page_title
stringlengths 1
91
| page_text
stringlengths 0
34.2k
|
|---|---|
Erythropoiesis-stimulating agent | Erythropoiesis-stimulating agents (ESA) are medications which stimulate the bone marrow to make red blood cells. They are used to treat anemia due to end stage kidney disease, chemotherapy, major surgery, or certain treatments in HIV/AIDS. In these situations they decrease the need for blood transfusions. The different agents are more or less equivalent. They are given by injection.Common side effects may include joint pain, rash, vomiting, and headache. Serious side effects may include heart attacks, stroke, increased cancer growth, or pure red cell aplasia. It is unclear if use is safe during pregnancy. They work similar to naturally occurring erythropoietin.They were first approved for medical use in the United States in 1989. It is on the World Health Organizations List of Essential Medicines. Commercially available agents include epoetin alfa and darbepoetin alfa, and biosimilars. Use among athletes is prohibited by the World Anti-Doping Agency.
Medical uses
ESAs are used to maintain hemoglobin at the lowest level that both minimizes transfusions and best meets a persons needs. Medical speciality professional organizations do not recommend the use of ESAs in people with chronic kidney disease (CKD) who have hemoglobin levels greater than 10 g/dL and do not have anemia symptoms. In preterm babies ESAs may help reduce the need for red blood cell transfusions.The 2020 Cochrane Anaesthesia Review Group review of Erythropoietin plus iron versus control treatment including placebo or iron for preoperative anaemic adults undergoing non‐cardiac surgery demonstrated that patients were much less likely to require red cell transfusion and in those transfused, the volumes were unchanged (mean difference -0.09, 95% CI -0.23 to 0.05). Pre-op Hb concentration was increased in those receiving high dose EPO, but not low dose.There is no evidence that one agent is better than another in the setting of CKD.
Failure
ESAs may fail to achieve an adequate therapeutic response when one or more of the following is present:
Occult blood loss and/or iron deficiency
Vitamin B12 or folate deficiency
Infection and inflammation
Inadequate dialysis
Hyperparathyroidism
Aluminum toxicity
Patient adherence
Hypothyroidism
Primary disease activity
Transplant rejection
Malignancy
Pure red cell aplasia
Types
The following types of ESAs are available:
Erythropoietin (Epo)
Epoetin alfa (Procrit, Epogen)
Epoetin beta (NeoRecormon)
Epoetin zeta (Silapo, Retacrit)
Darbepoetin alfa (Aranesp)
Methoxy polyethylene glycol-epoetin beta (Mircera)
Available forms
Recombinant erythropoietin has a variety of glycosylation patterns giving rise to alpha, beta, delta, and omega forms:
Darbepoetin alfa, which early literature during its development often termed as novel erythropoiesis-stimulating protein (NESP), is a form created by five substitutions (Asn-30, Thr-32, Val-87, Asn-88 and Thr-90) that create two new N-glycosylation sites. This glycoprotein has a longer terminal half-life, meaning it is possible to administer it less frequently.
Misuse
Erythropoiesis-stimulating agents have a history of use as blood doping agents in endurance sports, such as horseracing, boxing, cycling, rowing, distance running, race walking, snowshoeing, cross country skiing, biathlon, mixed martial arts, and triathlon. The overall oxygen delivery system (blood oxygen levels, as well as heart stroke volume, vascularization, and lung function) is one of the major limiting factors to muscles ability to perform endurance exercise. Therefore, the primary reason athletes may use ESAs is to improve oxygen delivery to muscles, which directly improves their endurance capacity. With the advent of recombinant erythropoietin in the 1990s, the practice of autologous and homologous blood transfusion has been partially replaced by injecting erythropoietin such that the body naturally produces its own red cells. ESAs increase hematocrit (% of blood volume that is red cell mass) and total red cell mass in the body, providing a good advantage in sports where such practice is banned. In addition to ethical considerations in sports, providing an increased red cell mass beyond the natural levels reduces blood flow due to increased viscosity, and increases the likelihood of thrombosis and stroke. Due to dangers associated with using ESAs, their use should be limited to the clinic where anemic patients are boosted back to normal hemoglobin levels (as opposed to going above the normal levels for performance advantage, leading to an increased risk of death).Though EPO was believed to be widely used in the 1990s in certain sports, there was no way at the time to directly test for it, until in 2000, when a test developed by scientists at the French national antidoping laboratory (LNDD) and endorsed by the World Anti-Doping Agency (WADA) was introduced to detect pharmaceutical EPO by distinguishing it from the nearly identical natural hormone normally present in an athletes urine. The first EPO-doping cases were found by the Swiss Laboratory for Doping Analyses.In 2002, at the Winter Olympic Games in Salt Lake City, Dr. Don Catlin, the founder and then-director of the UCLA Olympic Analytical Lab, reported finding darbepoetin alfa, a form of erythropoietin, in a test sample for the first time in sports. At the 2012 Summer Olympics in London, Alex Schwazer, the gold medalist in the 50-kilometer race walk in the 2008 Summer Olympics in Beijing, tested positive for EPO and was disqualified.Since 2002, EPO tests performed by US sports authorities have consisted of only a urine or "direct" test. From 2000 to 2006, EPO tests at the Olympics were conducted on both blood and urine. However, several compounds have been identified that can be taken orally to stimulate endogenous EPO production. Most of the compounds stabilize the hypoxia-inducible transcription factors which activate the EPO gene. The compounds include oxo-glutarate competitors, but also simple ions such as cobalt(II) chloride.Inhalation of a xenon/oxygen mixture activates production of the transcription factor HIF-1-alpha, which leads to increased production of erythropoietin and improved performance. It has been used for this purpose in Russia since at least 2004.
Cycling
Recombinant EPO is believed to have come into use in cycling about 1990. In theory, EPO use can increase VO2max by a significant amount, making it useful for endurance sports like cycling. Italian antidoping advocate Sandro Donati has claimed that the history of doping in cycling can be traced to the Italian Dr Francesco Conconi at the University of Ferrara. Conconi had worked on the idea of giving athletes transfusions of their own blood in the 1980s. Donati felt this work "opened the road to EPO . . . because blood doping was a trial to understand the role of EPO".Dr. Michele Ferrari, a former student and protege of Conconi, had a controversial interview mentioning the drug in 1994, just after his Gewiss-Ballan team had a remarkable performance in the La Flèche Wallonne race. Ferrari told lEquipe journalist Jean-Michel Rouet that EPO had no "fundamental" effect on performance and that if his riders used it, it would not "scandalize" himself. After the journalist pointed out several riders were suspected of dying from EPO, Ferrari said EPO was not dangerous, and only abuse of it was dangerous, saying, "Its also dangerous to drink 10 liters of orange juice." The orange juice comment has been widely misquoted. Ferrari was fired shortly after, but continued to work in the industry with top riders, allegedly including Lance Armstrong. That same year, Sandro Donati, working for the Italian National Olympic Committee, presented a report accusing Conconi of being linked to the use of EPO in the sport.In 1997, the Union Cycliste Internationale (UCI) instituted a new rule that riders testing above 50% haematocrit were not only immediately disqualified, but banned from racing for two weeks. Robert Millar, former racer, later wrote for Cycling News that the 50% limit was "an open invitation to dope to that level", pointing out that normally haematocrit levels would start "around 40-42%" and drop during the course of a "grand tour", but after EPO, they were staying at 50% for "weeks at a time". By 1998, EPO use had become widespread, and the Festina affair tarnished the 1998 Tour de France. One manager offered a 270,000-franc-per-month raise to Christophe Bassons if he would use EPO, but Bassons refused.In the 1998 Tour de France Stuart OGrady won one stage, held the Tour de France yellow jersey for three days, and came second in the points classification with the assistance of EPO. In 2010, Floyd Landis admitted to using performance-enhancing drugs, including EPO, throughout his career as a professional cyclist. In 2012, the USADA released a report on its investigation into massive doping by the US Postal Service cycling team under the leadership of Lance Armstrong. The report contained affidavits from numerous riders on the team, including Frankie Andreu, Tyler Hamilton, George Hincapie, Floyd Landis, Levi Leipheimer, and others, outlining that they and Armstrong used a cocktail of performance-enhancing substances for the Tour de France, most notably EPO, during Armstrongs seven consecutive Tour wins. It detailed how Armstrong and the Postal manager, Johan Bruyneel, forced other team members to dope as well. It also went to the root of their doping network, targeting the shadowy doctors and back room enablers who helped cyclists procure and administer drugs as well as highly placed executives who helped to avoid doping controls and hide positive test results. Armstrong was subsequently stripped of all of his victories from 1998 onward—including his Tour wins and his performance in the 2000 Summer Olympics. The UCI concurred with the decision. While several of the doping offenses took place outside the normal eight-year statute of limitations for doping offenses, USADA contended the statute of limitations did not apply due to Armstrongs "fraudulent concealment" of his doping. Longstanding precedent in U.S. law holds that the statute of limitations does not apply in cases of fraudulent conduct by a defendant. In accordance with this decision, Tour organizers removed Armstrongs name and results from the races history.Witnesses testified that code words used for EPO included "Edgar", "Poe", "Edgar Allan Poe", and "Zumo" (Spanish for juice).
Dynepo
Dynepo is the brand name for a form of EPO developed by Shire Pharmaceuticals. The first development steps were performed by HMR and Aventis. Aventis obtained the license in Europe in 2002. The company expected to launch the product in Europe in 2006, although patents held by the American biotechnology company Amgen, Inc. may have precluded its sale in the United States.Dynepo was made in cultured human cells. It was therefore expected to have an authentic human form of sialic acid and other oligosaccharide residues. It was hoped that this would make a longer-acting product than existing brands. There were concerns that such production would also make Dynepo undetectable in the urine tests for EPO used, at that time, to detect doping by athletes. Dynepo was withdrawn from European markets on 17 February 2009, for commercial reasons. On July 1, 2009, professional cycling team Silence–Lotto announced that Thomas Dekker was tested positive for Dynepo on a test taken on December 24, 2007, while Dekker was riding for Rabobank.
References
External links
Media related to Erythropoiesis-stimulating agents at Wikimedia Commons
"Erythropoietin". Drug Information Portal. U.S. National Library of Medicine.
"Epoetin alfa". Drug Information Portal. U.S. National Library of Medicine.
"Epoetin beta". Drug Information Portal. U.S. National Library of Medicine.
"Darbepoetin Alfa". Drug Information Portal. U.S. National Library of Medicine.
"Methoxy polyethylene glycol-epoetin beta". Drug Information Portal. U.S. National Library of Medicine. |
Adrenaline (disambiguation) | Adrenaline is a hormone and neurotransmitter also known as epinephrine.
Adrenaline or adrenalin may also refer to:
Adrenalin, a trademarked adrenaline product of Parke-Davis
Music
Adrenalin (band), an American rock group
Adrenaline (album), a 1995 album by Deftones
Adrenalin, a 2010 album by Faizal Tahir
"Adrenaline", a song by Bauhaus on the album Go Away White
"Adrenaline", a song by Emma Pollock on the album Watch the Fireworks
"Adrenaline" (Gavin Rossdale song), 2002
"Adrenaline" (Shinedown song), 2013
"Adrenalin/Distant Dreams (Part Two)", a 1980 single by Throbbing Gristle
"Adrenaline", a song by 12 Stones on the 2007 album Anthem for the Underdog
"Adrenaline", a song by The Roots on the 1999 album Things Fall Apart
"Adrenaline", a song by Rosetta Stone (band) on the 1993 album Adrenaline
Adrenaline, a 2003-2012 metal band
Adrenaline, a song from their 2004 EP Inspired by Anger used in FlatOut
Other
Adrenaline (autobiography), by Zlatan Ibrahimović
Adrenaline (novel), by James Robert Baker
Adrenalin: Fear the Rush, a 1996 action film
ADRenalin (Luxembourg), the youth wing of the Alternative Democratic Reform Party, a conservative political party in Luxembourg
Adrenaline (film), a 2015 film
Adrenalin (character), a character in the Asterix comic Asterix and the Chieftains Daughter
AMD Radeon Software, Adrenalin Edition
See also
Adrenalina (disambiguation) |
Metanx | Metanx is a prescription medical food made by Alfasigma that contains L-methylfolate (as Metafolin, a calcium salt of vitamin B9), methylcobalamin (vitamin B12) and pyridoxal 5-phosphate (vitamin B6). It is a vitamin B supplement. Metanx is indicated for the dietary management of peripheral neuropathy (i.e. DPN).
Ingredients
Metanx contains the following active ingredients (per capsule):
Folate
L-methylfolate (Metafolin): 3 mg
Pyridoxal 5-phosphate: 35 mg
Methylcobalamin: 2 mg
Indication and usage
Metanx is used for treating:
Painful diabetic neuropathy,
Diabetic foot ulcers,
Endothelial dysfunction associated with diabetic peripheral neuropathy,
Hyperhomocysteinemia.
== References == |
Novolin | Novolin is the brand name of three distinct insulin-containing products manufactured by Novo Nordisk:
Novolin 70/30, an insulin preparation containing mixed NPH and regular insulin, respectively
Novolin N, an insulin preparation containing NPH insulin
Novolin R, an insulin preparation containing regular insulin
See also
Insulin (medication)
== References == |
Ibandronic acid | Ibandronic acid is a bisphosphonate medication used in the prevention and treatment of osteoporosis and metastasis-associated skeletal fractures in people with cancer. It may also be used to treat hypercalcemia (elevated blood calcium levels). It is typically formulated as its sodium salt ibandronate sodium.
It was patented in 1986 by Boehringer Mannheim and approved for medical use in 1996.
Medical uses
Ibandronate is indicated for the treatment and prevention of osteoporosis in post-menopausal women. In May 2003, the U.S. Food and Drug Administration (FDA) approved Ibandronate as a daily treatment for post-menopausal osteoporosis. The basis for this approval was a three-year, randomized, double-blind, placebo-controlled trial women with post-menopausal osteoporosis. Every participant also received daily oral doses of calcium and 400IUs [international units] of vitamin D. At the studys conclusion, both doses significantly reduced the occurrence risk of new vertebral fractures by 50–52 percent when compared to the effects of the placebo drug.
Ibandronate is efficacious for the prevention of metastasis-related bone fractures in multiple myeloma, breast cancer, and certain other cancers.
Adverse effects
In 2008, the U.S Food and Drug Administration (FDA) issued a communication warning of the possibility of severe and sometimes incapacitating bone, joint or muscle pain. A study conducted by the American Society of Bone and Mineral Research concluded that long-term use of bisphosphonates, including Boniva, may increase the risk of a rare but serious fracture of the femur.
The drug also has been associated with osteonecrosis of the jaw, relatively rare but serious condition.
Pharmacology
Brand names
Ibandronic acid is marketed under the trade names Boniva in the US, Bondronat in Europe, Bonviva in Asia, Bandrone in India, Ibandrix in Ecuador, Adronil in Pakistan, Bondrova in Bangladesh and Bonprove in Egypt, Fosfonat in Mexico.
References
External links
"Ibandronic acid". Drug Information Portal. U.S. National Library of Medicine. |
Fluvastatin | Fluvastatin is a member of the statin drug class, used to treat hypercholesterolemia and to prevent cardiovascular disease.
It was patented in 1982 and approved for medical use in 1994. It is on the World Health Organizations List of Essential Medicines.
Adverse effects
Adverse effects are comparable to other statins. Common are nausea, indigestion, insomnia and headache. Myalgia (muscle pain), and rarely rhabdomyolysis, characteristic side effects for statins, can also occur.
Interactions
Contrary to lovastatin, simvastatin and atorvastatin, fluvastatin has no relevant interactions with drugs that inhibit the liver enzyme CYP3A4, and a generally lower potential for interactions than most other statins. Fluconazole, a potent inhibitor of CYP2C9, does increase fluvastatin levels.
Pharmacology
Mechanism of action
Fluvastatin works by blocking the liver enzyme HMG-CoA reductase, which facilitates an important step in cholesterol synthesis.
Pharmacodynamics
In a Cochrane systematic review the dose-related magnitudes of fluvastatin on blood lipids was determined. Over the dose range of 10 to 80 mg/day total cholesterol was reduced by 10.7% to 24.9%, LDL cholesterol by 15.2% to 34.9%, and triglycerides by 3% to 17.5%.
Pharmacokinetics
The drug is quickly and almost completely (98%) absorbed from the gut. Food intake slows down absorption, but does not decrease it. Due to its first-pass effect, bioavailability is lower: about 24–30% according to different sources. Over 98% of the substance is bound to plasma proteins.Several cytochrome P450 enzymes (mainly CYP2C9, but also CYP3A4 and CYP2C8) are involved in the metabolism of fluvastatin, which makes is less liable to interactions than most other statins. The main metabolite is inactive and is called "N-desisopropyl propionic acid" in the literature.93–95% of the drug is excreted via the feces, less than 2% of which in form of the original substance.
Names
Fluvastatin is the INN. Brandnames include Lescol, Canef, Vastin.
Research
Data from the Cholesterol Treatment Trialists’ (CTT) publication was used to determine the effects of fluvastatin, atorvastatin and rosuvastatin on LDL cholesterol lowering and reduction of myocardial infarction. In two RCTs an average dose of 72 mg/day fluvastatin reduced LDL cholesterol by 31.9%, and reduced myocardial infarction, relative risk, 0.68 (95% CI 0.55 to 0.85) as compared to placebo. In five RCTs a mean atorvastatin dose of 26 mg/day reduced LDL cholesterol by 44.0% and reduced myocardial infarction, relative risk, 0.67 (95% CI 0.58 to 0.77) as compared to placebo. In four RCTs a mean rosuvastatin dose of 16 mg/day reduced LDL cholesterol by 48.8% and reduced myocardial infarction, relative risk, 0.82 (95% CI 0.73 to 0.93) as compared to placebo. Thus despite reducing LDL cholesterol by a much lesser amount with fluvastatin than atorvastatin and rosuvastatin, fluvastatin reduced myocardial infarction similarly to atorvastatin and to a greater degree than rosuvastatin.
== References == |
Febuxostat | Febuxostat, sold under the brand names Uloric and Adenuric among others, is a medication used long-term to treat gout due to high uric acid levels. It is generally recommended only for people who cannot take allopurinol. When initially started, medications such as NSAIDs are often recommended to prevent gout flares. It is taken by mouth.Common side effects include liver problems, nausea, joint pain, and a rash. Serious side effects include an increased risk of death as compared with allopurinol, Stevens–Johnson syndrome, and anaphylaxis. Use is not recommended during pregnancy or breastfeeding. It inhibits xanthine oxidase, thus reducing production of uric acid in the body.Febuxostat was approved for medical use in the European Union in 2008 and in the United States in 2009. A generic version was approved in 2019 and is available as of 2020.
Medical uses
Febuxostat is used to treat chronic gout and hyperuricemia. Febuxostat is typically recommended only for people who cannot tolerate allopurinol. National Institute for Health and Clinical Excellence concluded that febuxostat is more effective than standard doses of allopurinol, but not more effective than higher doses of allopurinol.
Febuxostat is in the US pregnancy category C; there are no adequate and well-controlled studies in pregnant women.
Side effects
The adverse effects associated with febuxostat therapy include nausea, diarrhea, arthralgia, headache, increased hepatic serum enzyme levels and rash.On 15 November 2017, the FDA issued a safety alert indicating that the preliminary results from a safety clinical trial showed an increased risk of heart-related death with febuxostat compared to allopurinol in people with a history of cardiovascular diseases. The FDA required Takeda to conduct this safety study when the medicine was approved in 2009. The febuxostat drug labels already carry a warning and precaution about cardiovascular events because the clinical trials conducted before approval showed a higher rate of heart-related problems in patients treated with febuxostat compared to allopurinol. These problems included heart attacks, strokes, and heart-related deaths. As a result, the FDA required an additional safety clinical trial after the drug was approved and on the market to better understand these differences, and that trial was finished recently.
The safety trial was conducted in over 6,000 patients with gout treated with either febuxostat or allopurinol. The primary outcome was a combination of heart-related death, non-deadly heart attack, non-deadly stroke, and a condition of inadequate blood supply to the heart requiring urgent surgery. The preliminary results show that overall, febuxostat did not increase the risk of these combined events compared to allopurinol. However, when the outcomes were evaluated separately, febuxostat showed an increased risk of heart-related deaths and death from all causes.
Drug interactions
Febuxostat is contraindicated with concomitant use of theophylline and chemotherapeutic agents, namely azathioprine and 6-mercaptopurine, because it could increase blood plasma concentrations of these drugs and thereby their toxicity.
Pharmacology
Mechanism of action
Febuxostat is a non-purine-selective inhibitor of xanthine oxidase. It works by non-competitively blocking the molybdenum pterin center, which is the active site of xanthine oxidase. Xanthine oxidase is needed to oxidize successively hypoxanthine and xanthine to uric acid. Thus, febuxostat inhibits xanthine oxidase, thereby reducing production of uric acid. Febuxostat inhibits both the oxidized and the reduced forms of xanthine oxidase by virtue of its tight binding to the molybdenum pterin site.
Pharmacokinetics
After oral intake, at least 84% of the febuxostat dose is absorbed in the gut, and highest blood plasma concentrations are reached after 60 to 90 minutes. When taken together with a fatty meal, febuxostat reaches lower concentrations in the body; but this is not considered clinically relevant. When in the bloodstream, 99.2% of the substance is bound to the plasma protein albumin, and 82–91% of the active metabolites are bound to plasma proteins.
Febuxostat has three active metabolites in humans, which are formed mainly by a number of cytochrome P450 liver enzymes (CYP1A1, 1A2, 2C8, 2C9). One of them is a dicarboxylic acid, the other two are hydroxylated derivatives. These, as well as the original drug, are further glucuronidated, mainly by the enzymes UGT1A1, 1A8, and 1A9. Febuxostat and its metabolites are eliminated via the urine (49% of the total substance, comprising 3% unchanged febuxostat, 30% febuxostat glucuronide, 13% active metabolites and their glucuronides, and 3% unknown entities) and via the faeces (45%, of which 12% unchanged febuxostat, 1% glucuronide, 25% active metabolites and their glucuronides, and 7% unknown entities). Elimination half-life is five to eight hours.
History
Febuxostat was discovered by scientists at the Japanese pharmaceutical company Teijin in 1998. Teijin partnered the drug with TAP Pharmaceuticals in the US and Ipsen in Europe.Ipsen obtained marketing approval for febuxostat from the European Medicines Agency in April 2008, Takeda obtained FDA approval in February 2009, and Teijin obtained approval from the Japanese authorities in 2011. Ipsen exclusively licensed its European rights to Menarini in 2009. Teijin partnered with Astellas for distribution in China and southeast Asia.
Society and culture
Cost
In the UK, NICE has found that febuxostat has a higher cost/benefit ratio than allopurinol and on that basis recommended febuxostat as a second-line drug for people who cannot use allopurinol.In 2010, before it became generic in the United States, it cost about US$160 per month as opposed to allopurinol which was about $US14 per month.
Trade names
Febuxostat is marketed as Adenuric in Europe, Australia, New Zealand and Pakistan. In Pakistan it is launched by SOLACE Pharmaceuticals a sister subsidiary of SJG, Uloric in the US, Goturic and Goutex in Latin America, Feburic in Japan, Donifoxate in Egypt and is generic in several countries and is available by many names in those countries.
References
External links
"Febuxostat". Drug Information Portal. U.S. National Library of Medicine. |
Cold medicine | Cold medicines are a group of medications taken individually or in combination as a treatment for the symptoms of the common cold and similar conditions of the upper respiratory tract. The term encompasses a broad array of drugs, including analgesics, antihistamines and decongestants, among many others. It also includes drugs which are marketed as cough suppressants or antitussives, but their effectiveness in reducing cough symptoms is unclear or minimal.While they have been used by 10% of American children in any given week, they are not recommended in Canada or the United States in children six years or younger because of lack of evidence showing effect and concerns of harm. One version with codeine, guaifenesin, and pseudoephedrine was the 213th most commonly prescribed medication in 2017, in the United States, with more than two million prescriptions.
Types
There are a number of different cough and cold medications, which may be used for various coughing symptoms. The commercially available products may include various combinations of any one or more of the following types of substances:
Mucokinetics, or mucolytics, are a class of drugs which aid in the clearance of mucus from the airways, lungs, bronchi, and trachea. Examples are carbocisteine, ambroxol, and bromhexine.
Expectorants are substances claimed to make coughing easier while enhancing the production of mucus and phlegm. Two examples are acetylcysteine and guaifenesin.
Antitussives, or cough suppressants, are substances which suppress the coughing itself. Examples are codeine, pholcodine, dextromethorphan, noscapine, and butamirate.
Antihistamines, for allergic rhinitis may produce mild sedation and reduce other associated symptoms, like a runny nose and watery eyes. Examples are diphenhydramine, chlorpheniramine, brompheniramine, loratadine, and cetirizine.
Decongestants may improve nasal congestion in a sinus infections. Examples are ephedrine, phenylephrine, pseudoephedrine, and oxymetazoline.
Fever or pain medication. Examples are paracetamol (acetaminophen) and NSAIDs such as ibuprofen or naproxen.
Also employed are various substances supposed to soften the coughing, like honey or supplement syrup.
Effectiveness
The efficacy of cough medication is questionable, particularly in children. A 2014 Cochrane review concluded that "There is no good evidence for or against the effectiveness of OTC medicines in acute cough". Some cough medicines may be no more effective than placebos for acute coughs in adults, including coughs related to upper respiratory tract infections. The American College of Chest Physicians emphasizes that cough medicines are not designed to treat whooping cough, a cough that is caused by bacteria and can last for months. No over-the-counter cough medicines have been found to be effective in cases of pneumonia. They are not recommended in those who have COPD, chronic bronchitis, or the common cold. There is not enough evidence to make recommendations for those who have a cough in cancer.
Medications
Dextromethorphan (DXM) may be modestly effective in decreasing cough in adults with viral upper respiratory infections. However, in children it has not been found to be effective.
Codeine was once viewed as the "gold standard" in cough suppressants, but this position is now questioned. Some placebo-controlled trials have found that it is ineffective against some forms of cough, including acute cough in children. It is thus not recommended for children. Additionally, there is no evidence that hydrocodone is useful in children. Similarly, a 2012 Dutch guideline does not recommend its use to treat acute cough.
A number of other commercially available cough treatments have not been shown to be effective in viral upper respiratory infections. These include for adults: antihistamines, antihistamine-decongestant combinations, benzonatate, anti asthmatic-expectorant-mucolytic combinations, expectorant-bronchodilator combinations, leukotriene inhibitors, ambroxol, and guaifenesin, sometimes with analgesics, antipyretics, anti inflammatories, and anticholinergics; and for children: antihistamines, decongestants for clearing the nose, or combinations of these and leukotriene inhibitors for allergy and asthma. However, antihistamines cannot be used as an empirical therapy in case of chronic, or non-specific cough, especially in very young children. Long term diphenhydramine use is associated with negative outcomes in older people.
Alternative medicine
A small study found honey may be a minimally effective cough treatment due to "well-established antioxidant and antimicrobial effects" and a tendency to soothe irritated tissue. A Cochrane review found there was weak evidence to recommend for or against the use of honey in children as a cough remedy. In light of these findings, the Cochrane study they found honey was better than no treatment, placebo, or diphenhydramine but not better than dextromethorphan for relieving cough symptoms. Honeys use as a cough treatment has been linked on several occasions to infantile botulism and accordingly should not be used in children less than one year old.Many alternative treatments are used to treat the common cold, though data on effectiveness is generally limited. A 2007 review states that, "alternative therapies (i.e., Echinacea, vitamin C, and zinc) are not recommended for treating common cold symptoms; however,...Vitamin C prophylaxis may modestly reduce the duration and severity of the common cold in the general population and may reduce the incidence of the illness in persons exposed to physical and environmental stresses." A 2014 review also found insufficient evidence for Echinacea, where no clinical relevance was proven to provide benefit for treating the common cold, despite a weak benefit for positive trends. Similarly, a 2014 systematic review showed that garlic may prevent occurrences of the common cold but there was insufficient evidence of garlic in treating the common cold and studies reported adverse effects of a rash and odour. Therefore, more research need to be done to prove that the benefits out weight the harms.
A 2009 review found that the evidence supporting the effectiveness of zinc is mixed with respect to cough, and a 2011 Cochrane review concluded that zinc "administered within 24 hours of onset of symptoms reduces the duration and severity of the common cold in healthy people". A 2003 review concluded: "Clinical trial data support the value of zinc in reducing the duration and severity of symptoms of the common cold when administered within 24 hours of the onset of common cold symptoms." Zinc gel in the nose may lead to long-term or permanent loss of smell. The FDA therefore discourages its use.
Recreational usage
Cough medicines, especially those containing dextromethorphan and codeine, are often abused as recreational drugs. Abuse may result in hallucinations, loss of consciousness and death.
Adverse effects
A number of accidental overdoses and well-documented adverse effects suggested caution in children. The FDA in 2015 warned that the use of codeine-containing cough medication in children may cause breathing problems. Cold syrup overdose has been linked to visual and auditory hallucinations as well as rapid involuntary jaw, tongue, and eye movements in children.
History
Heroin was originally marketed as a cough suppressant in 1898. It was, at the time, believed to be a non-addictive alternative to other opiate-containing cough syrups. This was quickly realized not to be true as heroin readily breaks down into morphine in the body. Morphine was already known to be addictive.
Society and culture
Brands
Some brand names include: Benilyn, Sudafed, Robitussin and Vicks among others. Most contain a number of active ingredients.Sudafed is a brand manufactured by McNeil Laboratories. The original formulation contains the active ingredient pseudoephedrine, but formulations without pseudoephedrine are also being sold under the brand. In 2016, it was one of the biggest selling branded over-the-counter medications sold in Great Britain, with sales of £34.4 million. The effectiveness of phenylephrine by mouth as a nasal decongestant is questionable.Gees Linctus is a cough medicine which contains opium tincture. New Zealand in 2019 moved it to prescription only.Coricidin, Coricidin D, or Coricidin HBP, is the brand name of a combination of dextromethorphan and chlorpheniramine maleate (an antihistamine). Varieties may also contain acetaminophen and guaifenesin.Codral is a brand name manufactured by Johnson & Johnson and sold primarily in Australia and New Zealand. Codral is the highest-selling cold and flu medication in Australia.
Economics
In the United States, several billion dollars are spent on over-the-counter products per year.
Poisoning
According to The New York Times, at least eight mass poisonings have occurred as a result of counterfeit cough syrup in which medical-grade glycerin has been replaced with diethylene glycol, an inexpensive, yet toxic, glycerin substitute marketed for industrial use. In May 2007, 365 deaths were reported in Panama, which were associated with cough syrup containing diethylene glycol. In 2022, the deaths of 66 children in The Gambia were linked to four pediatric cough syrup medications that contained diethylene glycol and ethylene glycol.In 2022, the Food and Drug Administration issued a warning against cooking foods in cough syrup, after a video of someone preparing “NyQuil chicken” became popular on social media. Cough syrup is designed to be stored at room temperature and its properties can change when it is heated, making it potentially deadly. Heated cough syrup can also vaporize, leading to inhalation hazards.
See also
Nin Jiom Pei Pa Koa, a Chinese herbal cough syrup
Throat lozenge
Toxic cough syrup
== References == |
Vedolizumab | Vedolizumab, sold under the brand name Entyvio, is a monoclonal antibody medication developed by Millennium Pharmaceuticals, Inc. for the treatment of ulcerative colitis and Crohns disease. It binds to integrin α4β7 (LPAM-1, lymphocyte Peyers patch adhesion molecule 1, a dimer of Integrin alpha-4 and Integrin beta-7). Blocking the α4β7 integrin results in gut-selective anti-inflammatory activity.
Medical use
Ulcerative colitis and Crohns disease
Vedolizumab has been approved for use in adults with moderate to severe ulcerative colitis or Crohns disease having a poor response to tumor necrosis factor (TNF) blockers or corticosteroids, or for those who are steroid-dependent.
Checkpoint inhibitor colitis
Vedolizumab may be used to treat steroid refractory checkpoint inhibitor induced colitis, if infliximab is ineffective or contraindicated.
Clinical trials
Ulcerative colitis
Vedolizumab has been investigated in several studies in adult patients. and at least 6 have results reported|date=June 2020}} Patients with moderate to severe active disease in whom conventional therapy or TNF-alpha antagonists were ineffective or could not be tolerated received either vedolizumab or placebo. The main measure of effectiveness was the proportion of patients whose symptoms improved after six weeks of treatment. Vedolizumab was shown to be more effective than placebo: 47% (106 out of 225) of patients who received vedolizumab showed an improvement in symptoms, compared with 26% (38 out of 149) of patients who received placebo. The study also showed that vedolizumab maintained the effect up to 52 weeks more effectively than placebo. Moreover, vedolizumab treatment was shown to achieve higher percentage of clinical remissions (31.3% vs. 22.5%) in patients with ulcerative colitis in comparison to adalimumab treatment.
Crohns disease
In one main study in adult patients with moderate to severe active Crohns disease in whom conventional therapy or TNF-alpha antagonists were ineffective or could not be tolerated, vedolizumab was shown to be more effective than placebo: 15% (32 out of 220) of patients receiving vedolizumab showed improved symptoms after 6 weeks of treatment, compared with 7% (10 out of 148) of patients on placebo. The maintenance of the effect up to 52 weeks was more effective with vedolizumab than with placebo.
History
The cell line used to develop vedolizumab was created by physician scientists at the Massachusetts General Hospital in Boston as a result of work executed in Dr. Robert Colvins lab. This was part of a program to analyze the molecular basis of lymphocyte activation. An antibody was isolated that reacted with long term activated antigen-specific (tetanus toxoid) T-lymphocytes originally isolated from blood lymphocytes. The cell lines were created in Dr. Jim T. Kurnicks lab. Although the antibody did not block primary activation of T-lymphocytes, it appeared late after activation with a number of lymphocytic stimuli, and was named "Act-1" because it was the first activation marker identified by this group of investigators. Dr. Andrew Lazarovits, a postdoctoral fellow in the laboratory, discovered the murine homologue of MLN0002, chiefly published the original key papers, and up until the late 1990s, coordinated and led the studies for its development and application for Crohns disease and ulcerative colitis. Dr. Lynn Bairds group showed the antibody reacted with a single protein band of 63Kd, and Dr. Atul Bhans group showed that it stained tissue lymphocytes but did not react with non-lymphoid tissues. Although Act-1 had limited efficacy in its ability to prevent kidney rejection in a sub-human primate transplantation model, Dr. Lazarovits continued to investigate the activities of Act-1 when he returned to Canada to become the Director of Transplantation at the University of Western Ontario.It was later determined that the Act-1 monoclonal antibody reacted with an α4β7 integrin that was subsequently shown to interact with a gut-associated addressin, MadCAM. Early work with Dr. Bruce Yacyshyn showed differential expression in inflammatory bowel disease. Dr. Lazarovits isolated the antibody to produce the murine homologue MLN002 which he licensed with the Massachusetts General Hospital to Millennium Pharmaceuticals of Boston for further development. Scientists at LeukoSite realized the potential of this antibody to treat inflammatory bowel disease, and this company was eventually acquired by Millennium which took an exclusive license to the cell line from Massachusetts General Hospital. In vivo proof of concept ultimately led to the decision to humanize the antibody and move it into clinical trials as "Vedolizumab". In addition to its reactivity to gut-associated lymphoid tissues, Act-1 antibody also stains large numbers of lymphocytes in rheumatoid synovium, and has been shown by Dr. A. A. Ansari of Emory University to prevent or delay onset of AIDS in a monkey-model of Simian Immunodeficiency Virus-induced AIDS. Thus, reactivity with this antibody may show widespread applicability in inflammatory processes of diverse etiologies.
Society and culture
Legal status
Takeda filed a Marketing Authorization Application (MAA) in the European Union on 7 March 2013 and a Biologic License Application (BLA) with the U.S. Food and Drug Administration on 21 June 2013 for both Crohns disease and ulcerative colitis. On 4 September 2013, vedolizumab was given a Priority Review Status, which functions to expedite potential acceptance to market.In March 2014, 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 vedolizumab (brand name Entyvio).In May 2014, vedolizumab (Entyvio) was approved by the FDA for treatment of both moderate-to-severe ulcerative colitis and moderate-to-severe Crohns disease. In May 2014, Entyvio was approved for medical use in the European Union. In April 2015, Health Canada approved Entyvio.
Research
Vedolizumab eventually completed a number of phase III clinical trials for Crohns Disease and Ulcerative Colitis (GEMINI I, GEMINI II, and GEMINI III) that demonstrate that vedolizumab is an effective and well tolerated drug. The results of the GEMINI 1 and GEMINI 2 randomized, placebo controlled multicenter trials of induction and maintenance therapy in Crohns disease and ulcerative colitis have been published. An additional clinical trial, GEMINI LTS (Long-term Safety), is still being run.
HIV infectionIn October 2016, scientists from Emory University and National Institute of Allergy and Infectious Diseases (NIAID) published a paper which claimed that they applied daily ART (antiretroviral therapy) of 90 days followed by simianized (rhesus macaques) anti α4β7 antibody on SIV+ rhesus macaques for 23 weeks. Twenty three months after stopping both ART and anti-α4β7 antibody treatment, the in vivo SIV level still remained undetectable. Therefore, treating HIV+ people with ART and anti-α4β7 simultaneously may be a new therapy that could potentially lead to an HIV infection cure. In mice vedolizumab was not able to prevent or control HIV-infections. Phase 1 clinical trial of that therapy has been initialized by NIAID since May 2016. For each of the participants, they will get vedolizumab infusions every four weeks for 30 weeks. Before the 23rd week of vedolizumab infusions, cART (combination ART) is kept. During the 30 weeks, blood draws are repeated for baseline tests. After the 22-week-cART is stopped, both viral load and CD4 count will be monitored biweekly. If HIV viral load goes high or their CD4 cell counts decrease by too much during when vedolizumab is used alone, cART will be brought back on the participants. The published results from this clinical trial suggest "that blockade of α4β7 may not be an effective strategy for inducing virological remission in HIV-infected individuals after ART interruption" because only one patient showed prolonged virus suppression.
References
External links
"Vedolizumab". Drug Information Portal. U.S. National Library of Medicine. |
Benzonatate | Benzonatate, sold under the brand name Tessalon among others, is a medication used to try to help with the symptoms of cough and hiccups. It is taken by mouth. Use is not recommended in those under the age of ten. Effects generally begin within 20 minutes and last up to eight hours.Side effects include sleepiness, dizziness, headache, upset stomach, skin rash, hallucinations, and allergic reactions. Excessive doses may cause seizures, irregular heartbeat, and death. Chewing or sucking on the capsule can lead to laryngospasm, bronchospasm, and circulatory collapse. It is unclear if use in pregnancy or breastfeeding is safe. It works by numbing stretch receptors in the lungs and suppressing the cough reflex in the brain.Benzonatate was approved for medical use in the United States in 1958. It is available as a generic medication. It is not available in many countries. In 2019, it was the 105th most commonly prescribed medication in the United States, with more than 6 million prescriptions.
Medical uses
Cough
Benzonatate is a prescription non-opioid alternative for the symptomatic relief of cough. It has been shown to improve cough associated with a variety of respiratory conditions including asthma, bronchitis, pneumonia, tuberculosis, pneumothorax, opiate-resistant cough in lung cancer, and emphysema.Benzonatate also reduces the consistency and volume of sputum production associated with cough in those with chronic obstructive pulmonary disorder (COPD).Compared to codeine, benzonatate has been shown to be more effective in reducing the frequency of induced cough in experiments.Benzonatate does not treat the underlying cause of the cough.
Hiccups
Benzonatate has been shown to have use in the suppression of hiccups.
Intubation
Benzonatate acts as a local anesthetic and the liquid inside the capsule can be applied in the mouth to numb the oropharynx for awake intubation. However, there can be life-threatening adverse effects when the medication is absorbed by the oral mucosa, including choking, hypersensitivity reactions, and circulatory collapse.
Contraindications
Hypersensitivity to benzonatate or any related compounds is a contraindication to its administration.
Side effects
Benzonatate is generally well-tolerated if the liquid-capsule is swallowed intact. Potential adverse effects to benzonatate include:
Constipation, dizziness, fatigue, stuffy nose, nausea, headache are frequently reported.
Sedation, a feeling of numbness in the chest, sensation of burning in the eyes, a vague "chilly" sensation, itchiness, and rashes are also possible.
Ingestion of a small handful of capsules has caused seizures, cardiac arrhythmia, and death in adults.
Hypersensitivity reactions
Benzonatate is structurally related to anesthetic medications of the para-aminobenzoic acid (PABA) class which includes procaine and tetracaine. Procaine and tetracaine, previously used heavily in the fields of dentistry and anesthesiology, have fallen out of favor due to allergies associated with their metabolites. Similarly, severe hypersensitivity reactions to benzonatate have been reported and include symptoms of laryngospasm, bronchospasm, and cardiovascular collapse. These reactions are possibly associated with chewing, sucking, or crushing the capsule in the mouth.
Improper use
Benzonatate should be swallowed whole. Crushing or sucking on the liquid-filled capsule, or "softgel," will cause release of benzonatate from the capsule and can produce a temporary local anesthesia of the oral mucosa. Rapid development of numbness of the tongue and choking can occur. In severe cases, excessive absorption can lead to laryngospasm, bronchospasm, seizures, and circulatory collapse. This may be due to a hypersensitivity reaction to benzonatate or a systemic local anesthetic toxicity, both of which have similar symptoms. There is a potential for these adverse effects to occur at a therapeutic dose, that is, a single capsule, if chewed or sucked on in the mouth.
