer
Lung cancer
Oliguria
Pregnancy
QT interval prolongation
Sunlight (UV) exposure
Grapefruit juice
Topical use
Occlusive dressing
Known or suspected malignant lesions
Nethertons syndrome or similar skin diseases
Certain skin infections
Side effects
By mouth or intravenous use
Side effects can be severe and include infection, cardiac damage, hypertension, blurred vision, liver and kidney problems (tacrolimus nephrotoxicity), hyperkalemia, hypomagnesemia, hyperglycemia, diabetes mellitus, itching, lung damage (sirolimus also causes lung damage), and various neuropsychiatric problems such as loss of appetite, insomnia, posterior reversible encephalopathy syndrome, confusion, weakness, depression, vivid nightmares, cramps, neuropathy, seizures, tremors, and catatonia.In addition, it may potentially increase the severity of existing fungal or infectious conditions such as herpes zoster or polyoma viral infections.
Carcinogenesis and mutagenesis
In people receiving immunosuppressants to reduce transplant graft rejection, an increased risk of malignancy (cancer) is a recognised complication. The most common cancers are non-Hodgkins lymphoma and skin cancers. The risk appears to be related to the intensity and duration of treatment.
Topical use
The most common adverse events associated with the use of topical tacrolimus ointments, especially if used over a wide area, include a burning or itching sensation on the initial applications, with increased sensitivity to sunlight and heat on the affected areas. Less common are flu-like symptoms, headache, cough, and burning eyes.
Cancer risks
Tacrolimus and a related drug for eczema (pimecrolimus) were suspected of carrying a cancer risk, though the matter is still a subject of controversy. The FDA issued a health warning in March 2005 for the drug, based on animal models and a small number of patients. Until further human studies yield more conclusive results, the FDA recommends that users be advised of the potential risks. However, current practice by UK dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of these new drugs.
Interactions
Also like cyclosporin, it has a wide range of interactions. Tacrolimus is primarily metabolised by the cytochrome P450 system of liver enzymes, and there are many substances that interact with this system and induce or inhibit the systems metabolic activity.Interactions include that with grapefruit which increases tacrolimus plasma concentrations. As infections are a major cause of morbidity and mortality in the post-transplant patient, the most commonly reported interactions include interactions with anti-microbial drugs. Macrolide antibiotics including erythromycin and clarithromycin, as well as several of the newer classes of antifungals, especially of the azole class (fluconazole, voriconazole), increase tacrolimus levels by competing for cytochrome enzymes.
Pharmacology
Mechanism of action
Tacrolimus is a macrolide calcineurin inhibitor. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor nuclear factor of activated T-cells (NF-AT), which moves to the nucleus of the T-cell and increases the activity of genes coding for IL-2 and related cytokines. Tacrolimus prevents the dephosphorylation of NF-AT.In detail, tacrolimus reduces peptidylprolyl isomerase activity by binding to the immunophilin FKBP12 (FK506 binding protein), creating a new complex. This FKBP12–FK506 complex interacts with and inhibits calcineurin, thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription. Although this activity is similar to that of cyclosporin, the incidence of acute rejection is reduced by tacrolimus use over cyclosporin use. Although short-term immunosuppression concerning patient and graft survival is found to be similar between the two drugs, tacrolimus results in a more favorable lipid profile, and this may have important long-term implications given the prognostic influence of rejection on graft survival.
Pharmacokinetics
Oral tacrolimus is slowly absorbed in the gastrointestinal tract, with a total bioavailability of 20 to 25% (but with variations from 5 to 67%) and highest blood plasma concentrations (Cmax) reached after one to three hours. Taking the drug together with a meal, especially one rich in fat, slows down resorption and reduces bioavailability. In the blood, tacrolimus is mainly bound to erythrocytes; only 5% are found in the plasma, of which more than 98.8% are bound to plasma proteins.The substance is metabolized in the liver, mainly via CYP3A, and in the intestinal wall. All metabolites found in the circulation are inactive. Biological half-life varies widely and seems to be higher for healthy persons (43 hours on average) than for patients with liver transplants (12 hours) or kidney transplants (16 hours), due to differences in clearance. Tacrolimus is predominantly eliminated via the faeces in form of its metabolites.When applied locally on eczema, tacrolimus has little to no bioavailability.
Pharmacogenetics
The predominant enzyme responsible for metabolism of tacrolimus is CYP3A5. Genetic variations within CYP3A5 that result in changes to the activity of the CYP3A5 protein can affect concentrations of tacrolimus within the body. In particular, individuals who are homozygous for the G allele at the single nucleotide polymorphism (SNP) rs776746 (also known as CYP3A5 *3/*3) have a non-functional CYP3A5 protein. The frequency of the G allele varies worldwide, from 4% in some African populations to 80–90% in Caucasian populations. Across a large number of studies, individuals homozygous for the G allele have been shown to have higher concentrations of tacrolimus and require lower doses of the drug, as compared to individuals who are not homozygous for the G allele. Achieving target concentrations of tacrolimus is important – if levels are too low, then there is a risk of transplant rejection, if levels are too high, there is a risk of drug toxicities. There is evidence to suggest that dosing patients based on rs776746 genotype can result in faster and more frequent achievement of target tacrolimus levels. However, there is a lack of consistent evidence as to whether dosing based on rs776746 genotype results in improved clinical outcomes (such as a decreased risk for transplant rejection or drug toxicities), likely because patients taking tacrolimus are subject to therapeutic drug monitoring.Studies have shown that genetic polymorphisms of genes other than CYP3A5, such as NR1I2 (encoding PXR), also significantly influence the pharmacokinetics of tacrolimus.