Psychiatric effects
Isolated cases of bizarre behavior, mental confusion, and visual hallucinations have been reported during concurrent use with other prescribed medications. Central nervous system effects associated with other para-aminobenozic acid (PABA) derivative local anesthetics, for example procaine or tetracaine, could occur with benzonatate and should be considered.
Children
Safety and efficacy in children below the age of 10 have not been established. Accidental ingestion resulting in death has been reported in children below the age of 10. Benzonatate may be attractive to children due to its appearance, a round-shaped liquid-filled gelatin capsule, which looks like candy. Chewing or sucking of a single capsule can cause death of a small child. Signs and symptoms can occur rapidly after ingestion (within 15–20 minutes) and include restlessness, tremors, convulsions, coma, and cardiac arrest. Death has been reported within one hour of ingestion.
Pregnancy and breast feeding
In the U.S., benzonatate is classified by the U.S. Food and Drug Administration (FDA) as pregnancy category C. It is not known if benzonatate can cause fetal harm to a pregnant woman or if it can affect reproduction capacity. Animal reproductive studies have not yet been conducted with benzonatate to evaluate its teratogenicity. Benzonatate should only be given to a pregnant woman if it is clearly needed.It is not known whether benzonatate is excreted in human milk. It is recommended to exercise caution when benzonatate is given to a nursing woman.
Overdose
Benzonatate is chemically similar to other local anesthetics such as tetracaine and procaine, and shares their pharmacology and toxicology.Benzonatate overdose is characterized by symptoms of restlessness, tremors, seizures, abnormal heart rhythms (cardiac arrhythmia), cerebral edema, absent breathing (apnea), fast heart beat (tachycardia), and in severe cases, coma and death. Symptoms develop rapidly, typically within 1 hour of ingestion. Treatment focuses on removal of gastric contents and on managing symptoms of sedation, convulsions, apnea, and cardiac arrhythmia.Despite a long history of safe and appropriate usage, the safety margin of benzonatate is reportedly narrow. Toxicity above the therapeutic dose is relatively low and ingestion of a small handful of pills can cause symptoms of overdose. Children are at an increased risk for toxicity, which have occurred with administration of only one or two capsules.Due to increasing usage of benzonatate and rapid onset of symptoms, there are accumulating cases of benzonatate overdose deaths, especially in children.
Pharmacology
Benzonatate is chemically similar to other local anesthetics such as tetracaine and procaine, and shares their pharmacology.
Mechanism of action
Similar to other local anesthetics, benzonatate is a potent voltage-gated sodium channel inhibitor. After absorption and circulation to the respiratory tract, benzonatate acts as a local anesthetic, decreasing the sensitivity of vagal afferent fibers and stretch receptors in the bronchi, alveoli, and pleura in the lower airway and lung. This dampens their activity and reduces the cough reflex. Benzonatate also has central antitussive activity on the cough center in central nervous system at the level of the medulla. However, there is minimal inhibition of the respiratory center at a therapeutic dosage.
Pharmacokinetics
The antitussive effect of benzonatate begins within 15 to 20 minutes after oral administration and typically lasts between 3 and 8 hours.Benzonatate is hydrolyzed by plasma butyrylcholinesterase (BChE) to the metabolite 4-(butylamino)benzoic acid (BABA) as well as polyethylene glycol monomethyl esters. Like many other local anesthetic esters, the hydrolysis of the parent compound is rapid. There are concerns that those with pseudocholinesterase deficiencies may have an increased sensitivity to benzonatate as this hydrolysis is impaired, leading to increased levels of circulating medication.
Chemical structure
Benzonatate is a butylamine, structurally related to other polyglycol ester local anesthetics such as procaine and tetracaine. The molecular weight of benzonatate is 603.7 g/mol. However, the reference standard for benzonatate is a mixture of n-ethoxy compounds, differing in the abundance of 7-9 repeating units, with an average molecular weight of 612.23 g/mol. There is also evidence that the compound is not uniform between manufacturers.
Society and culture
Benzonatate was first made available in the U.S. in 1958 as a prescription medication for the treatment of cough in individuals over the age of 10. There are a variety of prescription opioid-based cough relievers, such as hydrocodone and codeine, but have unwanted side effects and potential of abuse and diversion. However, benzonatate is currently the only prescription non-opioid antitussive and its usage has been rapidly increasing. The exact reasons of this increase are unclear.
Economics
In the United States between 2004 and 2009, prescriptions increased 50% from 3.1 million to 4.7 million, the market share of benzonatate among antitussives increased from 6.3% to 13%, and the estimated number of children under the age of 10 years receiving benzonatate increased from 10,000 to 19,000. Throughout this same period, greater than 90% of prescriptions were given to those 18 or older. The majority of prescriptions were given by general, family, internal, and osteopathic physicians with pediatricians account for about 3% of prescribed benzonatate.In 2019, it was the 105th most commonly prescribed medication in the United States, with more than 6 million prescriptions.
Brand names
Tessalon is a brand name version of benzonatate manufactured by Pfizer, Inc. It is available as perles or capsules. Zonatuss was a brand name manufactured by Atley Pharmaceuticals, Inc. and Vertical Pharmaceuticals, Inc.
References
External links
"Benzonatate". Drug Information Portal. U.S. National Library of Medicine. |
Doxylamine | Doxylamine, sold under the brand name Unisom among others, is an antihistamine medication which is used in the treatment of insomnia and allergies. In combination with pyridoxine (vitamin B6), it is also used to treat morning sickness in pregnant women. Doxylamine is available over-the-counter, and is used in nighttime cold medicines, such as NyQuil, as well as in pain medications containing acetaminophen and codeine, to help with sleep. The medication is taken by mouth.
Side effects of doxylamine include dizziness, drowsiness, grogginess, and dry mouth, among others. Doxylamine is an antihistamine—specifically an inverse agonist of the histamine H1 receptor—and to a lesser extent an anticholinergic—specifically an antagonist of the muscarinic acetylcholine receptors M1 through M5. It is a first-generation antihistamine and crosses the blood-brain barrier into the brain, thereby producing centrally mediated sedative and hypnotic effects.
Doxylamine was first described in 1948 or 1949. Several of the first-generation antihistamines, including doxylamine, are the most widely used sleep medications in the world.
Medical uses
Doxylamine is an antihistamine used to treat sneezing, runny nose, watery eyes, hives, skin rash, itching, and other cold or allergy symptoms. It is also used as a short-term treatment for insomnia.
Insomnia
The first-generation sedating antihistamines diphenhydramine, doxepin, doxylamine, and pyrilamine are the most widely used medications in the world for preventing and treating insomnia. As of 2004, doxylamine and diphenhydramine, which are both over-the-counter medications, were the agents most commonly used to treat short-term insomnia. As of 2008 and 2017, over-the-counter antihistamines were not recommended by the American Academy of Sleep Medicine for treatment of chronic insomnia "due to the relative lack of efficacy and safety data". Neither version of their guidelines explicitly included or mentioned doxylamine, although diphenhydramine was discussed. A 2015 systematic review of over-the-counter sleep aids including doxylamine found little evidence to inform the use of doxylamine for treatment of insomnia.A major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found that doxylamine had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4 weeks of 0.47 (95% CI 0.06 to 0.89). The certainty of evidence was rated as moderate. No data were available for doxylamine in terms of longer-term treatment (3 months). For comparison, the other sedating antihistamines assessed, doxepin and trimipramine, had effect sizes (SMD) at 4 weeks of 0.30 (95% CI –0.05 to 0.64) (very low certainty evidence) and 0.55 (95% CI –0.11 to 1.21) (very low certainty evidence), respectively.Doses of doxylamine that have been used for sleep range from 5 to 50 mg, with 25 mg being the typical dose.
Morning sickness
Doxylamine is used in the combination drug pyridoxine/doxylamine to treat morning sickness (nausea and vomiting of pregnancy). It is the only medication approved by the United States Food and Drug Administration for the treatment of morning sickness.
Available forms
Doxylamine is used medically as doxylamine succinate, the succinate salt of doxylamine, and is available both alone (brand names Decapryn, Doxy-Sleep-Aid, Unisom) and in combination with pyridoxine (a form of vitamin B6) (brand names Bendectin, Bonjesta, Diclegis). Doxylamine is available alone as immediate-release oral tablets containing 25 mg doxylamine succinate. Oral tablets containing 12.5 mg doxylamine succinate as well as oral capsules containing 25 mg doxylamine succinate were also previously available but were discontinued. The combination of doxylamine and pyridoxine is available in the form of extended- and delayed-release oral tablets containing 10 to 20 mg doxylamine succinate and 10 to 20 mg pyridoxine hydrochloride. Doxylamine alone is available over-the-counter, whereas doxylamine in combination with pyridoxine is a prescription-only medication. Doxylamine is also available in over-the-counter nighttime cold medicine products such as NyQuil Cold & Flu (contains acetaminophen, doxylamine succinate 6.25 to 12.5 mg, and dextromethorphan hydrobromide), where it serves as the sedating component.
Contraindications
The fetal safety rating of doxylamine is "A" (no evidence of risk).
Side effects
Side effects of doxylamine include dizziness, drowsiness, and dry mouth, among others. Doxylamine is a potent anticholinergic and has a side-effect profile common to such drugs, including blurred vision, dry mouth, constipation, muscle incoordination, urinary retention, mental confusion, and delirium.Because of its relatively long elimination half-life (10–12 hours), doxylamine is associated with next-day effects including sedation, drowsiness, grogginess, dry mouth, and tiredness when used as a hypnotic. This may be described as a "hangover effect". The shorter elimination half-life of diphenhydramine (4–8 hours) compared to doxylamine may give it an advantage over doxylamine as a sleep aid in this regard.Antihistamines like doxylamine are sedating initially but tolerance occurs with repeated use and can result in rebound insomnia upon discontinuation.Occasional case reports of coma and rhabdomyolysis have been reported with doxylamine. This is in contrast to diphenhydramine.Studies of doxylamines carcinogenicity in mice and rats have produced positive results for both liver and thyroid cancer, especially in the mouse. The carcinogenicity of the drug in humans is not well-studied, and the International Agency for Research on Cancer lists the drug as "not classifiable as to its carcinogenicity to humans".
Overdose
Doxylamine is generally safe for administration to healthy adults. Doses of doxylamine of up to 1,600 mg/day for 6 months have been given to adults with schizophrenia, with little toxicity encountered. The median lethal dose (LD50) is estimated to be ~500 mg/kg in humans. Symptoms of overdose may include dry mouth, dilated pupils, insomnia, night terrors, euphoria, hallucinations, seizures, rhabdomyolysis, and death. Fatalities have been reported from doxylamine overdose. These have been characterized by coma, tonic-clonic (or grand mal) seizures and cardiorespiratory arrest. Children appear to be at a high risk for cardiorespiratory arrest. A toxic dose for children of more than 1.8 mg/kg has been reported. A 3-year-old child died 18 hours after ingesting 1,000 mg doxylamine succinate. Rarely, an overdose results in rhabdomyolysis and acute kidney injury.
Pharmacology
Pharmacodynamics
Doxylamine acts primarily as an antagonist or inverse agonist of the histamine H1 receptor. This action is responsible for its antihistamine and sedative properties. To a lesser extent, doxylamine acts as an antagonist of the muscarinic acetylcholine receptors, an action responsible for its anticholinergic and (at high doses) deliriant effects.
Pharmacokinetics
The bioavailability of doxylamine is 24.7% for oral administration and 70.8% for intranasal administration. The Tmax of doxylamine is 1.5 to 2.5 hours. Its elimination half-life is 10 to 12 hours (range 7 to 15 hours). Doxylamine is metabolized in the liver primarily by the cytochrome P450 enzymes CYP2D6, CYP1A2, and CYP2C9. The main metabolites are N-desmethyldoxylamine, N,N-didesmethyldoxylamine, and doxylamine N-oxide. Doxylamine is eliminated 60% in the urine and 40% in feces.
Chemistry
Doxylamine is a member of the ethanolamine class of antihistamines. Other antihistamines from this group include bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, orphenadrine, and phenyltoloxamine.
History
Doxylamine is a first-generation antihistamine and was discovered by Nathan Sperber and colleagues and was first reported in 1948 or 1949. It has been the antihistamine component of NyQuil since 1966.Bendectin, a combination of doxylamine, pyridoxine (vitamin B6), and dicyclomine (an anticholinergic antispasmodic agent), was marketed for treatment of morning sickness in 1956. This product was reformulated in 1976 to remove dicyclomine. The reformulated product was voluntarily discontinued by the manufacturer in the United States in 1983 due to concerns about an alleged association with congenital limb defects. However, these concerns have not been supported by studies. In 2013, doxylamine/pyridoxine was reintroduced in the United States under the brand name Diclegis. The combination was not removed from the market in Canada, where it had been marketed since 1979.
Society and culture
Formulations
Doxylamine is primarily used as the succinic acid salt, doxylamine succinate.
It is the sedating ingredient of NyQuil (generally in combination with dextromethorphan and acetaminophen).
In Commonwealth countries, such as Australia, Canada, South Africa, and the United Kingdom, doxylamine is available prepared with paracetamol (acetaminophen) and codeine under the brand name Dolased, Propain Plus, Syndol, or Mersyndol, as treatment for tension headache and other types of pain.
Doxylamine succinate is used in general over-the-counter sleep-aids branded as Somnil (South Africa), Dozile, Donormyl, Lidène (France, Russian Federation), Dormidina (Spain, Portugal), Restavit, Unisom-2, Sominar (Thailand), Sleep Aid (generic, Australia) and Dorminox (Poland).
In the United States:
Doxylamine succinate is the active ingredient in many over-the-counter sleep-aids branded under various names.
Doxylamine succinate and pyridoxine (Vitamin B6) are the ingredients of Diclegis, approved by the FDA in April 2013 becoming the only drug approved for morning sickness with a class A safety rating for pregnancy (no evidence of risk).
In Canada:
Doxylamine succinate and pyridoxine (vitamin B6) are the ingredients of Diclectin, which is used to prevent morning sickness.
It is also available in combination with vitamin B6 and folic acid under the brand name Evanorm (marketed by Ion Healthcare).
In India
Doxylamine preparations are available typically in combination with Pyridoxine that may also contain folic acid. Doxylamine usage is thus restricted for pregnant women.
== References == |
Carac | Carac may refer to
a trade name of the drug Fluorouracil
a sweet pie specialty of Swiss origin, see Carac (pastry) |
Unasyn | Unasyn is the trade name for two related antibiotic drugs:
Ampicillin/sulbactam, a fixed-dose combination medication of the penicillin antibiotic combination ampicillin/sulbactam
Sultamicillin, an oral form of the penicillin antibiotic combination ampicillin/sulbactam |
Margetuximab | Margetuximab, sold under the brand name Margenza, is a chimeric IgG monoclonal antibody medication against HER2 used for the treatment of cancer.The most common adverse drug reactions in combination with chemotherapy are fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, infusion-related reactions, palmar-plantar erythrodysesthesia, and extremity pain.This drug was created by Raven biotechnologies, which was later acquired by MacroGenics. It was engineered to increase affinity for CD16A polymorphisms and decrease affinity for FcγRIIB (CD32B), an inhibitory receptor.It binds to the same target (epitope) as trastuzumab, on the HER2 receptor.
Medical uses
Margetuximab is indicated, in combination with chemotherapy, for the treatment of adults with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.
History
It is in phase III clinical trials for combination therapy in metastatic breast cancer in collaboration with Merck. Phase II trials are also in progress for gastric cancer and esophageal cancer.In June 2020, it received orphan drug designation from the U.S. Food and Drug Administration (FDA).Efficacy was evaluated in SOPHIA (NCT02492711), a randomized, multicenter, open-label trial of 536 participants with IHC 3+ or ISH-amplified HER2+ metastatic breast cancer who had received prior treatment with other anti-HER2 therapies. Participants were randomized (1:1) to margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Randomization was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), number of lines of therapy in the metastatic setting (≤ 2, > 2), and number of metastatic sites (≤ 2, > 2). The trial was conducted at 166 sites in the United States and 16 other countries.It was approved for medical use in the United States in December 2020.
References
External links
"Margetuximab". Drug Information Portal. U.S. National Library of Medicine. |
Clobetasol propionate | Clobetasol propionate is a corticosteroid used to treat skin conditions such as eczema, contact dermatitis, seborrheic dermatitis, and psoriasis. It is applied to the skin as a cream, ointment, or shampoo. Use should be short term and only if other weaker corticosteroids are not effective. Use is not recommended in rosacea or perioral dermatitis.Common side effects include skin irritation, dry skin, redness, pimples, and telangiectasia. Serious side effects may include adrenal suppression, allergic reactions, cellulitis, and Cushings syndrome. Use in pregnancy and breastfeeding is of unclear safety. Clobetasol is believed to work by activating steroid receptors. It is a US Class I (Europe: class IV) corticosteroid, making it one of the strongest available.
Clobetasol propionate was patented in 1968 and came into medical use in 1978. It is available as a generic medication. In 2019, it was the 180th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Medical uses
Clobetasol propionate is used for the treatment of various skin disorders including eczema, herpes labialis, psoriasis, and lichen sclerosus. It is also used to treat several auto-immune diseases including alopecia areata, lichen planus (auto immune skin nodules), and mycosis fungoides (T-cell skin lymphoma). It is used as first-line treatment for both acute and chronic GVHD of the skin.Clobetasol propionate is used cosmetically for skin whitening, although this use is controversial. The U.S. Food and Drug Administration has not approved it for that purpose, and sales without a prescription are illegal in the U.S. Nonetheless, skin-whitening creams containing this ingredient can sometimes be found in beauty supply stores in New York City and on the internet. It is also sold internationally, and does not require a prescription in some countries. Whitening creams with clobetasol propionate, such as Hyprogel, can make skin thin and easily bruised, with visible capillaries, and acne. It can also lead to hypertension, elevated blood sugar, suppression of the bodys natural steroids, and stretch marks, which may be permanent.Clobetasol propionate is, along with mercury and hydroquinone, "amongst the most toxic and most used agents in lightening products." Many products sold illegally have higher concentrations of clobetasol propionate than is permitted for prescription drugs.
Contraindications
According to the California Environmental Protection Agency, clobetasol propionate should not be used by pregnant women, or women expecting to become pregnant soon, as studies with rats shows a risk of birth defects:
"Studies in the rat following oral administration at dosage levels up to 50 mcg/kg per day revealed that the females exhibited an increase in the number of resorbed embryos and a decrease in the number of living fetuses at the highest dose. Pregnancy: Teratogenic Effects (i.e., possibility of causing abnormalities in fetuses): Pregnancy Category C: Clobetasol propionate has not been tested for teratogenicity when applied topically; however, it is absorbed percutaneously, and when administered subcutaneously it was a significant teratogen in both the rabbit and mouse. Clobetasol propionate has greater teratogenic potential than steroids that are less potent. There are no adequate and well-controlled studies of the teratogenic effects of clobetasol propionate in pregnant women. Temovate Cream and Ointment should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."
Forms
Clobetasol propionate is marketed and sold worldwide under numerous names, including Clobex, Clob-x (Colombia), Clovate, Clobet (Biolab Thailand) Clonovate (T.O. Chemicals, Thailand), Cormax (Watson, US), Haloderm (Switzerland, by ELKO Org), Pentasol (Colombia), Cosvate, Clop (Cadila Healthcare, India), Propysalic (India), Temovate (US), Dermovate (GlaxoSmithKline, Canada, Estonia, Pakistan, Switzerland, Portugal, Romania, Israel), Olux, ClobaDerm, Tenovate, Dermatovate (Brazil, Mexico), Butavate, Movate, Novate, Salac (Argentina), and Powercort, Lotasbat and Kloderma (Indonesia), Lemonvate (Italy), Delor (Ethiopia), Psovate (Turkey).
References
External links
"Clobetasol propionate". Drug Information Portal. U.S. National Library of Medicine. |
Desflurane | Desflurane (1,2,2,2-tetrafluoroethyl difluoromethyl ether) is a highly fluorinated methyl ethyl ether used for maintenance of general anesthesia. Like halothane, enflurane, and isoflurane, it is a racemic mixture of (R) and (S) optical isomers (enantiomers). Together with sevoflurane, it is gradually replacing isoflurane for human use, except in economically undeveloped areas, where its high cost precludes its use. It has the most rapid onset and offset of the volatile anesthetic drugs used for general anesthesia due to its low solubility in blood.
Some drawbacks of desflurane are its low potency, its pungency and its high cost (though at low flow fresh gas rates, the cost difference between desflurane and isoflurane appears to be insignificant). It may cause tachycardia and airway irritability when administered at concentrations greater than 10 vol%. Due to this airway irritability, desflurane is infrequently used to induce anesthesia via inhalation techniques.
Though it vaporizes very readily, it is a liquid at room temperature. Anaesthetic machines are fitted with a specialized anaesthetic vaporiser unit that heats liquid desflurane to a constant temperature. This enables the agent to be available at a constant vapor pressure, negating the effects fluctuating ambient temperatures would otherwise have on its concentration imparted into the fresh gas flow of the anesthesia machine.
Desflurane, along with enflurane and to a lesser extent isoflurane, has been shown to react with the carbon dioxide absorbent in anesthesia circuits to produce detectable levels of carbon monoxide through degradation of the anesthetic agent. The CO2 absorbent Baralyme, when dried, is most culpable for the production of carbon monoxide from desflurane degradation, although it is also seen with soda lime absorbent as well. Dry conditions in the carbon dioxide absorbent are conducive to this phenomenon, such as those resulting from high fresh gas flows.
Pharmacology
As of 2005 the exact mechanism of the action of general anaesthetics has not been delineated. Desflurane is known to act as a positive allosteric modulator of the GABAA and glycine receptors, and as a negative allosteric modulator of the nicotinic acetylcholine receptor, as well as affecting other ligand-gated ion channels.
Stereochemistry
Desflurane medications are a racemate of two enantiomers.
Physical properties
Global-warming potential
Desflurane is a greenhouse gas. The twenty-year global-warming potential, GWP(20), for desflurane is 3714, meaning that one tonne of desflurane emitted is equivalent to 3714 tonnes of carbon dioxide in the atmosphere, much higher than sevoflurane or isoflurane. In addition to global warming potentials, drug potency and fresh gas flow rates must be considered for meaningful comparisons between anesthetic gases. When a steady state hourly amount of anesthetic necessary for 1 minimum alveolar concentration (MAC) at 2 liters per minute (LPM) for Sevoflurane, and 1 LPM for Desflurane and Isoflurane is weighted by the GWP, the clinically relevant quantities of each anesthetic can then be compared. On a per-MAC-hour basis, the total life cycle GHG impact of desflurane is more than 20 times higher than Isoflurane and Sevoflurane (1 minimal alveolar concentration-hour). One paper finds anesthesia gases used globally contribute the equivalent of 1 million cars to global warming. This estimate is commonly cited as a reason to neglect pollution prevention by anesthesiologists, however this is problematic. This estimate is extrapolated from only one U.S. institutions anesthetic practices, and this institution uses virtually no Desflurane. Researchers neglected to include nitrous oxide in their calculations, and reported an erroneous average of 17 kg CO2e per anesthetic. However, institutions that utilize some Desflurane and account for nitrous oxide have reported an average of 175–220 kg CO2e per anesthetic. Sulbaek-Andersons group therefore likely underestimated the total worldwide contribution of inhaled anesthetics, and yet still advocates for inhaled anesthetic emissions prevention.
References
Further reading
Eger, Eisenkraft, Weiskopf. The Pharmacology of Inhaled Anesthetics. 2003.
Rang, Dale, Ritter, Moore. Pharmacology 5th Edition. 2003.
Martin Bellgardt: Evaluation der Sedierungstiefe und der Aufwachzeiten frisch operierter Patienten mit neurophysiologischem Monitoring im Rahmen der Studie: Desfluran versus Propofol zur Sedierung beatmeter Patienten. Bochum, Dissertation, 2005 (pdf)
Susanne Lohmann: Verträglichkeit, Nebenwirkungen und Hämodynamik der inhalativen Sedierung mit Desfluran im Rahmen der Studie: Desfluran versus Propofol zur Sedierung beatmeter Patienten. Bochum, Dissertation, 2006 (pdf Archived 2016-03-04 at the Wayback Machine)
Patel SS, Goa KL (1995). "Desflurane. A review of its pharmacodynamic and pharmacokinetic properties and its efficacy in general anaesthesia". Drugs. 50 (4): 742–67. doi:10.2165/00003495-199550040-00010. PMID 8536556.
External links
"Desflurane". Drug Information Portal. U.S. National Library of Medicine. |
Etoposide | Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. It is also used for hemophagocytic lymphohistiocytosis. It is used by mouth or injection into a vein.Side effects are very common. They can include low blood cell counts, vomiting, loss of appetite, diarrhea, hair loss, and fever. Other severe side effects include allergic reactions and low blood pressure. Use during pregnancy will likely harm the fetus. Etoposide is in the topoisomerase inhibitor family of medication. It is believed to work by damaging DNA.Etoposide was approved for medical use in the United States in 1983. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Etoposide is used as a form of chemotherapy for cancers such as Kaposi’s sarcoma, Ewings sarcoma, lung cancer, testicular cancer, lymphoma, nonlymphocytic leukemia, and glioblastoma multiforme. It is often given in combination with other drugs (such as bleomycin in treating testicular cancer). It is also sometimes used in a conditioning regimen prior to a bone marrow or blood stem cell transplant.
Administration
It is given intravenously (IV) or orally in capsule or tablet form. If the drug is given IV, it must be done slowly over a 30- to 60-minute period because it can lower blood pressure as it is being administered. Blood pressure is checked often during infusing, with the speed of administration adjusted accordingly.
Side effects
Common are:
infusion site reactions
low blood pressure
hair loss
pain and or burning at the IV site
constipation or diarrhea
metallic food taste
bone marrow suppression, leading to:
decreased white blood cell counts (leading to increased susceptibility to infections)
low red blood cell counts (anemia)
low platelet counts (leading to easy bruising and bleeding)Less common are:
nausea and vomiting
allergic-type reactions
rash
fever, often occurring shortly after IV administration and not due to infection
mouth sores
acute myeloid leukemia (which can be treated with etoposide itself)When given with warfarin, it may cause bleeding.
Pharmacology
Mechanism of action
Etoposide forms a ternary complex with DNA and the topoisomerase II enzyme, which is an enzyme that aids in relaxing negative or positive supercoils in DNA. Topoisomerase II normally will form a double-stranded break in one DNA double-strand, allow another to pass through, and re-ligate the broken strands. Etoposides binding prevents topoisomerase II from re-ligating the broken DNA strands, which causes the DNA breaks made by topoisomerase II to stay broken, and also prevents the topoisomerase II molecule from leaving the site and relieving tension elsewhere. This results in a double-strand break in the DNA that can have various deleterious effects on the cell, and depletion of topoisomerase II available to relieve further tension. Cancer cells rely on this enzyme more than healthy cells, since they divide more rapidly. Therefore, this causes errors in DNA synthesis and promotes apoptosis of the cancer cell.
Chemistry
Etoposide is a semisynthetic derivative of podophyllotoxin from the rhizome of the wild mandrake (Podophyllum peltatum). More specifically, it is a glycoside of podophyllotoxin with a D-glucose derivative. It is chemically similar to the anti-cancer drug teniposide, being distinguished only by a methyl group where teniposide has a thienyl. Both these compounds have been developed with the aim of creating less toxic derivatives of podophyllotoxin.The substance is a white to yellow-brown, crystalline powder. It is soluble in organic solvents.It is used in form of its salt etoposide phosphate.
History
Etoposide was first synthesized in 1966 and U.S. Food and Drug Administration approval was granted in 1983.The nickname VP-16 likely comes from a compounding of the last name of one of the chemists who performed early work on the drug (von Wartburg) and podophyllotoxin. Another scientist who was integral in the development of podophyllotoxin-based chemotherapeutics was the medical pharmacologist Hartmann F. Stähelin.
References
External links
"Etoposide". Drug Information Portal. U.S. National Library of Medicine.
"Etoposide phosphate". Drug Information Portal. U.S. National Library of Medicine.
"Etoposide". National Cancer Institute. 12 August 2008.
"Etoposide". NCI Drug Dictionary. National Cancer Institute. |
Tebentafusp | Tebentafusp, sold under the brand name Kimmtrak, is an anti-cancer medication used to treat uveal melanoma (eye cancer).The most common side effects include cytokine release syndrome, rash, pyrexia (fever), pruritus (itching), fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting.Tebentafusp is a bispecific gp100 peptide-HLA-directed CD3 T cell engager. It was approved for medical use in the United States in January 2022.
Medical uses
Tebentafusp is indicated for HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma.
History
Efficacy was evaluated in IMCgp100-202 (NCT03070392), a randomized, open-label, multicenter trial of 378 participants with metastatic uveal melanoma. Participants were required to be HLA-A*02:01 genotype positive identified by a central assay. Participants were excluded if prior systemic therapy or localized liver-directed therapy were administered. Prior surgical resection of oligometastatic disease was permitted. Participants with clinically significant cardiac disease or symptomatic, untreated brain metastases were excluded.The U.S. Food and Drug Administration (FDA) granted Immunocores application for tebentafusp priority review, breakthrough therapy, and orphan drug designations.
Society and culture
Legal status
On 24 February 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kimmtrak, intended for the treatment of uveal melanoma. The applicant for this medicinal product is Immunocore Ireland Limited. Tebentafusp was approved for medical use in the European Union in April 2022.
References
External links
"Tebentafusp". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03070392 for "Safety and Efficacy of IMCgp100 Versus Investigator Choice in Advanced Uveal Melanoma" at ClinicalTrials.gov |
Olanzapine/fluoxetine | Olanzapine/fluoxetine (trade name Symbyax, created by Eli Lilly and Company) is a fixed-dose combination medication containing olanzapine (Zyprexa), an atypical antipsychotic, and fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI). Olanzapine/fluoxetine is primarily used to treat the depressive episodes of bipolar I disorder as well as treatment-resistant depression.
Medical uses
Olanzapine/fluoxetine was approved by the U.S. Food and Drug Administration (FDA) to treat the depressive episodes of bipolar I disorder in 2003. In 2009, it was granted approval for the treatment of treatment-resistant depression.Olanzapine/fluoxetine, or other antidepressant/antipsychotic combinations, are sometimes prescribed off-label for anxiety disorders, eating disorders, obsessive–compulsive disorder (OCD), and posttraumatic stress disorder (PTSD).
Side effects
Possible side effects of olanzapine/fluoxetine include all those of the two component drugs: olanzapine (side effects) and fluoxetine (side effects). Common side effects include suicidal thoughts, increased appetite, weight gain, drowsiness, fatigue, dry mouth, swelling, tremor, blurred vision, and difficulty concentrating.Olanzapine/fluoxetine could produce a severe allergic reaction and should not be used if the patient has previously experienced an allergic reaction to either fluoxetine or olanzapine.Olanzapine is correlated with an increase in blood sugar. Patients with diabetes, or those at risk for developing it, require careful monitoring.In rare cases, olanzapine/fluoxetine may cause neuroleptic malignant syndrome.Like other SSRIs, olanzapine/fluoxetine carries a boxed warning stating that it could increase the risk of suicidal thoughts and behaviors in patients aged 24 and under. The warning also states that olanzapine/fluoxetine may increase the risk of death in elderly patients with dementia-related psychosis.
See also
Amitriptyline/perphenazine
Aripiprazole/sertraline
"California rocket fuel"
Flupentixol/melitracen
Tranylcypromine/trifluoperazine
References
External links
"Fluoxetine hydrochloride mixture with Olanzapine". Drug Information Portal. U.S. National Library of Medicine. |
Lithium (medication) | Certain lithium compounds, also known as lithium salts, are used as psychiatric medication, primarily for bipolar disorder and for major depressive disorder. In these disorders, it sometimes reduces the risk of suicide. Lithium is taken orally.Common side effects include increased urination, shakiness of the hands, and increased thirst. Serious side effects include hypothyroidism, diabetes insipidus, and lithium toxicity. Blood level monitoring is recommended to decrease the risk of potential toxicity. If levels become too high, diarrhea, vomiting, poor coordination, sleepiness, and ringing in the ears may occur. Lithium is teratogenic, especially during the first trimester of pregnancy and at higher dosages. The use of lithium while breastfeeding is controversial; however, many international health authorities advise against it, and the long-term outcomes of perinatal lithium exposure have not been studied. The American Academy of Pediatrics lists lithium as contraindicated for pregnancy and lactation. The United States Food and Drug Administration categorizes lithium as having positive evidence of risk for pregnancy and possible hazardous risk for lactation.Lithium salts are classified as mood stabilizers. How lithium works is not specifically known.In the nineteenth century, lithium was used in people who had gout, epilepsy, and cancer. Its use in the treatment of mental disorders began with Carl Lange in Denmark and William Alexander Hammond in New York City, who used lithium to treat mania from the 1870s onwards, based on now-discredited theories involving its effect on uric acid. Use of lithium for mental disorders was re-established (on a different theoretical basis) in 1948 by John Cade in Australia. It is on the World Health Organizations List of Essential Medicines, and is available as a generic medication. In 2019, it was the 205th most commonly prescribed medication in the United States, with more than 2 million prescriptions.
Medical uses
In 1970, lithium was approved by the United States Food and Drug Administration (FDA) for the treatment of bipolar disorder, which remains its primary use in the United States. It is sometimes used when other treatments are not effective in a number of other conditions, including major depression, schizophrenia, disorders of impulse control, and some psychiatric disorders in children. Because the FDA has not approved lithium for the treatment of other disorders, such use is off-label. In mood disorders, of which bipolar disorder is one, it decreases the risk of suicide. This benefit is not seen with other medications.
Bipolar disorder
Lithium is primarily used as a maintenance drug in the treatment of bipolar disorder to stabilize mood and prevent manic episodes, but it may also be helpful in the acute treatment of manic episodes. Lithium carbonate treatment was previously considered to be unsuitable for children; however, more recent studies show its effectiveness for treatment of early-onset bipolar disorder in children as young as eight. The required dosage is slightly less than the toxic level (representing a low therapeutic index), requiring close monitoring of blood levels of lithium carbonate during treatment. A limited amount of evidence suggests lithium carbonate may contribute to treatment of substance use disorders for some people with bipolar disorder.
Schizophrenic disorders
Lithium is recommended for the treatment of schizophrenic disorders only after other antipsychotics have failed; it has limited effectiveness when used alone. The results of different clinical studies of the efficacy of combining lithium with antipsychotic therapy for treating schizophrenic disorders have varied.
Major depressive disorder
Lithium is widely prescribed as a treatment for depression.
Augmentation
If therapy with antidepressants does not fully treat the symptoms of major depressive disorder (MDD) then a second augmentation agent is sometimes added to the therapy. Lithium is one of the few augmentation agents for antidepressants to demonstrate efficacy in treating MDD in multiple randomized controlled trials and it has been prescribed (off-label) for this purpose since the 1980s.
Monotherapy
There are a few old studies indicating efficacy of lithium for acute depression with lithium having the same efficacy as tricyclic antidepressants. A recent study concluded that lithium works best on chronic and recurrent depression when compared to modern antidepressant (i.e. citalopram) but not for patients with no history of depression.
Prevention of suicide
Meta-analyses have yielded differing results regarding the efficacy of lithium for preventing suicide and suicidality. Nonetheless, it remains widely used for these purposes.
Monitoring
Those who use lithium should receive regular serum level tests and should monitor thyroid and kidney function for abnormalities, as it interferes with the regulation of sodium and water levels in the body, and can cause dehydration. Dehydration, which is compounded by heat, can result in increasing lithium levels. The dehydration is due to lithium inhibition of the action of antidiuretic hormone, which normally enables the kidney to reabsorb water from urine. This causes an inability to concentrate urine, leading to consequent loss of body water and thirst.Lithium concentrations in whole blood, plasma, serum or urine may be measured using instrumental techniques as a guide to therapy, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Serum lithium concentrations are usually in the range of 0.5–1.3 mmol/L (0.5–1.3 mEq/L) in well-controlled people, but may increase to 1.8–2.5 mmol/L in those who accumulate the drug over time and to 3–10 mmol/L in acute overdose.Lithium salts have a narrow therapeutic/toxic ratio, so should not be prescribed unless facilities for monitoring plasma concentrations are available. Doses are adjusted to achieve plasma concentrations of 0.4 to 1.2 mmol Li+/L on samples taken 12 hours after the preceding dose.
Given the rates of thyroid dysfunction, thyroid parameters should be checked before lithium is instituted and monitored after 3–6 months and then every 6–12 months.Given the risks of kidney malfunction, serum creatinine and eGFR should be checked before lithium is instituted and monitored after 3–6 months at regular interval. Patients who have a rise in creatinine on three or more occasions, even if their eGFR is > 60 ml/min/
1.73m2 require further evaluation, including a urinalysis for haematuria, proteinuria, a review of their medical history with attention paid to cardiovascular, urological and medication history, and blood pressure control and management. Overt proteinuria should be further quantified with a urine protein to creatinine ratio.
Discontinuation
For patients who have achieved long term remission, it is recommended to discontinue lithium gradually and in a controlled fashion.
Cluster headaches, migraine and hypnic headache
Studies testing prophylactic use of lithium in cluster headaches (when compared to verapamil), migraine attacks and hypnic headache indicate good efficacy.
Adverse effects
Sources for the following lists.
Very Common (> 10% incidence) adverse effects of lithium include
Confusion
Constipation (usually transient, but can persist in some)
Decreased memory
Diarrhea (usually transient, but can persist in some)
Dry mouth
EKG changes — usually benign changes in T waves
Hand tremor (usually transient, but can persist in some) with an incidence of 27%. If severe, psychiatrist may lower lithium dosage, change lithium salt type or modify lithium preparation from long to short acting (despite lacking evidence for these procedures) or use pharmacological help
Headache
Hyperreflexia — overresponsive reflexes
Leukocytosis — elevated white blood cell count
Muscle weakness (usually transient, but can persist in some)
Myoclonus — muscle twitching
Nausea (usually transient)
Polydipsia — increased thirst
Polyuria — increased urination
Renal (kidney) toxicity which may lead to chronic kidney failure
Vomiting (usually transient, but can persist in some)
Vertigo
Weight gainCommon (1–10%) adverse effects include
Acne
Extrapyramidal side effects — movement-related problems such as muscle rigidity, parkinsonism, dystonia, etc.
Euthyroid goitre — i.e. the formation of a goitre despite normal thyroid functioning
Hypothyroidism — a deficiency of thyroid hormone.
Hair loss/hair thinningUnknown
Sexual dysfunction
HypoglycemiaLithium carbonate can induce a 1–2 kg of weight gain. Weight gain may be a source of low self-esteem for the clinically depressed.In addition to tremors, lithium treatment appears to be a risk factor for development of parkinsonism-like symptoms, although the causal mechanism remains unknown.Most side effects of lithium are dose-dependent. The lowest effective dose is used to limit the risk of side effects.
Hypothyroidism
The rate of hypothyroidism is around six times higher in people who take lithium. Low thyroid hormone levels in turn increase the likelihood of developing depression. People taking lithium thus should routinely be assessed for hypothyroidism and treated with synthetic thyroxine if necessary.Because lithium competes with the antidiuretic hormone in the kidney, it increases water output into the urine, a condition called nephrogenic diabetes insipidus. Clearance of lithium by the kidneys is usually successful with certain diuretic medications, including amiloride and triamterene. It increases the appetite and thirst ("polydypsia") and reduces the activity of thyroid hormone (hypothyroidism). The latter can be corrected by treatment with thyroxine and does not require the lithium dose to be adjusted. Lithium is also believed to permanently affect renal function, although this does not appear to be common.
Pregnancy and breast feeding
Lithium is a teratogen, causing birth defects in a small number of newborn babies. Case reports and several retrospective studies have demonstrated possible increases in the rate of a congenital heart defect known as Ebsteins anomaly, if taken during a womans pregnancy. As a consequence, fetal echocardiography is routinely performed in pregnant women taking lithium to exclude the possibility of cardiac anomalies. Lamotrigine seems to be a possible alternative to lithium in pregnant women for the treatment of acute bipolar depression or for the management of bipolar patients with normal mood. Gabapentin and clonazepam are also indicated as antipanic medications during the childbearing years and during pregnancy. Valproic acid and carbamazepine also tend to be associated with teratogenicity.
While it appears to be safe to use while breastfeeding a number of guidelines list it as a contraindication including the British National Formulary.
Kidney damage
Lithium has been associated with several forms of kidney injury. It is estimated that impaired urinary concentrating ability is present in at least half of individuals on chronic lithium therapy, a condition called lithium-induced nephrogenic diabetes insipidus. Continued use of lithium can lead to more serious kidney damage in an aggravated form of diabetes insipidus. Chronic kidney disease caused by lithium has not been proven with various contradicting results presented by a 2018 review. In rare cases, some forms of lithium-caused kidney damage may be progressive and lead to end-stage kidney failure with a reported incidence of 0.2% to 0.7%.
Hyperparathyroidism
Lithium-associated hyperparathyroidism is the leading cause of hypercalcemia in lithium-treated patients. Lithium may lead to exacerbation of pre-existing primary hyperparathyroidism or cause an increased set-point of calcium for parathyroid hormone suppression, leading to parathyroid hyperplasia.
Interactions
Lithium plasma concentrations are known to be increased with concurrent use of diuretics—especially loop diuretics (such as furosemide) and thiazides—and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. Lithium concentrations can also be increased with concurrent use of ACE inhibitors such as captopril, enalapril, and lisinopril.Lithium is primarily cleared from the body through glomerular filtration, but some is then reabsorbed together with sodium through the proximal tubule. Its levels are therefore sensitive to water and electrolyte balance. Diuretics act by lowering water and sodium levels; this causes more reabsorption of lithium in the proximal tubules so that the removal of lithium from the body is less, leading to increased blood levels of lithium. ACE inhibitors have also been shown in a retrospective case-control study to increase lithium concentrations. This is likely due to constriction of the afferent arteriole of the glomerulus, resulting in decreased glomerular filtration rate and clearance. Another possible mechanism is that ACE inhibitors can lead to a decrease in sodium and water. This will increase lithium reabsorption and its concentrations in the body.There are also drugs that can increase the clearance of lithium from the body, which can result in decreased lithium levels in the blood. These drugs include theophylline, caffeine, and acetazolamide. Additionally, increasing dietary sodium intake may also reduce lithium levels by prompting the kidneys to excrete more lithium.Lithium is known to be a potential precipitant of serotonin syndrome in people concurrently on serotonergic medications such as antidepressants, buspirone and certain opioids such as pethidine (meperidine), tramadol, oxycodone, fentanyl and others. Lithium co-treatment is also a risk factor for neuroleptic malignant syndrome in people on antipsychotics and other antidopaminergic medications.High doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy has been reported.
Indeed, these and other antipsychotics have been associated with increased risk of lithium neurotoxicity, even with low therapeutic lithium doses.
Overdose
Lithium toxicity, which is also called lithium overdose and lithium poisoning, is the condition of having too much lithium in the blood. This condition also happens in persons that are taking lithium in which the lithium levels are affected by drug interactions in the body.
In acute toxicity, people have primarily gastrointestinal symptoms such as vomiting and diarrhea, which may result in volume depletion. During acute toxicity, lithium distributes later into the central nervous system resulting in mild neurological symptoms, such as dizziness.In chronic toxicity, people have primarily neurological symptoms which include nystagmus, tremor, hyperreflexia, ataxia, and change in mental status. During chronic toxicity, the gastrointestinal symptoms seen in acute toxicity are less prominent. The symptoms are often vague and nonspecific.If the lithium toxicity is mild or moderate, lithium dosage is reduced or stopped entirely. If the toxicity is severe, lithium may need to be removed from the body.
Mechanism of action
The specific biochemical mechanism of lithium action in stabilizing mood is unknown.Upon ingestion, lithium becomes widely distributed in the central nervous system and interacts with a number of neurotransmitters and receptors, decreasing norepinephrine release and increasing serotonin synthesis.Unlike many other psychoactive drugs, Li+ typically produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations.
Lithium may also increase the release of serotonin by neurons in the brain. In vitro studies performed on serotonergic neurons from rat raphe nuclei have shown that when these neurons are treated with lithium, serotonin release is enhanced during a depolarization compared to no lithium treatment and the same depolarization.Lithium both directly and indirectly inhibits GSK3β (glycogen synthase kinase 3β) which results in the activation of mTOR. This leads to an increase in neuroprotective mechanisms by facilitating the Akt signaling pathway. GSK-3β is a downstream target of monoamine systems. As such, it is directly implicated in cognition and mood regulation. During mania, GSK-3β is activated via dopamine overactivity. GSK-3β inhibits the transcription factors β-catenin and cyclic AMP (cAMP) response element binding protein (CREB), by phosphorylation. This results in a decrease in the transcription of important genes encoding for neurotrophins. In addition, several authors proposed that pAp-phosphatase could be one of the therapeutic targets of lithium. This hypothesis was supported by the low Ki of lithium for human pAp-phosphatase compatible within the range of therapeutic concentrations of lithium in the plasma of people (0.8–1 mM). The Ki of human pAp-phosphatase is ten times lower than that of GSK3β (glycogen synthase kinase 3β). Inhibition of pAp-phosphatase by lithium leads to increased levels of pAp (3′-5′ phosphoadenosine phosphate), which was shown to inhibit PARP-1.Another mechanism proposed in 2007 is that lithium may interact with nitric oxide (NO) signalling pathway in the central nervous system, which plays a crucial role in neural plasticity. The NO system could be involved in the antidepressant effect of lithium in the Porsolt forced swimming test in mice. It was also reported that NMDA receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test, indicating the possible involvement of NMDA receptor/NO signaling in the action of lithium in this animal model of learned helplessness.
Lithium possesses neuroprotective properties by preventing apoptosis and increasing cell longevity.Although the search for a novel lithium-specific receptor is ongoing, the high concentration of lithium compounds required to elicit a significant pharmacological effect leads mainstream researchers to believe that the existence of such a receptor is unlikely.
Oxidative metabolism
Evidence suggests that mitochondrial dysfunction is present in patients with bipolar disorder.Oxidative stress and reduced levels of anti-oxidants (such as glutathione) lead to cell death. Lithium may protect against oxidative stress by up-regulating complex I and II of the mitochondrial electron transport chain.
Dopamine and G-protein coupling
During mania, there is an increase in neurotransmission of dopamine that causes a secondary homeostatic down-regulation, resulting in decreased neurotransmission of dopamine, which can cause depression. Additionally, the post-synaptic actions of dopamine are mediated through G-protein coupled receptors. Once dopamine is coupled to the G-protein receptors, it stimulates other secondary messenger systems that modulate neurotransmission. Studies found that in autopsies (which do not necessarily reflect living people), people with bipolar disorder had increased G-protein coupling compared to people without bipolar disorder. Lithium treatment alters the function of certain subunits of the dopamine associated G-protein, which may be part of its mechanism of action.
Glutamate and NMDA receptors
Glutamate levels are observed to be elevated during mania. Lithium is thought to provide long-term mood stabilization and have anti-manic properties by modulating glutamate levels. It is proposed that lithium competes with magnesium for binding to NMDA glutamate receptor, increasing the availability of glutamate in post-synaptic neurons, leading to a homeostatic increase in glutamate re-uptake which reduces glutamatergic transmission.
The NMDA receptor is also affected by other neurotransmitters such as serotonin and dopamine. Effects observed appear exclusive to lithium and have not been observed by other monovalent ions such as rubidium and caesium.
GABA receptors
GABA is an inhibitory neurotransmitter that plays an important role in regulating dopamine and glutamate neurotransmission. It was found that patients with bipolar disorder had lower GABA levels, which results in excitotoxicity and can cause apoptosis (cell loss). Lithium has been shown to increase the level of GABA in plasma and cerebral spinal fluid. Lithium counteracts these degrading processes by decreasing pro-apoptotic proteins and stimulating release of neuroprotective proteins. Lithiums regulation of both excitatory dopaminergic and glutamatergic systems through GABA may play a role in its mood stabilizing effects.
Cyclic AMP secondary messengers
Lithiums therapeutic effects are thought to be partially attributable to its interactions with several signal transduction mechanisms. The cyclic AMP secondary messenger system is shown to be modulated by lithium. Lithium was found to increase the basal levels of cyclic AMP but impair receptor coupled stimulation of cyclic AMP production. It is hypothesized that the dual effects of lithium are due to the inhibition of G-proteins that mediate cyclic AMP production. Over a long period of lithium treatment, cyclic AMP and adenylate cyclase levels are further changed by gene transcription factors.
Inositol depletion hypothesis
Lithium treatment has been found to inhibit the enzyme inositol monophosphatase, involved in degrading inositol monophosphate to inositol required in PIP2 synthesis. This leads to lower levels of inositol triphosphate, created by decomposition of PIP2. This effect has been suggested to be further enhanced with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression. It is known with good certainty that signals from the receptors coupled to the phosphoinositide signal transduction are affected by lithium. myo-inositol is also regulated by the high affinity sodium mI transport system (SMIT). Lithium is hypothesized to inhibit mI entering the cells and mitigating the function of SMIT. Reductions of cellular levels of myo-inositol results in the inhibition of the phosphoinositide cycle.
Neurotrophic Factors
Various neurotrophic factors such as BDNF and mesencephalic astrocyte-derived neurotrophic factor have been shown to be modulated by various mood stabilizers.
History
Lithium was first used in the 19th century as a treatment for gout after scientists discovered that, at least in the laboratory, lithium could dissolve uric acid crystals isolated from the kidneys. The levels of lithium needed to dissolve urate in the body, however, were toxic. Because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders, Carl Lange in Denmark and William Alexander Hammond in New York City used lithium to treat mania from the 1870s onwards. By the turn of the 20th century, as theory regarding mood disorders evolved and so-called "brain gout" disappeared as a medical entity, the use of lithium in psychiatry was largely abandoned; however, a number of lithium preparations were still produced for the control of renal calculi and uric acid diathesis. As accumulating knowledge indicated a role for excess sodium intake in hypertension and heart disease, lithium salts were prescribed to patients for use as a replacement for dietary table salt (sodium chloride). This practice and the sale of lithium itself were both banned in 1949, following publication of reports detailing side effects and deaths.Also in 1949, the Australian psychiatrist John Cade rediscovered the usefulness of lithium salts in treating mania. Cade was injecting rodents with urine extracts taken from manic patients in an attempt to isolate a metabolic compound which might be causing mental symptoms. Since uric acid in gout was known to be psychoactive, (adenosine receptors on neurons are stimulated by it; caffeine blocks them), Cade needed soluble urate for a control. He used lithium urate, already known to be the most soluble urate compound, and observed that it caused the rodents to become tranquil. Cade traced the effect to the lithium ion itself, and after ingesting lithium himself to ensure its safety in humans, he proposed lithium salts as tranquilizers. He soon succeeded in controlling mania in chronically hospitalized patients with them. This was one of the first successful applications of a drug to treat mental illness, and it opened the door for the development of medicines for other mental problems in the next decades.The rest of the world was slow to adopt this treatment, largely because of deaths which resulted from even relatively minor overdosing, including those reported from use of lithium chloride as a substitute for table salt. Largely through the research and other efforts of Denmarks Mogens Schou and Paul Baastrup in Europe, and Samuel Gershon and Baron Shopsin in the U.S., this resistance was slowly overcome. Following the recommendation of the APA Lithium Task Force (William Bunney, Irvin Cohen (Chair), Jonathan Cole, Ronald R. Fieve, Samuel Gershon, Robert Prien, and Joseph Tupin), the application of lithium in manic illness was approved by the United States Food and Drug Administration in 1970, becoming the 50th nation to do so. In 1974, this application was extended to its use as a preventive agent for manic-depressive illness.
Fieve, who had opened the first lithium clinic in North America in 1966, helped popularize the psychiatric use of lithium through his national TV appearances and his bestselling book, Moodswing. In addition, Fieve and David L. Dunner developed the concept of "rapid cycling" bipolar disorder based on non-response to lithium.
Lithium has now become a part of Western popular culture. Characters in Pi, Premonition, Stardust Memories, American Psycho, Garden State, and An Unmarried Woman all take lithium. Its the chief constituent of the calming drug in Ira Levins dystopian This Perfect Day. Sirius XM Satellite Radio in North America has a 1990s alternative rock station called Lithium, and several songs refer to the use of lithium as a mood stabilizer. These include: "Equilibrium met Lithium" by South African artist Koos Kombuis, "Lithium" by Evanescence, "Lithium" by Nirvana, "Lithium and a Lover" by Sirenia, "Lithium Sunset", from the album Mercury Falling by Sting, and "Lithium" by Thin White Rope.
7 Up
As with cocaine in Coca-Cola, lithium was widely marketed as one of a number of patent medicine products popular in the late-19th and early-20th centuries, and was the medicinal ingredient of a refreshment beverage. Charles Leiper Grigg, who launched his St. Louis-based company The Howdy Corporation, invented a formula for a lemon-lime soft drink in 1920. The product, originally named "Bib-Label Lithiated Lemon-Lime Soda", was launched two weeks before the Wall Street Crash of 1929. It contained the mood stabilizer lithium citrate, and was one of a number of patent medicine products popular in the late-19th and early-20th centuries. Its name was soon changed to 7 Up. All American beverage makers were forced to remove lithium in 1948. Despite the 1948 ban, in 1950 the Painesville Telegraph still carried an advertisement for a lithiated lemon beverage.
Salts and product names
Many different lithium salts can be used as medication, including lithium carbonate, lithium acetate, lithium sulfate, lithium citrate, lithium orotate and lithium gluconate.
Lithium carbonate (Li2CO3), sold under several trade names, is the most commonly prescribed, while lithium citrate (Li3C6H5O7) is also used in conventional pharmacological treatments. Lithium orotate (C5H3LiN2O4), has been presented as an alternative. Lithium bromide and lithium chloride have been used in the past as table salt; however, they fell out of use in the 1940s, when it was discovered they were toxic in those large doses. Many other lithium salts and compounds exist, such as lithium fluoride and lithium iodide, but they are presumed to be as toxic or more so than the chloride and have never been evaluated for pharmacological effects.
As of 2017 lithium was marketed under many brand names worldwide, including Cade, Calith, Camcolit, Carbolim, Carbolit, Carbolith, Carbolithium, Carbolitium, Carbonato de Litio, Carboron, Ceglution, Contemnol, D-Gluconsäure, Lithiumsalz, Efadermin (Lithium and Zinc Sulfate), Efalith (Lithium and Zinc Sulfate), Elcab, Eskalit, Eskalith, Frimania, Hypnorex, Kalitium, Karlit, Lalithium, Li-Liquid, Licarb, Licarbium, Lidin, Ligilin, Lilipin, Lilitin, Limas, Limed, Liskonum, Litarex, Lithane, Litheum, Lithicarb, Lithii carbonas, Lithii citras, Lithioderm, Lithiofor, Lithionit, Lithium, Lithium aceticum, Lithium asparagicum, Lithium Carbonate, Lithium Carbonicum, Lithium Citrate, Lithium DL-asparaginat-1-Wasser, Lithium gluconicum, |
Lithium (medication) | Lithium-D-gluconat, Lithiumcarbonaat, Lithiumcarbonat, Lithiumcitrat, Lithiun, Lithobid, Lithocent, Lithotabs, Lithuril, Litiam, Liticarb, Litijum, Litio, Litiomal, Lito, Litocarb, Litocip, Maniprex, Milithin, Neurolepsin, Plenur, Priadel, Prianil, Prolix, Psicolit, Quilonium, Quilonorm, Quilonum, Téralithe, and Theralite.
Research
Tentative evidence in Alzheimers disease showed that lithium may slow progression. It has been studied for its potential use in the treatment of amyotrophic lateral sclerosis (ALS), but a study showed lithium had no effect on ALS outcomes.
See also
Lithia water
Sodium in biology
References
Further reading
Mota de Freitas, Duarte; Leverson, Brian D.; Goossens, Jesse L. (2016). "Chapter 15. Lithium in Medicine: Mechanisms of Action". In Astrid, Sigel; Helmut, Sigel; Roland K.O., Sigel (eds.). The Alkali Metal Ions: Their Role in Life. Metal Ions in Life Sciences. Vol. 16. Springer. pp. 557–584. doi:10.1007/978-3-319-21756-7_15. PMID 26860311.
External links
"Lithium". Drug Information Portal. U.S. National Library of Medicine.
"Exposing lithiums circadian action"
https://web.archive.org/web/20040811012851/http://www.psycheducation.org/depression/meds/moodstabilizers.htm
"Lithium Basics"
CID 11125 — PubChem Compound Summary (Lithium Carbonate)
N05AN01 (WHO) |
Megestrol | Megestrol (INN, BAN) is a progestin of the 17α-hydroxyprogesterone group which was never marketed and is not currently used clinically. Its acylated derivative megestrol acetate is also a progestogen, which, in contrast to megestrol itself, has been extensively used as a pharmaceutical drug.
Synthesis
See also
Megestrol acetate
Medroxyprogesterone
Medroxyprogesterone acetate
== References == |
Diroximel fumarate | Diroximel fumarate, sold under the brand name Vumerity, is a medication used for the treatment of relapsing forms of multiple sclerosis (MS). It acts as an immunosuppressant and anti-inflammatory drug. Its most common adverse effects are flushing and gastrointestinal problems.Diroximel fumarate was approved for medical use in the United States in October 2019, and in the European Union in November 2021.
Medical uses
Diroximel fumarate is used for the treatment of relapsing-remitting multiple sclerosis. In the US, it is additionally approved for other relapsing forms of MS such as clinically isolated syndrome and active secondary progressive disease.
Available forms
The drug is available as a white delayed-release capsule that is resistant to gastric acid and only dissolves in the intestine.
Contraindications
Under the European Unions label, the drug is contraindicated in people with progressive multifocal leukoencephalopathy (PML), a disease of the brain caused by a virus. In the US, combination with the closely related drug dimethyl fumarate is contraindicated.
Side effects
No systematic studies of adverse effects under diroximel fumarate are available. The most common side effects in studies with dimethyl fumarate were flushing (in 34% of patients treated with the drug, versus 5% in the placebo group) and gastrointestinal effects such as diarrhoea (14% versus 10%), nausea (12% versus 9%), abdominal pain (9% versus 4%), vomiting (8% versus 5%), and indigestion (5% versus 3%). Three percent of patients stopped the treatment because of flushing, 4% because of gastrointestinal side effects. A rare but potentially fatal adverse effect may be PML, which has been observed under treatment with dimethyl fumarate.
Overdose
No specific antidote is known. Adverse effects caused by overdosing diroximel fumarate are treated symptomatically.
Interactions
Diroximel fumarate does not interact with cytochrome P450 enzymes or P-glycoprotein. Its active metabolite, monomethyl fumarate, has a relatively low plasma protein binding of 27 to 45%. Therefore, its potential for pharmacokinetic interactions is considered to be low.Inactivated vaccines can be given under diroximel fumarate therapy, based on experience with other immunosuppressant drugs, such as studies with tetanus, pneumococcal and meningococcal vaccines. No studies regarding the effectiveness of these vaccines under diroximel fumarate have been conducted. No data are available regarding combination with live vaccines, chemotherapy or immunosuppressants. Nephrotoxicity could be increased when the drug is combined with aminoglycoside antibiotics, diuretics, NSAIDs or lithium.
Pharmacology
Mechanism of action
The drugs mechanism of action is not well understood. In preclinical studies it activated nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor that is up-regulated under oxidative stress.
Pharmacokinetics
The pharmacokinetics of diroximel fumarate has been found to be practically identical to that of dimethyl fumarate. Both are prodrugs of monomethyl fumarate.Taking the drug with a high-calorie, high-fat meal slows down absorption, but has no relevant effect on overall absorption. The US label recommends not taking the drug together with high-calorie and high-fat meals.After ingestion, the substance is cleaved by esterase enzymes before reaching the systemic circulation, resulting in monomethyl fumarate (MMF), the active metabolite, and hydroxyethyl succinimide (HES), which is inactive. Diroximel fumarate itself is not present in the bloodstream. MMF reaches highest concentrations in the blood plasma 2.5 to 3 hours after ingestion. When in the bloodstream, 27 to 45% are bound to plasma proteins.MMF is further metabolized to fumarate, citrate and glucose, ultimately entering the citric acid cycle and being broken down to carbon dioxide (CO2). About 60% of the substance leave the body as CO2 via the lungs, 15.5% are eliminated with the urine (according to another source, less than 0.3%), and 0.9% are eliminated with the faeces. The terminal half-life is one hour.HES is eliminated mainly with the urine (58 to 63%).
Chemistry
The substance is a white to off-white powder. It is slightly soluble in water; that is, its solubility is between 1:100 and 1:1000. The molecule is achiral. The double bond of the fumarate moiety has E configuration.
History
This drug was formulated by Alkermes in collaboration with Biogen.
Society and culture
Legal status
Diroximel fumarate was approved for medical use in the United States in October 2019.On 16 September 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 Vumerity, intended for the treatment of adults with relapsing remitting multiple sclerosis. The applicant for this medicinal product is Biogen Netherlands B.V. It was approved for medical use in the European Union in November 2021.
References
External links
"Diroximel fumarate". Drug Information Portal. U.S. National Library of Medicine. |
Irinotecan | Irinotecan, sold under the brand name Camptosar among others, is a medication used to treat colon cancer, and small cell lung cancer. For colon cancer it is used either alone or with fluorouracil. For small cell lung cancer it is used with cisplatin. It is given intravenously.Common side effects include diarrhea, vomiting, bone marrow suppression, hair loss, shortness of breath, and fever. Other severe side effects include blood clots, colon inflammation, and allergic reactions. Those with two copies of the UGT1A1*28 gene variant are at higher risk for side effects. Use during pregnancy can result in harm to the baby. Irinotecan is a topoisomerase inhibitor—it blocks the topoisomerase I enzyme, resulting in DNA damage and cell death.Irinotecan was approved for medical use in the United States in 1996. It is on the World Health Organizations List of Essential Medicines. It is made from the natural compound camptothecin which is found in the Chinese ornamental tree Camptotheca acuminata.
Medical uses
Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. This includes the regimen FOLFIRI, which consists of infusional 5-fluorouracil, leucovorin, and irinotecan. The regimen XELIRI consists of capecitabine and irinotecan.It may also be used together with fluorouracil and folinic acid for pancreatic cancer following failure of initial treatment.
Side effects
The most significant adverse effects of irinotecan include diarrhea, nausea and vomiting, neutropenia and fever, infections of blood or lungs (sepsis, pneumonia), shock, dehydration, kidney failure and thrombocytopenia (low levels of blood platelets).
Diarrhea
Irinotecan-associated diarrhea is severe and clinically significant, sometimes leading to severe dehydration requiring hospitalization or intensive care unit admission. This side-effect is managed with the aggressive use of antidiarrheals such as loperamide or atropine with the first loose bowel movement.
Immunosuppression
The immune system is adversely impacted by irinotecan. This is reflected in – sometimes dramatically – lowered white blood cell counts in the blood, in particular the neutrophils. The patient may experience neutropenia (a clinically significant decrease of neutrophils in the blood).
Mechanism of action
Camptothecin, one of the four major structural classifications of plant-derived anti-cancerous compounds, is a cytotoxic alkaloid which consists of a pentacyclic ring structure containing a pyrrole (3, 4 β) quinoline moiety, an S-configured lactone form, and a carboxylate form. Camptothecin is an inhibitor of topoisomerase I. Its analogue, irinotecan, is activated by hydrolysis to SN-38, and is then inactivated by glucuronidation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.The molecular action of irinotecan occurs by trapping a subset of topoisomerase-1-DNA cleavage complexes, those with a guanine +1 in the DNA sequence. One irinotecan molecule stacks against the base pairs flanking the topoisomerase-induced cleavage site and poisons (inactivates) the topoisomerase 1 enzyme.
Interactive pathway
Click on genes, proteins and metabolites below to link to respective articles.
Pharmacokinetics
Administration
Irinotecan can be administrated by 30- or 90-minute intravenous infusions of either 125 mg/m2 weekly for four of every six weeks or 350 mg/m2 every three weeks.
Distribution
Irinotecan is a hydrophilic compound with a large volume of distribution (400 L/m2). At physiological pH, irinotecan and its active metabolite ethyl-10-hydroxy-camptothecin (SN-38) are present in two pH-dependent equilibrium isoforms; the anti tumor active lactone ring which hydrolyzed to the carboxylate isoform.In plasma, the majority of irinotecan and SN-38 are bound to albumin, which stabilizes their lactone forms. In blood, irinotecan and SN-38 are bound to platelets and red blood cells.Irinotecan has a linear pharmacokinetic. Population pharmacokinetic models assumed a three-compartmental model for irinotecan and a two-compartmental model for SN-38.SN-38 has a short distribution half-life (approximately 8 min). It reached its peak plasma concentration within 2 h after infusion. Also SN-38 exhibit a second peak in the plasma concentration because of its enterohepatic re-circulation and its release from erythrocytes.
Metabolism
Activation by carboxylesterases and butyrylcholinesteras
About 2–5% of the pro-drug irinotecan is hydrolyzed into its active metabolite SN-38 in the liver by two carboxylesterase converting enzymes (CES1 and CES2) and in plasma by butyrylcholinesterase (hBChE). CES2 has a 12.5-fold higher affinity for irinotecan than CES1. While, butyrylcholinesterase has a 6-fold higher activity for irinotecan than CES. After conversion, SN-38 is actively transported to the liver by the organic anion transporting polypeptide (OATP) 1B1 transporter.
Inactivation by uridine diphosphate glucuronosyltransferases
SN-38 is inactivated by glucuronidation to SN-38G (β-glucuronide conjugate) by several uridine diphosphate glucuronosyltransferase enzymes (UGTs) in the liver (UGT1A1, UGT1A9) and extra-hepatic (UGT1A1, UGT1A7, UGT1A10) and excreted into the bile. Several UGT polymorphisms affects irinotecan pharmacokinetics, for example, the decreased UGT1 activity, may lead to severe toxicity. Also, UGT1A1 conjugates bilirubin and bilirubin glucuronidation is another risk factor for increased toxicity
De-conjugation by β-glucuronidases
The intestinal bacteria produced β-glucuronidases that de-conjugate SN-38G to SN-38 resulting in entero-hepatic re-circulation of SN-38.
Metabolism by cytochrome P450 enzymes
Irinotecan is metabolized by intrahepatic cytochrome P450 enzymes, CYP3A4 and CYP3A5 into inactive metabolites APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin) and NPC (7-ethyl-10-[4-amino-1-piperidino] carbonyloxycamptothecin). NPC can be further converted by CES1 and CES2 in the liver to SN-38. Induction or inhibition of CYP3A enzymes by smoking, some herbs and medications may result in interactions with irinotecan.
Transport to bile
Irinotecan is transported to bile by the ATP-binding cassette (ABC) transporter proteins: ABCB1, ABCC1, ABCC2, and ABCG2.
Elimination
Irinotecan clearance is mainly biliary (66%) and estimated 12–21 L/h/m2. All metabolites, except SN-38G, are mainly excreted in feces. Irinotecan elimination half-lives were reported between 5 to18 h. SN-38 half-lives were reported between 6 and 32 h.There is high (30%) interindividual variability in irinotecan pharmacokinetic parameters which can be altered by several factors including age, sex, dose, administration timing, hepatic function, enzyme activity or hematocrit levels.
Pharmacogenomics
Irinotecan is converted by an enzyme into its active metabolite SN-38, which is in turn inactivated by the enzyme UGT1A1 by glucuronidation.
*28 variant patients
People with variants of the UGT1A1 called TA7, also known as the "*28 variant", express fewer UGT1A1 enzymes in their liver and often have Gilberts syndrome. During chemotherapy, they effectively receive a larger than expected dose because their bodies are not able to clear irinotecan as fast as others. In studies this corresponds to higher incidences of severe neutropenia and diarrhea.In 2004, a clinical study was performed that both validated prospectively the association of the *28 variant with greater toxicity and the ability of genetic testing in predicting that toxicity before chemotherapy administration.In 2005, the FDA made changes to the labeling of irinotecan to add pharmacogenomics recommendations, such that irinotecan recipients with a homozygous (both of the two gene copies) polymorphism in UGT1A1 gene, to be specific, the *28 variant, should be considered for reduced drug doses. Irinotecan is one of the first widely used chemotherapy agents that is dosed according to the recipients genotype.
Approval
Irinotecan received accelerated approval from the U.S. Food and Drug Administration (FDA) in 1996, and full approval in 1998.
Names
During development, it was known as CPT-11.
Formulations
A liposome encapsulated version of irinotecan sold as Onivyde by Merrimack Pharmaceuticals, was approved by FDA in October 2015, to treat metastatic pancreatic cancer. It was approved for medical use in the European Union in October 2016.
See also
Etirinotecan pegol, an experimental derivative of irinotecan with a longer half-life in the human body
References
Further reading
Dean L (2015). "Irinotecan Therapy and UGT1A1 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520360. Bookshelf ID: NBK294473.
External links
"Irinotecan". Drug Information Portal. U.S. National Library of Medicine.
"Irinotecan hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Irinotecan Pathway on PharmGKB |
Sulindac | Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) of the arylalkanoic acid class that is marketed as Clinoril. Imbaral (not to be confused with mebaral) is another name for this drug. Its name is derived from sul(finyl)+ ind(ene)+ ac(etic acid)
It was patented in 1969 and approved for medical use in 1976.
Medical uses
Like other NSAIDs, it is useful in the treatment of acute or chronic inflammatory conditions. Sulindac is a prodrug, derived from sulfinylindene, that is converted in the body to the active NSAID. More specifically, the agent is converted by liver enzymes to a sulfide that is excreted in the bile and then reabsorbed from the intestine. This is thought to help maintain constant blood levels with reduced gastrointestinal side effects. Some studies have shown sulindac to be relatively less irritating to the stomach than other NSAIDs except for drugs of the COX-2 inhibitor class. The exact mechanism of its NSAID properties is unknown, but it is thought to act on enzymes COX-1 and COX-2, inhibiting prostaglandin synthesis.
Its usual dosage is 150-200 milligrams twice per day, with food. It should not be used by persons with a history of major allergic reactions (urticaria or anaphylaxis) to aspirin or other NSAIDs, and should be used with caution by persons having pre-existing peptic ulcer disease. Sulindac is much more likely than other NSAIDs to cause damage to the liver or pancreas, though it is less likely to cause kidney damage than other NSAIDs.
Sulindac seems to have a property, independent of COX-inhibition, of reducing the growth of polyps and precancerous lesions in the colon, especially in association with familial adenomatous polyposis, and may have other anti-cancer properties.
Adverse effects
In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.
Society and culture
Litigation
In September 2010 a federal jury in New Hampshire awarded $21 million to Karen Bartlett, a woman who developed Stevens–Johnson syndrome/Toxic epidermal necrolysis as a result of taking a generic brand of sulindac manufactured by Mutual Pharmaceuticals for her shoulder pain. Ms. Bartlett sustained severe injuries including the loss of over 60% of her surface skin and permanent near-blindness. The case had been appealed to the United States Supreme Court, where the main issue was whether federal law preempts Ms. Bartletts claim. On June 24, 2013, the Supreme Court ruled 5–4 in favor of Mutual Pharmaceuticals, throwing out the earlier $21 million jury verdict.
Synthesis
Rxn of p-fluorobenzyl chloride (1) with the anion of diethylmethyl malonate (2) gives intermediate diester (3), saponification of which and subsequent decarboxylation leads to 4. {Alternatively it can be formed by Perkin reaction between p-fluorobenzaldehyde and propionic anhydride in the presence of NaOAc, followed by catalytic hydrogenation of the olefinic bond using a palladium on carbon catalyst.}
Polyphosphoric acid (PPA) cyclization leads to 5-fluoro-2-methyl-3-indanone (4). A Reformatsky reaction with zinc amalgam and bromoacetic ester leads to carbinol (5), which is then dehydrated with tosic acid to indene 6. {Alternatively, this step can be performed in a Knoevenagel condensation with cyanoacetic acid, which is then further decarboxylated.}
The active methylene group is condensed with p-methylthiobenzaldehyde, using sodium methoxide as catalyst, and then saponified to give Z (7) which in turn oxidized with sodium metaperiodate to sulfoxide 8, the antiinflammatory agent sulindac.
References
External links
RxList information on Sulindac
Drug Profile
Jury Awards $21 Million |
Neomycin | Neomycin is an aminoglycoside antibiotic that displays bactericidal activity against gram-negative aerobic bacilli and some anaerobic bacilli where resistance has not yet arisen. It is generally not effective against gram-positive bacilli and anaerobic gram-negative bacilli. Neomycin comes in oral and topical formulations, including creams, ointments, and eyedrops. Neomycin belongs to the aminoglycoside class of antibiotics that contain two or more amino sugars connected by glycosidic bonds.
Neomycin was discovered in 1949 by microbiologist Selman Waksman and his student Hubert Lechevalier at Rutgers University. Neomycin received approval for medical use in 1952. Rutgers University was granted the patent for neomycin in 1957.
Discovery
Neomycin was discovered in 1949 by the microbiologist Selman Waksman and his student Hubert Lechevalier at Rutgers University. It is produced naturally by the bacterium Streptomyces fradiae. Synthesis requires specific nutrient conditions in either stationary or submerged aerobic conditions. The compound is then isolated and purified from the bacterium.
Medical uses
Neomycin is typically applied as a topical preparation, such as Neosporin (neomycin/polymyxin B/bacitracin). The antibiotic can also be administered orally, in which case it is usually combined with other antibiotics. Neomycin is not absorbed from the gastrointestinal tract and has been used as a preventive measure for hepatic encephalopathy and hypercholesterolemia. By killing bacteria in the intestinal tract, Neomycin keeps ammonia levels low and prevents hepatic encephalopathy, especially before gastrointestinal surgery.
Waksman and Lechevalier originally noted that neomycin was active against streptomycin-resistant bacteria as well as Mycobacterium tuberculosis, the causative agent for tuberculosis. Neomycin has also been used to treat small intestinal bacterial overgrowth. Neomycin is not administered via injection, as it is extremely nephrotoxic (damaging to kidney function) even when compared to other aminoglycosides. The exception is when neomycin is included, in small quantities, as a preservative in some vaccines – typically 25 μg per dose.
Spectrum
Similar to other aminoglycosides, neomycin has excellent activity against gram-negative bacteria and is partially effective against gram-positive bacteria. It is relatively toxic to humans, with allergic reactions noted as a common adverse reaction (see: hypersensitivity). Physicians sometimes recommend using antibiotic ointments without neomycin, such as Polysporin. The following represents minimum inhibitory concentration (MIC) susceptibility data for a few medically significant gram-negative bacteria.
Enterobacter cloacae: >16 μg/ml
Escherichia coli: 1 μg/ml
Proteus vulgaris: 0.25 μg/ml
Side effects
In 2005–06, Neomycin was the fifth-most-prevalent allergen in patch test results (10.0%). It is also a known GABA gamma-Aminobutyric acid antagonist and can be responsible for seizures and psychosis. Like other aminoglycosides, neomycin has been shown to be ototoxic, causing tinnitus, hearing loss, and vestibular problems in a small number of patients. Patients with existing tinnitus or sensorineural hearing loss are advised to speak with a healthcare practitioner about the risks and side effects prior to taking this medication.
Molecular biology
Activity
Neomycins antibacterial activity stems from its binding to the 30S subunit of the prokaryotic ribosome, where it inhibits prokaryotic translation of mRNA.Neomycin also exhibits a high binding affinity for phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid component of cell membranes.
Resistance
Neomycin resistance is conferred by either one of two kanamycin kinase genes. Genes conferring neomycin-resistance are commonly included in DNA plasmids used to establish stable mammalian cell lines expressing cloned proteins in culture. Many commercially available protein expression plasmids contain a neo-resistance gene as a selectable marker.
Biosynthetic pathway
Neomycin was first isolated from the Streptomyces fradiae and Streptomyces albogriseus in 1949 (NBRC 12773). Neomycin is a mixture of neomycin B (framycetin); and its epimer neomycin C, the latter component accounting for some 5–15% of the mixture. It is a basic compound that is most active with an alkaline reaction. It is also thermostable and soluble in water (while insoluble in organic solvents). Neomycin has good activity against gram-positive and gram-negative bacteria, but is ototoxic. Its use is thus restricted to the oral treatment of intestinal infections.Neomycin B is composed of four linked moieties: D-neosamine, 2-deoxystreptamine (2-DOS), D-ribose, and L-neosamine.
Neomycin A, also called neamine, contains D-neosamine and 2-deoxystreptamine. Six genes are responsible for neamine biosynthesis: DOIS gene (btrC, neo7); L-glutamine:DOI aminotransferase gene (btrS, neo6); a putative glycosyltransferase gene (btrM, neo8); a putative aminotransferase (similar to glutamate-1-semialdehyde 2,1-aminomutase) gene (btrB, neo18); a putative alcohol dehydrogenase gene (btrE, neo5); and another putative dehydrogenase (similar to chorine dehydrogenase and related flavoproteins) gene (btrQ, neo11). A deacetylase acting to remove the acetyl group on N-acetylglucosamine moieties of aminoglycoside intermediates (Neo16) remains to be clarified (sequence similar to BtrD).Next is the attachment of the D-ribose via ribosylation of neamine, using 5-phosphoribosyl-1-diphosphate (PRPP) as the ribosyl donor (BtrL, BtrP); glycosyltransferase (potential homologues RibF, LivF, Parf) gene (Neo15).Neosamine B (L-neosamine B) is most likely biosynthesized in the same manner as the neosamine C (D-niosamine) in neamine biosynthesis, but with an additional epimerization step required to account for the presence of the epimeric neosamine B in neomycin B.
Neomycin C can undergo enzymatic synthesis from ribostamycin.
Composition
Standard grade neomycin is composed of several related compounds including neomycin A (neamine), neomycin B (framycetin), neomycin C, and a few minor compounds found in much lower quantities. Neomycin B is the most active component in neomycin followed by neomycin C and neomycin A. Neomycin A is an inactive degradation product of the C and B isomers. The quantities of these components in neomycin vary from lot-to-lot depending on the manufacturer and manufacturing process.
DNA binding
Aminoglycosides such as neomycin are known for their ability to bind to duplex RNA with high affinity. The association constant for neomycin with A-site RNA is in the 109 M−1 range. However, more than 50 years after its discovery, its DNA-binding properties were still unknown. Neomycin has been shown to induce thermal stabilization of triplex DNA, while having little or almost no effect on the B-DNA duplex stabilization. Neomycin was also shown to bind to structures that adopt an A-form structure, triplex DNA being one of them. Neomycin also includes DNA:RNA hybrid triplex formation.
== References == |
Afatinib | Afatinib, sold under the brand name Gilotrif among others, is a medication used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications. It is taken by mouth.It is mainly used to treat cases of NSCLC that harbour mutations in the epidermal growth factor receptor (EGFR) gene.It is on the World Health Organizations List of Essential Medicines.
Medical uses
It has received regulatory approval for use as a treatment for non-small cell lung cancer, although there is emerging evidence to support its use in other cancers such as breast cancer.
Adverse effects
Adverse effects by frequency include:
Very common (>10% frequency)
Common (1–10% frequency)
Uncommon (0.1-1% frequency)
Keratitis
Interstitial lung disease
Mechanism of action
Like lapatinib and neratinib, afatinib is a protein kinase inhibitor that also irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases. Afatinib is not only active against EGFR mutations targeted by first generation tyrosine-kinase inhibitors (TKIs) like erlotinib or gefitinib, but also against less common mutations which are resistant to these drugs. However, it is not active against the T790M mutation which generally requires third generation drugs like osimertinib. Because of its additional activity against Her2, it is being investigated for breast cancer as well as other EGFR and Her2 driven cancers.
Clinical trials
In March 2010, a Phase III trial in NSCLC patients called Lux-Lung 5 began with this drug.
Fall 2010 interim results suggested the drug extended progression-free survival threefold compared to placebo, but did not extend overall survival. In May 2012, the Phase IIb/III trial Lux-Lung 1 came to the same conclusion.In January 2015, a Phase III trial in people with NSCLC suggested the drug extended life expectancy in stage IV NSCLC adenocarcinoma with EGFR Mutation type del 19-positive tumors, compared to cisplatin-based chemotherapy by a year (33 months vs. 21 months). It also shows strong activity against exon 18 mutations (particularly G719) and is currently the preferred EGFR-TKI therapy for exon 18 mutations (particularly G719x).Phase II results for breast cancer that over-expresses the protein human epidermal growth factor receptor 2 (Her2-positive breast cancer) were described as promising by the authors, with 19 of 41 patients achieving benefit from afatinib. Double-blind Phase III trials are under way to confirm or refute this finding. Her2-negative breast cancers showed limited or no response to the drug.
Society and culture
Brand names
In Bangladesh under the trade name Afanix.
References
External links
"Afatinib". Drug Information Portal. U.S. National Library of Medicine.
"Afatinib dimaleate". Drug Information Portal. U.S. National Library of Medicine. |
Estradiol/norethisterone acetate | Estradiol/norethisterone acetate (E2/NETA), sold under the brand name Activella among others, is a combination of estradiol (E2) and norethisterone acetate (NETA) which is used in the treatment of vasomotor symptoms, vulvar and vaginal atrophy, and osteoporosis associated with menopause. Activella specifically is marketed by Novo Nordisk and is supplied as film-coated tablets containing 1 mg estradiol and 0.5 mg norethisterone acetate. CombiPatch is a combination of estradiol and NETA provided as a transdermal patch.
See also
Ethinylestradiol/norethisterone acetate
Ethinylestradiol/norelgestromin
Estradiol/levonorgestrel
List of combined sex-hormonal preparations
== References == |
Sildenafil | Sildenafil, sold under the brand name Viagra, among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. It is unclear if it is effective for treating sexual dysfunction in women. It is taken by mouth or by injection into a vein. Onset is typically within twenty minutes and lasts for about two hours.Common side effects include headaches, heartburn, and flushed skin. Caution is advised in those with cardiovascular disease. Rare but serious side effects include a prolonged erection (priapism) that can lead to damage to the penis, vision problems, and hearing loss. Sildenafil should not be taken by people on nitrates such as nitroglycerin (glycerin trinitrate), as this may result in a serious drop in blood pressure. Sildenafil should not be taken within four hours of taking an alpha blocker.