History
Tacrolimus was discovered in 1987; it was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975. It is produced by a soil bacterium, Streptomyces tsukubensis. The name tacrolimus is derived from "Tsukuba macrolide immunosuppressant".Tacrolimus was first approved by the US Food and Drug Administration (FDA) in 1994, for use in liver transplantation; the indications were extended to include kidney transplants. Generic versions of tacrolimus were approved in the US in 2017.Tacrolimus was approved for medical use in the European Union in 2002, for the treatment of moderate to severe atopic dermatitis. In 2007, the indications were expanded to include the prophylaxis of transplant rejection in adult kidney or liver allograft recipients and the treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adults. In 2009, the indications were expanded to include the prophylaxis of transplant rejection in adult and paediatric, kidney, liver or heart allograft recipients and the treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adults and children.
Available forms
A branded version of the drug is owned by Astellas Pharma, and is sold under the brand name Prograf, given twice daily. A number of other manufacturers hold marketing authorisation for alternative brands of the twice-daily formulation.Once-daily formulations with marketing authorisation include Advagraf (Astellas Pharma) and Envarsus (marketed as Envarsus XR in US by Veloxis Pharmaceuticals and marketed in Europe by Chiesi). These formulations are intended to reduce pharmacokinetic variation in blood levels and facilitate compliance with dosing.The topical formulation is marketed by LEO Pharma under the name Protopic.
Biosynthesis
The biosynthesis of tacrolimus is hybrid synthesis of both type 1 polyketide synthases (PKS 1) and nonribosomal peptide syntheses (NRPS). The research shows the hybrid synthesis consists of ten modules of type 1 polyketide synthase and one module of nonribosomal peptide synthase. The synthetic enzymes for tacrolimus are found in 19 gene clusters named fkb. The 19 genes are fkbQ, fkbN, fkbM, fkbD, fkbA, fkbP, fkbO, fkbB, fkbC, fkbL, fkbK, fkbJ, fkbI, fkbH, fkbG, allD, allR, allK and allA.There are several possible ways of biosynthesis of tacrolimus. The fundamental units for biosynthesis are following: one molecule of 4,5-dihydroxycyclohex-1-enecarboxylic acid (DHCHC) as a starter unit, four molecules of malonyl-CoA, five molecules of methylmalonyl-CoA, one molecule of allylmalonyl-CoA as elongation units. However, two molecules of malonyl-CoA are able to be replaced by two molecules of methoxymalonyl CoA. Once two malonyl-CoA molecules are replaced, post-synthase tailoring steps are no longer required where two methoxymalonyl CoA molecules are substituted. The biosynthesis of methoxymalonyl CoA to Acyl Carrier protein is proceeded by five enzymes (fkbG, fkbH, fkbI, fkbJ, and fkbK). Allylmalonyl-CoA is also able to be replaced by propionylmalonyl-CoA.The starter unit, DHCHC from the chorismic acid is formed by fkbO enzyme and loaded onto CoA-ligase domain (CoL). Then, it proceeds to NADPH dependent reduction(ER). Three enzymes, fkbA,B,C enforce processes from the loading module to the module 10, the last step of PKS 1. fkbB enzyme is responsible of allylmalonyl-CoA synthesis or possibly propionylmalonyl-CoA at C21, which it is an unusual step of general PKS 1. As mentioned, if two methoxymalonyl CoA molecules are substituted for two malonyl-CoA molecules, they will take place in module 7 and 8 (C13 and C15), and fkbA enzyme will enforce this process. After the last step (module 10) of PKS 1, one molecule of L-pipecolic acid formed from L-lysine and catalyzed through fkbL enzyme synthesizes with the molecule from the module 10. The process of L-pipecolic acid synthesis is NRPS enforced by fkbP enzyme. After synthesizing the entire subunits, the molecule is cyclized. After the cyclization, the pre-tacrolimus molecule goes through the post-synthase tailoring steps such as oxidation and S-adenosyl methionine. Particularly fkbM enzyme is responsible of alcohol methylation targeting the alcohol of DHCHC starter unit (Carbon number 31 depicted in brown), and fkbD enzyme is responsible of C9 (depicted in green). After these tailoring steps, the tacrolimus molecule becomes biologically active.
Research
Lupus nephritis
Tacrolimus has been shown to reduce the risk of serious infections while also increasing remission of kidney function in lupus nephritis.