Sildenafil acts by blocking phosphodiesterase 5 (PDE5), an enzyme that promotes breakdown of cGMP, which regulates blood flow in the penis. It requires sexual arousal to work. It also results in dilation of the blood vessels in the lungs.Pfizer originally discovered the medication in 1989 while looking for a treatment for heart-related chest pain. It was approved for medical use in the United States and in the European Union in 1998. In 2017, it was the 217th-most commonly prescribed medication in the United States, with more than two million prescriptions. That same year, it also became available as a generic medication after final patents by Pfizer expired. In the United Kingdom, it is available over the counter. Most of the Active Pharmaceutical Ingredient (API) in Sildenafil, Sildenafil citrate, is produced in Pfizers Ringaskiddy complex, County Cork, which is Pfizers largest production facility outside of the United States.
Medical uses
Sexual dysfunction
The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete sexual intercourse). Its use is now one of the standard treatments for erectile dysfunction, including for men with diabetes mellitus.
Antidepressant-associated sexual dysfunction
Tentative evidence suggests that sildenafil may help men who experience antidepressant-induced erectile dysfunction.
Pulmonary hypertension
While sildenafil improves some markers of disease in people with pulmonary arterial hypertension, it does not appear to affect the risk of death or serious side effects.
Raynauds phenomenon
Sildenafil and other PDE5 inhibitors are used off-label to alleviate vasospasm and treat severe ischemia and ulcers in fingers and toes for people with secondary Raynauds phenomenon; these drugs have moderate efficacy for reducing the frequency and duration of vasospastic episodes. As of 2016, their role more generally in Raynauds was not clear.
High-altitude pulmonary edema
Sildenafil has been studied for high-altitude pulmonary edema, but its use is currently not recommended for that indication.
Adverse effects
In clinical trials, the most common adverse effects of sildenafil use included headache, flushing, indigestion, nasal congestion, and impaired vision, including photophobia and blurred vision. Some sildenafil users have complained of seeing everything tinted blue (cyanopsia). This cyanopsia can be explained because Sildenafil, while selective for PDE5, does have a minor level of selectivity for PDE6, which is the phosphodiesterase found in the retina. Patients thus taking the drug may experience colorvision abnormalities. Some complained of blurriness and loss of peripheral vision. In July 2005, the U.S. Food and Drug Administration (FDA) found that sildenafil could lead to vision impairment in rare cases, and a number of studies have linked sildenafil use with non-arteritic anterior ischemic optic neuropathy.Rare but serious adverse effects found through postmarketing surveillance include prolonged erections, severe low blood pressure, myocardial infarction (heart attack), ventricular arrhythmias, stroke, increased intraocular pressure, and sudden hearing loss. In October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including sildenafil, required a more prominent warning of the potential risk of sudden hearing loss.
Interactions
Care should be exercised by people who are also taking protease inhibitors for the treatment of HIV infection. Protease inhibitors inhibit the metabolism of sildenafil, effectively multiplying the plasma levels of sildenafil, increasing the incidence and severity of side effects. Those using protease inhibitors are recommended to limit their use of sildenafil to no more than one 25 mg dose every 48 hours. Other drugs that interfere with the metabolism of sildenafil include erythromycin and cimetidine, both of which can also lead to prolonged plasma half-life levels.The use of sildenafil and an α1 blocker (typically prescribed for hypertension or for urologic conditions, such as benign prostatic hypertrophy) at the same time may lead to low blood pressure, but this effect does not occur if they are taken at least 4 hours apart.
Contraindications
Contraindications include:
Concomitant use of nitric oxide donors, organic nitrites and nitrates, such as:
nitroglycerin
isosorbide mononitrate
isosorbide dinitrate
sodium nitroprusside
alkyl nitrites (commonly known as "poppers")
Concomitant use of soluble guanylyl cyclase stimulators, such as riociguat
Known hypersensitivity to sildenafilSildenafil should not be used if sexual activity is inadvisable due to underlying cardiovascular risk factors.
Nonmedical use
Recreational use
Sildenafils popularity with young adults has increased over the years. Sildenafils trade name, Viagra, is widely recognized in popular culture, and the drugs association with treating erectile dysfunction has led to its recreational use. The reasons behind such use include the belief that the drug increases libido, improves sexual performance, or permanently increases penis size. Studies on the effects of sildenafil when used recreationally are limited, but suggest it has little effect when used by those who do not have erectile dysfunction. In one study, a 25 mg dose was shown to cause no significant change in erectile quality, but did reduce the postejaculatory refractory time. This study also noted a significant placebo effect in the control group.Unprescribed recreational use of sildenafil and other PDE5 inhibitors is noted as particularly high among users of illegal drugs. Sildenafil is sometimes used to counteract the effects of other substances, often illicit. Some users mix it with methylenedioxymethamphetamine (MDMA, ecstasy), other stimulants, or opiates in an attempt to compensate for the common side effect of erectile dysfunction, a combination known as "sextasy", "rockin and rollin" or "trail mix". Mixing it with amyl nitrite, another vasodilator, is particularly dangerous and potentially fatal.
Jet lag research
The 2007 Ig Nobel Prize in Aviation went to Patricia V. Agostino, Santiago A. Plano, and Diego A. Golombek of Universidad Nacional de Quilmes, Argentina, for their discovery that sildenafil helps treat jet lag recovery in hamsters.
Sports
Professional athletes have been documented using sildenafil, believing the opening of their blood vessels will enrich their muscles. In turn, they believe it will enhance their performances.
Analogs
Acetildenafil and other synthetic structural analogs of sildenafil which are PDE5 inhibitors have been found as adulterants in a number of "herbal" aphrodisiac products sold over-the-counter. These analogs have not undergone any of the rigorous testing that drugs like sildenafil have passed, and thus have unknown side-effect profiles. Some attempts have been made to ban these drugs, but progress has been slow so far, as, even in those jurisdictions that have laws targeting designer drugs, the laws are drafted to ban analogs of illegal drugs of abuse, rather than analogs of prescription medicines. However, at least one court case has resulted in a product being taken off the market.The U.S. Food and Drug Administration (FDA) has banned numerous products claiming to be Eurycoma longifolia that, in fact, contain only analogs of sildenafil. Sellers of such fake herbals typically respond by just changing the names of their products.
Detection in biological fluids
Sildenafil and/or N-desmethylsildenafil, its major active metabolite, may be quantified in plasma, serum, or whole blood to assess pharmacokinetic status in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdose.
Mechanism of action
Sildenafil protects cyclic guanosine monophosphate (cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum. Nitric oxide (NO) in the corpus cavernosum of the penis binds to guanylate cyclase receptors, which results in increased levels of cGMP, leading to smooth muscle relaxation (vasodilation) of the intimal cushions of the helicine arteries. This smooth muscle relaxation leads to vasodilation and increased inflow of blood into the spongy tissue of the penis, causing an erection. Robert F. Furchgott, Ferid Murad, and Louis Ignarro won the Nobel Prize in Physiology or Medicine in 1998 for their independent study of the metabolic pathway of nitric oxide in smooth muscle vasodilation.
The molecular mechanism of smooth muscle relaxation involves the enzyme CGMP-dependent protein kinase, also known as PKG. This kinase is activated by cGMP and it phosphorylates multiple targets in the smooth muscle cells, namely myosin light chain phosphatase, RhoA, IP3 receptor, phospholipase C, and others. Overall, this results in a decrease in intracellular calcium and desensitizing proteins to the effects of calcium, engendering smooth muscle relaxation.Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. The molecular structure of sildenafil is similar to that of cGMP and acts as a competitive binding agent of PDE5 in the corpus cavernosum, resulting in more cGMP and increased penile response to sexual stimulation. Without sexual stimulation, and therefore lack of activation of the NO/cGMP system, sildenafil should not cause an erection. Other drugs that operate by the same mechanism include tadalafil (Cialis) and vardenafil (Levitra).
Sildenafil is broken down in the liver by hepatic metabolism using cytochrome p450 enzymes, mainly CYP450 3A4 (major route), but also by CYP2C9 (minor route) hepatic isoenzymes. The major product of metabolisation by these enzymes is N-desmethylated sildenafil, which is metabolised further. This metabolite also has an affinity for the PDE receptors, about 40% of that of sildenafil. Thus, the metabolite is responsible for about 20% of sildenafils action. Sildenafil is excreted as metabolites predominantly in the feces (about 80% of administered oral dose) and to a lesser extent in the urine (around 13% of the administered oral dose). If taken with a high-fat meal, absorption is reduced; the time taken to reach the maximum plasma concentration increases by around one hour, and the maximum concentration itself is decreased by nearly one-third.
Route of administration
When taken by mouth sildenafil for erectile dysfunction results in an average time to onset of erections of 27 minutes (ranging from 12 to 70 minutes).
Under the tongue use of sildenafil for erectile dysfunction results in an average onset of action of 15 minutes and lasting for an average of 40 minutes.
There are also mouth spray preparations of sildenafil for faster onset of action.
Chemical synthesis
The preparation steps for synthesis of sildenafil are:
Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate
Hydrolysis with aqueous sodium hydroxide (NaOH) to free acid
Nitration with oleum/fuming nitric acid
Carboxamide formation with refluxing thionyl chloride/NH4OH
Reduction of nitro group to amino group
Acylation with 2-ethoxybenzoyl chloride
Cyclization
Sulfonation to the chlorosulfonyl derivative
Condensation with 1-methylpiperazine.
History
Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizers Sandwich, Kent, research facility in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a symptom of ischaemic heart disease). The first clinical trials were conducted in Morriston Hospital in Swansea. Phase I clinical trials under the direction of Ian Osterloh suggested the drug had little effect on angina, but it could induce marked penile erections. Pfizer therefore decided to market it for erectile dysfunction, rather than for angina; this decision became an often-cited example of drug repositioning. The drug was patented in 1996, approved for use in erectile dysfunction by the FDA on 27 March 1998, becoming the first oral treatment approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year. It soon became a great success: annual sales of Viagra peaked in 2008 at US$1.934 billion.
Society and culture
Marketing and sales
In the US, even though sildenafil is available only by prescription from a doctor, it was advertised directly to consumers on TV (famously being endorsed by former United States Senator Bob Dole and football star Pelé). Numerous sites on the Internet offer Viagra for sale after an "online consultation", often a simple web questionnaire. The Viagra name has become so well known that many fake aphrodisiacs now call themselves "herbal viagra" or are presented as blue tablets imitating the shape and colour of Pfizers product. Viagra is also informally known as "vitamin V", "the blue pill", or "blue diamond", as well as various other nicknames.
In 2000, Viagra sales accounted for 92% of the global market for prescribed erectile dysfunction pills. By 2007, Viagras global share had plunged to about 50% due to several factors, including the entry of Cialis and Levitra, along with several counterfeits and clones, and reports of vision loss in people taking PDE5 inhibitors. In 2008, the FDA forced Pfizer to remove Viva Cruiser, an advergame for Viagra, from appearing on Forbes.com, after the game failed to disclose risk information about the drug.In February 2007, it was announced that Boots, the UK pharmacy chain, would try over-the-counter sales of Viagra in stores in Manchester, England. Men between the ages of 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist. In 2017, the Medicines and Healthcare products Regulatory Agency (MHRA) enacted legislation that expanded this nationwide, allowing a particular branded formulation of Sildenafil, Viagra Connect (50 mg), to be sold over the counter and without a prescription throughout the UK from early 2018. While the sale remains subject to a consultation with a pharmacist, the other restrictions from the trial have been removed, allowing customers over the age of 18 to purchase an unlimited number of pills. The decision was made, in part, to reduce online sales of counterfeit and potentially dangerous erectile dysfunction treatments.
On 6 May 2013, Pfizer, which manufactures Viagra, told the Associated Press they will begin selling the drug directly to people on its website.Pfizers patents on Viagra expired outside the US in 2012; in the US they were set to expire, but Pfizer settled litigation with each of Mylan and Teva which agreed that both companies could introduce generics in the US on 11 December 2017. In December 2017, Pfizer released its own generic version of Viagra.As of 2018, the U.S. Food and Drug Administration has approved fifteen drug manufacturers to market generic sildenafil in the United States. Seven of these companies are based in India. This is likely to lead to dramatic price reductions.
Counterfeits
Counterfeit Viagra, despite generally being cheaper, can contain harmful substances or substances that affect how Viagra works, such as blue printer ink, amphetamines, metronidazole, boric acid, and rat poison.Viagra is one of the worlds most counterfeited medicines. According to a Pfizer study, around 80% of sites claiming to sell Viagra were selling counterfeits.
Regional issues
Brazil
Pfizers patent on sildenafil citrate expired in Brazil in 2010.
Canada
In Canada, Pfizers patent 2,324,324 for Revatio (sildenafil used to treat pulmonary hypertension) was found invalid by the Federal Court in June 2010, on an application by Ratiopharm Inc.On 8 November 2012, the Supreme Court of Canada ruled that Pfizers patent 2,163,446 on Viagra was invalid from the beginning because the company did not provide full disclosure in its application. The decision, Teva Canada Ltd. v. Pfizer Canada Inc., pointed to section 27(3)(b) of The Patent Act which requires that disclosure must include sufficient information "to enable any person skilled in the art or science to which it pertains" to produce it. It added further: "As a matter of policy and sound statutory interpretation, patentees cannot be allowed to game the system in this way. This, in my view, is the key issue in this appeal."Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision. To remain competitive, Pfizer then reduced the price of Viagra in Canada. However, on 9 November 2012, Pfizer filed a motion for a re-hearing of the appeal in the Supreme Court of Canada, on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent. Finally, on 22 April 2013, the Supreme Court of Canada invalidated Pfizers patent altogether.
China
Manufacture and sale of sildenafil citrate drugs is common in China, where Pfizers patent claim is not widely enforced.
Egypt
Egypt approved Viagra for sale in 2002, but soon afterwards allowed local companies to produce generic versions of the drug, citing the interests of poor people who would not be able to afford Pfizers price.
European Union
Pfizers patent on sildenafil citrate expired in some member countries of the EU, Austria, Denmark, France, Germany, Ireland, Italy, The Netherlands, Spain, Sweden, the United Kingdom and Switzerland on 21 June 2013. A UK patent held by Pfizer on the use of PDE5 inhibitors (see below) as treatment of impotence was invalidated in 2000 because of obviousness; this decision was upheld on appeal in 2002.
India
Manufacture and sale of sildenafil citrate drugs known as "generic Viagra" is common in India, where Pfizers patent claim does not apply. Trade names include Kamagra (Ajanta Pharma), Silagra (Cipla), Edegra (Sun Pharmaceutical), Penegra (Zydus Cadila), Manly (Cooper Pharma) and Zenegra (Alkem Laboratories).
New Zealand
Sildenafil was reclassified in New Zealand in 2014 so it could be bought over the counter from a pharmacist. It is thought that this reduced sales over the Internet and was safer as men could be referred for medical advice if appropriate.
South Korea
In 1999 South Korea granted two patents to Pfizer related to sildenafil. The first document guaranteed sole production and sale of the substance until 2012, while the second gave Pfizer the exclusive use to treating erectile dysfunction with sildenafil until 2014. In 2011 Hanmi Pharmaceutical and CJ CheilJedang launched a suit against the exclusive use patent. The Korean Court system made a ruling against Pfizer in June 2012, allowing for the unhindered domestic production of generic prescription sildenafil.During 2012 Viagra lost its position as the top selling erectile dysfunction treatment in South Korea. This development was credited largely "due to the introduction of generic products." Generic sildenafil became publicly available in May. Sales of PalPal by Hanmi Pharmaceuticals totalled ₩22 billion or about 86% the market share of Viagra that year. By 2017 there were over 50 generic sildenafil pills available. During that year Viagra sales slumped to 38% that of Palpal.
United Kingdom
There were 2,958,199 prescriptions for Sildenafil in 2016 in England, compared with 1,042,431 in 2006.In 2018, Viagra Connect, a particular formulation of Sildenafil marketed by Pfizer, became available for sale without a prescription in the UK, in an attempt to widen availability and reduce demand for counterfeit products.
United States
Sildenafil is available as a generic drug in the United States, labeled for pulmonary arterial hypertension. As of 2016 branded pills cost about 50 times more than generic ones. In the United States as of 2015 the branded 50 mg pill cost is between 25.17 and US$37.88.In the United States, Pfizer received two patents for sildenafil: one for its indication to treat cardiovascular disease (marketed as Revatio) and another for its indication to treat erectile dysfunction (marketed as Viagra). The substance is the same under both trade names.In 1992, Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases. This would be marketed as Revatio. The patent was published in 1993 and expired in 2012. The patent on Revatio (indicated for pulmonary arterial hypertension rather than erectile dysfunction) expired in late 2012. Generic versions of this low-dose form of sildenafil have been available in the U.S. from a number of manufacturers, including Greenstone, Mylan, and Watson, since early 2013. Health care providers may prescribe generic sildenafil for erectile dysfunction. However, the generic is not available in the same dosages as branded Viagra, so using dosages typically required for treating ED requires patients to take multiple pills.In 1994, Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction. This would be marketed as Viagra. This patent was published in 2002 and will expire in 2019. Teva sued to have the latter patent invalidated, but Pfizer prevailed in an August 2011 federal district court case. An agreement with Pfizer allowed Teva to begin to provide the generic drug in December 2017.
References
External links
"Sildenafil". Drug Information Portal. U.S. National Library of Medicine.
"Sildenafil citrate". Drug Information Portal. U.S. National Library of Medicine.
Viagra at The Periodic Table of Videos (University of Nottingham) |
Clocortolone | Clocortolone (Cloderm) is a topical steroid. It is used in the form of an ester, clocortolone pivalate, and applied as a cream. It is used for the treatment of dermatitis and is considered a medium-strength corticosteroid. It is unusual among steroids in that it contains a chlorine atom and a fluorine atom.
Pharmacology
Clocortolone is an upper-mid potency topical corticosteroid formulation. It is rated at a class 4 potency on a scale of 1 (highest potency) to 7 (lowest potency). Most patients are treated with mid-potency topical corticosteroids, for they are an effective medium between safety and efficacy for short and long-term conditions.
Vital to the pharmacological action of clocortolone is the presence and location of its functional groups. There were several molecular modifications done to create clocortolone pivalate, including beta-hydroxylation at C-11, methylation at C-16, double bonds at C-12, esterification at C-21, and halogenation at C-6 and C-9. It is common in the medical community to associate halogenation of topical corticosteroids with adverse effects. This notion is, in fact, incorrect—it is both the presence and location of halogenation in steroids that matter. In comparison to all other topical corticosteroids, the combination of the chlorine at C-9 and the fluorine at C-6 is unique to clocortolone. Clocortolone pivalate, due to its unique nature, has both upper-mid potency and the safety profile associated with a lower potency topical corticosteroid. This versatility allows for Cloderm cream to be a treatment option for a variety of patients.
Cream vehicle
Clocortolone pivalate 0.1% is formulated in a cream that contains three ingredients which assist in stratum corneum permeability barrier integrity: white petrolatum (occlusive), mineral oil (humectant), and stearyl alcohol (long-chain fatty alcohol emollient). This cream does not contain lanolin, fragrance, nor propylene glycol, all of which have been known to be problematic for some patients.
Clinical studies
In Phase III trials, Cloderm was found to be especially useful in treating eczema, atopic dermatitis, and psoriasis. Phase III trials also showed rapid action and relief for the majority of the patients involved. There is no age restriction on the use of clocortolone pivalate 0.1% cream. Clinical trials comparing clocortolone pivalate 0.1% topical cream with vehicle in atopic dermatitis/eczematous dermatitis, psoriasis, and contact dermatitis included pediatric patients (N=44). The mean age of pediatric subjects was 10 years (range 3–14 years). Clocortolone pivalate 0.1% cream was efficacious for the majority (75%) of the pediatric patients in these trials, with no serious adverse effects occurring in either group.In six parallel, double-blind, placebo-controlled trials, patients with atopic dermatitis/eczematous dermatitis were randomized to treatment with clocortolone pivalate 0.1% topical cream (total n=109) or vehicle (total n=100), applied three times daily over a duration of 14 days. According to evaluations completed by the physician investigators, a significantly higher proportion of patients in the clocortolone pivalate group than patients in the vehicle group demonstrated a good or excellent response at Days 4, 7, and 14.Due to the chronic and lengthy nature of some steroid responsive dermatoses such as atopic dermatitis and psoriasis, a study of 27 patients was conducted, wherein these patients were treated with Cloderm from 30 days up to 7 months. The results of these treatments showed a low rate of adverse reactions and no signs of striae, atrophy, or hypopigmentation. Adverse reactions that were experienced included burning, itching, irritation, dryness, and/or folliculitis.Additionally, a clinical study investigated the potential of hypothalamic–pituitary–adrenal (HPA) axis suppression. Ten men with no major health issues applied 30g of clocortolone pivalate 0.1% cream twice a day for 21 days while wearing a plastic sweat suit for twelve hours per day. Through the measurements of plasma cortisol and urinary 17-ketosteroid levels, the investigators monitored effects on the HPA axis, and no signs of adrenal suppression were evident.In total to date, 559 patients have participated in clinical trials involving Cloderm, and there was little evidence of local and/or systemic adverse effects. Specifically, only 4.4 percent experienced adverse events, most of which were local application-site reactions, such as dryness, stinging, burning, or itching.
Regulation history
Cloderm, the brand formulation of clocortolone pivalate 0.1% cream, was approved by the
Food and Drug Administration in 1977 for the treatment of corticoid responsive dermatoses.
Commercialization
Manufacturing process
Clocortolone is synthesized by the reaction of 6α-fluoro-16α-methyl-21-hydroxy-1,4,9(11)-pregnatriene-3,20-dione with tert-butyl hypochlorite.
Commercialization history
The synthesis of clocortolone was invented and patented by Emanuel Kaspar and Rainer Philippson in 1973 with United States Patent 3,729,495. The original assignee of the patent was Schering AG, a research-centered German pharmaceutical company. The rights to Clocortolone were then sold to Germapharm, and then to Coria Laboratories, Ltd. of DFB Pharmaceuticals, Inc., a Fort Worth-based pharmaceutical company. Coria Laboratories, Ltd., the dermatology division of DFB Pharmaceuticals, Inc., was then sold to Valeant Pharmaceuticals in 2008. In 2011, Promius Pharma, LLC, an affiliate of Dr. Reddys Laboratories, and Valeant Pharmaceuticals International, Inc. announced that they had signed a joint agreement for Cloderm. Per this collaborative agreement, Promius Pharma made an upfront payment will continue to pay royalties as the consideration for the right to manufacture, distribute and market Cloderm in the United States.
Price listing
In August 2016 Cloderm Cream 0.1% clocortolone pivalate was priced at $3.64 per gram and $140.98 per 45 gm tube.
See also
Budesonide
== References == |
Fostemsavir | Fostemsavir, sold under the brand name Rukobia, is an antiretroviral medication for adults living with HIV/AIDS who have tried multiple HIV medications and whose HIV infection cannot be successfully treated with other therapies because of resistance, intolerance or safety considerations.The most common adverse reaction is nausea. Severe adverse reactions included elevations in liver enzymes among participants also infected with hepatitis B or C virus, and changes in the immune system (immune reconstitution syndrome).Fostemsavir is an HIV entry inhibitor and a prodrug of temsavir (BMS-626529). Fostemsavir is a human immunodeficiency virus type 1 (HIV-1) gp120-directed attachment inhibitor.It was approved for medical use in the United States in July 2020, and in the European Union in February 2021. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
Medical uses
Fostemsavir in combination with other antiretroviral(s), is indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations.
Adverse effects
Fostemsavir may cause a serious condition called immune reconstitution syndrome, similar to other approved drugs for treatment of HIV-1 infection. This condition can happen at the beginning of HIV-1 treatment when the immune system may get stronger and begin to fight infections that have been hidden in the body for a long time. Other serious side effects include heart rhythm problems due to prolongation of heart electrical activity (QT prolongation) and an increase of liver enzymes in patients with hepatitis B or C virus co-infection.
History
It was under development by ViiV Healthcare / GlaxoSmithKline for use in the treatment of HIV infection. When the active form of fostemsavir binds to the gp120 protein of the virus, it prevents initial viral attachment to the host CD4+ T cell and entry into the host immune cell; its method of action is a first for HIV drugs. Because it targets a different step of the viral lifecycle, it offers promise for individuals with virus that has become highly resistant to other HIV drugs. Since the function of gp120 that this drug inhibits is highly conserved, the drug is unlikely to promote resistance to itself. Investigators found that enfuvirtide-resistant and ibalizumab-resistant HIV envelopes remained susceptible to fostemsavir. Conversely, fostemsavir-resistant HIV remained susceptible to all the entry inhibitors. Furthermore, HIV isolates that do not require the CD4 receptor for cell entry were also susceptible to fostemsavir, and the virus did not escape the attachment inhibitor by becoming CD4-independent. Prior in vitro studies showed that fostemsavir inhibits both CCR5-tropic and CXCR4-tropic HIV.
Fostemsavir was approved for medical use in the United States in July 2020.The safety and efficacy of fostemsavir, taken twice daily by mouth, were evaluated in a clinical trial of 371 heavily treatment-experienced adult participants who continued to have high levels of virus (HIV-RNA) in their blood despite being on antiretroviral drugs. Two hundred seventy-two participants were treated in the main trial arm, and an additional 99 participants received fostemsavir in a different arm of the trial. Most participants had been treated for HIV for more than 15 years (71 percent), had been exposed to five or more different HIV treatment regimens before entering the trial (85 percent) and/or had a history of AIDS (86 percent). Participants in the main cohort of the trial received either fostemsavir or a placebo twice daily for eight days, in addition to their failing antiretroviral regimen. On the eighth day, participants treated with fostemsavir had a significantly greater decrease in levels of HIV-RNA in their blood compared to those taking the placebo. After the eighth day, all participants received fostemsavir with other antiretroviral drugs. After 24 weeks of fostemsavir plus other antiretroviral drugs, 53 percent of participants achieved HIV RNA suppression, where levels of HIV were low enough to be considered undetectable. After 96 weeks, 60 percent of participants continued to have HIV RNA suppression.The clinical trial (NCT02362503) was conducted at 108 sites in 23 countries in North America, South America, Europe, Australia, Taiwan and South Africa.The U.S. Food and Drug Administration (FDA) granted the application for fostemsavir fast track, priority review, and breakthrough therapy designations. The FDA granted the approval of Rukobia to ViiV Healthcare.On 10 December 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 Rukobia, intended for the treatment of multi-drug resistant HIV-1 infection. The applicant for this medicinal product is ViiV Healthcare B.V. Fostemsavir was approved for medical use in the European Union in February 2021.
References
Further reading
Kozal M, Aberg J, Pialoux G, Cahn P, Thompson M, Molina JM, et al. (March 2020). "Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection". N. Engl. J. Med. 382 (13): 1232–1243. doi:10.1056/NEJMoa1902493. PMID 32212519.
External links
"Fostemsavir". Drug Information Portal. U.S. National Library of Medicine.
"Fostemsavir tromethamine". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02362503 for "Attachment Inhibitor Comparison in Heavily Treatment Experienced Patients" at ClinicalTrials.gov |
Stiripentol | Stiripentol, sold under the brand name Diacomit, is an anticonvulsant medication used for the treatment of Dravet syndrome - a serious genetic brain disorder.The most common side effects include loss of appetite, weight loss, insomnia (difficulty sleeping), drowsiness, ataxia (inability to co‑ordinate muscle movements), hypotonia (low muscle strength) and dystonia (muscle disorders).
Medical uses
In the European Union, stiripentol is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in people with severe myoclonic epilepsy in infancy (SMEI, Dravets syndrome) whose seizures are not adequately controlled with clobazam and valproate.In the United States, stiripentol is indicated for the treatment of seizures associated with Dravet syndrome in people two years of age and older taking clobazam. There are no clinical data to support the use of stiripentol as monotherapy in Dravet syndrome.It is used in some countries as an add-on therapy with sodium valproate and clobazam for treating children with Dravet syndrome whose seizures are not adequately controlled. As of 2017, it was not known whether stiripentol remains useful as children become adolescents or adults.
Contraindications
Stiripentol must not be used in people who have had psychoses (a serious mental state with a distorted sense of reality) with attacks of delirium (a mental state with confusion, excitement, restlessness and hallucinations).
Adverse effects
Very common (more than 10% of people) adverse effects include loss of appetite, weight loss, insomnia, drowsiness, ataxia, hypotonia, and dystonia.Common (between 1% and 10% of people) adverse effects include neutropenia (sometimes severe), aggressiveness, irritability, behavior disorders, opposing behavior, hyperexcitability, sleep disorders, hyperkinesias, nausea, vomiting, and elevated gamma-glutamyltransferase.
Interactions
Stiripentol inhibits several cytochrome P450 isoenzymes and so interacts with many anticonvulsants and other medicines.
Pharmacology
As with most anticonvulsants, the precise mechanism of action is unknown. Regardless, stiripentol has been shown to have anticonvulsant effects of its own.
Stiripentol increases GABAergic activity. At clinically relevant concentrations, it enhances central GABA neurotransmission through a barbiturate-like effect, since it increases the duration of opening of GABA-A receptor channels in hippocampal slices. It has also been shown to increase GABA levels in brain tissues by interfering with its reuptake and metabolism. Specifically, it has been shown to inhibit lactate dehydrogenase, which is an important enzyme involved in the energy metabolism of neurons. Inhibition of this enzyme can make neurons less prone to fire action potentials, likely through activation of ATP-sensitive potassium channels.Stiripentol also improves the effectiveness of many other anticonvulsants, possibly due to its inhibition of certain enzymes, slowing the drugs metabolism and increasing blood plasma levels.
Chemistry
Stiripentol is an α-ethylene alcohol; its chemical formula is 4,4-dimethyl-1-[3,4-(methylendioxy)-phenyl]-1penten-3-ol. It is chiral and used medically as the racemate. The R enantiomer appears to be around 2.5 times more active than the S enantiomer.
History
Stiripentol was discovered in 1978 by scientists at Biocodex and clinical trials started over the next few years. It was originally developed for adults with focal seizures, but failed a Phase III trial.In December 2001, the European Medicines Agency (EMA) granted stiripentol orphan drug status (designation number EU/3/01/071) for the treatment of severe myoclonic epilepsy of infancy (SMEI, also known as Dravets syndrome) in children and in January 2007, the EMA granted the drug a marketing authorisation for use of the drug as an add-on to other anti-seizure drugs. It was approved in Canada for this use in May 2013. As of 2017, it was also approved for this use in Japan.In August 2018, stiripentol was approved by the US Food and Drug Administration (FDA) as an adjunctive therapy for Dravet Syndrome.
Society and culture
Economics
Prior to approval in the US, parents of children with Dravet Syndrome were paying around $1,000 for a month supply to obtain it from Europe.
References
External links
"Stiripentol". Drug Information Portal. U.S. National Library of Medicine. |
Emapalumab | Emapalumab, sold under the brand name Gamifant, is an anti-interferon-gamma (IFNγ) antibody medication used for the treatment of hemophagocytic lymphohistiocytosis (HLH), which has no cure.The most common side effects include infections, hypertension, infusion-related reactions, and pyrexia.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
Medical uses
Emapalumab is used to treat primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy.
Adverse effects
In the clinical trials that lead to emapalumabs FDA approval, the most commonly reported adverse effects were infections (56%), high blood pressure (41%), infusion reactions (27%), and fever (24%). Serious adverse effects occurred in about half of the subjects studied in the clinical trial that led to its FDA approval.
Pharmacology
Mechanism of action
In the setting of HLH, over-secretion of IFN-γ is thought to contribute to the pathogenesis of the disease. Emapalumab binds and neutralizes IFN-γ, preventing it from inducing pathological effects.
Pharmacokinetics
Like other antibody-based medications, which are made of amino acid chains called polypeptides, emapalumab is broken down into smaller peptides via the bodys normal catabolism.
Society and culture
Legal status
The U.S. Food and Drug Administration (FDA) granted orphan drug designations in 2010 and 2020, and breakthrough therapy designation in 2016, on the basis of preliminary data from the phase II trial.In July 2020, and again in November 2020, the European Medicines Agency (EMA) recommended the refusal of the marketing authorization for emapalumab.
Research
The research name of emapalumab was NI-0501. A phase II/III trial began in 2013 and is ongoing as of August 2018. The trial targets patients under the age of 18 who have failed to improve on conventional treatments. This study was realised in the context of an EU-funded FP7 project, named FIGHT-HLH (306124).
References
External links
"Emapalumab". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT01818492 for "A Study to Investigate the Safety and Efficacy of an Anti-IFNγ mAb in Children Affected by Primary Haemophagocytic Lymphohistiocytosis" at ClinicalTrials.gov |
Mebendazole | Mebendazole (MBZ), sold under the brand name Vermox among others, is a medication used to treat a number of parasitic worm infestations. This includes ascariasis, pinworm infection, hookworm infections, guinea worm infections, hydatid disease, and giardia, among others. It is taken by mouth.Mebendazole is usually well tolerated. Common side effects include headache, vomiting, and ringing in the ears. If used at large doses it may cause bone marrow suppression. It is unclear if it is safe in pregnancy. Mebendazole is a broad-spectrum antihelminthic agent of the benzimidazole type.Mebendazole came into use in 1971, after it was developed by Janssen Pharmaceutica in Belgium. It is on the World Health Organizations List of Essential Medicines. Mebendazole is available as a generic medication.
Medical use
Mebendazole is a highly effective, broad-spectrum antihelmintic indicated for the treatment of nematode infestations, including roundworm, hookworm, whipworm, threadworm (pinworm), and the intestinal form of trichinosis prior to its spread into the tissues beyond the digestive tract. Other drugs are used to treat worm infections outside the digestive tract, as mebendazole is poorly absorbed into the bloodstream. Mebendazole is used alone in those with mild to moderate infestations. It kills parasites relatively slowly, and in those with very heavy infestations, it can cause some parasites to migrate out of the digestive system, leading to appendicitis, bile duct problems, or intestinal perforation. To avoid this, heavily infested patients may be treated with piperazine, either before or instead of mebendazole. Piperazine paralyses the parasites, causing them to pass in the feces. It is also used rarely in the treatment of cystic echinococcosis, also known as hydatid disease. Evidence for effectiveness for this disease, however, is poor.Mebendazole and other benzimidazole antithelmetics are active against both larval and adult stages of nematodes, and in the cases of roundworm and whipworm, kill the eggs, as well. Paralysis and death of the parasites occurs slowly, and elimination in the feces may require several days.
Special populations
Mebendazole has been shown to cause ill effects in pregnancy in animal models, and no adequate studies of its effects in human pregnancy have been conducted. Whether it can be passed by breastfeeding is unknown.
Adverse effects
Mebendazole sometimes causes diarrhea, abdominal pain, and elevated liver enzymes. In rare cases, it has been associated with a dangerously low white blood cell count, low platelet count, and hair loss, with a risk of agranulocytosis in rare cases.
Drug interactions
Carbamazepine and phenytoin lower serum levels of mebendazole. Cimetidine does not appreciably raise serum mebendazole (in contrast to the similar drug albendazole), consistent with its poor systemic absorption.Stevens–Johnson syndrome and the more severe toxic epidermal necrolysis can occur when mebendazole is combined with high doses of metronidazole.
Mechanism
Mebendazole works by selectively inhibiting the synthesis of microtubules via binding to the colchicine binding site of β-tubulin, thereby blocking polymerisation of tubulin dimers in intestinal cells of parasites. Disruption of cytoplasmic microtubules leads to blocking the uptake of glucose and other nutrients, resulting in the gradual immobilization and eventual death of the helminths.Poor absorption in the digestive tract makes mebendazole an efficient drug for treating intestinal parasitic infections with limited adverse effects. However mebendazole has an impact on mammalian cells, mostly by inhibiting polymeration of tubulin dimers, thereby disrupting essential microtubule structures such as mitotic spindle. Disassembly of the mitotic spindle then leads to apoptosis mediated via dephosphorylation of Bcl-2 which allows pro-apoptotic protein Bax to dimerize and initiate programmed cell death.
Society and culture
Availability
Mebendazole is available as a generic medication. Mebendazole is distributed in international markets by Johnson and Johnson and a number of generic manufacturers.
Research
Several studies show mebendazole exhibits potent antitumor properties. mebendazole significantly inhibited cancer cell growth, migration, and metastatic formation of adrenocortical carcinoma, both in vitro and in vivo. Treatment of lung cancer cell lines with mebendazole caused mitotic arrest, followed by apoptotic cell death with the feature of caspase activation and cytochrome c release. Mebendazole induced a dose- and time-dependent apoptotic response in human lung cancer cell lines, and apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells.
The anti-cancer effect of mebendazole comes from preclinical studies and case reports.
References
External links
"Mebendazole". Drug Information Portal. U.S. National Library of Medicine. |
Rifampicin/isoniazid/pyrazinamide | Rifampicin/isoniazid/pyrazinamide, also known as rifampin/isoniazid/pyrazinamide, and sold under the trade name Rifater, is a medication used to treat tuberculosis. It is a fixed dose combination of rifampicin, isoniazid, and pyrazinamide. It is used either by itself or along with other antituberculosis medication. It is taken by mouth.Side effects are those of the underlying medications. These may include poor coordination, loss of appetite, nausea, joint pain, feeling tired, and numbness. Severe side effects include liver problems. Use in those under the age of 15 may not be appropriate. It is unclear if use in pregnancy is safe for the baby.Rifampicin/isoniazid/pyrazinamide was approved for medical use in the United States in 1994. It is on the World Health Organizations List of Essential Medicines.
Medical uses
The hope of a fixed-dose combination pill is to increase the likelihood that people will take all of three medications. Also, if people forget to take one or two of their drugs, they might not then develop resistance to the remaining drugs.
Society and culture
It is manufactured by Aventis.
See also
Tuberculosis treatment
Rifampicin + isoniazid + ethambutol
== References == |
Quinine | Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to Plasmodium falciparum that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg cramps, quinine is not recommended for this purpose due to the risk of serious side effects. It can be taken by mouth or intravenously. Malaria resistance to quinine occurs in certain areas of the world. Quinine is also used as an ingredient in tonic water to impart a bitter taste.Common side effects include headache, ringing in the ears, vision issues, and sweating. More severe side effects include deafness, low blood platelets, and an irregular heartbeat. Use can make one more prone to sunburn. While it is unclear if use during pregnancy causes harm to the baby, treating malaria during pregnancy with quinine when appropriate is still recommended. Quinine is an alkaloid, a naturally occurring chemical compound. How it works as a medicine is not entirely clear.Quinine was first isolated in 1820 from the bark of a cinchona tree, which is native to Peru, and its molecular formula was determined by Strecker in 1854. The class of chemical compounds to which it belongs is thus called the cinchona alkaloids. Bark extracts had been used to treat malaria since at least 1632 and it was introduced to Spain as early as 1636 by Jesuit missionaries returning from the New World. It is on the World Health Organizations List of Essential Medicines. Treatment of malaria with quinine marks the first known use of a chemical compound to treat an infectious disease.
Uses
Medical
As of 2006, quinine is no longer recommended by the World Health Organization (WHO) as a first-line treatment for malaria, because there are other substances that are equally effective with fewer side effects. They recommend that it be used only when artemisinins are not available. Quinine is also used to treat lupus and arthritis.
Quinine was frequently prescribed as an off-label treatment for leg cramps at night, but this has become less common due to a warning from the US Food and Drug Administration (FDA) that such practice is associated with life-threatening side effects. Quinine can also act as a competitive inhibitor of monoamine oxidase (MAO), an enzyme that removes neurotransmitters from the brain. As an MAO inhibitor, it has potential to serve as a treatment for individuals with psychological disorders similar to antidepressants that inhibit MAO.
Available forms
Quinine is a basic amine and is usually provided as a salt. Various existing preparations include the hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate. In the United States, quinine sulfate is commercially available in 324-mg tablets under the brand name Qualaquin.
All quinine salts may be given orally or intravenously (IV); quinine gluconate may also be given intramuscularly (IM) or rectally (PR). The main problem with the rectal route is that the dose can be expelled before it is completely absorbed; in practice, this is corrected by giving a further half dose. No injectable preparation of quinine is licensed in the US; quinidine is used instead.
Beverages
Quinine is a flavor component of tonic water and bitter lemon drink mixers. On the soda gun behind many bars, tonic water is designated by the letter "Q" representing quinine.Tonic water was initially marketed as a means of delivering quinine to consumers in order to offer anti-malarial protection. According to tradition, because of the bitter taste of anti-malarial quinine tonic, British colonials in India mixed it with gin to make it more palatable, thus creating the gin and tonic cocktail, which is still popular today. While it is possible to drink enough tonic water to temporarily achieve quinine levels that offer anti-malarial protection, this is not a sustainable long-term means of protection.In France, quinine is an ingredient of an apéritif known as quinquina, or "Cap Corse," and the wine-based apéritif Dubonnet. In Spain, quinine (also known as "Peruvian bark" for its origin from the native cinchona tree) is sometimes blended into sweet Malaga wine, which is then called "Malaga Quina". In Italy, the traditional flavoured wine Barolo Chinato is infused with quinine and local herbs, and is served as a digestif. In Scotland, the company A.G. Barr uses quinine as an ingredient in the carbonated and caffeinated beverage Irn-Bru. In Uruguay and Argentina, quinine is an ingredient of a PepsiCo tonic water named Paso de los Toros. In Denmark, it is used as an ingredient in the carbonated sports drink Faxe Kondi made by Royal Unibrew.
As a flavouring agent in drinks, quinine is limited to less than 83 parts per million in the United States, and 100 mg⁄l in the European Union.
Scientific
Quinine (and quinidine) are used as the chiral moiety for the ligands used in Sharpless asymmetric dihydroxylation as well as for numerous other chiral catalyst backbones. Because of its relatively constant and well-known fluorescence quantum yield, quinine is used in photochemistry as a common fluorescence standard.
Contraindications
Because of the narrow difference between its therapeutic and toxic effects, quinine is a common cause of drug-induced disorders, including thrombocytopenia and thrombotic microangiopathy. Even from minor levels occurring in common beverages, quinine can have severe adverse effects involving multiple organ systems, among which are immune system effects and fever, hypotension, hemolytic anemia, acute kidney injury, liver toxicity, and blindness. In people with atrial fibrillation, conduction defects, or heart block, quinine can cause heart arrhythmias, and should be avoided.Quinine can cause hemolysis in G6PD deficiency (an inherited deficiency), but this risk is small and the physician should not hesitate to use quinine in people with G6PD deficiency when there is no alternative.
Adverse effects
Quinine can cause unpredictable serious and life-threatening blood and cardiovascular reactions including low platelet count and hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), long QT syndrome and other serious cardiac arrhythmias including torsades de pointes, blackwater fever, disseminated intravascular coagulation, leukopenia, and neutropenia. Some people who have developed TTP due to quinine have gone on to develop kidney failure. It can also cause serious hypersensitivity reactions including anaphylactic shock, urticaria, serious skin rashes, including Stevens–Johnson syndrome and toxic epidermal necrolysis, angioedema, facial edema, bronchospasm, granulomatous hepatitis, and itchiness.The most common adverse effects involve a group of symptoms called cinchonism, which can include headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, and disturbance in color perception. More severe cinchonism includes vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in heart rhythms. Cinchonism is much less common when quinine is given by mouth, but oral quinine is not well tolerated (quinine is exceedingly bitter and many people will vomit after ingesting quinine tablets). Other drugs, such as Fansidar (sulfadoxine with pyrimethamine) or Malarone (proguanil with atovaquone), are often used when oral therapy is required. Quinine ethyl carbonate is tasteless and odourless, but is available commercially only in Japan. Blood glucose, electrolyte and cardiac monitoring are not necessary when quinine is given by mouth.
Quinine has diverse unwanted interactions with numerous prescription drugs, such as potentiating the anticoagulant effects of warfarin.
Mechanism of action
Quinine is used for its toxicity to the malarial pathogen, Plasmodium falciparum, by interfering with its ability to dissolve and metabolize hemoglobin. As with other quinoline antimalarial drugs, the precise mechanism of action of quinine has not been fully resolved, although in vitro studies indicate it inhibits nucleic acid and protein synthesis, and inhibits glycolysis in P. falciparum. The most widely accepted hypothesis of its action is based on the well-studied and closely related quinoline drug, chloroquine. This model involves the inhibition of hemozoin biocrystallization in the heme detoxification pathway, which facilitates the aggregation of cytotoxic heme. Free cytotoxic heme accumulates in the parasites, causing their deaths. Quinine may target the malaria purine nucleoside phosphorylase enzyme.
Chemistry
The UV absorption of quinine peaks around 350 nm (in UVA). Fluorescent emission peaks at around 460 nm (bright blue/cyan hue). Quinine is highly fluorescent (quantum yield ~0.58) in 0.1 M sulfuric acid solution.
Synthesis
Cinchona trees remain the only economically practical source of quinine. However, under wartime pressure during World War II, research towards its synthetic production was undertaken. A formal chemical synthesis was accomplished in 1944 by American chemists R.B. Woodward and W.E. Doering. Since then, several more efficient quinine total syntheses have been achieved, but none of them can compete in economic terms with isolation of the alkaloid from natural sources. The first synthetic organic dye, mauveine, was discovered by William Henry Perkin in 1856 while he was attempting to synthesize quinine.
Biosynthesis
In the first step of quinine biosynthesis, the enzyme strictosidine synthase catalyzes a stereoselective Pictet–Spengler reaction between tryptamine and secologanin to yield strictosidine. Suitable modification of strictosidine leads to an aldehyde. Hydrolysis and decarboxylation would initially remove one carbon from the iridoid portion and produce corynantheal. Then the tryptamine side-chain were cleaved adjacent to the nitrogen, and this nitrogen was then bonded to the acetaldehyde function to yield cinchonaminal. Ring opening in the indole heterocyclic ring could generate new amine and keto functions. The new quinoline heterocycle would then be formed by combining this amine with the aldehyde produced in the tryptamine side-chain cleavage, giving cinchonidinone. For the last step, hydroxylation and methylation gives quinine.
Catalysis
Quinine and other Cinchona alkaloids can be used as catalysts for stereoselective reactions in organic synthesis.: Table 3B Plate 560 For example, the quinine-catalyzed Michael addition of a malononitrile to α,β-enones gives a high degree of sterechemical control.
History
Quinine was used as a muscle relaxant by the Quechua people, who are indigenous to Peru, Bolivia and Ecuador, to halt shivering. The Quechua would mix the ground bark of cinchona trees with sweetened water to offset the barks bitter taste, thus producing something similar to tonic water.Spanish Jesuit missionaries were the first to bring cinchona to Europe. The Spanish had observed the Quechuas use of cinchona and were aware of the medicinal properties of cinchona bark by the 1570s or earlier: Nicolás Monardes (1571) and Juan Fragoso (1572) both described a tree, which was subsequently identified as the cinchona tree, whose bark was used to produce a drink to treat diarrhea. Quinine has been used in unextracted form by Europeans since at least the early 17th century.A popular story of how it was brought to Europe by the Countess of Chinchon was debunked by medical historian Alec Haggis around 1941. During the 17th century, malaria was endemic to the swamps and marshes surrounding the city of Rome. It had caused the deaths of several popes, many cardinals and countless common Roman citizens. Most of the Catholic priests trained in Rome had seen malaria patients and were familiar with the shivering brought on by the febrile phase of the disease.
The Jesuit Agostino Salumbrino (1564–1642), an apothecary by training who lived in Lima (now in present-day Peru), observed the Quechua using the bark of the cinchona tree to treat such shivering. While its effect in treating malaria (and malaria-induced shivering) was unrelated to its effect in controlling shivering from rigors, it was a successful medicine against malaria. At the first opportunity, Salumbrino sent a small quantity to Rome for testing as a malaria treatment. In the years that followed, cinchona bark, known as Jesuits bark or Peruvian bark, became one of the most valuable commodities shipped from Peru to Europe. When King Charles II was cured of malaria at the end of the 17th Century with quinine, it became popular in London. It remained the antimalarial drug of choice until the 1940s, when other drugs took over.The form of quinine most effective in treating malaria was found by Charles Marie de La Condamine in 1737. In 1820, French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou first isolated quinine from the bark of a tree in the genus Cinchona – probably Cinchona pubescens – and subsequently named the substance. The name was derived from the original Quechua (Inca) word for the cinchona tree bark, quina or quina-quina, which means "bark of bark" or "holy bark". Prior to 1820, the bark was dried, ground to a fine powder, and mixed into a liquid (commonly wine) in order to be drunk. Large-scale use of quinine as a malaria prophylaxis started around 1850. In 1853 Paul Briquet published a brief history and discussion of the literature on "quinquina".Quinine played a significant role in the colonization of Africa by Europeans. The availability of quinine for treatment had been said to be the prime reason Africa ceased to be known as the "white mans grave". A historian said, "it was quinines efficacy that gave colonists fresh opportunities to swarm into the Gold Coast, Nigeria and other parts of west Africa".To maintain their monopoly on cinchona bark, Peru and surrounding countries began outlawing the export of cinchona seeds and saplings in the early 19th century. In 1865, Manuel Incra Mamani collected seeds from a plant particularly high in quinine and provided them to Charles Ledger. Ledger sent them to his brother, who sold them to the Dutch government. Mamani was arrested on a seed collecting trip in 1871, and beaten so severely, likely because of providing the seeds to foreigners, that he died soon afterwards.By the late 19th century the Dutch grew the plants in Indonesian plantations. Soon they became the main suppliers of the tree. In 1913 they set up the Kina Bureau, a cartel of cinchona producers charged with controlling price and production. By the 1930s Dutch plantations in Java were producing 22 million pounds of cinchona bark, or 97% of the worlds quinine production. U.S. attempts to prosecute the Kina Bureau proved unsuccessful.During World War II, Allied powers were cut off from their supply of quinine when Germany conquered the Netherlands, and Japan controlled the Philippines and Indonesia. The US had obtained four million cinchona seeds from the Philippines and began operating cinchona plantations in Costa Rica. Additionally, they began harvesting wild cinchona bark during the Cinchona Missions. Such supplies came too late. Tens of thousands of US troops in Africa and the South Pacific died of malaria due to the lack of quinine. Despite controlling the supply, the Japanese did not make effective use of quinine, and thousands of Japanese troops in the southwest Pacific died as a result.Quinine remained the antimalarial drug of choice until after World War II. Since then, other drugs that have fewer side effects, such as chloroquine, have largely replaced it.Bromo Quinine were brand name cold tablets containing quinine, manufactured by Grove Laboratories. They were first marketed in 1889 and available until at least the 1960s.Conducting research in central Missouri, Dr. John S. Sappington independently developed an anti-malaria pill from quinine. Sappington began importing cinchona bark from Peru in 1820. In 1832, using quinine derived from the cinchona bark, Sappington developed a pill to treat a variety of fevers, such as scarlet fever, yellow fever, and influenza in addition to malaria. These illnesses were widespread in the Missouri and Mississippi valleys. He manufactured and sold "Dr. Sappingtons Anti-Fever Pills" across Missouri. Demand became so great that within three years, Dr. Sappington founded a company known as Sappington and Sons to sell his pills nationwide.
Society and culture
Natural occurrence
The bark of Remijia contains 0.5–2% of quinine. The bark is cheaper than bark of Cinchona. As it has an intense taste, it is used for making tonic water.
Regulation in the US
From 1969, to 1992, the US Food and Drug Administration (FDA) received 157 reports of health problems related to quinine use, including 23 which had resulted in death. In 1994, the FDA banned the marketing of over-the-counter quinine as a treatment for nocturnal leg cramps. Pfizer Pharmaceuticals had been selling the brand name Legatrin for this purpose. Also sold as a Softgel (by SmithKlineBeecham) as Q-vel. Doctors may still prescribe quinine, but the FDA has ordered firms to stop marketing unapproved drug products containing quinine. The FDA is also cautioning consumers about off-label use of quinine to treat leg cramps. Quinine is approved for treatment of malaria, but was also commonly prescribed to treat leg cramps and similar conditions. Because malaria is life-threatening, the risks associated with quinine use are considered acceptable when used to treat that condition.Though Legatrin was banned by the FDA for the treatment of leg cramps, the drug manufacturer URL Mutual has branded a quinine-containing drug named Qualaquin. It is marketed as a treatment for malaria and is sold in the United States only by prescription. In 2004, the CDC reported only 1,347 confirmed cases of malaria in the United States.
Cutting agent
Quinine is sometimes detected as a cutting agent in street drugs such as cocaine and heroin.
Other animals
Quinine is used as a treatment for Cryptocaryon irritans (commonly referred to as white spot, crypto or marine ich) infection of marine aquarium fish.
References
Further reading
Schroeder-Lein G (2008). The encyclopedia of Civil War medicine. Armonk, NY: Sharpe, Inc.
Hobhouse, Henry (2005) [1986]. Seeds of Change: Six Plants That Transformed Mankind. Berkeley, CA: Counterpoint. ISBN 978-1-59376-049-6.
Stockwell HR (1982). "Aeromedical considerations of malaria prophylaxis with mefloquine hydrochloride". Aviation, Space, and Environmental Medicine. 3 (10): 1011–13. PMID 6983345.
Wolff RS, Wirtschafter D, Adkinson C (June 1997). "Ocular quinine toxicity treated with hyperbaric oxygen". Undersea & Hyperbaric Medicine. 24 (2): 131–4. PMID 9171472. Archived from the original on 11 August 2011. Retrieved 13 August 2008.
Slater L (2009). War and disease : biomedical research on malaria in the twentieth century. New Brunswick, NJ: Rutgers University Press.
Lloyd, Henry D. (June 1884). "Lords of Industry". The North American Review. University of Northern Iowa. 138 (331): 535–553. ISSN 0029-2397. JSTOR 25118388.
World Health Organization (2015). Guidelines for the treatment of malaria, 3rd ed (3rd ed.). World Health Organization (WHO). hdl:10665/162441. ISBN 9789241549127.
External links
Quinine at the Drug Information Portal
Quinine at the International Programme on Chemical Safety
"Quinine". Resource Center. Chemwatch. |
Talc | Talc, or talcum, is a clay mineral, composed of hydrated magnesium silicate with the chemical formula Mg3Si4O10(OH)2. Talc in powdered form, often combined with corn starch, is used as baby powder. This mineral is used as a thickening agent and lubricant. It is an ingredient in ceramics, paints, and roofing material. It is a main ingredient in many cosmetics. It occurs as foliated to fibrous masses, and in an exceptionally rare crystal form. It has a perfect basal cleavage and an uneven flat fracture, and it is foliated with a two-dimensional platy form.
The Mohs scale of mineral hardness, based on scratch hardness comparison, defines value 1 as the hardness of talc, the softest mineral. When scraped on a streak plate, talc produces a white streak; though this indicator is of little importance, because most silicate minerals produce a white streak. Talc is translucent to opaque, with colors ranging from whitish grey to green with a vitreous and pearly luster. Talc is not soluble in water, and is slightly soluble in dilute mineral acids.Soapstone is a metamorphic rock composed predominantly of talc.
Etymology
The word "talc" derives from Medieval Latin talcum, which in turn originates from Arabic: طلق ṭalq which, derives from Persian: تالک tālk. In ancient times, the word was used for various related minerals, including talc, mica, and selenite.
Formation
Talc dominantly forms from the metamorphism of magnesian minerals such as serpentine, pyroxene, amphibole, and olivine, in the presence of carbon dioxide and water. This is known as "talc carbonation" or "steatization" and produces a suite of rocks known as talc carbonates.
Talc is primarily formed by hydration and carbonation by this reaction:
serpentine2 Mg3Si2O5(OH)4 + carbon dioxide3 CO2 → talcMg3Si4O10(OH)2 + magnesite3 MgCO3 + water3 H2OTalc can also be formed via a reaction between dolomite and silica, which is typical of skarnification of dolomites by silica-flooding in contact metamorphic aureoles:
dolomite3 CaMg(CO3)2 + silica4 SiO2 + waterH2O → talcMg3Si4O10(OH)2 + calcite3 CaCO3 + carbon dioxide3 CO2Talc can also be formed from magnesium chlorite and quartz in blueschist and eclogite metamorphism by the following metamorphic reaction:
chlorite + quartz → kyanite + talc + waterTalc is also found as a diagenetic mineral in sedimentary rocks where it can form from the transformation of metastable hydrated magnesium-clay precursors such as kerolite, sepiolite, or stevensite that can precipitate from marine and lake water in certain conditions.In this reaction, the ratio of talc and kyanite depends on aluminium content, with more aluminous rocks favoring production of kyanite. This is typically associated with high-pressure, low-temperature minerals such as phengite, garnet, and glaucophane within the lower blueschist facies. Such rocks are typically white, friable, and fibrous, and are known as
whiteschist.
Talc is a trioctahedral layered mineral; its structure is similar to pyrophyllite, but with magnesium in the octahedral sites of the composite layers. The crystal structure of talc is described as TOT, meaning that it is composed of parallel TOT layers weakly bonded to each other by weak van der Waals forces. The TOT layers in turn consist of two tetrahedral sheets (T) strongly bonded to the two faces of a single trioctahedral sheet (O). It is the weak bonding between TOT layers that gives talc its perfect basal cleavage and softness.The tetrahedral sheets consist of silica tetrahedra, which are silicon ions surrounded by four oxygen ions. The tetrahedra each share three of their four oxygen ions with neighboring tetrahedra to produce a hexagonal sheet. The remaining oxygen ion (the apical oxygen ion) is available to bond with the trioctahedral sheet.The trioctahedral sheet has the structure of a sheet of the mineral brucite. Apical oxygens take the place of some of the hydroxyl ions that would be present in a brucite sheet, bonding the tetrahedral sheets tightly to the trioctahedral sheet.Tetrahedral sheets have a negative charge, since their bulk composition is Si4O104-. The trioctahedral sheet has an equal positive charge, since its bulk composition is Mg3(OH)24+ The combined TOT layer thus is electrically neutral.Because the hexagons in the T and O sheets are slightly different in size, the sheets are slightly distorted when they bond into a TOT layer. This breaks the hexagonal symmetry and reduces it to monoclinic or triclinic symmetry. However, the original hexahedral symmetry is discernible in the pseudotrigonal character of talc crystals.
Occurrence
Talc is a common metamorphic mineral in metamorphic belts that contain ultramafic rocks, such as soapstone (a high-talc rock), and within whiteschist and blueschist metamorphic terranes. Prime examples of whiteschists include the Franciscan Metamorphic Belt of the western United States, the western European Alps especially in Italy, certain areas of the Musgrave Block, and some collisional orogens such as the Himalayas, which stretch along Pakistan, India, Nepal, and Bhutan.
Talc carbonate ultramafics are typical of many areas of the Archaean cratons, notably the komatiite belts of the Yilgarn Craton in Western Australia. Talc-carbonate ultramafics are also known from the Lachlan Fold Belt, eastern Australia, from Brazil, the Guiana Shield, and from the ophiolite belts of Turkey, Oman, and the Middle East.
China is the key world talc and steatite producing country with an output of about 2.2M tonnes(2016), which accounts for 30% of total global output. The other major producers are Brazil (12%), India (11%), the U.S. (9%), France (6%), Finland (4%), Italy, Russia, Canada, and Austria (2%, each).Notable economic talc occurrences include the Mount Seabrook talc mine, Western Australia, formed upon a polydeformed, layered ultramafic intrusion. The France-based Luzenac Group is the worlds largest supplier of mined talc. Its largest talc mine at Trimouns near Luzenac in southern France produces 400,000 tonnes of talc per year.
Conflict mineral
Extraction in disputed areas of Nangarhar province, Afghanistan, has led the international monitoring group Global Witness to declare talc a conflict resource, as the profits are used to fund armed confrontation between the Taliban and Islamic State.
Uses
Talc is used in many industries, including paper making, plastic, paint and coatings (e.g. for metal casting molds), rubber, food, electric cable, pharmaceuticals, cosmetics, and ceramics. A coarse grayish-green high-talc rock is soapstone or steatite, used for stoves, sinks, electrical switchboards, etc. It is often used for surfaces of laboratory table tops and electrical switchboards because of its resistance to heat, electricity, and acids.
In finely ground form, talc finds use as a cosmetic (talcum powder), as a lubricant, and as a filler in paper manufacture. It is used to coat the insides of inner tubes and rubber gloves during manufacture to keep the surfaces from sticking. Talcum powder, with heavy refinement, has been used in baby powder, an astringent powder used to prevent diaper rash (nappy rash). The American Academy of Pediatrics recommends that parents avoid using baby powder because it poses a risk of respiratory problems, including breathing trouble and serious lung damage if inhaled. The small size of the particles makes it difficult to keep them out of the air while applying the powder. Zinc oxide-based ointments are a much safer alternative.Soapstone (massive talc) is often used as a marker for welding or metalworking.Talc is also used as food additive or in pharmaceutical products as a glidant. In medicine, talc is used as a pleurodesis agent to prevent recurrent pleural effusion or pneumothorax. In the European Union, the additive number is E553b.
Talc may be used in the processing of white rice as a buffing agent in the polishing stage.
Due to its low shear strength, talc is one of the oldest known solid lubricants. Also, limited use is made of talc as a friction-reducing additive in lubricating oils.Talc is widely used in the ceramics industry in both bodies and glazes. In low-fire art-ware bodies, it imparts whiteness and increases thermal expansion to resist crazing. In stonewares, small percentages of talc are used to flux the body and therefore improve strength and vitrification. It is a source of MgO flux in high-temperature glazes (to control melting temperature). It is also employed as a matting agent in earthenware glazes and can be used to produce magnesia mattes at high temperatures.
ISO standard for quality (ISO 3262)
Patents are pending on the use of magnesium silicate as a cement substitute. Its production requirements are less energy-intensive than ordinary Portland cement (at a heating requirement of around 650 °C for talc compared to 1500 °C for limestone to produce Portland cement), while it absorbs far more carbon dioxide as it hardens. This results in a negative carbon footprint overall, as the cement substitute removes 0.6 tonnes of CO2 per tonne used. This contrasts with a positive carbon footprint of 0.4 tonnes per tonne of conventional cement.Talc is used in the production of the materials that are widely used in the building interiors such as base content paints in wall coatings. Other areas that use talc to a great extent are organic agriculture, the food industry, cosmetics, and hygiene products such as baby powder and detergent powder.
Talc is sometimes used as an adulterant to illegal heroin, to expand volume and weight and thereby increase its street value. With intravenous use, it may lead to pulmonary talcosis, a granulomatous inflammation in the lungs.
Sterile talc powder
Sterile talc powder (NDC 63256-200-05) is a sclerosing agent used in the procedure of pleurodesis. This can be helpful as a cancer treatment to prevent pleural effusions (an abnormal collection of fluid in the space between the lungs and the thoracic wall). It is inserted into the space via a chest tube, causing it to close up, so fluid cannot collect there. The product can be sterilized by dry heat, ethylene oxide, or gamma irradiation.
Safety
Suspicions have been raised that talc use contributes to certain types of disease, mainly cancers of the ovaries and lungs. According to the IARC, talc containing asbestos is classified as a group 1 agent (carcinogenic to humans), talc use in the perineum is classified as group 2B (possibly carcinogenic to humans), and talc not containing asbestos is classified as group 3 (unclassifiable as to carcinogenicity in humans). Reviews by Cancer Research UK and the American Cancer Society conclude that some studies have found a link, but other studies have not.The studies discuss pulmonary issues, lung cancer, and ovarian cancer. One of these, published in 1993, was a US National Toxicology Program report, which found that cosmetic grade talc containing no asbestos-like fibres was correlated with tumor formation in rats forced to inhale talc for 6 hours a day, five days a week over at least 113 weeks. A 1971 paper found particles of talc embedded in 75% of the ovarian tumors studied.
Research published in 1995 and 2000 concluded that it was plausible that talc could cause ovarian cancer, but no conclusive evidence was shown. The Cosmetic Ingredient Review Expert Panel concluded in 2015 that talc, in the concentrations currently used in cosmetics, is safe. In 2018, Health Canada issued a warning, advising against inhaling talcum powder or using it in the female perineal area.
Industrial grade
In the United States, the Occupational Safety and Health Administration and National Institute for Occupational Safety and Health have set occupational exposure limits to respirable talc dusts at 2 mg/m3 over an eight-hour workday. At levels of 1000 mg/m3, inhalation of talc is considered immediately dangerous to life and health.
Food grade
The United States Food and Drug Administration considers talc (magnesium silicate) generally recognized as safe (GRAS) to use as an anticaking agent in table salt in concentrations smaller than 2%.
Association with asbestos
One particular issue with commercial use of talc is its frequent co-location in underground deposits with asbestos ore. Asbestos is a general term for different types of fibrous silicate minerals, desirable in construction for their heat resistant properties. There are six varieties of asbestos; the most common variety in manufacturing, white asbestos, is in the serpentine family. Serpentine minerals are sheet silicates; although not in the serpentine family, talc is also a sheet silicate, with two sheets connected by magnesium cations. The frequent co-location of talc deposits with asbestos may result in contamination of mined talc with white asbestos, which poses serious health risks when dispersed into the air and inhaled. Stringent quality control since 1976, including separating cosmetic- and food-grade talc from "industrial"-grade talc, has largely eliminated this issue, but it remains a potential hazard requiring mitigation in the mining and processing of talc. A 2010 US FDA survey failed to find asbestos in a variety of talc-containing products. A 2018 Reuters investigation asserted that pharmaceuticals company Johnson & Johnson knew for decades that there was asbestos in its baby powder, and in 2020 the company stopped selling its baby powder in the US and Canada. There were calls for Johnson & Johnsons largest shareholders to force the company to end global sales of baby powder, and hire an independent firm to conduct a racial justice audit as it had been marketed to African American and overweight women. On August 11, 2022, the company announced it would stop making talc-based powder by 2023 and replace it with cornstarch-based powders. The company said the talc-based powder is safe to use and does not contain asbestos.
Litigation
In 2006 the International Agency for Research on Cancer classified talcum powder as a possible human carcinogen if used in the female genital area. Despite this, no federal agency in the US acted to remove talcum powder from the market or add warnings.In February 2016, as the result of a lawsuit against Johnson & Johnson (J&J), a St. Louis jury awarded $72 million to the family of an Alabama woman who died from ovarian cancer. The family claimed that the use of talcum powder was responsible for her cancer.
In May 2016, a South Dakota woman was awarded $55 million as the result of another lawsuit against J&J. The woman had used Johnson & Johnsons Baby Powder for more than 35 years before being diagnosed with ovarian cancer in 2011.In October 2016, a St. Louis jury awarded $70.1 million to a Californian woman with ovarian cancer who had used Johnsons Baby Powder for 45 years.In August 2017, a Los Angeles jury awarded $417 million to a Californian woman, Eva Echeverria, who developed ovarian cancer as a "proximate result of the unreasonably dangerous and defective nature of talcum powder", her lawsuit against Johnson & Johnson stated. On 20 October 2017, Los Angeles Superior Court judge Maren Nelson dismissed the verdict. The judge stated that Echeverria proved there is "an ongoing debate in the scientific and medical community about whether talc more probably than not causes ovarian cancer and thus (gives) rise to a duty to warn", but not enough to sustain the jurys imposition of liability against Johnson & Johnson stated, and concluded that Echeverria did not adequately establish that talc causes ovarian cancer.In July 2018, a court in St. Louis awarded a $4.7bn claim ($4.14bn in punitive damages and $550m in compensatory damages) against J&J to 22 claimant women, concluding that the company had suppressed evidence of asbestos in its products for more than four decades.At least 1,200 to 2,000 other talcum powder-related lawsuits were pending as of 2016.
See also
Pyrophyllite – Aluminium silicate hydroxide phyllosilicate mineral
Serpentinite – Rock formed by hydration and metamorphic transformation of olivine
Sillimanite – Nesosilicate mineral
== References == |
Compound | Compound may refer to:
Architecture and built environments
Compound (enclosure), a cluster of buildings having a shared purpose, usually inside a fence or wall
Compound (fortification), a version of the above fortified with defensive structures
Compound (migrant labour), a hostel for migrant workers such as those historically connected with mines in South Africa
The Compound, an area of Palm Bay, Florida, US
Komboni or compound, a type of slum in Zambia
Government and law
Composition (fine), a legal procedure in use after the English Civil War
Committee for Compounding with Delinquents, an English Civil War institution that allowed Parliament to compound the estates of Royalists
Compounding treason, an offence under the common law of England
Compounding a felony, a previous offense under the common law of England
Linguistics
Compound (linguistics), a word that consists of more than one radical element
Compound sentence (linguistics), a type of sentence made up of two or more independent clauses and no subordinate (dependent) clauses
Science, technology, and mathematics
Biology and medicine
Compounding, the mixing of drugs in pharmacy
Compound fracture, a complete fractures of bone where at least one fragment has damaged the skin, soft tissue or surrounding body cavity
Compound leaf, a type of leaf being divided into smaller leaflets
Chemistry and materials science
Chemical compound, combination of two or more elements
Plastic compounding, a method of preparing plastic formulations
Vehicles and engines
Compound engine, a steam engine in which steam is expanded through a series of two or three cylinders before exhaust
Turbo-compound engine, an internal combustion engine where exhaust gases expand through power-turbines
Compounding pressure, a method in which pressure in a steam turbine is made to drop in a number of stages
Other uses in science, technology, and mathematics
Compound bow, a type of bow for archery
Polyhedral compound, a polyhedron composed of multiple polyhedra sharing the same centre
Other uses
Common names
Compound (music), an attribute of a time signature
Compound interest, in finance, unpaid interest that is added to the principal
Compound chocolate, an inexpensive chocolate substitute that uses cocoa but excludes cocoa butter
Proper names
The Compound (book), a 2008 young adult novel by S. A. Bodeen
Compound (company), a venture capital firm previously known as Metamorphic Ventures
Eisenhuth Horseless Vehicle Company, or Compound, a former US automobile manufacturer
See also
Composite (disambiguation) |
Loncastuximab tesirine | Loncastuximab tesirine , sold under the brand name Zynlonta, is a monoclonal antibody conjugate medication used to treat large B-cell lymphoma. It is an antibody-drug conjugate (ADC) composed of a humanized antibody targeting the protein CD19.Loncastuximab tesirine was approved for medical use in the United States in April 2021.
Medical uses
Loncastuximab tesirine is indicated for the treatment of adults with relapsed or refractory large B-cell lymphoma.
Technology
The humanized monoclonal antibody is stochastically conjugated via a valine-alanine cleavable, maleimide linker to a cytotoxic (anticancer) pyrrolobenzodiazepine (PBD) dimer. The antibody binds to CD19, a protein which is highly expressed on the surface of B-cell hematological tumors including certain forms of lymphomas and leukemias. After binding to the tumor cells the antibody is internalized, the cytotoxic drug PBD is released and the cancer cells are killed. PBD dimers are generated out of PBD monomers, a class of natural products produced by various actinomycetes. PBD dimers work by crosslinking specific sites of the DNA, blocking the cancer cells’ division that cause the cells to die. As a class of DNA-crosslinking agents they are significantly more potent than systemic chemotherapeutic drugs.
Clinical trials
Two phase I trials are evaluating the medication in people with relapsed or refractory B-cell non-Hodgkin’s lymphoma and relapsed or refractory B-cell acute lymphoblastic leukemia. At the 14th International Conference on Malignant Lymphoma interim results from a Phase I, open-label, dose-escalating study designed to evaluate the treatment of loncastuximab tesirine in relapsed or refractory non-Hodgkin’s lymphoma were presented. Among the patients enrolled at the time of the data cutoff the overall response rate was 61% in the total patient population (42% complete response and 19% partial response) and in patients with relapsing or refractory diffuse large B-cell lymphoma (DLBCL) the overall response rate was 57% (43% complete response and 14% partial response).
History
Loncastuximab tesirine was granted orphan drug designation by the U.S. Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma.
Society and culture
Legal status
On 15 September 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Zynlonta, intended for the treatment of adults with diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL). The applicant for this medicinal product is ADC Therapeutics (NL) B.V.
Research
Given its mechanism of action, loncastiximab tesirinine may be appealing in patients ineligible for CAR-T cell therapy.
References
External links
"Loncastuximab tesirine". Drug Information Portal. U.S. National Library of Medicine.
"Loncastuximab tesirine-lpyl". NCI Drug Dictionary. National Cancer Institute.
"Loncastuximab tesirine-lpyl". National Cancer Institute. 21 May 2021.
Clinical trial number NCT03589469 for "Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (LOTIS-2)" at ClinicalTrials.gov |
Pyrazinamide | Pyrazinamide is a medication used to treat tuberculosis. For active tuberculosis, it is often used with rifampicin, isoniazid, and either streptomycin or ethambutol. It is not generally recommended for the treatment of latent tuberculosis. It is taken by mouth.Common side effects include nausea, loss of appetite, muscle and joint pains, and rash. More serious side effects include gout, liver toxicity, and sensitivity to sunlight. It is not recommended in those with significant liver disease or porphyria. It is unclear if use during pregnancy is safe but it is likely okay during breastfeeding. Pyrazinamide is in the antimycobacterial class of medications. How it works is not entirely clear.Pyrazinamide was first made in 1936, but did not come into wide use until 1972. It is on the World Health Organizations List of Essential Medicines. Pyrazinamide is available as a generic medication.
Medical uses
Pyrazinamide is only used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis and as directly observed therapy (DOT). It is never used on its own. It has no other indicated medical uses. In particular, it is not used to treat other mycobacteria; Mycobacterium bovis and Mycobacterium leprae are innately resistant to pyrazinamide.
Pyrazinamide is used in the first 2 months of treatment to reduce the duration of treatment required. Regimens not containing pyrazinamide must be taken for 9 months or more.
Pyrazinamide is a potent antiuricosuric drug and consequently has an off-label use in the diagnosis of causes of hypouricemia and hyperuricosuria. It acts on URAT1.
Adverse effects
The most common (roughly 1%) side effect of pyrazinamide is joint pains (arthralgia), but this is not usually so severe that patients need to stop taking it. Pyrazinamide can precipitate gout flares by decreasing renal excretion of uric acid.The most dangerous side effect of pyrazinamide is hepatotoxicity, which is dose-related. The old dose for pyrazinamide was 40–70 mg/kg daily and the incidence of drug-induced hepatitis has fallen significantly since the recommended dose has been reduced to 12–30 mg/kg daily. In the standard four-drug regimen (isoniazid, rifampicin, pyrazinamide, ethambutol), pyrazinamide is the most common cause of drug-induced hepatitis. It is not possible to clinically distinguish pyrazinamide-induced hepatitis from hepatitis caused by isoniazid or rifampicin; test dosing is required (this is discussed in detail in tuberculosis treatment)Other side effects include nausea and vomiting, anorexia, sideroblastic anemia, skin rash, urticaria, pruritus, dysuria, interstitial nephritis, malaise, rarely porphyria, and fever.
Pharmacokinetics
Pyrazinamide is well absorbed orally. It crosses inflamed meninges and is an essential part of the treatment of tuberculous meningitis. It is metabolised by the liver and the metabolic products are excreted by the kidneys.
Pyrazinamide is routinely used in pregnancy in the UK and the rest of the world; the World Health Organization (WHO) recommends its use in pregnancy; and extensive clinical experience shows that it is safe. In the US, pyrazinamide is not used in pregnancy, citing insufficient evidence of safety. Pyrazinamide is removed by haemodialysis, so doses should always be given at the end of a dialysis session.
Mechanism of action
Pyrazinamide is a prodrug that stops the growth of M. tuberculosis.
Pyrazinamide diffuses into the granuloma of M. tuberculosis, where the tuberculosis enzyme pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid. Under acidic conditions of pH 5 to 6, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH.Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesize fatty acids although this has been discounted. The accumulation of pyrazinoic acid was also suggested to disrupt membrane potential and interfere with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. However, since an acidic environment is not essential for pyrazinamide susceptibility and pyrazinamide treatment does not lead to intrabacterial acidification nor rapid disruption of membrane potential, this model has also been discounted. Pyrazinoic acid was proposed to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation, but more detailed experiments have shown that it does not have this activity.The current hypothesis is that pyrazinoic acid blocks synthesis of coenzyme A. Pyrazinoic acid binds weakly to aspartate decarboxylase (PanD), triggering its degradation. This is an unusual mechanism of action in that pyrazinamide does not directly block the action of its target, but indirectly triggers its destruction.
Resistance
Mutations in the pncA gene of M. tuberculosis, which encodes a pyrazinamidase and converts pyrazinamide to its active form pyrazinoic acid, are responsible for the majority of pyrazinamide resistance in M. tuberculosis strains. A few pyrazinamide-resistant strains with mutations in the rpsA gene have also been identified. However, a direct association between these rpsA mutations and pyrazinamide resistance has not been established. The pyrazinamide-resistant M. tuberculosis strain DHMH444, which harbors a mutation in the carboxy terminal coding region of rpsA, is fully susceptible to pyrazinoic acid and pyrazinamide resistance of this strain was previously associated with decreased pyrazinamidase activity. Further, this strain was found to be susceptible to pyrazinamide in a mouse model of tuberculosis. Thus, current data indicate that rpsA mutations are not likely to be associated with pyrazinamide resistance. Currently, three main methods of testing are used for pyrazinamide resistance: 1) phenotypic tests where a tuberculosis strain is grown in the presence of increasing concentrations of pyrazinamide, 2) measuring levels of pyrazinamidase enzyme produced by the tuberculosis strain, or 3) looking for mutations in the pncA gene of tuberculosis. Concerns exist that the most widely used method for phenotypic resistance testing may overestimate the number of resistant strains.Global resistance of tuberculosis to pyrazinamide has been estimated to be in 16% of all cases, and 60% of people with multidrug-resistant tuberculosis.
Abbreviations
The abbreviations PZA and Z are standard, and used commonly in the medical literature, although best practice discourages the abbreviating of drug names to prevent mistakes.
Presentation
Pyrazinamide is a generic drug, and is available in a wide variety of presentations. Pyrazinamide tablets form the bulkiest part of the standard tuberculosis treatment regimen. Pyrazinamide tablets are so large, some people find them impossible to swallow: pyrazinamide syrup is an option.
Pyrazinamide is also available as part of fixed-dose combinations with other TB drugs such as isoniazid and rifampicin (Rifater is an example).
History
Pyrazinamide was first discovered and patented in 1936, but not used against tuberculosis until 1952. Its discovery as an antitubercular agent was remarkable since it has no activity against tuberculosis in vitro, due to not being active at a neutral pH, so would ordinarily not be expected to work in vivo. However, nicotinamide was known to have activity against tuberculosis and pyrazinamide was thought to have a similar effect. Experiments in mice at Lederle and Merck confirmed its ability to kill tuberculosis and it was rapidly used in humans.
References
External links
"Pyrazinamide". Drug Information Portal. U.S. National Library of Medicine. |
Oxybutynin | Oxybutynin, sold as under the brand names Ditropan among others, is a medication used to treat overactive bladder. It works similar to tolterodine, Darifenacin, and Solifenacin. While used for bed wetting in children, evidence to support this use is poor. It is taken by mouth or applied to the skin.Common side effects include dry mouth, constipation, dizziness, trouble sleeping, and urinary tract infections. Serious side effects may include urinary retention and an increased risk of heat stroke. Use in pregnancy appears safe but has not been well studied while use in breastfeeding is of unclear safety. It is an antimuscarinic and works by blocking the effects of acetylcholine on smooth muscle.Oxybutynin was approved for medical use in the United States in 1975. It is available as a generic medication. In 2019, it was the 112th most commonly prescribed medication in the United States, with more than 5 million prescriptions.
Medical use
The immediate and slow release versions work equally.In people with overactive bladder, transdermal oxybutynin decreased the number of incontinence episodes and increased average voided volume. There was no difference between transdermal oxybutynin and extended-release oral tolterodine.Tentative evidence supports the use of oxybutynin in hyperhidrosis (excessive sweating).
Adverse effects
Common adverse effects that are associated with oxybutynin and other anticholinergics include: dry mouth, difficulty in urination, constipation, blurred vision, drowsiness, and dizziness. Anticholinergics have also been known to induce delirium.Oxybutynins tendency to reduce sweating can be dangerous. Reduced sweating increases the risk of heat exhaustion and heat stroke in apparently safe situations where normal sweating keeps others safe and comfortable. Adverse effects of elevated body temperature are more likely for the elderly and for those with health issues, especially multiple sclerosis.N-Desethyloxybutynin is an active metabolite of oxybutynin that is thought responsible for much of the adverse effects associated with the use of oxybutynin. N-Desethyloxybutynin plasma levels may reach as much as six times that of the parent drug after administration of the immediate-release oral formulation. Alternative dosage forms have been developed in an effort to reduce blood levels of N-desethyloxybutynin and achieve a steadier concentration of oxybutynin than is possible with the immediate release form. The long-acting formulations also allow once-daily administration instead of the twice-daily dosage required with the immediate-release form. The transdermal patch, in addition to the benefits of the extended-release oral formulations, bypasses the first-pass hepatic effect that the oral formulations are subject to. In those with overflow incontinence because of diabetes or neurological diseases like multiple sclerosis or spinal cord trauma, oxybutynin can worsen overflow incontinence since the fundamental problem is that the bladder is not contracting.
A large study linked the development of dementia in those over 65 to the use of oxybutynin, due to its anticholinergic properties.
Contraindications
Oxybutynin chloride is contraindicated in patients with untreated narrow angle glaucoma, and in patients with untreated narrow anterior chamber angles—since anticholinergic drugs may aggravate these conditions. It is also contraindicated in partial or complete obstruction of the gastrointestinal tract, hiatal hernia, gastroesophageal reflux disease, paralytic ileus, intestinal atony of the elderly or debilitated patient, megacolon, toxic megacolon complicating ulcerative colitis, severe colitis, and myasthenia gravis. It is contraindicated in patients with obstructive uropathy and in patients with unstable cardiovascular status in acute hemorrhage. Oxybutynin chloride is contraindicated in patients who have demonstrated hypersensitivity to the product.
Pharmacology
Oxybutynin chloride exerts direct antispasmodic effect on smooth muscle and inhibits the muscarinic action of acetylcholine on smooth muscle. It exhibits one-fifth of the anticholinergic activity of atropine on the rabbit detrusor muscle, but four to ten times the antispasmodic activity. No blocking effects occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).
Sources say the drug is absorbed within one hour and has an elimination half-life of 2 to 5 hours. There is a wide variation among individuals in the drugs concentration in blood. This, and its low concentration in urine, suggest that it is eliminated through the liver.