Ulcerative colitis
Tacrolimus has been used to suppress the inflammation associated with ulcerative colitis (UC), a form of inflammatory bowel disease. Although almost exclusively used in trial cases only, tacrolimus has shown to be significantly effective in the suppression of flares of UC. A 2022 updated Cochrane systematic review found that tacrolimus may be superior to placebo in achieving remission and improvement in UC.
References
Further reading
Lv X, Qi J, Zhou M, et al. (March 2020). "Comparative efficacy of 20 graft-versus-host disease prophylaxis therapies for patients after hematopoietic stem-cell transplantation: A multiple-treatments network meta-analysis". Crit. Rev. Oncol. Hematol. 150: 102944. doi:10.1016/j.critrevonc.2020.102944. PMID 32247246. S2CID 214794350.
External links
"Tacrolimus". Drug Information Portal. U.S. National Library of Medicine.
"Tacrolimus Injection". MedlinePlus.
"Tacrolimus Topical". MedlinePlus.
Tacrolimus at the US National Library of Medicine Medical Subject Headings (MeSH)
"FDA Approves New Use of Transplant Drug Based on Real-World Evidence". U.S. Food and Drug Administration (FDA). 30 September 2021. |
Gemtuzumab ozogamicin | Gemtuzumab ozogamicin, sold under the brand name Mylotarg, is an antibody-drug conjugate (a drug-linked monoclonal antibody) that is used to treat acute myeloid leukemia.The most common grade 3 and higher adverse reactions that occurred during Induction 1 and Intensification 2 in ≥ 5% of people who received gemtuzumab ozogamicin were infection, febrile neutropenia, decreased appetite, hyperglycemia, mucositis, hypoxia, hemorrhage, increased transaminase, diarrhea, nausea, and hypotension.
Medical uses
In the United States, gemtuzumab ozogamicin is indicated for newly diagnosed CD33-positive acute myeloid leukemia (AML) for adults and children one month and older and for the treatment of relapsed or refractory CD33-positive AML in adults and children two years and older.
Mechanism and side effects
Gemtuzumab is a monoclonal antibody to CD33 linked to a cytotoxic agent from the class of calicheamicins (ozogamicin). CD33 is expressed in most leukemic blast cells but also in normal hematopoietic cells, the intensity diminishing with maturation of stem cells.Common side effects of administration included shivering, fever, nausea and vomiting. Serious side effects included severe myelosuppression (suppressed activity of bone marrow, which is involved in formation of various blood cells [found in 98% of patients]), disorder of the respiratory system, tumor lysis syndrome, Type III hypersensitivity, venous occlusion, and death.
History
Gemtuzumab ozogamicin was created in a collaboration between Celltech and Wyeth that began in 1991. The same collaboration later produced inotuzumab ozogamicin. Celltech was acquired by UCB in 2004 and Wyeth was acquired by Pfizer in 2009.In the United States, it was approved under an accelerated-approval process by the FDA in 2000, for use in patients over the age of 60 with relapsed acute myelogenous leukemia (AML); or those who are not considered candidates for standard chemotherapy.
The accelerated approval was based on the surrogate endpoint of response rate. It was the first antibody-drug conjugate to be approved.Within the first year after approval, the FDA required a black box warning be added to gemtuzumab packaging. The drug was noted to increase the risk of veno-occlusive disease in the absence of bone marrow transplantation. Later the onset of VOD was shown to occur at increased frequency in gemtuzumab patients even following bone marrow transplantation. The drug was discussed in a 2008 JAMA article, which criticized the inadequacy of postmarketing surveillance of biologic agents.A randomized Phase III comparative controlled trial (SWOG S0106) was initiated in 2004, by Wyeth in accordance with the FDA accelerated-approval process. The study was stopped on August 20, 2009, prior to completion due to worrisome outcomes. Among the patients evaluated for early toxicity, fatal toxicity rate was significantly higher in the gemtuzumab combination therapy group vs the standard therapy group. Mortality was 5.7% with gemtuzumab and 1.4% without the agent (16/283 = 5.7% vs 4/281 = 1.4%; P = .01).In June 2010, Pfizer withdrew Mylotarg from the market at the request of the US FDA. However, some other regulatory authorities did not agree with the FDA decision, with Japans Pharmaceuticals and Medical Devices Agency stating in 2011 that the "risk-benefit balance of gemtuzumab ozogamicin has not changed from its state at the time of approval".In 2017, Pfizer reapplied for US and EU approval, based on a meta-analysis of prior trials and results of the ALFA-0701 clinical trial, an open-label Phase III trial in 280 older people with AML. In September 2017, gemtuzumab ozogamicin was approved again for use in the United States and in the European Union.
See also
Inotuzumab ozogamicin
References
Further reading
AusPAR: Gemtuzumab ozogamicin. Therapeutic Goods Administration (TGA) (Report). October 2020.
External links
"Gemtuzumab ozogamicin". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT00372593 for "Combination Chemotherapy With or Without Gemtuzumab in Treating Young Patients With Newly Diagnosed Acute Myeloid Leukemia" at ClinicalTrials.gov |
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