Chemistry
Oxybutynin contains one stereocenter. Commercial formulations are sold as the racemate. The (R)-enantiomer is a more potent anticholinergic than either the racemate or the (S)-enantiomer, which is essentially without anticholinergic activity at doses used in clinical practice. However, (R)-oxybutynin administered alone offers little or no clinical benefit above and beyond the racemic mixture. The other actions (calcium antagonism, local anesthesia) of oxybutynin are not stereospecific. (S)-Oxybutynin has not been clinically tested for its spasmolytic effects, but may be clinically useful for the same indications as the racemate, without the unpleasant anticholinergic side effects.
Brand names
Oxybutynin is available by mouth in generic formulation and under the brand names Ditropan, Lyrinel XL, Ditrospam, Kentera, and Aquiette, as a transdermal patch under the brand name Oxytrol, and as a topical gel under the brand name Gelnique.
See also
Arecoline
References
External links
"Oxybutynin". Drug Information Portal. U.S. National Library of Medicine. |
Acarbose | Acarbose (INN) is an anti-diabetic drug used to treat diabetes mellitus type 2 and, in some countries, prediabetes. It is a generic sold in Europe and China as Glucobay (Bayer AG), in North America as Precose (Bayer Pharmaceuticals), and in Canada as Prandase (Bayer AG). It is cheap and popular in China, but not in the U.S. One physician explains the use in the U.S. is limited because it is not potent enough to justify the side effects of diarrhea and flatulence. However, a recent large study concludes "acarbose is effective, safe and well tolerated in a large cohort of Asian patients with type 2 diabetes." A possible explanation for the differing opinions is an observation that acarbose is significantly more effective in patients eating a relatively high carbohydrate Eastern diet.It is a starch blocker, and inhibits alpha glucosidase, an intestinal enzyme that releases glucose from larger carbohydrates. It is composed of an acarviosin moiety with a maltose at the reducing terminus. Acarbose is also degraded to maltose and acarviosin by the glucosidase cyclomaltodextrinase from gut bacteria Lactobacillus plantarum.
Natural distribution
In nature, acarbose is synthesized by soil bacteria Actinoplanes sp through its precursor valienamine. And acarbose is also degraded by gut bacteria Lactobacillus plantarum and soil bacteria Thermus sp by acarbose degrading glucosidases.
Mechanism of action
Acarbose inhibits enzymes (glycoside hydrolases) needed to digest carbohydrates, specifically, alpha-glucosidase enzymes in the brush border of the small intestines, and pancreatic alpha-amylase. It locks up the enzymes by mimicking the transisition state of the substrate with its amine linkage. However, bacterial alpha-amylases from gut microbiome are able to degrade acarbose.Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, whereas the membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the small intestine. Inhibition of these enzyme systems reduces the rate of digestion of complex carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules. In diabetic patients, the short-term effect of these drug therapies is to decrease current blood glucose levels; the long-term effect is a reduction in HbA1c level. This reduction averages an absolute decrease of 0.7%, which is a decrease of about 10% in typical HbA1c values in diabetes studies.
Combination therapy
The combination of acarbose with metformin results in greater reductions of HbA1c, fasting blood glucose and post-prandial glucose than either agent alone.
Dosing
Since acarbose prevents the digestion of complex carbohydrates, the drug should be taken at the start of main meals (taken with first bite of meal). Moreover, the amount of complex carbohydrates in the meal will determine the effectiveness of acarbose in decreasing postprandial hyperglycemia. Adults may take doses of 25 mg 3 times daily, increasing to 100 mg 3 times a day. However the maximum dose per day is 600 mg.
Side-effects
Since acarbose prevents the degradation of complex carbohydrates into glucose, some carbohydrate will remain in the intestine and be delivered to the colon. In the colon, bacteria digest the complex carbohydrates, causing gastrointestinal side-effects such as flatulence (78% of patients) and diarrhea (14% of patients). Since these effects are dose-related, in general it is advised to start with a low dose and gradually increase the dose to the desired amount. One study found that gastrointestinal side effects decreased significantly (from 50% to 15%) over 24 weeks, even on constant dosing.If a patient using acarbose has a bout of hypoglycemia, the patient must eat something containing monosaccharides, such as glucose tablets or gel (GlucoBurst, Insta-Glucose, Glutose, Level One) and a doctor should be called. Because acarbose blocks the breakdown of table sugar and other complex sugars, fruit juice or starchy foods will not effectively reverse a hypoglycemic episode in a patient taking acarbose.Hepatitis has been reported with acarbose use. It usually goes away when the medicine is stopped. Therefore, liver enzymes should be checked before and during use of this medicine.
Life extension
In studies conducted by three independent laboratories by the US National Institute on Agings intervention testing programme, acarbose was shown to extend the lifespan of female mice by 5% and of male mice by 22%.
Metabolism
Acarbose degradation is the unique feature of glycoside hydrolases in gut microbiota, acarbose degrading glucosidase, which hydrolyze acarbose into an acarviosine-glucose and glucose. Human enzymes do transform acarbose: the pancreatic alpha-amylase is able to perform a rearrangement reaction, moving the glucose unit in the "tail" maltose to the "head" of the molecule. Analog drugs with the "tail" glucose removed or flipped to an α(1-6) linkage resist this transformation.It has been reported that the maltogenic alpha-amylase from Thermus sp. IM6501 (ThMA) and a cyclodextrinase (CDase) from Streptococcus pyogenes could hydrolyse acarbose to glucose and acarviosine-glucose, ThMA can further hydrolyze acarviosine-glucose into acarviosin and glucose. A cyclomaltodextrinase (CDase) from gut bacteria Lactobacillus plantarum degraded acarbose via two different modes of action to produce maltose and acarviosin, as well as glucose and acarviosine-glucose, suggest that acarbose resistance is caused by in the human microbiome. The microbiome-derived acarbose kinases are also specific to phosphorylate and inactivate acarbose. The molecular modeling showed the interaction between gut bacterial acarbose degrading glucosidase and human α-amylase.
In molecular biology
Acarbose is described chemically as a pseudotetrasaccharide, specifically a maltotetraose mimic inhibitor. As an inhibitor that mimics some natural substrates, it is useful for elucidating the structure of sugar-digesting enzymes, by binding into the same pocket.
References
External links
"Acarbose". Drug Information Portal. U.S. National Library of Medicine.
"Probing the Pancreas" - by Craig D. Reid, Ph.D. (US FDA Consumer Article) |
Dronabinol | The International Nonproprietary Name Dronabinol, also known as delta-9-tetrahydrocannabinol, or under the trade names Marinol, Syndros, Reduvo and Adversa, is a generic name for the molecule of delta-9-tetrahydrocannabinol in the pharmaceutical context. It has indications as an appetite stimulant, antiemetic, and sleep apnea reliever and is approved by the FDA as safe and effective for HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting only.Dronabinol is the principal psychoactive constituent enantiomer form, (−)-trans-Δ9-tetrahydrocannabinol, found in cannabis. Dronabinol does not include any other tetrahydrocannabinol (THC) isomers or any cannabidiol.
Medical uses
Appetite stimulant and anti-emetic
Dronabinol is used to stimulate appetite and therefore weight gain in patients with HIV/AIDS and cancer. It is also used to treat chemotherapy-induced nausea and vomiting.
Analgesic
Dronabinol demonstrated analgesic efficacy in a majority of studies in chronic pain, the data in acute pain is less conclusive.
Cannabis addiction
Dronabinol may be useful in treating cannabis addiction as it has been shown to reduce cannabis withdrawal symptoms and the subjective effects of marijuana.
Sleep apnea
Dronabinol demonstrates significant improvement in sleep apnea scores. Phase 2B clinical trials were completed in 2017 for FDA approval for this indication.
Overdose
A mild overdose of dronabinol presents drowsiness, dry-mouth, euphoria, and tachycardia; whereas a severe overdose presents lethargy, slurred speech, decreased motor coordination, and postural hypotension.
History
While dronabinol was initially approved by the United States Food and Drug Administration on May 31, 1985, it was not until May 13, 1986, the Drug Enforcement Administration (DEA) issued a Final Rule and Statement of Policy authorizing the "rescheduling of synthetic dronabinol in sesame oil and encapsulated in soft gelatin capsules from Schedule I to Schedule II" (DEA 51 FR 17476-78). This permitted medical use of Marinol, albeit with the severe restrictions associated with Schedule II status. For instance, refills of Marinol prescriptions were not permitted.
On April 29, 1991, the Commission on Narcotic Drugs, in accordance with article 2, paragraphs 5 and 6, of the Convention on Psychotropic Substances of 1971, decided that Δ9-tetrahydrocannabinol (also referred to as Δ9-THC) and its stereochemical variants should be transferred from Schedule I to Schedule II of that Convention. This released Δ9-THC from many of the restrictions imposed by the Convention, facilitating the its marketing as medication.An article published in the April–June 1998 issue of the Journal of Psychoactive Drugs found that "Healthcare professionals have detected no indication of scrip-chasing or doctor-shopping among the patients for whom they have prescribed dronabinol". The authors state that Marinol has a low potential for abuse.In 1999, in the United States, Marinol was rescheduled from Schedule II to III of the Controlled Substances Act, reflecting a finding that THC had a potential for abuse less than that of cocaine and heroin. This rescheduling constituted part of the argument for a 2002 petition for removal of cannabis from Schedule I of the Controlled Substances Act, in which petitioner Jon Gettman noted, "Cannabis is a natural source of dronabinol (THC), the ingredient of Marinol, a Schedule III drug. There are no grounds to schedule cannabis in a more restrictive schedule than Marinol".In 2003, the World Health Organization Expert Committee on Drug Dependence recommended transferring THC to Schedule IV of the Convention, citing its medical uses and low abuse potential. In 2019, the Committee recommended transferring Δ9-THC to Schedule I of the Single Convention on Narcotic Drugs of 1961, but its recommendations were rejected by the United Nations Commission on Narcotic Drugs.
Society and culture
Brand names
Dronabinol is marketed as Marinol and Syndros, a registered trademark of Solvay Pharmaceuticals. Dronabinol is also marketed, sold, and distributed by PAR Pharmaceutical Companies under the terms of a license and distribution agreement with SVC pharma LP, an affiliate of Rhodes Technologies for Marinol and Insys Pharmaceuticals for Syndros. Dronabinol is available as a prescription drug (under Marinol and Syndros ) in several countries including the United States, Germany, South Africa and Australia. In Canada, Tetra Bio-Pharma filed a New Drug Submission (NDS) with Health Canada for its Dronabinol Soft Gel capsules to be marketed as REDUVO™. Tetra has two other dronabinol drugs with new routes of administration which limit first-pass metabolism; an inhaled THC-based dronabinol drug and their mucoadhesive-delivery dronabinol drug Adversa®, which are both in the accelerated 505(b)(2) New Drug Application (NDA) pathway for the U.S. and Canadian markets.
In the United States, Marinol is a Schedule III drug, available by prescription, considered to be non-narcotic and to have a low risk of physical or mental dependence. Efforts to get cannabis rescheduled as analogous to Marinol have not succeeded thus far, though a 2002 petition has been accepted by the DEA. As a result of the rescheduling of Marinol from Schedule II to Schedule III, refills are now permitted for this substance. Marinols U.S. Food and Drug Administration (FDA) approval for medical use has raised much controversy as to why cannabis is still illegal at the federal level.
Comparisons with medical cannabis
Female cannabis plants not only contain dronabinol but at least 113 other cannabinoids, including cannabidiol (CBD), thought to be the major anticonvulsant that helps people with multiple sclerosis; and cannabichromene (CBC), an anti-inflammatory which may contribute to the pain-killing effect of cannabis.It takes over one hour for Marinol to reach full systemic effect, compared to seconds or minutes for smoked or vaporized cannabis. Mark Kleiman, director of the Drug Policy Analysis Program at UCLAs School of Public Affairs said of Marinol, "It wasnt any fun and made the user feel bad, so it could be approved without any fear that it would penetrate the recreational market, and then used as a club with which to beat back the advocates of whole cannabis as a medicine."Clinical trials comparing the use of cannabis extracts with Marinol in the treatment of cancer cachexia have demonstrated equal efficacy and well-being among subjects in the two treatment arms. United States federal law currently registers dronabinol as a Schedule III controlled substance, but all other cannabinoids remain Schedule I, except synthetics like nabilone and HU-308.
See also
Cannabinoids
11-Hydroxy-THC, metabolite of THC
Anandamide, 2-Arachidonoylglycerol, endogenous cannabinoid agonists
Tetrahydrocannabinol
Cannabidiol (CBD)
Cannabinol (CBN), a metabolite of THC
Dimethylheptylpyran
Parahexyl
Tetrahydrocannabinolic acid, the biosynthetic precursor for THC
HU-210, WIN 55,212-2, JWH-133, synthetic cannabinoid agonists (neocannabinoids)
Medical cannabis (pharmaceutical cannabinoids)
Epidiolex (prescription form of purified cannabidiol derived from hemp used for treating some rare neurological diseases)
Sativex
Nabilone, a novel synthetic cannabinoid analog (neocannabinoid)
HU-308, a highly potent synthetic cannabinoid CB2 agonist
References
External links
Medlineplus.gov on Dronabinol |
Trifluridine | Trifluridine (also called trifluorothymidine; abbreviation TFT or FTD) is an anti-herpesvirus antiviral drug, used primarily on the eye. It was sold under the trade name Viroptic by Glaxo Wellcome, now merged into GlaxoSmithKline. The brand is now owned by Monarch Pharmaceuticals, which is wholly owned by King Pharmaceuticals.
Trifluridine was approved for medical use in 1980. It is also a component of the anti-cancer drug trifluridine/tipiracil, which is taken by mouth.
Medical uses
Trifluridine eye drops are used for the treatment of keratitis and keratoconjunctivitis caused by the herpes simplex virus types 1 and 2, as well as for prevention and treatment of vaccinia virus infections of the eye.A Cochrane Systematic Review showed that trifluridine and aciclovir were a more effective treatment than idoxuridine or vidarabine, significantly increasing the relative number of successfully healed eyes in one to two weeks.For cancer treatment, the combination trifluridine/tipiracil is used.
Adverse effects
Common side effects of trifluridine eye drops include transient burning, stinging, local irritation, and edema of the eyelids.Adverse effects of the anti-cancer formulation have only been evaluated for the combination trifluridine/tipiracil, not for the individual components.
Interactions
Only in vitro interaction studies are available. In these, trifluridine used the concentrative nucleoside transporter 1 (CNT1) and equilibrative nucleoside transporters 1 (ENT1) and 2 (ENT2). Drugs that interact with these transporters could influence blood plasma concentrations of trifluridine. Being a thymidine phosphorylase inhibitor, trifluridine could also interact with substrates of this enzyme such as zidovudine.For the eye drops, trifluridine absorption is negligible, rendering interactions basically irrelevant.
Pharmacology
Mechanism of action (eye drops)
It is a nucleoside analogue, a modified form of deoxyuridine, similar enough to be incorporated into viral DNA replication, but the –CF3 group added to the uracil component blocks base pairing, thus interfering with viral DNA replication.
Pharmacokinetics (eye drops)
Trifluridine passes the cornea and is found in the aqueous humour. Systemic absorption is negligible.
Pharmacokinetics (oral)
Pharmacokinetic data of oral trifluridine have only been evaluated in combination with tipiracil, which significantly affects biotransformation of the former. At least 57% of trifluridine are absorbed from the gut, and highest blood plasma concentrations are reached after two hours in cancer patients. The substance has no tendency to accumulate in the body. Plasma protein binding is over 96%. Trifluridine is metabolised by the enzyme thymidine phosphorylase to 5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (FTY), and also by glucuronidation. Elimination half-life is 1.4 hours on the first day and increases to 2.1 hours on the twelfth day. It is mainly excreted via the kidneys.Tipiracil causes Cmax (highest blood plasma concentrations) of trifluridine to increase 22-fold, and its area under the curve 37-fold, by inhibiting thymidine phosphorylase.
Chemistry
The substance is a white crystalline powder. It is freely soluble in methanol and acetone; soluble in water, ethanol, 0.01 M hydrochloric acid, and 0.01 M sodium hydroxide; sparingly soluble in isopropyl alcohol and acetonitrile; slightly soluble in diethyl ether; and very slightly soluble in isopropyl ether.
References
External links
Costin D, Dogaru M, Popa A, Cijevschi I (2004). "Tratamentul cu trifluridină în infecția oculară herpetică" [Trifluridine therapy in herpetic in keratitis]. Rev Med Chir Soc Med Nat Iasi (in Romanian). 108 (2): 409–12. PMID 15688823.
Kuster P, Taravella M, Gelinas M, Stepp P (1998). "Delivery of trifluridine to human cornea and aqueous using collagen shields". CLAO J. 24 (2): 122–4. PMID 9571274.
OBrien W, Taylor J (1991). "Therapeutic response of herpes simplex virus-induced corneal edema to trifluridine in combination with immunosuppressive agents". Invest Ophthalmol Vis Sci. 32 (9): 2455–61. PMID 1907950.
"Trifluridine Ophthalmic Solution, 1%" (PDF). Retrieved 2007-03-24. |
Cannabidiol | Cannabidiol (CBD) is a phytocannabinoid discovered in 1940. It is one of 113 identified cannabinoids in cannabis plants, along with tetrahydrocannabinol (THC), and accounts for up to 40% of the plants extract. As of 2019, clinical research on CBD included studies related to anxiety, cognition, movement disorders, and pain, but there is insufficient high-quality evidence that cannabidiol is effective for these conditions. Nevertheless, CBD is a popular herbal dietary supplement, widely promoted with unproven claims of particular therapeutic benefits. The global market size for CBD was predicted to exceed US$47 billion by 2028.Cannabidiol can be taken internally in multiple ways, including by inhaling cannabis smoke or vapor, by mouth, and as an aerosol spray into the cheek. It may be supplied as CBD oil containing only CBD as the active ingredient (excluding tetrahydrocannabinol [THC] or terpenes), CBD-dominant hemp extract oil, capsules, dried cannabis, or prescription liquid solution. CBD does not have the same psychoactivity as THC, and will negate the psychoactive effects of THC on the body if both are present. As of 2018, the mechanism of action for its biological effects has not been determined. Unlike THC, which acts on the cannabinoid receptor type 1 (CB1) as a partial agonist, CBD instead is a negative allosteric modulator of CB1 receptors.In the United States, the cannabidiol drug Epidiolex was approved by the Food and Drug Administration in 2018 for the treatment of two epilepsy disorders. While the 2018 United States Farm Bill removed hemp and hemp extracts (including CBD) from the Controlled Substances Act, the marketing and sale of CBD formulations for medical use or as an ingredient in dietary supplements or manufactured foods remains illegal under FDA regulation, as of 2021.
Medical uses
Cannabidiol is the generic name of the drug and its INN.
Research
As of 2019, there was limited high-quality evidence for cannabidiol having a neurological effect in humans.
Epilepsy
In the United States, the FDA has indicated only one brand of prescription cannabidiol called "Epidiolex" for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex in people one year of age and older. While Epidiolex treatment is generally well tolerated, it is associated with minor adverse effects, such as gastrointestinal upset, decreased appetite, lethargy, sleepiness and poor sleep quality.In the European Union, cannabidiol (Epidyolex) is indicated for use as adjunctive therapy of seizures associated with Lennox Gastaut syndrome (LGS) or Dravet syndrome (DS), in conjunction with clobazam, for people two years of age and older. In 2020, the label for Epidiolex in the US was expanded to include seizures associated with tuberous sclerosis complex. Epidiolex/Epidyolex is the first prescription formulation of plant-derived cannabidiol approved by regulatory bodies in the US and Europe.
Other uses
Research on other uses for cannabidiol includes several neurological disorders, but the findings have not been confirmed to establish such uses in clinical practice. In October 2019, the FDA issued an advisory warning that the effects of CBD during pregnancy or breastfeeding are unknown, indicating that the safety, doses, interactions with other drugs or foods, and side effects of CBD are not clinically defined, and may pose a risk to the mother and infant.Many claims are made for the therapeutic benefit of cannabidiol that are not backed by sound evidence. Some claims, such as treatment of cancer, are pseudoscience.In 2020, the label for Epidiolex in the US was expanded to include treatment of seizures associated with tuberous sclerosis complex.
Non-intoxicating effects
Cannabidiol does not appear to have any intoxicating effects such as those caused by ∆9-THC in cannabis, but it is under preliminary research for its possible anti-anxiety and anti-psychotic effects. As the legal landscape and understanding about the differences in medical cannabinoids unfolds, experts are working to distinguish "medical cannabis" (with varying degrees of psychotropic effects and deficits in executive function) from "medical CBD therapies", which would commonly present as having a reduced or non-psychoactive side-effect profile.Various strains of "medical cannabis" are found to have a significant variation in the ratios of CBD-to-THC and are known to contain other non-psychotropic cannabinoids. Any psychoactive cannabis, regardless of its CBD content, is derived from the flower (or bud) of the genus Cannabis. As defined by US federal law, non-psychoactive hemp (also commonly termed "industrial hemp"), regardless of its CBD content, is any part of the cannabis plant, whether growing or not, containing a ∆9-tetrahydrocannabinol concentration of no more than 0.3% on a dry-weight basis. Certain standards are required for legal growing, cultivating, and producing the hemp plant, but there are no federal standards for quality being enforced in the hemp industry. Certain state regulations are in place, but vary state to state. For instance, the Colorado Industrial Hemp Program registers growers of industrial hemp and samples crops to verify that the dry-weight THC concentration does not exceed 0.3%.
Side effects
Research indicates that cannabidiol may reduce adverse effects of THC, particularly those causing intoxication and sedation, but only at high doses. Safety studies of cannabidiol showed it is well tolerated, but may cause tiredness, somnolence, sedation, diarrhea, or changes in appetite as common adverse effects with the most common being somnolence and sedation. Side effects of CBD are dose related. Epidiolex documentation lists sleepiness, insomnia and poor quality sleep, decreased appetite, diarrhea, and fatigue. Low doses of cannabidiol cause DNA damage in human-derived cell lines. Recently published data also suggest that cannabidiol is a carcinogen.
Potential interactions
Laboratory evidence indicated that cannabidiol may reduce THC clearance, increasing plasma concentrations which may raise THC availability to receptors and enhance its effect in a dose-dependent manner. In vitro, cannabidiol inhibited the activity of voltage-dependent sodium and potassium channels, which may affect neural activity. A recent study using X-ray crystallography showed that CBD binds inside the sodium channel pore at a novel site at the interface of the fenestrations and the central hydrophobic cavity of the channel. Binding at this site blocks the transmembrane-spanning sodium ion translocation pathway, providing a molecular mechanism for channel inhibition, which could contribute to a reduced excitability. A small clinical trial reported that CBD partially inhibited the CYP2C-catalyzed hydroxylation of THC to 11-OH-THC. Little is known about potential drug interactions, but CBD mediates a decrease in clobazam metabolism.
Veterinary medicine
Research
The number of research projects and scientific publications on cannabidiol and other cannabinoids in pets has surged in the late 2010s.
As of December 2020, there are no hemp-derived, cannabinoid-rich registered veterinary medicinal products in any of the major regions (see Legal status across countries).
In the US and other territories there are, however, numerous veterinary nutraceutical products available OTC. The lack of clarity in the regulations governing veterinary hemp food supplements allows for products of questionable quality to flood the market, which may pose a risk to the wellbeing of pets and owners.
To understand better the benefits of CBD and associated compounds for the quality of life of animals, companies specialized in CBD products for animals have been funding research projects.
Canine osteoarthritis
CBDs ability to help regulate the endocannabinoid system and reduce the release of excitatory neurotransmitters could result in a retrograde inhibitory signal that lessens chronic pain responses. Studies in dogs with chronic pain associated with osteoarthritis showed an increase in level of activity in animals receiving CBD-rich food supplements.
Epilepsy
From the results seen in humans with drugs such as Epidiolex and Sativex in scientific studies and reviews, it could be expected that CBD-based products would be helpful to manage seizures in dogs. However, despite the numerous case reports presented by veterinary neurologists supporting the benefits of CBD as adjunctive therapy, as of December 2020, published controlled studies have not shown a statistically significant decrease in the number of seizures across the groups receiving CBD. Further research in this area is required before any clear conclusion can be drawn.
Pharmacokinetics
The oral bioavailability of CBD varies greatly across species and it is linked to the presentation and the time of administration. A 24-hour kinetic examination in dogs showed that the absorption of the cannabidiolic acid (CBDA) does occur, and that this molecule is absorbed least twice as well as CBD post oral ingestion.It was found that the major metabolites of CBD in humans (7-OH-CBD and 7-COOH-CBD) are not prevalent in dogs, while 6-OH-CBD was found to be the primary metabolite in dogs receiving a CBD-enriched cannabis-derived herbal extract, suggesting that canine and human CBD metabolic route might be somewhat different.
Pharmacology
Pharmacodynamics
Cannabidiol has low affinity for the cannabinoid CB1 and CB2 receptors, although it acts as an antagonist of CB1/CB2 agonists, despite this low affinity. The core effect of antagonism of CB1 receptors is reduced binding affinity of THC and any of its related isomers. Cannabidiol may be an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor that is expressed in the caudate nucleus and putamen in the brain. It also may act as an inverse agonist of GPR3, GPR6, and GPR12. CBD has been shown to act as a serotonin 5-HT1A receptor partial agonist. At higher concentrations, CBD acts as an inverse agonist of 5-HT1A receptors. It is an allosteric modulator of the μ- and δ-opioid receptors as well. The pharmacological effects of CBD may involve PPARγ agonism, inhibition of voltage-gated cation channels, and intracellular calcium release.
Pharmacokinetics
The oral bioavailability of cannabidiol is approximately 6% in humans, while its bioavailability via inhalation is 11 to 45% (mean 31%). The elimination half-life of CBD is 18–32 hours. Cannabidiol is metabolized in the liver as well as in the intestines by the cytochrome P450 enzymes CYP2B6, CYP2C19, CYP2D6, CYP2J2, and CYP3A4, and by the isoenzymes UGT1A7, UGT1A9, and UGT2B7, forming a variety of metabolites such as 7-hydroxycannabidiol as well as the 6α- and 6β-hydroxy isomers and derivatives hydroxylated on the alkyl side chain, followed by glucuronidation. CYP3A4 facilitates decarbonylation of CBD to liberate carbon monoxide, a bioactive gasotransmitter and pharmaceutical candidate. CBD may have a wide margin in dosing.
Pharmaceutical preparations
Nabiximols (brand name Sativex), an oromucosal spray made of a complex botanical mixture containing cannabidiol (CBD), delta-9-tetrahydrocannabinol (THC), and additional cannabinoid and non-cannabinoid constituents from cannabis sativa plants, was approved by Health Canada in 2005, to treat central neuropathic pain in multiple sclerosis, and in 2007, for cancer-related pain. In New Zealand, Sativex is "approved for use as an add-on treatment for symptom improvement in people with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication."Epidiolex is an orally administered cannabidiol solution. It was approved in 2018, by the US Food and Drug Administration (FDA) for treatment of two rare forms of childhood epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, and seizures associated with tuberous sclerosis complex. In the US, it is approved in these indications for patients one year of age and older.
Chemistry
At room temperature, cannabidiol is a colorless crystalline solid. In strongly basic media and the presence of air, it is oxidized to a quinone. Under acidic conditions it cyclizes to THC, which also occurs during pyrolysis, but not during combustion (smoking). The synthesis of cannabidiol has been accomplished by several research groups.
Biosynthesis
Cannabis produces CBD-carboxylic acid through the same metabolic pathway as THC, until the next to last step, where CBDA synthase performs catalysis instead of THCA synthase.
Isomerism
Pyrolysis
In the typical operating temperature range of e-cigarettes (250–400 °C), 25–52% of CBD is transformed into other chemical substances: Δ9-THC, Δ8-THC, cannabinol and cannabichromene as predominant pyrolysates. From a chemical point of view, CBD in e-cigarettes can be considered as a precursor of THC.
History
Efforts to isolate the active ingredients in cannabis were made in the 19th century. Cannabidiol was studied in 1940 from Minnesota wild hemp and Egyptian Cannabis indica resin. The chemical formula of CBD was proposed from a method for isolating it from wild hemp. Its structure and stereochemistry were determined in 1963.
Plant breeding
Selective breeding of cannabis plants has expanded and diversified as commercial and therapeutic markets develop. Some growers in the US succeeded in lowering the proportion of CBD-to-THC to accommodate customers who preferred varietals that were more mind-altering due to the higher THC and lower CBD content. In the US, hemp is classified by the federal government as cannabis containing no more than 0.3% THC by dry weight. This classification was established in the 2018 Farm Bill and was refined to include hemp-sourced extracts, cannabinoids, and derivatives in the definition of hemp.
Society and culture
Foods and beverages
Food and beverage products containing cannabidiol were widely marketed in the United States as early as 2017. Hemp seed ingredients which do not naturally contain THC or CBD (but which may be contaminated with trace amounts on the outside during harvesting) were declared by the US Food and Drug Administration (FDA) as Generally recognized as safe (GRAS) in December 2018. CBD itself has not been declared GRAS, and under US federal law is illegal to sell as a food, dietary supplement, or animal feed. State laws vary considerably as non-medical cannabis and derived products have been legalized in some jurisdictions in the 2010s.
The global market size for CBD was predicted to exceed US$47 billion by 2028.Similar to energy drinks and protein bars which may contain vitamin or herbal additives, food and beverage items can be infused with CBD as an alternative means of ingesting the substance. In the United States, numerous products are marketed as containing CBD, but in reality contain little or none. Some companies marketing CBD-infused food products with claims that are similar to the effects of prescription drugs have received warning letters from the Food and Drug Administration for making unsubstantiated health claims. In February 2019, the New York City Department of Health announced plans to fine restaurants that sell food or drinks containing CBD, beginning in October 2019.
Sports
Cannabidiol has been used by professional and amateur athletes across disciplines and countries, with the World Anti-Doping Agency removing CBD from its banned substances list. The United States Anti-Doping Agency and United Kingdom-Anti-Doping Agency do not have anti-CBD policies, with the latter stating that, "CBD is not currently listed on the World Anti-Doping Agency Prohibited List. As a result, it is permitted to use in sport, though the intended benefits are unclear and not backed by clinical evidence. All other cannabinoids (including but not limited to cannabis, hashish, marijuana, and THC) are prohibited in-competition. The intention of the regulations is to prohibit cannabinoids that activate the same receptors in the brain as activated by THC." In 2019, the cannabis manufacturer, Canopy Growth, acquired majority ownership of BioSteel Sports Nutrition, which is developing CBD products under endorsement by numerous professional athletes. The National Hockey League Alumni Association began a project with Canopy Growth to determine if CBD or other cannabis products might improve neurological symptoms and quality of life in head-injured players. Numerous professional athletes use CBD, primarily for treating pain.
Legal status
Australia
Prescription medicine (Schedule 4) for therapeutic use containing two percent (2.0%) or less of other cannabinoids commonly found in cannabis (such as ∆9-THC). A Schedule 4 drug under the SUSMP is a Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by state or territory legislation to prescribe and should be available from a pharmacist on prescription.In June 2020, the Australian Therapeutic Goods Administration (TGA) published a consultation on a proposal to pave the way to make "low dose" CBD available to consumer/patients via pharmacists only through moving products from Schedule 4 to 3. Any products sold would need to have their safety, quality and efficacy pre-assessed by the TGA and be formally approved for sale (details to be outlined by TGA). They would be made available to over 18s only, with the maximum daily dose of 60 mg/day, up to 2% THC finished product allowed, 30-day maximum supply, plant-derived or synthetic. This proposal is based on an initial literature review on the safety of low dose CBD published by the TGA in April 2020. Epidyolex was approved, for the adjunctive therapy of seizures associated with Lennox-Gastaut syndrome or with Dravet syndrome, on 18 September 2020, and added to the ARTG on 21 September 2020.
Bulgaria
In 2020, Bulgaria became the first country in the European Union to allow retail sales of food products and supplements containing CBD, despite the ongoing discussion within the EU about the classification of CBD as a novel food. But there exists a legal gap because of the lack of a legally-permissible minimum amount of THC in the products containing cannabinoids.
Canada
In October 2018, cannabidiol became legal for recreational and medical use by the federal Cannabis Act. As of August 2019, CBD products in Canada could only be sold by authorized retailers or federally licensed medical companies, limiting their access to the general public. Nonetheless, with online delivery services and over 2,600 authorized cannabis retail stores as of October 2021, accessibility has steadily increased over time. The Canadian government states that CBD products "are subject to all of the rules and requirements that apply to cannabis under the Cannabis Act and its regulations." It requires "a processing licence to manufacture products containing CBD for sale, no matter what the source of the CBD is, and that CBD and products containing CBD, such as cannabis oil, may only be sold by an authorized retailer or licensed seller of medical CBD." Edible CBD products were scheduled to be permitted for sale in Canada on October 17, 2019, for human consumption.As of August 2020, it is still illegal to carry cannabis and cannabis-derived products (including products containing CBD) across the Canadian border. If one carries any amount of cannabis for any purpose (including medical), it needs to be declared to the Canada Border Services Agency. Not declaring it is a serious criminal offence.
European Union
In 2019, the European Commission announced that CBD and other cannabinoids would be classified as "novel foods", meaning that CBD products would require authorization under the EU Novel Food Regulation stating that because "this product was not used as a food or food ingredient before May 15, 1997, before it may be placed on the market in the EU as a food or food ingredient, a safety assessment under the Novel Food Regulation is required." The recommendation – applying to CBD extracts, synthesized CBD, and all CBD products, including CBD oil – was scheduled for a final ruling by the European Commission in March 2019. If approved, manufacturers of CBD products would be required to conduct safety tests and prove safe consumption, indicating that CBD products would not be eligible for legal commerce until at least 2021. In December 2020, the European Commission concluded that CBD should not be considered as drug and can be qualified as food.Cannabidiol is listed in the EU Cosmetics Ingredient Database (CosIng). However, the listing of an ingredient, assigned with an INCI name, in CosIng does not mean it is to be used in cosmetic products or is approved for such use.Several industrial hemp varieties can be legally cultivated in Western Europe. A variety such as "Fedora 17" has a cannabinoid profile consistently around 1%, with THC less than 0.3%.
Hong Kong
In 2022, the HKSAR Government proposed a ban on any use of cannabidiol (including for academic research and by medical professionals) within the Hong Kong territory, making Hong Kong the first jurisdiction to have complete prohibition of cannabidiol, in part due to the possible presence of THC which is illegal in Hong Kong.
New Zealand
In 2017, the government made changes to the regulations so that restrictions would be removed, which meant a doctor was able to prescribe cannabidiol to patients.The passing of the Misuse of Drugs (Medicinal Cannabis) Amendment Act in December 2018 means cannabidiol is no longer a controlled drug in New Zealand, but is a prescription medicine under the Medicines Act, with the restriction that "the tetrahydrocannabinols (THCs) and specified substances within the product must not exceed 2 percent of the total CBD, tetrahydrocannabinol (THC) and other specified substances.".
Russian Federation
According to a document received in response to an appeal to the Ministry of Internal Affairs of the Russian Federation, measures of state control in the Russian Federation regarding CBD have not been established. However, there is also a response from the Ministry of Health of the Russian Federation indicating that CBD can be considered as an isomer of restricted THC. But the "isomer" argument is vague as progesterone, which is freely sold in pharmacies, is also an isomer of THC, all three being C21H30O2. On February 17, 2020, the deputy of the Moscow City Duma Darya Besedina sent an official request to the Prime Minister of the Russian Federation Mikhail Mishustin with a request to eliminate that legal ambiguity by publishing official explanations and, if necessary, making required changes in the corresponding government decree.
Sweden
Cannabidiol is classified as a medical product in Sweden. However, in July 2019, Supreme Court of Sweden ruled that CBD oil with any concentration of THC falls under the narcotic control laws.
Switzerland
While THC remains illegal, cannabidiol is not subject to the Swiss Narcotic Acts because this substance does not produce a comparable psychoactive effect. Cannabis products containing less than 1% THC can be sold and purchased legally.
Ukraine
On 7 April 2021 the Ukrainian government legalised use of isolated cannabidiol. Additionally, it approved Nabiximols, a cannabidiol-containing drug, for medical use.
United Kingdom
Cannabidiol, in an oral-mucosal spray formulation combined with delta-9-tetrahydrocannabinol, is a product available by prescription for the relief of severe spasticity due to multiple sclerosis (where other anti-spasmodics have not been effective).Until 2017, products containing cannabidiol marketed for medical purposes were classed as medicines by the UK regulatory body, the Medicines and Healthcare products Regulatory Agency (MHRA), and could not be marketed without regulatory approval for the medical claims. As of 2018, cannabis oil is legal to possess, buy, and sell in the UK, providing the product does not contain more than 1 milligram of THC and is not advertised as providing a medicinal benefit.In January 2019, the UK Food Standards Agency indicated it would regard CBD products, including CBD oil, as a novel food having no history of use before May 1997, and stated that such products must have authorisation and proven safety before being marketed. The deadline for companies with existing products to submit a full and validated novel foods application with the FSA is 31 March 2021; failure to do so before this date will exclude those companies from selling CBD. New products containing CBD after this deadline will require a fully approved application.In February 2020, the UK FSA advised vulnerable people, such as pregnant women, breastfeeding mothers, and those already taking medication for other medical concerns not to take CBD. The FSA further recommended that healthy adults should not consume more than 70 mg CBD per day.
United Nations
Cannabidiol is not scheduled under the Convention on Psychotropic Substances or any other UN drug treaties. In 2018, the World Health Organization recommended that CBD remain unscheduled.
United States
As of 2021, cannabidiol extracted from marijuana remains a Schedule I Controlled Substance, and is not approved as a prescription drug or dietary supplement or allowed for interstate commerce in the United States. CBD derived from hemp (with 0.3% THC or lower) is legal to sell as a cosmetics ingredient or for other purposes not regulated by the FDA, but cannot be sold under federal law as an ingredient in food, dietary supplement, or animal feed. It is a common misconception that the legal ability to sell hemp (which may contain CBD), and hemp extracts and derivatives (including CBD), makes CBD legal for sale as a supplement or medicine.In September 2018, following its approval by the FDA for rare types of childhood epilepsy, the GW Pharmaceuticals drug Epidiolex was rescheduled (by the Drug Enforcement Administration) as a Schedule V drug to allow for its prescription use. Epidiolex still requires rescheduling in some states before it can be prescribed in those states.In 2013, a CNN program that featured Charlottes Web cannabis brought increased attention to the use of CBD in the treatment of seizure disorders. Since then, 16 states have passed laws to allow the use of CBD products with a physicians recommendation (instead of a prescription) for treatment of certain medical conditions. This is in addition to the 30 states that have passed comprehensive medical cannabis laws, which allow for the use of cannabis products with no restrictions on THC content. Of these 30 states, eight have legalized the use and sale of cannabis products without requirement for a physicians recommendation. As of October 2020, CBD was not an FDA-approved drug eligible for interstate commerce, and the FDA encouraged manufacturers to follow procedures for drug approval.Federal illegality has made it difficult historically to conduct research on CBD. Cannabidiol is currently the subject of an FDA investigational new drug evaluation, and is not considered legal as a dietary supplement or food ingredient, as of October 2020. CBD is openly sold in head shops and health food stores in some states where such sales have not been explicitly legalized.State and local governments may also regulate cannabidiol. For example, the Massachusetts Department of Agricultural Resources issued a rule in June 2019 aligning state CBD regulations with FDA regulations. This means that although recreational marijuana is legal in the state, CBD cannot legally be sold in food or as a dietary supplement under state law.
Health concerns
In November 2019, the FDA issued concerns about the safety of cannabidiol, stating that CBD use has potential to cause liver injury, interfere with the mechanisms of prescription drugs, produce gastrointestinal disorders, or affect alertness and mood. In October 2020, the FDA updated its safety concerns about CBD, acknowledging the unknown effects of protracted use, how it affects the developing brain, fetus or infants during breastfeeding, whether it interacts with dietary supplements or prescription drugs, whether male fertility is affected, and its possible side effects, such as drowsiness.
Mislabeling and poisoning
Studies conducted by the FDA from 2014 through 2019 have determined that a majority of CBD products are not accurately labeled with the amount of CBD they contain. For example |
Cannabidiol | , a 2017 analysis of cannabidiol content in oil, tincture, or liquid vape products purchased online in the United States showed that 69% were mislabeled, with 43% having higher and 26% having lower content than stated on product labels.In 2020, the FDA conducted a study of 147 CBD products and found that half contained THC.As of September 2019, 1,085 people contacted US poison control centers about CBD-induced illnesses, doubling the number of cases over the 2018 rate and increasing by 9 times the case numbers of 2017. Of cases reported in 2019, more than 33% received medical attention and 46 people were admitted to a hospital intensive care unit, possibly due to exposure to other products, or drug interactions with CBD.
2018 Farm Bill and hemp
The 2014 Farm Bill legalized the sale of "non-viable hemp material" grown within states participating in the Hemp Pilot Program which defined hemp as cannabis containing less than 0.3% of THC. The 2018 United States Farm Bill removed the hemp plant and all "derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9 tetrahydrocannabinol concentration of not more than 0.3 percent on a dry weight basis," including CBD, from the Controlled Substances Act, making them legal to manufacture in the United States. The FDA retains regulatory authority over hemp-derived CBD, while the DEA is not involved in the regulation of legally-compliant hemp and hemp products. The 2018 Farm Bill requires that research and development of CBD for a therapeutic purpose would have to be conducted under notification and reporting to the FDA. In the United States, hemp-derived CBD is legal to sell for industrial purposes or as a cosmetics ingredient, but under FDA regulation it cannot be marketed for medical use or as an ingredient in food, dietary supplements, or animal feed.
FDA warning letters
From 2015 to May 2022, the FDA issued dozens of warning letters to American manufacturers of CBD products for false advertising and illegal interstate marketing of CBD as an unapproved drug to treat diseases, such as cancer, osteoarthritis, symptoms of opioid withdrawal, Alzheimers disease, and pet disorders. Chemical analysis of CBD products found that many did not contain the levels of CBD claimed in advertising.In December 2020, the Federal Trade Commission (FTC) initiated a law enforcement crackdown on American companies marketing CBD products as unapproved drugs. The warning also applied to hemp CBD capsules and oil that were being marketed illegally while not adhering to the federal definition of a dietary supplement.
See also
Hash oil
Hemp oil
List of investigational antipsychotics
List of investigational analgesics
References
Further reading
External links
"Cannabidiol". Drug Information Portal. U.S. National Library of Medicine. |
Carvedilol | Carvedilol, sold under the brand name Coreg among others, is a medication used to treat high blood pressure, congestive heart failure (CHF), and left ventricular dysfunction in people who are otherwise stable. For high blood pressure, it is generally a second-line treatment. It is taken by mouth.Common side effects include dizziness, tiredness, joint pain, low blood pressure, nausea, and shortness of breath. Severe side effects may include bronchospasm. Safety during pregnancy or breastfeeding is unclear. Use is not recommended in those with liver problems. Carvedilol is a nonselective beta blocker and alpha-1 blocker. How it improves outcomes is not entirely clear but may involve dilation of blood vessels.Carvedilol was patented in 1978 and approved for medical use in the United States in 1995. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2020, it was the 26th most commonly prescribed medication in the United States, with more than 23 million prescriptions.
Medical uses
Carvedilol is indicated in the management of congestive heart failure (CHF), commonly as an adjunct to angiotensin-converting-enzyme inhibitor (ACE inhibitors) and diuretics. It has been clinically shown to reduce mortality and hospitalizations in people with CHF. The mechanism behind its positive effect when used long-term in clinically stable CHF patients is not fully understood, but is thought to contribute to remodeling of the heart, improving upon its structure and function.Carvedilol reduces the risk of death, hospitalizations, and recurring heart attacks for patients with reduced heart function following a heart attack. Carvedilol has also been proven to reduce death and hospitalization in patients with severe heart failure.In practice, carvedilol has been used in the treatment of uncomplicated hypertension, yet studies suggest it has relatively ineffective blood pressure-lowering effects when compared with other blood pressure-lowering therapies or other beta blockers.
Available forms
Carvedilol is available in the following forms:
Oral tablet
Extended-release (24-hour) oral capsule (approved by the FDA in 2006)
Contraindications
Carvedilol should not be used in patients with bronchial asthma or bronchospastic conditions due to increased risk of bronchoconstriction. It should not be used in people with second- or third-degree atrioventricular block, sick sinus syndrome, severe bradycardia (unless a permanent pacemaker is in place), or a decompensated heart condition. People with severe hepatic impairment should use carvedilol with caution.
Side effects
The most common side effects (>10% incidence) of carvedilol include:
Dizziness
Fatigue
Low blood pressure
Diarrhea
Weakness
Slowed heart rate
Weight gain
Erectile dysfunctionCarvedilol is not recommended for people with uncontrolled bronchospastic disease (e.g. current asthma symptoms) as it can block receptors that assist in opening the airways.Carvedilol may mask symptoms of low blood sugar, resulting in hypoglycemia unawareness. This is termed beta blocker induced hypoglycemia unawareness.
Pharmacology
Pharmacodynamics
Carvedilol is both a non-selective β-adrenergic receptor antagonist (β1, β2) and an α-adrenergic receptor antagonist (α1). The S(–) enantiomer accounts for the beta-blocking activity whereas the S(–) and R(+) enantiomers have alpha-blocking activity. The affinity (Ki) of carvedilol for the β-adrenergic receptors is 0.32 nM for the human β1-adrenergic receptor and 0.13 to 0.40 nM for the β2-adrenergic receptor.Using rat proteins, carvedilol has shown affinity for a variety of targets including the β1-adrenergic receptor (Ki = 0.24–0.43 nM), β2-adrenergic receptor (Ki = 0.19–0.25 nM), α1-adrenergic receptor (Ki = 3.4 nM), α2-adrenergic receptor (Ki = 2,168 nM), 5-HT1A receptor (Ki = 3.4 nM), 5-HT2 receptor (Ki = 207 nM), H1 receptor (Ki = 3,034 nM), D2 receptor (Ki = 213 nM), μ-opioid receptor (Ki = 2,700 nM), veratridine site of voltage-gated sodium channels (IC50 = 1,260 nM), serotonin transporter (Ki = 528 nM), norepinephrine transporter (Ki = 2,406 nM), and dopamine transporter (Ki = 627 nM). It is an antagonist of the human 5-HT2A receptors with moderate affinity (Ki = 547 nM), although it is unclear if this is significant for its pharmacological actions given its much stronger activity at adrenergic receptors.Carvedilol reversibly binds to β-adrenergic receptors on cardiac myocytes. Inhibition of these receptors prevents a response to the sympathetic nervous system, leading to decreased heart rate and contractility. This action is beneficial in heart failure patients where the sympathetic nervous system is activated as a compensatory mechanism. Carvedilol blockade of α1-adrenergic receptors causes vasodilation of blood vessels. This inhibition leads to decreased peripheral vascular resistance and an antihypertensive effect. There is no reflex tachycardia response due to carvedilol blockade of β1-adrenergic receptors on the heart.
Pharmacokinetics
Carvedilol is about 25% to 35% bioavailable following oral administration due to extensive first-pass metabolism. Absorption is slowed when administered with food, however, it does not show a significant difference in bioavailability. Taking carvedilol with food decreases the risk of orthostatic hypotension.The majority of carvedilol is bound to plasma proteins (98%), mainly to albumin. Carvedilol is a basic, hydrophobic compound with a steady-state volume of distribution of 115 L. Plasma clearance ranges from 500 to 700 mL/min. Carvedilol is lipophilic and easily crosses the blood–brain barrier in animals, and hence is not thought to be peripherally selective.The compound is metabolized by liver enzymes, CYP2D6 and CYP2C9 via aromatic ring oxidation and glucuronidation, then further conjugated by glucuronidation and sulfation. The three active metabolites exhibit only one-tenth of the vasodilating effect of the parent compound. However, the 4-hydroxyphenyl metabolite is about 13-fold more potent in β-blockade than the parent.The mean elimination half-life of carvedilol following oral administration ranges from 7 to 10 hours. The pharmaceutical product is a mix of two enantiomorphs, R(+)-carvedilol and S(–)-carvedilol, with differing metabolic properties. R(+)-Carvedilol undergoes preferential selection for metabolism, which results in a fractional half-life of about 5 to 9 hours, compared with 7 to 11 hours for the S(-)-carvedilol fraction.
References
Further reading
External links
"Carvedilol". Drug Information Portal. U.S. National Library of Medicine. |
Auranofin | Auranofin is a gold salt classified by the World Health Organization as an antirheumatic agent. It has the brand name Ridaura.
Use
Auranofin is used to treat rheumatoid arthritis. It improves arthritis symptoms including painful or tender and swollen joints and morning stiffness. Auranofin is a safer treatment compared to the more common injectable gold thiolates (gold sodium thiomalate and gold thioglucose), but meta-analysis of 66 clinical trials concluded that it is somewhat less effective.The drug was approved for the treatment of rheumatoid arthritis in 1985. No longer a first-line treatment for rheumatoid arthritis, due to its adverse effects, "most of which are associated with long-term use for chronic disease. The most common adverse effects are gastrointestinal complaints such as loose stools, abdominal cramping and watery diarrhea, which can develop in the early months of treatment. The development of loose stools occurs in 40 % of patients, while watery diarrhea is reported in just 2–5 % of patients, and in most cases these symptoms were alleviated by reducing or splitting the dose".
Research
HIV infection
Auranofin is under investigation as a means of reducing the viral reservoir of HIV that lies latent in the bodys T-cells despite treatment with antiretroviral therapy. The drug was shown to reduce the amount of latent virus in monkey trials. A human study testing auranofin and other investigational treatments is ongoing in Brazil. Preliminary results show that auranofin contributed to a decrease in the viral reservoir.
Amebiasis
Auranofin has been identified in a high-throughput drug screen as 10 times more potent than metronidazole against Entamoeba histolytica, the protozoan agent of human amebiasis. Assays of thioredoxin reductase and transcriptional profiling suggest that the effect of auranofin on the enzyme enhances the sensitivity of the trophozoites to reactive oxygen-mediated killing in mouse and hamster models; the results are marked reductions of the number of parasites, the inflammatory reaction to the infestation, and the damage to the liver.
Acanthamoeba Keratitis and Primary Amoebic Meningoencephalitis
Auranofin may be useful in the prevention and control of Acanthamoeba infections, and in the treatment of primary amoebic meningoencephalitis, caused by pathogenic free-living amoebae Acanthamoeba spp and Naegleria fowleri, respectively.
Tuberculosis
In a cell-based screen, auranofin showed potent activity against replicating and non-replicating M. tuberculosis as well as other gram-positive bacteria. Auranofin protected mice from an otherwise lethal infection with methicillin-resistant S. aureus (MRSA). The drug acts in a similar manner in bacteria as in parasites by inhibiting thioredoxin reductase (TrxR). Studies in humans are needed to evaluate the potential of this drug to treat Gram-positive bacterial infections in humans.
Ovarian cancer
Drug-screening reveals auranofin induces apoptosis in ovarian cancer cells in vitro.
COVID-19
Auranofin may inhibit replication of SARS-CoV-2, the virus responsible for causing COVID-19 in cell culture. Inflammation may also be reduced.
Etymology
The brand name Ridaura was coined from the phrase Remission-Inducing Drug + Auranofin.
References
Further reading
External links
Media related to Auranofin at Wikimedia Commons
MedlinePlus DrugInfo medmaster-a685038 |
Acetohydroxamic acid | Acetohydroxamic acid (also known as AHA or by the trade name Lithostat) is a drug that is a potent and irreversible enzyme inhibitor of the urease enzyme in various bacteria and plants; it is usually used for urinary tract infections. The molecule is similar to urea but is not hydrolyzable by urease; it thus disrupts the bacterias metabolism through competitive inhibition.
Orphan drug
In 1983 the US Food and Drug Administration approved acetohydroxamic acid (AHA) as an orphan drug for "prevention of so-called struvite stones" under the newly enacted Orphan Drug Act of 1983. AHA cannot be patented because it is a standard chemical compound.
See also
Salicylhydroxamic acid
== References == |
Bosutinib | Bosutinib (rINN/USAN; codenamed SKI-606, marketed under the trade name Bosulif) is a small molecule BCR-ABL and src tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia.
Originally synthesized by Wyeth, it is being developed by Pfizer.
Mechanism
It is an ATP-competitive Bcr-Abl tyrosine-kinase inhibitor with an additional inhibitory effect on Src family kinases (including Src, Lyn and Hck). It has also shown activity against the receptors for platelet derived growth factor and vascular endothelial growth factor. Bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines, but did not inhibit T315I and V299L mutant cells.Bosutinib is metabolized through CYP3A4.
Medical uses
Bosutinib received US FDA and EU European Medicines Agency approval in September 2012, and March 2013, respectively for the treatment of adults with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.
Contraindications
Bosutinib has two known absolute contraindications, which are: known hypersensitivity to bosutinib and liver impairment.
Interactions
Bosutinib is both a substrate and an inhibitor of P-glycoprotein (P-gp) and CYP3A4. Hence P-gp and CYP3A4 inhibitors may increase plasma levels of bosutinib. Likewise CYP3A4 inducers may reduce plasma concentrations of bosutinib. It may also alter the metabolism and uptake (into the GIT by means of its P-gp inhibitory effects) of other drugs that are substrates for P-gp and CYP3A4.
Notes
See also
Discovery and development of Bcr-Abl tyrosine kinase inhibitors
References
External links
"Bosutinib". Drug Information Portal. U.S. National Library of Medicine. |
Oxazepam | Oxazepam is a short-to-intermediate-acting benzodiazepine. Oxazepam is used for the treatment of anxiety and insomnia and in the control of symptoms of alcohol withdrawal syndrome.
It is a metabolite of diazepam, prazepam, and temazepam, and has moderate amnesic, anxiolytic, anticonvulsant, hypnotic, sedative, and skeletal muscle relaxant properties compared to other benzodiazepines.It was patented in 1962 and approved for medical use in 1964.
Medical uses
It is an intermediate-acting benzodiazepine with a slow onset of action, so it is usually prescribed to individuals who have trouble staying asleep, rather than falling asleep. It is commonly prescribed for anxiety disorders with associated tension, irritability, and agitation. It is also prescribed for drug and alcohol withdrawal, and for anxiety associated with depression. Physicians may use oxazepam outside its approved indications to treat social phobia, post-traumatic stress disorder, insomnia, premenstrual syndrome, and other conditions.
Side effects
The side effects of oxazepam are similar to those of other benzodiazepines, and may include dizziness, drowsiness, headache, memory impairment, paradoxical excitement, and anterograde amnesia, but does not affect transient global amnesia. Side effects due to rapid decrease in dose or abrupt withdrawal from oxazepam may include abdominal and muscle cramps, convulsions, depression, inability to fall asleep or stay asleep, sweating, tremors, or vomiting.In September 2020, the U.S. Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.
Tolerance, dependence and withdrawal
Oxazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, addiction, and benzodiazepine withdrawal syndrome. Withdrawal from oxazepam or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can occur, though, at standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible by a slow and gradual dose reduction regimen.
Contraindications
Oxazepam is contraindicated in myasthenia gravis, chronic obstructive pulmonary disease, and limited pulmonary reserve, as well as severe hepatic disease.
Special precautions
Benzodiazepines require special precautions if used in the elderly, during pregnancy, in children, alcohol- or drug-dependent individuals, and individuals with comorbid psychiatric disorders. Benzodiazepines including oxazepam are lipophilic drugs and rapidly penetrate membranes, so rapidly crosses over into the placenta with significant uptake of the drug. Use of benzodiazepines in late pregnancy, especially high doses, may result in floppy infant syndrome.
Pregnancy
Oxazepam when taken during the third trimester, causes a definite risk to the neonate including a severe benzodiazepine withdrawal syndrome including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.
Interactions
As oxazepam is an active metabolite of diazepam, an overlap in possible interactions is likely with other drugs or food, with exception of the pharmacokinetic CYP450 interactions (e.g. with cimetidine). Precautions and following the prescription are required when taking oxazepam (or other benzodiazepines) in combinations with antidepressant medication (SSRIs such as fluoxetine, sertraline, and paroxetine, or multiple reuptake inhibitors such as bupropion, duloxetine, or venlafaxine), potent painkillers (opioids, e.g. morphine, oxycodone or methadone). Concurrent use of these medicines (as well as other benzodiazepines) can interact in a way that is difficult to predict. Drinking alcohol when taking oxazepam is not recommended. Concomitant use of oxazepam and alcohol can lead to increased sedation, severe problems with coordination (ataxia), decreased muscle tone, and in severe cases or in predisposed patients, even to life-threatening intoxications with respiratory depression, coma, and collapse. There is a risk of blood circulation collapse, possibly the same condition as blood circulation syncope, when oxazepam is used in combination with quetiapine, an antipsychotic.
Overdose
Oxazepam is generally less toxic in overdose than other benzodiazepines. Important factors which affect the severity of a benzodiazepine overdose include the dose ingested, the age of the patient, and health status prior to overdose. Benzodiazepine overdoses can be much more dangerous if a coingestion of other CNS depressants such as opiates or alcohol has occurred. Symptoms of an oxazepam overdose include:
Respiratory depression
Excessive somnolence
Altered consciousness
Central nervous system depression
Occasionally cardiovascular and pulmonary toxicity
Rarely, deep coma
Pharmacology
Oxazepam is an intermediate-acting benzodiazepine of the 3-hydroxy family; it acts on benzodiazepine receptors, resulting in increased effect of GABA to the GABAA receptor which results in inhibitory effects on the central nervous system. The half-life of oxazepam is between 6 and 9 hours. It has been shown to suppress cortisol levels. Oxazepam is the most slowly absorbed and has the slowest onset of action of all the common benzodiazepines according to one British study.Oxazepam is an active metabolite formed during the breakdown of diazepam, nordazepam, and certain similar drugs. It may be safer than many other benzodiazepines in patients with impaired liver function because it does not require hepatic oxidation, but rather, it is simply metabolized by glucuronidation, so oxazepam is less likely to accumulate and cause adverse reactions in the elderly or people with liver disease. Oxazepam is similar to lorazepam in this respect.
Preferential storage of oxazepam occurs in some organs, including the heart of the neonate. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate, and withdrawal of oxazepam during pregnancy and breast feeding is recommended, as oxazepam is excreted in breast milk.2 mg of oxazepam equates to 1 mg of diazepam according to the benzodiazepine equivalency converter, therefore 20 mg of oxazepam according to BZD equivalency equates to 10 mg of diazepam and 15 mg oxazepam to 7.5 mg diazepam (rounded up to 8 mg of diazepam). Some BZD equivalency converters use 3 to 1 (oxazepam to diazepam), 1 to 3 (diazepam to oxazepam) as the ratio (3:1 and 1:3), so 15 mg of oxazepam would equate to 5 mg of diazepam.
Chemistry
Oxazepam exists as a racemic mixture. Early attempts to isolate enantiomers were unsuccessful; the corresponding acetate has been isolated as a single enantiomer. Given the different rates of epimerization that occur at different pH levels, it was determined that there would be no therapeutic benefit to the administration of a single enantiomer over the racemic mixture.
Frequency of use
Oxazepam, along with diazepam, nitrazepam, and temazepam, were the four benzodiazepines listed on the pharmaceutical benefits scheme and represented 82% of the benzodiazepine prescriptions in Australia in 1990–1991.
It is in several countries the benzodiazepine of choice for novice users, due to a low chance of accumulation and a relatively slow absorption speed.
Society and culture
Misuse
Oxazepam has the potential for misuse, defined as taking the drug to achieve a high, or continuing to take the drug in the long term against medical advice. Benzodiazepines, including diazepam, oxazepam, nitrazepam, and flunitrazepam, accounted for the largest volume of forged drug prescriptions in Sweden from 1982 to 1986. During this time, a total of 52% of drug forgeries were for benzodiazepines, suggesting they were a major prescription drug class of abuse.However, due to its slow rate of absorption and its slow onset of action, oxazepam has a relatively low potential for abuse compared to some other benzodiazepines, such as temazepam, flunitrazepam, or triazolam, which have a high potential for abuse similar to barbiturates.
Legal status
Oxazepam is a Schedule IV drug under the Convention on Psychotropic Substances.
Brand names
It is marketed under many brand names worldwide, including: Alepam, Alepan, Anoxa, Anxiolit, Comedormir, durazepam, Murelax, Nozepam, Oksazepam, Opamox, Ox-Pam, Oxa-CT, Oxabenz, Oxamin, Oxapam, Oxapax, Oxascand, Oxaze, Oxazepam, Oxazépam, Oxazin, Oxepam, Praxiten, Purata, Selars, Serax, Serenal, Serepax, Seresta, Séresta, Serpax, Sobril, Tazepam, Vaben, and Youfei.It is also marketed in combination with hyoscine as Novalona and in combination with alanine as Pausafrent T.
Environmental concerns
In 2013, a laboratory study which exposed European perch to oxazepam concentrations equivalent to those present in European rivers (1.8 micrograms liter−1) found that they exhibited increased activity, reduced sociality, and higher feeding rate. In 2016, a follow-up study which exposed salmon smolt to oxazepam for seven days before letting them migrate observed increased intensity of migratory behaviour compared to controls. A 2019 study associated this faster, bolder behaviour in exposed smolt to increased mortality due to a higher likelihood of being predated on.On the other hand, a 2018 study from the same authors, which kept 480 European perch and 12 northern pikes in 12 ponds over 70 days, half of them control and half spiked with oxazepam, found no significant difference in either perch growth or mortality. However, it suggested that the latter could be explained by the exposed perch and pike being equally hampered by oxazepam, rather than the lack of an overall effect. Lastly, a 2021 study built on these results by comparing two whole lakes filled with perch and pikes - one control while the other was exposed to oxazepam 11 days into experiment, at concentrations between 11 and 24 μg L−1, which is 200 times greater than the reported concentrations in the European rivers. Even so, there were no measurable effects on pike behaviour after the addition of oxazepam, while the effects on perch behaviour were found to be negligible. The authors concluded that the effects previously attributed to oxazepam were instead likely caused by a combination of fish being stressed by human handling and small aquaria, followed by being exposed to a novel environment.
References
External links
Inchem - Oxazepam |
Dengue vaccine | Dengue vaccine is a vaccine used to prevent dengue fever in humans. Development of dengue vaccines began in the 1920s, but was hindered by the need to create immunity against all four dengue serotypes.As of 2021, one version is commercially available, known as CYD-TDV, and sold under the brand name Dengvaxia. The vaccine is only recommended in those who have previously had dengue fever or populations in which most people have been previously infected. The value of the vaccine is limited by the fact that it may increase the risk of severe dengue in those who have not previously been infected. In 2017, more than 733,000 children and more than 50,000 adult volunteers were vaccinated with CYD-TDV regardless of serostatus, which led to a controversy.In March 2021, the European Medicines Agency accepted the filing package for vaccine candidate TAK-003, which is designated for people not previously infected.There are other vaccine candidates in development including live attenuated, inactivated, DNA and subunit vaccines.
History
In December 2018, Dengvaxia was approved in the European Union.In May 2019, Dengvaxia was approved in the United States as the first vaccine approved for the prevention of dengue disease caused by all dengue virus serotypes (1, 2, 3 and 4) in people ages nine through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas. Dengue is endemic in the U.S. territories of American Samoa, Guam, Puerto Rico and the U.S. Virgin Islands.The safety and effectiveness of the vaccine was determined in three randomized, placebo-controlled studies involving approximately 35,000 individuals in dengue-endemic areas, including Puerto Rico, Latin America and the Asia Pacific region. The vaccine was determined to be approximately 76 percent effective in preventing symptomatic, laboratory-confirmed dengue disease in individuals 9 through 16 years of age who previously had laboratory-confirmed dengue disease. Dengvaxia has already been approved in 19 countries and the European Union.Dengvaxia is not approved in the U.S. for use in individuals not previously infected by any dengue virus serotype or for whom this information is unknown.Dengvaxia is a live, attenuated vaccine that is administered as three separate injections, with the initial dose followed by two additional shots given six and twelve months later.The U.S. Food and Drug Administration (FDA) granted the application for Dengvaxia priority review designation and a tropical disease priority review voucher. The approval of Dengvaxia was granted to Sanofi Pasteur.
CYD-TDV (Dengvaxia)
CYD-TDV, sold under the brand name Dengvaxia and made by Sanofi Pasteur, is a live attenuated tetravalent chimeric vaccine made using recombinant DNA technology by replacing the PrM (pre-membrane) and E (envelope) structural genes of the yellow fever attenuated 17D strain vaccine with those from the four dengue serotypes. Evidence indicates that CYD-TDV is partially effective in preventing infection, but may lead to a higher risk of severe disease in those who have not been previously infected and then do go on to contract the disease. It is not clear why the vaccinated seronegative population have more serious adverse outcomes. A plausible hypothesis is the phenomenon of antibody-dependent enhancement (ADE). American virologist Scott Halstead was one of the first researchers to identify the ADE phenomenon. Dr. Halstead and his colleague Dr. Phillip Russell proposed that the vaccine only be used after antibody testing, to rule out prior dengue exposure and avoid vaccination of sero-negative individuals.Common side effects include headache, pain at the site of injection, and general muscle pains. Severe side effects may include anaphylaxis. Use is not recommended in people with poor immune function. Safety of use during pregnancy is unclear. Dengvaxia is a weakened but live vaccine and works by triggering an immune response against four types of dengue virus.Dengvaxia became commercially available in 2016 in 11 countries: Mexico, the Philippines, Indonesia, Brazil, El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Thailand, and Singapore. In 2019 it was approved for medical use in the United States. It is on the World Health Organizations List of Essential Medicines. In Indonesia it costs about US$207 for the recommended three doses as of 2016.In 2017, the manufacturer recommended that the vaccine only be used in people who have previously had a dengue infection, as outcomes may be worsened in those who have not been previously infected. This led to a controversy in the Philippines where more than 733,000 children and more than 50,000 adult volunteers were vaccinated regardless of serostatus.The World Health Organization (WHO) recommends that countries should consider vaccination with the dengue vaccine CYD-TDV only if the risk of severe dengue in seronegative individuals can be minimized either through pre-vaccination screening or recent documentation of high seroprevalence rates in the area (at least 80% by age nine years).The WHO updated its recommendations regarding the use of Dengvaxia in 2018, based on long-term safety data stratified by serostatus on 29 November 2017. Seronegative vaccine recipients have an excess risk of severe dengue compared to unvaccinated seronegative individuals. For every 13 hospitalizations prevented in seropositive vaccinees, there would be 1 excess hospitalization in seronegative vaccinees per 1,000 vaccinees. WHO recommends serological testing for past dengue infection In 2017, the manufacturer recommended that the vaccine only be used in people who have previously had a dengue infection as otherwise there was evidence it may worsen subsequent infections. The initial protocol did not require baseline blood samples prior to vaccination in order to establish an understanding of increased risk of severe dengue in participants who had not been previously exposed. In November 2017, Sanofi acknowledged that some participants were put at risk of severe dengue if they had no prior exposure to the infection; subsequently the Philippine government suspended the mass immunization program with the backing of the WHO which began a review of the safety data.Phase III trials in Latin America and Asia involved over 31,000 children between the ages of two and 14 years. In the first reports from the trials, vaccine efficacy was 56.5% in the Asian study and 64.7% in the Latin American study in patients who received at least one injection of the vaccine. Efficacy varied by serotype. In both trials vaccine reduced by about 80% the number of severe dengue cases. An analysis of both the Latin American and Asian studies at the 3rd year of follow-up showed that the efficacy of the vaccine was 65.6% in preventing hospitalization in children older than nine years of age, but considerably greater (81.9%) for children who were seropositive (indicating previous dengue infection) at baseline. The vaccination series consists of three injections at 0, 6 and 12 months.
The vaccine was approved in Mexico, Philippines, and Brazil in December 2015, and in El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Indonesia, Thailand and Singapore in 2016. Tradenamed Dengvaxia, it is approved for use for those aged nine and older and can prevent all four serotypes.
TAK-003
TAK-003 or DENVax is a recombinant chimeric vaccine with DENV1, DENV3, and DENV4 components on a dengue virus type 2 (DENV2) backbone originally developed at Mahidol University in Bangkok and now funded by Inviragen (DENVax) and Takeda (TAK-003). Phase I and II trials were conducted in the United States, Colombia, Puerto Rico, Singapore and Thailand.
Based on the 18-month data published in the journal Lancet Infectious Diseases, indicated that TAK-003 produced sustained antibody responses against all four virus strains, regardless of previous dengue exposure and dosing schedule.Data from the phase III trial, which began in September 2016, show that TAK-003 was efficacious against symptomatic dengue. TAK-003 appears to not lack efficacy in seronegative people or potentially cause them harm, unlike CYD-TDV. The data appear to show only moderate efficacy in other dengue serotypes than DENV2.In March 2021, the European Medicines Agency accepted the filing package for TAK-003 intended for markets outside of the EU.
In development
TV-003/005
TV-003/005 is a tetravalent admixture of monovalent vaccines, that was developed by NIAID, that were tested separately for safety and immunogenicity. The vaccine passed Phase I trials and Phase II studies in US, Thailand, Bangladesh, India and Brazil.NIH has conducted Phase I and Phase II studies in over 1000 participants in the US. It has also conducted Human challenge studies while having conducted NHP model studies successfully.NIH has licensed their technology for further development and commercial scale manufacturing to Panacea Biotec, Serum Institute of India, Instituto Butantan, Vabiotech, Merck, and Medigen.In Brazil, Phase III studies are being conducted by Instituto Butantan in-collaboration with NIH. Panacea Biotec has conducted Phase II clinical studies in India.A company in Vietnam (Vabiotech) is conducting safety tests and developing a clinical trial plan. All four companies are involved in studies of a TetraVax-DV vaccine in conjunction with the US National Institutes of Health.
TDENV PIV
TDENV PIV (tetravalent dengue virus purified inactivated vaccine) is undergoing phase I trials as part of a collaboration between GlaxoSmithKline (GSK) and the Walter Reed Army Institute of Research (WRAIR). A synergistic formulation with another live attenuated candidate vaccine (prime-boost strategy) is also being evaluated in a phase II study. In prime-boosting, one type of vaccine is followed by a boost with another type in an attempt to improve immunogenicity.
V180
Merck is studying recombinant subunit vaccines expressed in Drosophila cells. As of 2019, it has completed phase I stage and V180 formulations found to be generally well tolerated.
DNA vaccines
In 2011, the Naval Medical Research Center attempted to develop a monovalent DNA plasmid vaccine, but early results showed it to be only moderately immunogenic.
Society and culture
Legal status
On 13 October 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Qdenga, intended for prophylaxis against dengue disease. The applicant for this medicinal product is Takeda GmbH. The active substance of Qdenga is dengue tetravalent vaccine (live, attenuated), a viral vaccine containing live attenuated dengue viruses which replicate locally and elicit humoral and cellular immune responses against the four dengue virus serotypes.
Economics
In Indonesia, it costs about US$207 for the recommended three doses as of 2016.
Philippines controversy
The 2017 dengue vaccine controversy in the Philippines involved a vaccination program run by the Philippines Department of Health (DOH). The DOH vaccinated schoolchildren with Sanofi Pasteurs CYD-TDV (Dengvaxia) dengue vaccine. Some of the children who received the vaccine had never been infected by the dengue virus before. The program was stopped when Sanofi Pasteur advised the government that the vaccine could put previously uninfected people at a somewhat higher risk of a severe case of dengue fever. A political controversy erupted over whether the program was run with sufficient care and who should be held responsible for the alleged harm to the vaccinated children.
References
External links
"Dengue Vaccines". Drug Information Portal. U.S. National Library of Medicine.
Dengue vaccine research. World Health Organization (WHO)
Dengue Vaccine Initiative Archived 2 August 2015 at the Wayback Machine
Dengue Vaccines at the US National Library of Medicine Medical Subject Headings (MeSH) |
Etidronic acid | Etidronic acid, also known as etidronate, is a non-nitrogenous bisphosphonate used as a medication, detergent, water treatment, and cosmetic.
It was patented in 1966 and approved for medical use in 1977.
Use
Medical
Etidronic acid is a bisphosphonate used to strengthen bone, treat osteoporosis, and treat Pagets disease of bone.
Bisphosphonates primarily reduce osteoclastic activity, which prevents bone resorption, and thus moves the bone resorption/formation equilibrium toward the formation side and hence makes bone stronger on the long run. Etidronate, unlike other bisphosphonates, also prevents bone calcification. For this reason, other bisphosphonates, such as alendronate, are preferred when fighting osteoporosis. To prevent bone resorption without affecting too much bone calcification, etidronate must be administered only for a short time once in a while, for example for two weeks every 3 months. When given on a continuous basis, say every day, etidronate will altogether prevent bone calcification. This effect may be useful and etidronate is in fact used this way to fight heterotopic ossification. But in the long run, if used on a continuous basis, it will cause osteomalacia.
Chemical
HEDP is used as a retardant in concrete, scale and corrosion inhibition in circulating cool water system, oil field and low-pressure boilers in fields such as electric power, chemical industry, metallurgy, fertilizer, etc. In light woven industry, HEDP is used as detergent for metal and nonmetal. In dyeing industry, HEDP is used as peroxide stabilizer and dye-fixing agent; In non-cyanide electroplating, HEDP is used as chelating agent. The dosage of 1–10 mg/L is preferred as scale inhibitor, 10–50 mg/L as corrosion inhibitor, and 1000–2000 mg/L as detergent. Usually, HEDP is also used together with polycarboxylic acid (superplasticizer), in which it acts as reducing agent.
Chelating agent and antioxidant
Etidronic acid is a chelating agent and may be added to bind or, to some extent, counter the effects of substances, such as calcium, iron or other metal ions, which may be discharged as a component of grey wastewater and could conceivably contaminate groundwater supplies. As a phosphonate it has corrosion inhibiting properties on unalloyed steel. Etidronic acid also acts to retard rancidification and oxidation of fatty acids.
HEDP and its salts are added to detergents and other cleaning agents to prevent the effects of hard water. It is also used in peroxide bleaching to prevent degradation of peroxides by transition metals.
Etidronic acid is listed as an ingredient of several cosmetic formulations where it is used for suppressing radical formation, emulsion stabiliser and viscosity control. While etidronic acid has not been limited from inclusion in cosmetics and does have legitimate uses, it is recommended that, as with most cosmetic products (particularly soaps), the product should be thoroughly rinsed from the skin after use.
Etidronic acid is also included among swimming pool chemicals. It is used as a stain inhibitor to prevent metal ions coming out of solution and staining the sides of swimming pools.
Etidronic acid is used in bars of soap.
Pharmacology
Synthesis
Etidronic acid can be prepared by reaction of Phosphorus trichloride with acetic acid in a tertiary amine, or by reaction of an acetic acid/acetic anhydride mixture with phosphorous acid.
== References == |
Droperidol | Droperidol /droʊˈpɛrIdɔːl/ (Inapsine, Droleptan, Dridol, Xomolix, Innovar [combination with fentanyl]) is an antidopaminergic drug used as an antiemetic (that is, to prevent or treat nausea) and as an antipsychotic. Droperidol is also often used as a rapid sedative in intensive-care treatment, and where "agitation aggression or violent behavior" are present.
History
Discovered at Janssen Pharmaceutica in 1961, droperidol is a butyrophenone which acts as a potent D2 (dopamine receptor) antagonist with some histamine and serotonin antagonist activity.
Medical use
It has a central antiemetic action and effectively prevents postoperative nausea and vomiting in adults using doses as low as 0.625 mg.
For treatment of nausea and vomiting, droperidol and ondansetron are equally effective; droperidol is more effective than metoclopramide. It has also been used as an antipsychotic in doses ranging from 5 to 10 mg given as an intramuscular injection, generally in cases of severe agitation in a psychotic patient who is refusing oral medication. Its use in intramuscular sedation has been replaced by intramuscular preparations of haloperidol, midazolam, clonazepam and olanzapine. Some practitioners recommend the use of 0.5 mg to 1 mg intravenously for the treatment of vertigo in an otherwise healthy elderly patients who have not responded to Epley maneuvers.
Black box warning
In 2001, the FDA changed the labeling requirements for droperidol injection to include a Black Box Warning, citing concerns of QT prolongation and torsades de pointes. The evidence for this is disputed, with 9 reported cases of torsades in 30 years and all of those having received doses in excess of 5 mg. QT prolongation is a dose-related effect, and it appears that droperidol is not a significant risk in low doses.
A study in 2015 showed that droperidol is relatively safe and effective for the management of violent and aggressive
adult patients in hospital emergency departments in doses of 10mg and above and that there was no increased risk of QT prolongation and torsades de pointes.
Side effects
Dysphoria, sedation, hypotension resulting from peripheral alpha adrenoceptor blockade, prolongation of QT interval which can lead to torsades de pointes, and extrapyramidal side effects such as dystonic reactions/neuroleptic malignant syndrome.
Chemistry
Droperidol is synthesized from 1-benzyl-3-carbethoxypiperidin-4-one,
which is reacted with o-phenylenediamine. Evidently, the first derivative that is formed under the reaction conditions, 1,5-benzodiazepine, rearranges into 1-(1-benzyl-1,2,3,6-tetrahydro-4-piridyl)-2-benzymidazolone. Debenzylation of the resulting product with hydrogen over a palladium catalyst, and subsequent alkylation of this using 4-chloro-4-fluorobutyrophenone yields droperidol.
C. Janssen, NV Res. Lab., GB 989755 (1962).
Janssen, P. A. J.; 1963, Belgian Patent BE 626307 .
F.J. Gardocki, J. Janssen, U.S. Patent 3,141,823 (1964).
P.A.J. Janssen, U.S. Patent 3,161,645 (1964).(See pimozide article for proposed mechanism of intramolecular rearrangement.)
References
Further reading
Scuderi PE (2003). "Droperidol: Many questions, few answers". Anesthesiology. 98 (2): 289–90. doi:10.1097/00000542-200302000-00002. PMID 12552182.
Lischke V, Behne M, Doelken P, Schledt U, Probst S, Vettermann J. Droperidol causes a dose-dependent prolongation of the QT interval. Department of Anesthesiology and Resuscitation, Johann Wolfgang Goethe-University Clinics, Frankfurt am Main, Germany.
Emergency Medicine Magazine : https://web.archive.org/web/20110527190715/http://www.emedmag.com/html/pre/tri/1005.asp |
Brompheniramine | Brompheniramine, sold under the brand name Dimetapp among others, is a first-generation antihistamine drug of the propylamine (alkylamine) class. It is indicated for the treatment of the symptoms of the common cold and allergic rhinitis, such as runny nose, itchy eyes, watery eyes, and sneezing. Like the other first-generation drugs of its class, it is considered a sedating antihistamine.It was patented in 1948 and came into medical use in 1955.
Side effects
Brompheniramines effects on the cholinergic system may include side-effects such as drowsiness, sedation, dry mouth, dry throat, blurred vision, and increased heart rate. It is listed as one of the drugs of highest anticholinergic activity in a study of anticholinergenic burden, including long-term cognitive impairment.
Pharmacology
Brompheniramine works by acting as an antagonist of histamine H1 receptors. It also functions as a moderately effective anticholinergic agent, and is likely an antimuscarinic agent similar to other common antihistamines such as diphenhydramine.
Brompheniramine is metabolised by cytochrome P450 isoenzymes in the liver.
Chemistry
Brompheniramine is part of a series of antihistamines including pheniramine (Naphcon) and its halogenated derivatives and others including fluorpheniramine, chlorpheniramine, dexchlorpheniramine (Polaramine), triprolidine (Actifed), and iodopheniramine. The halogenated alkylamine antihistamines all exhibit optical isomerism; brompheniramine products contain racemic brompheniramine maleate ,whereas dexbrompheniramine (Drixoral) is the dextrorotary (right-handed) stereoisomer.Brompheniramine is an analog of chlorpheniramine. The only difference is that the chlorine atom in the benzene ring is replaced with a bromine atom. It is also synthesized in an analogous manner.
History
Arvid Carlsson and his colleagues, working at the Swedish company Astra AB, were able to derive the first marketed selective serotonin reuptake inhibitor, zimelidine, from brompheniramine.
Names
Brand names include Bromfed, Dimetapp, Bromfenex, Dimetane, and Lodrane. All bromphemiramine preparations are marketed as the maleate salt.
See also
Pheniramine
Zimelidine
References
External links
"Brompheniramine". Drug Information Portal. U.S. National Library of Medicine. |
Copanlisib | Copanlisib (trade name Aliqopa AL-ih-KOH-pah; codenamed BAY 80-6946) is a drug which is approved by US FDA for the treatment of adult patients experiencing relapsed follicular lymphoma who have received at least two prior systemic therapies.Copanlisib has been shown to have an effect against survival and spread of cancerous B-cells.
Efficacy resulting in the approval of copanlisib was based on the subgroup of 104 patients with follicular lymphoma from a Phase 2 clinical trial. Of these, 59 percent had a complete or partial shrinkage of their tumors that lasted about 12 months.
To assess the safety of the drug, data from 168 adults with follicular lymphoma and other hematologic malignancies treated with copanlisib were evaluated.Copanlisib is administered as intravenous infusion on a weekly but intermittent schedule (three weeks on and one week off).
Copanlisib is currently approved only in the United States.
Adverse effects
Data for safety and efficacy of copanlisib are described in the consumer-targeted FDA Drug Trial Snapshot. Copanlisib can cause serious side effects including infections, hyperglycemia, hypertension, pneumonitis, neutropenia and skin rashes. The most common side effects of copanlisib are hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections and thrombocytopenia.
Copanlisib can cause harm to unborn babies. Patients with reproductive potential are thus advised to use effective contraception. Lactating patients are advised to not breastfeed.
Mechanism of action
Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B-cells. It has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines.
Regulatory history
Follicular lymphoma
For follicular lymphoma, the FDA awarded copanlisib orphan drug status in February 2015 and fast track designation in February 2016. The NDA for follicular lymphoma was granted priority review in May 2017.In September 2017, it received accelerated approval (FDA regulation 21 CFR Part 314 subpart H) for the treatment of adult patients experiencing relapsed follicular lymphoma who have received at least two prior systemic therapies. Further clinical trials are to be performed as a post-marketing requirement to verify the clinical benefit.
Other
Copanlisib was granted orphan drug status for the treatment of splenic, nodal and extranodal subtypes of marginal zone lymphoma.
Clinical trials
Phase II clinical trials are in progress for treatment of endometrial cancer, diffuse large B-cell lymphoma, cholangiocarcinoma, and non-Hodgkin lymphoma. Copanlisib in combination with R-CHOP or R-B (rituximab and bendamustine) is in a phase III trial for relapsed indolent non-Hodgkin lymphoma (NHL). Two separate phase III trials are investigating the use of copanlisib in combination with rituximab for indolent NHL and the other using copanlisib alone in cases of rituximab-refractory indolent NHL.In a preclinical study, copanlisib was effective in inhibiting HER2+ breast cancer cells with acquired resistance to the HER2-inhibitors trastuzumab and/or lapatinib. This effect was increased when copanlisib was administered along with the aforementioned HER2-inhibitors. Consequently, treatments of copanlisib with trastuzumab are being clinically trialled in HER2-positive breast cancer patients.
== References == |
Clindamycin/tretinoin | Clindamycin/tretinoin is a topical gel used in the treatment of acne. The two active ingredients are the antibiotic clindamycin phosphate (1.2%) and tretinoin (0.025%), a retinoid. The two active ingredients perform different functions, the clindamycin is active against gram-positive bacteria, including streptococci and penicillin-resistant staphylococci. The Tretinoin element acts to reduce the amount of oil released by oil glands in skin as well as encouraging skin cell replenishment. The topical treatment is stored in 2, 30, and 60 gram tubes and should be stored at 25°C (77°F), with the tube tightly shut away from light. Side effects may include peeling, redness, dryness, itching and photosensitivity. Also, topical clindamycin may rarely cause diarrhea or colitis. Sun exposure while using this preparation can cause skin irritation.
Citations
External links
Official Website |
Betamethasone | Betamethasone is a steroid medication. It is used for a number of diseases including rheumatic disorders such as rheumatoid arthritis and systemic lupus erythematosus, skin diseases such as dermatitis and psoriasis, allergic conditions such as asthma and angioedema, preterm labor to speed the development of the babys lungs, Crohns disease, cancers such as leukemia, and along with fludrocortisone for adrenocortical insufficiency, among others. It can be taken by mouth, injected into a muscle, or applied to the skin topically in cream, lotion, or liquid forms.Serious side effects include an increased risk of infection, muscle weakness, severe allergic reactions, and psychosis. Long-term use may cause adrenal insufficiency. Stopping the medication suddenly following long-term use may be dangerous. The cream commonly results in increased hair growth and skin irritation. Betamethasone belongs to the glucocorticoid class of medication. It is a stereoisomer of dexamethasone, the two compounds differing only in the spatial configuration of the methyl group at position 16 (see steroid nomenclature).Betamethasone was patented in 1958, and approved for medical use in the United States in 1961. The cream and ointment are on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In the United States, the pills and injectable solutions are more expensive than the cream.
Medical uses
Betamethasone is a corticosteroid that is available as a pill, by injection, and as an ointment, cream, lotion, gel, or aerosol (spray) for the skin, and a foam for the scalp. When given by injection, anti-inflammatory effects begin in around two hours and last for seven days.It is used as a topical cream to relieve skin irritation, such as itching and flaking from eczema. It is used as a treatment for local psoriasis, as betamethasone dipropionate and salicylic acid, or as the combination calcipotriol/betamethasone dipropionate. Betamethasone sodium phosphate is used orally and via injection with the same indications as other steroids. Many betamethasone-based pharmaceuticals include the steroid as the valerate ester.
In a randomized controlled trial betamethasone was shown to reduce some of the ataxia (poor coordination) symptoms associated with ataxia telangiectasia (A-T) by 28-31%.Betamethasone is also used to stimulate fetal lung maturation in order to prevent infant respiratory distress syndrome (IRDS) and to decrease the incidence and mortality from intracranial hemorrhage in premature infants.
A cream with 0.05% betamethasone appears effective in treating phimosis in boys, and often averts the need for circumcision. It has replaced circumcision as the preferred treatment method for some physicians in the British National Health Service.
Side effects
Euphoria
Depression
Adrenal suppression
Hypertension
Groupings of fine blood vessels becoming prominent under the skin, petechiae
Excessive hair growth (hypertrichosis)
EcchymosesProlonged use of this medicine on extensive areas of skin, broken or raw skin, skin folds, or underneath airtight dressings may on rare occasions result in enough corticosteroid being absorbed to have side effects on other parts of the body; for example, by causing a decrease in the production of natural hormones by the adrenal glands.
Betamethasone is also used prior to delivery of a preterm baby to help prepare the lungs for breathing. However, because betamethasone crosses the placenta, which is required for its beneficial effects, it may also be associated with complications, such as hypoglycemia and leukocytosis in newborns exposed in utero.
When injected into the epidural space or the spine, it may cause serious side effects like loss of vision, stroke, and paralysis.
Forms
Betamethasone is available in a number of compound forms: betamethasone dipropionate (branded as Diprosone, Diprolene, Celestamine, Procort (in Pakistan), and others), betamethasone sodium phosphate (branded as Bentelan in Italy) and betamethasone valerate (branded as Audavate, Betnovate, Celestone, Fucibet, and others). In the United States and Canada, betamethasone is mixed with clotrimazole and sold as Lotrisone and Lotriderm. It is also available in combination with salicylic acid (branded as Diprosalic) for using in psoriatic skin conditions. In some countries, it is also sold mixed with both clotrimazole and gentamicin to add an antibacterial agent to the mix.
Betamethasone sodium phosphate mixed with betamethasone acetate is available in the United States as Celestone Soluspan.
See also
Betamethasone/dexchlorpheniramine
References
External links
"Betamethasone". Drug Information Portal. U.S. National Library of Medicine.
"Betamethasone sodium phosphate". Drug Information Portal. U.S. National Library of Medicine.
"Betamethasone acetate mixture with betamethasone sodium phosphate". Drug Information Portal. U.S. National Library of Medicine. |
Lumacaftor/ivacaftor | Lumacaftor/ivacaftor, sold under the brand name Orkambi among others, is a combination of lumacaftor and ivacaftor used to treat people with cystic fibrosis who have two copies of the F508del mutation. It is unclear if it is useful in cystic fibrosis due to other causes. It is taken by mouth.Common side effects include shortness of breath, nausea, diarrhea, feeling tired, hearing problems, and rash. Severe side effects may include liver problems and cataracts. Ivacaftor increases the activity of the CFTR protein, while lumacaftor improves protein folding of the CFTR protein.It was approved for medical use in the United States in 2015, and in Canada in 2016. In the United States it costs more than $US 22,000 a month as of 2018. While its use was not recommended in the United Kingdom as of 2018, pricing was agreed upon in 2019 and it is expected to be covered by November of that year.
Medical use
The combination of lumacaftor/ivacaftor is used to treat people with cystic fibrosis who have two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein that causes the disease. This genetic abnormality is present in about half of cystic fibrosis cases in Canada. Its use is not recommended for anyone with cystic fibrosis in the United Kingdom as of 2018.While the medication resulted in improvement in the amount of air a person can breathe out in one second, the improvement seen did not reach a clinically important amount. The medication also does not appear to change a persons quality of life or the number of times a year a person has a worsening of lung function. Effects on life expectancy are unclear.
Side effects
Some people taking the combination drug had elevated transaminases; the combination drug should be used with caution for people with advanced liver disease and liver function should be measured for the first three months for all people starting the combination drug.People starting the combination have respiratory discomfort, and some children taking the combination drug developed cataracts.Lumacaftor/ivacaftor may interfere with hormonal contraceptives. Dosage of the combination drug should be reduced if the person is taking a drug that inhibits CYP3A, and inducers of CYP3A should not be used concomitantly.
Mechanism of action
F508del is a mutation that causes the CFTR protein to misfold and cells destroy such proteins soon after they are made; lumacaftor acts as a chaperone during protein folding and increases the number of CFTR proteins that are trafficked to the cell surface. Ivacaftor is a potentiator of CFTR that is already at the cell surface, increasing the probability that the defective channel will be open and allow chloride ions to pass through the channel pore. The two drugs have synergistic effects.
Physical properties
Each of lumacaftor and ivacaftor is a white to off-white powder that is practically insoluble in water. The combination drug is a single pill containing 200 mg of lumacaftor and 125 mg of ivacaftor.
History
Lumacaftor/ivacaftor was approved by the FDA in July 2015 under breakthrough therapy status and under a priority review. Previously approved for adults and pre-teens, approved on 8-7-18 for children age 2–5.
Society and culture
As of March 2016 the combination drug cost $259,000 a year in the United States.In Denmark, it was estimated in August 2015 that if the drug were introduced, the cost would amount to 2 million Danish krones (approximately 270,000 euro) each year per person.The Dutch Minister of Health announced in October 2017 that the drug would not be admitted to the public health insurance package, making it impossible to have treatment with the drug covered by Dutch health insurance. The minister stated that the price for the drug, negotiated to 170,000 euro per patient per year, is "unacceptably high in relation to the relatively modest effect, as determined by the (Dutch) Healthcare Institute". Approximately 750 patients are affected by this decision.
On 25 October, the Dutch Minister of Health announced that an agreement had been brokered with Vertex Pharmaceuticals, the company that manufactures the drug, resulting in admittance to the Dutch public health insurance package. Part of the agreement is that the result of the negotiation about the price of the treatment will not be disclosed.Protracted discussions within the United Kingdom were brought to a conclusion in September and October 2019 as NHS Scotland and NHS England both struck deals with Vertex respectively. This followed discussions where Vertex had wanted £105 000 per patient for Orkambi.The drug was not patented in Argentina, so can be made by other companies. Buyers clubs in the UK have been buying the generic version from the Argentinian company Gador.
References
External links
"Ivacaftor mixture with lumacaftor". Drug Information Portal. U.S. National Library of Medicine. |
Siklós | Siklós (Serbo-Croatian: Šikloš/Шиклош) is the 4th largest town in Baranya county, Hungary. The Malkocs Bey Mosque was built by the order of the Malkoçoğlu family.
Notable people
George Mikes, British author most famous for his humorous commentaries on various countries
Albert Siklós, composer
Rudolphus de Benyovszky, violinist and composer
Twin towns – sister cities
Siklós is twinned with:
Aiud, Romania
Donji Miholjac, Croatia
Feldbach, Austria
Fornovo di Taro, Italy
Moldava nad Bodvou, Slovakia
Gallery
References
External links
Media related to Siklós at Wikimedia Commons
Official website in Hungarian
Castle of Siklós
Programs of Siklós
All about Siklós Card |
Canakinumab | Canakinumab (INN), sold under the brand name Ilaris, is a medication for the treatment of systemic juvenile idiopathic arthritis (SJIA) and active Stills disease, including adult-onset Stills disease (AOSD). It is a human monoclonal antibody targeted at interleukin-1 beta. It has no cross-reactivity with other members of the interleukin-1 family, including interleukin-1 alpha.Common side effects include infections (colds and upper respiratory tract infections), abdominal pain and injection-site reactions.
Medical uses
Canakinumab was approved for the treatment of cryopyrin-associated periodic syndromes (CAPS) by the U.S. Food and Drug Administration (FDA) in June 2009 and by the European Medicines Agency (EMA) in October 2009. CAPS is a spectrum of autoinflammatory syndromes including Familial Cold Autoinflammatory Syndrome (FCAS), Muckle–Wells syndrome (MWS), and Neonatal-Onset Multisystem Inflammatory Disease (NOMID).
In September 2016, the FDA approved the use of canakinumab for three additional rare and serious auto-inflammatory diseases: tumor necrosis factor receptor associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD), and familial mediterranean fever (FMF).In June 2020, canakinumab was approved in the United States for the indication to treat active Stills disease, including adult-onset Stills disease (AOSD).In the European Union, canakinumab is indicated for autoinflammatory periodic fever syndromes, cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD), familial Mediterranean fever (FMF), Stills disease, and gouty arthritis.
Adverse effects
The FDA prescribing information for canakinumab (Ilaris) includes a warning for potential increased risk of serious infections due to IL-1 blockade. Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in people with rheumatic conditions, in particular Stills disease, and should be aggressively treated. Treatment with immunosuppressants may increase the risk of malignancies. People are advised not to receive live vaccinations during treatment.
History
Canakinumab was being developed by Novartis for the treatment of rheumatoid arthritis, but this trial was completed in October 2009. Canakinumab is also in phase I clinical trials as a possible treatment for chronic obstructive pulmonary disease, gout, and coronary artery disease (the CANTOS trial). It is also in trials for schizophrenia. In gout, it may result in better outcomes than a low dose of a steroid, but costs five thousand times more. One 150 mg subcutaneous injection, usually needed every two weeks, costs over $16,700.On 27 August 2017, the results of the CANTOS trial were announced at the European Society of Cardiology and published in The Lancet and The New England Journal of Medicine. Those treated in CANTOS had a 15% reduction in deaths from heart attacks, stroke and cardiovascular disease combined. However, there were serious side-effects and no statistically significant overall survival benefit. Although the CANTOS study says, "Overall, canakinumab was tolerated well with essentially identical discontinuation rates compared to placebo. Mild neutropenia and thrombocytopenia were slightly more common in those treated with canakinumab. Rates of death due to infection or sepsis were low but more likely in the canakinumab group compared to placebo (incidence rate 0.31 vs. 0.18 per 100 person-years, P = 0.02). In terms of the types of infections that occurred during follow up, only pseudomembranous colitis was more common in the canakinumab group; no evidence of opportunistic infection was observed, data emphasizing that canakinumab is not a clinically immunosuppressive intervention. Further demonstrating this issue, random allocation to canakinumab as compared to placebo in CANTOS resulted in large and highly significant dose-dependent reductions in cancer fatality, incident lung cancer, and fatal lung cancer." Nonetheless, David Goff, director of the division of cardiovascular sciences at the National Heart, Lung and Blood Institute feels the "public health impact potential is really substantial," and estimates that in the United States 3 million people might benefit from canakinumab. Further analysis on data from the CANTOS trial also showed a significant reduction in lung cancer incidence and mortality in the canakinumab treated group compared to placebo.
References
External links
"Canakinumab". Drug Information Portal. U.S. National Library of Medicine.
"Canakinumab (heavy chain)". Drug Information Portal. U.S. National Library of Medicine.
"Canakinumab (light chain)". Drug Information Portal. U.S. National Library of Medicine.
"Canakinumab". National Cancer Institute. |
Pyridoxine/doxylamine | Pyridoxine/doxylamine, sold under the brand name Diclectin among others, is a combination of pyridoxine hydrochloride (vitamin B6) and doxylamine succinate. It is generally used for nausea and vomiting of pregnancy (morning sickness); even though its efficacy has not been proven and subsequent research has led to the removal of recommendations in medical journals.
Medical uses
The combination of pyridoxine, commonly referred to as vitamin B6 and doxylamine may be an effective for the management of nausea and vomiting of pregnancy, but it is only recommended for use in a small number of cases after lifestyle, diet and vitamin B6. A 2018 review found the benefit was small.Doxylamine and pyridoxine are pregnancy compatible drugs, consistent with FDAs safety assessment of the combination product. They have been categorized by the FDA as a category A drug (no evidence of risk to the fetus). This letter classification system for risk in pregnancy is no longer being utilized and is currently being phased out by the FDA.
Medical organizations’ position
The American Congress of Obstetricians and Gynecologists (ACOG) states "Safe and effective treatments are available for more severe cases, and mild cases of nausea and vomiting of pregnancy may be resolved with lifestyle and dietary changes." The American Family Medicine recommends, "Initial treatment is conservative and includes dietary changes, emotional support, and vitamin B6 supplementation." This treatment has a Grade A, "consistent, good-quality patient-oriented evidence " while the addition of prescribing doxylamine has a Grade C, "consensus, disease-oriented evidence, usual practice, expert opinion, or case series."
Canadian Family Physician issued a correction stating of previous articles which stated Diclectin should be used as a first line therapy where incorrect and were based upon undisclosed conflicts of interest with the manufacturer and where not peer reviewed studies:"Recommendations in 2 articles published in Canadian Family Physician, “Nausea and vomiting of pregnancy. Evidence-based treatment algorithm” and “Treatment of nausea and vomiting in pregnancy. An updated algorithm,” have subsequently come under critical scrutiny. These articles were not subjected to standard peer review, and Canadian Family Physician acknowledges that upon closer inspection these articles did not provide satisfactory evidence that would have justified the recommendation of doxylamine-pyridoxine as a sole first-line treatment for nausea and vomiting in pregnancy (NVP). More recent Canadian NVP guidelines have been published; however, a subsequent re-analysis questions the conclusions of 1 of the studies cited in these guidelines to justify doxylamine-pyridoxine as a recommended first-line treatment for NVP. Additionally, for the articles in Canadian Family Physician there was an undisclosed conflict of interest with Duchesnay, the manufacturer of Diclectin, the combination of doxylamine-pyridoxine. Canadian Family Physician encourages readers to interpret previously published NVP recommendations with caution. Readers are also referred to the commentary “Motherisk and Canadian Family Physician” in the January 2017 issue of Canadian Family Physician." [Ed: bolding to help summarize information, note please follow link to article to see the footnotes from this article]
Adverse effects
Pyridoxine, vitamin B6, is a water-soluble vitamin and is generally recognized as having no adverse effects. After diet changes, it alone is recommended as the secondary treatment plan.
The most commonly reported adverse reaction of doxylamine is drowsiness. Other adverse drug reactions associated with doxylamine succinate may include: vertigo, nervousness, epigastric pain, headache, palpitation, diarrhea, disorientation, irritability, convulsions, urinary retention or insomnia.It is not recommended to take doxylamine with other medications of the same class, medications that act on the central nervous system (CNS) or with alcohol as this may increase the risk of adverse effects. To minimize the risk of particular adverse effects, doxylamine should not be used when taking any medication classified as a monoamine oxidase inhibitor (MAOI), and should be used with caution, if at all, when certain medical conditions are present.Because doxylamine is small enough on a molecular weight basis to pass into breastmilk, women should not breastfeed while using products with doxylamine as this may lead to adverse effects in the breastfed infant.
Safety in pregnancy
Due to the extensive scientific evidence demonstrating that there is no difference in the risk for birth defects or other adverse pregnancy outcomes between infants whose mothers take pyridoxine/doxylamine during pregnancy and those infants whose mothers do not take this drug combination, the two ingredients of the drug are considered pregnancy compatible (or category A drugs with the previous pregnancy risk factor classification system).
Since the mid-1950s, over 33 million women have used the combination drug of pyridoxine/doxylamine in pregnancy, and scientific analysis on more than 200,000 exposed pregnancies has been conducted to determine if the combination of pyridoxine and doxylamine is harmful to the unborn baby. No epidemiological studies have found any teratogenic effect.Two separate meta-analyses have been conducted that have assessed pregnancy outcomes following the use of a combination of pyridoxine and doxylamine with or without dicyclomine during the first trimester of pregnancy. The initial meta-analysis, published in 1988, combined data from 12 cohort and 5 case-control studies, and the subsequent meta-analysis, published in 1994, combined data from 16 cohort studies and 11 case control studies. These studies included over 200,000 Bendectin-exposed pregnancies and did not observe an increased risk for major malformations. Separate analyses were conducted for specific defects including cardiac defects, limb reduction defects, oral clefts, and genital tract malformations; no increased risks for these defects were found.In 1989, a report on the safety of the drug combination of pyridoxine/doxylamine for use in the management of NVP was prepared by a panel of Canadian and American experts for the Special Advisory Committee on Reproductive Physiology to the Health Protection Branch of Health Canada (currently called the Health Products and Food Branch). These scientific experts concluded that “numerous studies in animals and in humans that have been reported in the scientific and medical literature demonstrate that Bendectin is not a teratogen. The safety of Bendectin/Diclectin in the management of nausea and vomiting of pregnancy has been established by its use in many thousands of pregnant women”.A study was conducted to determine whether the combination drug of pyridoxine and doxylamine had an effect on the neurodevelopment of children exposed in utero. Results from this study observed no difference in intelligence quotient scores between children who were exposed to pyridoxine/doxylamine in utero and children who were not exposed.
History
The combination of doxylamine and vitamin B6 was first introduced to the US market as Bendectin in 1956. At that time, Bendectin was a 3 ingredients prescription medication. The third one, dicyclomine, a Pregnancy Category B anticholinergic/antispasmodic, was omitted from the formulation starting in 1976 due to its lack of efficacy.: 317 Bendectin (doxylamine/vitamin B6) was voluntarily removed from the market in 1983 by its manufacturer, Merrell Dow Pharmaceuticals, following numerous lawsuits alleging that it caused birth defects, although an FDA panel concluded that no association between Bendectin and birth defects had been demonstrated. In litigation, Bendectin was implicated as the cause of various fetal malformations and problems including limb and other musculoskeletal deformities, facial and brain damage, defects of the respiratory, gastrointestinal, cardiovascular and genital-urinary systems, blood disorders and cancer. The most famous case involving the drug is Daubert v. Merrell Dow Pharmaceuticals (1993). These suits were led by celebrity plaintiff attorney Melvin Belli . The star witness for the case against Bendectin, William McBride, was later found to have falsified research on teratogenic effects of the drug, and was struck off the medical register in Australia.An extensive review of the evidence submitted in legal proceedings regarding Bendectin has been summarized and found no evidence that the drug in clinical use was linked to birth defects.The FDA, in 1999, published a statement in the Federal Register that summarized their opinion regarding the safety of pyridoxine/doxylamine during pregnancy: “The FDA has determined that the drug product Bendectin, a tablet composed of pyridoxine hydrochloride 10 mg, and doxylamine succinate 10 mg, for the prevention of nausea of pregnancy was not withdrawn from the market for reasons of safety or effectiveness”.
On Monday April 8, 2013, the FDA approved the return of the doxylamine-pyridoxine combination under the new trademark name of Diclegis. The medication is manufactured by Duchesnay Inc, a company later shown to not disclose conflict of interests with authors, leading to Canadian Family Physician to correct several articles because of their behavior and the lack of research that shows that there was medically significant results.In July 2015, the drug company came under considerable scrutiny for promoting its drug through the American celebrity Kim Kardashian through the social media platforms Facebook and Instagram.In October 2015, Toronto, Canada physicians Drs. Navindra Persaud, Jessica Chin, and Mark Walker wrote a public letter to the Journal of Obstetrics and Gynaecology of Canada and raised concerns over the risks of Diclectin and recommended reconsidering it as the "first-line pharmacological treatment" against the nausea and vomiting of pregnancy. Dr. Persaud shared with news agencies that his only source of research data for this drug came from Health Canada and claimed he was only able to access the document by signing a confidentiality agreement.In January 2019, Canadian Family Physician issued a correction stating "Recommendations in 2 articles published in Canadian Family Physician, “Nausea and vomiting of pregnancy. Evidence-based treatment algorithm” and “Treatment of nausea and vomiting in pregnancy. An updated algorithm,” have subsequently come under critical scrutiny. These articles were not subjected to standard peer review, and Canadian Family Physician acknowledges that upon closer inspection these articles did not provide satisfactory evidence that would have justified the recommendation of doxylamine-pyridoxine as a sole first-line treatment for nausea and vomiting in pregnancy (NVP). More recent Canadian NVP guidelines have been published; however, a subsequent re-analysis questions the conclusions of 1 of the studies cited in these guidelines to justify doxylamine-pyridoxine as a recommended first-line treatment for NVP. Additionally, for the articles in Canadian Family Physician there was an undisclosed conflict of interest with Duchesnay, the manufacturer of Diclectin, the combination of doxylamine-pyridoxine. Canadian Family Physician encourages readers to interpret previously published NVP recommendations with caution. Readers are also referred to the commentary “Motherisk and Canadian Family Physician” in the January 2017 issue of Canadian Family Physician." [Ed: bolding to help summarize information, note please follow link to article to see the footnotes from this article]
Society and culture
From a legal perspective, the case through Daubert v. Merrell Dow Pharmaceuticals, 509 U.S. 579 (1993) set a new standard for admitting expert testimony in federal courts in lieu of the Frye standard.
See also
Daubert v. Merrell Dow Pharmaceuticals
Daubert standard
References
External links
FDA FederalRegister/Vol. 64, No. 152/August 9,1999/Determination That Bendectin Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness
FDA approves Diclegis for pregnant women experiencing nausea and vomiting, April 8, 2013
About Morning Sickness from MOTHERISK at the Hospital for Sick Children in Toronto |
Trolamine salicylate | Trolamine salicylate (Aspercreme, Aspergel) is an organic compound which is the salt formed between triethanolamine and salicylic acid.
It is used as an ingredient in sunscreens, analgesic creams, and cosmetics. The salicylic acid portion contributes to both the sun protection effect (by absorbing UVB radiation) and to the analgesic effect. The triethanolamine neutralizes the acidity of the salicylic acid. One benefit of this topical analgesic is that it has no odor, in contrast to other topical analgesics such as menthol.
The US Food and Drug Administration has not reviewed any of the over-the-counter products listed in the Daily Med database that contain trolamine salicylate. Also, the producers of trolamine salicylate products have not provided evidence to the FDA in support of claims that this chemical is directly absorbed through the skin into underlying tissue. Due to health concerns, in 2019 the FDA issued a proposed rule classifying the sunscreen use of trolamine salicylate as "not generally recognized as safe and effective." One study reported that trolamine salicylate does penetrate into, and persist within, underlying muscle tissue. The test subjects used either the trolamine salicylate product or a placebo while engaging in an exercise regimen designed to induce muscle soreness. The experimenters observed that those using the trolamine salicylate product exercised longer before reporting the onset of soreness, reported less intense soreness, and reported that their soreness did not last as long as the people who used the placebo.All of the trolamine salicylate-containing products listed in the two cited references are 10% solutions. These products are sold under various brand names, e.g. Aspercreme, and are marketed as topical analgesics for temporary relief of arthritis, simple backache, muscle strains, and sprains.
See also
Methyl salicylate
== References == |
Golodirsen | Golodirsen, sold under the brand name Vyondys 53, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). It is an antisense oligonucleotide drug of phosphorodiamidate morpholino oligomer (PMO) chemistry.The most common side effects include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms (nasopharyngitis) and nausea.
Medical uses
Golodirsen is indicated for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping.
Mechanism of action
Golodirsen has been provisionally approved for approximately 8% of all DMD patients amenable to exon 53 skipping. It works by inducing exon skipping in the dystrophin gene and thereby increasing the amount of dystrophin protein available to muscle fibers.
Adverse effects
The most common side effects include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms (nasopharyngitis) and nausea. In animal studies, no significant changes were seen in the male reproductive system of monkeys and mice following weekly subcutaneous administration. According to the reports obtained from the clinical trials, pain at the site of intravenous administration, back pain, oropharyngeal pain, sprain in ligaments, diarrhea, dizziness, contusion, flu, ear infection, rhinitis, skin abrasion, tachycardia, and constipation occurred at an elevated frequency in the treatment group, as compared to their placebo counterparts. Hypersensitivity reactions, including rash, fever, itching, hives, skin irritation (dermatitis) and skin peeling (exfoliation), have occurred in people who were treated with golodirsen.Renal toxicity was observed in animals who received golodirsen. Although renal toxicity was not observed in the clinical studies with golodirsen, potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Renal function should be monitored in those taking golodirsen.
Pharmacology
Pharmacokinetics
Following single or multiple intravenous infusions, the majority of drug elimination occurs within 24 hours of intravenous administration. The elimination half-life of golodirsen, in parity with eteplirsen was 3 to 6 hours.
Clinical benefits
As a first-generation drug, golodirsen is far away from being curative; clinical trial outcomes have demonstrated the drug to have a marginal effect on ameliorating DMD pathology. As of December 2019, golodirsen is approved for therapeutic use in the United States, as well as in the countries that automatically recognize the decisions of the US Food and Drug Administration, under the condition that its benefit will be demonstrated in a confirmatory clinical trial.
Society and culture
Golodirsen is one of the very few FDA-approved exon-skipping therapy for Duchenne muscular dystrophy (DMD), although the clinical benefits of the drug are yet to established. While the development of golodirsen needed huge financing, it is only applicable to a small subset of DMD patients. Sarepta Therapeutics has announced that golodirsen will cost in parity with eteplirsen, another drug of a similar kind, which may be as high as US$300,000 a year. Whether the patients should spend so much on a drug with questioned efficacy raises concerns. Also, the accelerated approval of golodirsen has paved the way for the patients to have early access to the drug, at the same time, it shrouded with controversy over a number of issues. A double-blind placebo-controlled confirmatory trial (NCT02500381) is ongoing to resolve the issues.
History
Golodirsen was developed by collaborative research led by Prof. Steve Wilton and Prof. Sue Fletcher in the Perron Institute and licensed to Sarepta Therapeutics by the University of Western Australia.In the pivotal clinical trial of golodirsen, dystrophin levels increased, on average, from 0.10% of normal at baseline to 1.02% of normal after 48 weeks of treatment with the drug or longer. The change was a surrogate endpoint and the trial did not establish clinical benefit of the drug, including changes to the subjects motor function.The pharmacological assessment of golodirsen did not include special population groups, e.g., pregnant and lactating women, the elderly, and patients with concurrent disease states. As DMD predominantly affects male children and young adults, and golodirsen is indicated for the treatment of pediatric patients, but primarily not for adult women, the elderly, and patients with comorbidity, it was not evaluated on them.The US Food and Drug Administration (FDA) approved golodirsen in December 2019, under the accelerated approval pathway. The application for golodirsen was granted fast track designation, priority review designation, orphan drug designation, and a rare pediatric disease priority review voucher.
References
External links
"Golodirsen". Drug Information Portal. U.S. National Library of Medicine (NLM). |
Dust mite allergy | Dust mite allergy, also known as house dust allergy, is a sensitization and allergic reaction to the droppings of house dust mites. The allergy is common and can trigger allergic reactions such as asthma, eczema or itching. It is the manifestation of a parasitosis. The mites gut contains potent digestive enzymes (notably peptidase 1) that persist in their feces and are major inducers of allergic reactions such as wheezing. The mites exoskeleton can also contribute to allergic reactions. Unlike scabies mites or skin follicle mites, house dust mites do not burrow under the skin and are not parasitic.The symptoms can be avoided or alleviated by a number of measures. In general, cutting down mite numbers may reduce these reactions while others say efforts to remove these mites from the environment have not been found to be effective. Immunotherapy may be useful in those affected. Subcutaneous injections have better evidence than under the tongue dosing. Topical steroids as nasal spray or inhalation may be used.
Severe dust mite infestation in the home has been linked to atopic dermatitis, and epidermal barrier damage has been documented.
Symptoms
Dust mite allergy symptoms include:
Cough
Facial pressure and pain
Itchy, red or watery eyes
Itchy nose, roof of the mouth or throat
Nasal congestion
Postnasal drip
Runny nose, sneezing
Swollen, blue-colored skin under the eyesIf the dust mite allergy contributes to asthma:
Audible whistling or wheezing sound when exhaling
Bouts of coughing or wheezing that are worsened by a respiratory virus such as a cold or the flu
Chest tightness or pain
Difficulty breathing
Trouble sleeping caused by shortness of breath, coughing or wheezing
Cross-reactivity to shellfish allergy
Tropomyosin, the major allergen in dust mites, is also responsible for shellfish allergy. Exposure to inhaled tropomyosins from dust mites is thought to be the primary sensitizer for shellfish allergy, an example of inhalant-to-food cross-reactivity. Epidemiological surveys have confirmed correlation between shellfish and dust mite sensitizations. An additional confirmation was seen in Orthodox Jews with no history of shellfish consumption, in that skin tests confirming dust mite allergy were also positive for shellfish tropomyosin. In addition to tropomyosin, the proteins arginine kinase and hemocyanin seem to have a role in cross-reactivity to dust mites.
Prevention
House dust mites are present indoors wherever humans live. Positive tests for dust mite allergies are extremely common among people with asthma. Dust mites are microscopic arachnids whose primary food is dead human skin cells, but they do not live on living people. They and their feces and other allergens that they produce are major constituents of house dust, but because they are so heavy they are not suspended for long in the air. They are generally found on the floor and other surfaces, until disturbed (by walking, for example). It could take somewhere between twenty minutes and two hours for dust mites to settle back down out of the air.
Dust mites are a nesting species that prefer a dark, warm, and humid climate. They flourish in mattresses, bedding, upholstered furniture, and carpets. Their feces include enzymes that are released upon contact with a moist surface, which can happen when a person inhales, and these enzymes can kill cells within the human body. House dust mites did not become a problem until humans began to use textiles, such as western style blankets and clothing.
Furniture
Furniture with wooden or leather surfaces reduces the dust mite population.
Bed linen
Hot tumble drying a bed linen for 1 hour will kill 99% of mites therein.Weekly changing the bed linen reduces the risk of exposure to dust mites.Cotton covers not covered with complete mattress covers are very likely to become colonized by bacteria and molds; they must be cleaned periodically (at least every second to third month). Here, the dust mites are beneficial as they return cotton to its original state after it has degraded by contact with bare skin.Dust mite eggs are freeze tolerant (−70 °C for 30 minutes); hatching can normally be prevented by exposure of fabrics to:
Direct sunlight for 3 hours or
Dry or wet heat of at least 60 °C (140 °F) for a minimum of 30 minutes.Dust mites drown in water.Good properties of anti-mite fabrics have been identified as being:
Thread count greater than 246.
Pore size of between 2 and 10 micrometres. This will prevent dust mite faecal pellets that can be small as 10 µm.
Allergen impenetrability >99%.
Dust leakage of less than 4%.
Breathability between 2 and 6 cm3 s−1 cm−2.
Indoor climate
Allergy patients are advised to keep the relative humidity below 50%, if possible. Very few mites can survive if the humidity is less than 45% (at 22 °C (72 °F)). However, they can survive if the humidity is high just for an hour and a half per day, for example due to moisture released to the air when cooking food.
Treatment
Allergen immunotherapy
Allergen immunotherapy (AIT, also known as desensitization or hypo-sensitization) is a treatment involved in administering the doses of allergens to accustom the body to substances that are generally harmless (pollen, house dust mites), thereby inducing specific long-term tolerance. Allergen immunotherapy is the only treatment that alters the disease mechanism.Immunotherapy can be administered orally (as sublingual tablets or sublingual drops), or by injections under the skin (subcutaneous). Subcutaneous immunotherapy is the most common form and has the largest body of evidence supporting its effectiveness.
Subcutaneous Immunotherapy (SCIT)
Subcutaneous Immunotherapy (SCIT) also known as Allergy Shots are series of shots/injections of the allergen given into the fat under the skin that have progressively larger amounts of allergen. These shots can be given to the Kids as young as 5 years old.
Sublingual immunotherapy (SLIT)
HDM-SLIT tablet, House Dust Mites (Dermatophagoides farinae and Dermatophagoides pteronyssinus) Allergen Extract (Trade-names: ODACTRA, ACARIZAX & MITICURE), is the only FDA approved allergen extract for the immunotherapic treatment of adolescents (12–17 years) and adults (18–65 years). It significantly treats house dust mite (HDM)-induced allergic rhinitis, with or without conjunctivitis. It has been approved in almost all over the world with countries like Japan, Russia, South-East Asia, Turkey, the Middle East, New Zealand and 14 European countries.
Further reading
List of mites associated with cutaneous reactions
List of allergens
House dust mite
Allergy
Asthma and Allergy Friendly
Allergic rhinitis
References
External links
House Dust Mite Injection (Dermatophagoides Pteronyssinus): Uses, Dosage, Side Effects, Interactions, Warning |
Telmisartan | Telmisartan, sold under the brand name Micardis among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combination telmisartan/hydrochlorothiazide, telmisartan/cilnidipine and telmisartan/amlodipine. Compared to other drugs in its class, Telmisartan has a relatively high dosing, on average 80 mg/day.
Common side effects include upper respiratory tract infections, diarrhea, and back pain. Serious side effects may include kidney problems, low blood pressure, and angioedema. Use in pregnancy may harm the baby and use when breastfeeding is not recommended. It is an angiotensin II receptor antagonist and works by blocking the effects of angiotensin II.Telmisartan was patented in 1991 and came into medical use in 1999. It is available as a generic medication. In 2018, it was the 292nd most commonly prescribed medication in the United States, with more than 1 million prescriptions.
Medical uses
Telmisartan is used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure.: 146
Contraindications
Telmisartan is contraindicated during pregnancy. Like other drugs affecting the renin–angiotensin system (RAS), telmisartan can cause birth defects, stillbirths, and neonatal deaths. It is not known whether the drug passes into the breast milk. Also it is contraindicated in bilateral renal artery stenosis in which it can cause kidney failure.
Side effects
Side effects are similar to other angiotensin II receptor antagonists and include tachycardia and bradycardia (fast or slow heartbeat), hypotension (low blood pressure) and edema (swelling of arms, legs, lips, tongue, or throat, the latter leading to breathing problems). Allergic reactions may also occur.
Interactions
Due to its mechanism of action, telmisartan increases blood potassium levels. Combination with potassium preparations or potassium-sparing diuretics could cause hyperkalaemia (excessive potassium levels). Combination with NSAIDs, especially in patients with impaired kidney function, has a risk of causing (usually reversible) kidney failure.
Pharmacology
Mechanism of action
Telmisartan is an angiotensin II receptor blocker that shows high affinity for the angiotensin II receptor type 1 (AT1), with a binding affinity 3000 times greater for AT1 than AT2.
In addition to blocking the renin–angiotensin system, telmisartan acts as a selective modulator of peroxisome proliferator-activated receptor gamma (PPAR-γ), a central regulator of insulin and glucose metabolism. It is believed that telmisartans dual mode of action may provide protective benefits against the vascular and renal damage caused by diabetes and cardiovascular disease (CVD).Telmisartans activity at the peroxisome proliferator-activated receptor delta (PPAR-δ) receptor has prompted speculation around its potential as a sport doping agent as an alternative to GW 501516. Telmisartan activates PPAR-δ receptors in several tissues.Also, telmisartan has a PPAR-γ agonist activity.: 171
Pharmacokinetics
The substance is quickly but to varying degrees absorbed from the gut. The average bioavailability is about 50% (42–100%). Food intake has no clinically relevant influence on the kinetics of telmisartan. Plasma protein binding is over 99.5%, mainly to albumin and alpha-1-acid glycoprotein. It has the longest half-life of any angiotensin II receptor blocker (ARB) (24 hours) and the largest volume of distribution among ARBs (500 liters). Less than 3% of telmisartan is inactivated by glucuronidation in the liver, and over 97% is eliminated in unchanged form via bile and faeces.
History
Society and culture
Telmisartan is available as a generic medication.
References
Further reading
Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. (April 2008). "Telmisartan, ramipril, or both in patients at high risk for vascular events". The New England Journal of Medicine. Massachusetts Medical Society. 358 (15): 1547–59. doi:10.1056/nejmoa0801317. hdl:2437/81925. PMID 18378520.
Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, et al. (September 2008). "Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial". Lancet. 372 (9644): 1174–83. doi:10.1016/S0140-6736(08)61242-8. PMID 18757085. S2CID 5203511. Retrieved 2019-11-26.
External links
"Telmisartan". Drug Information Portal. U.S. National Library of Medicine. |
Lemborexant | Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maintenance in adults. The medication is taken by mouth.Side effects of lemborexant include somnolence, fatigue, headache, and abnormal dreams. The medication is a dual orexin receptor antagonist (DORA). It acts as a selective dual antagonist of the orexin receptors OX1 and OX2. Lemborexant has a long elimination half-life of 17 to 55 hours and a time to peak of about 1 to 3 hours. It is not a benzodiazepine or Z-drug and does not interact with GABA receptors, instead having a distinct mechanism of action.Lemborexant was approved for medical use in the United States in December 2019. It is a schedule IV controlled substance in the United States and may have a low potential for misuse. Besides lemborexant, other orexin receptor antagonists including suvorexant and daridorexant have also been introduced.
Medical uses
Lemborexant is used in the treatment of insomnia in adults.A major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found that lemborexant had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4 weeks of 0.36 (95% CI 0.08 to 0.63) and at 3 months of 0.41 (95% CI 0.04 to 0.78). Lemborexant had similar effect sizes at 4 weeks as the other evaluated and marketed orexin receptor antagonists suvorexant (SMD 0.31, 95% CI 0.01 to 0.62) and daridorexant (SMD 0.23, 95% CI –0.01 to 0.48), whereas benzodiazepines and Z-drugs generally showed larger effect sizes (e.g., SMDs of 0.45 to 0.83) than lemborexant and the other orexin receptor antagonists. However, the review concluded that lemborexant and eszopiclone among all of the insomnia medications assessed had the best profiles overall in terms of efficacy, tolerability, and acceptability.Compared to benzodiazepines, there is a low risk of developing tolerance and dependence. Memory and attention are not affected the next morning when taking lemborexant.
Available forms
Lemborexant is available in the form of 5 and 10 mg oral film-coated tablets.
Side effects
Side effects of lemborexant include somnolence or fatigue (combined preferred terms of somnolence, lethargy, fatigue, and sluggishness) (6.9% at 5 mg and 9.6% at 10 mg vs. 1.3% for placebo), headache (5.9% at 5 mg and 4.5% at 10 mg vs. 3.4% for placebo), and nightmares or abnormal dreams (0.9% at 5 mg and 2.2% at 10 mg vs. 0.9% for placebo). Less common side effects include sleep paralysis (1.3% at 5 mg and 1.6% at 10 mg vs. 0% for placebo) and hypnagogic hallucinations (0.1% at 5 mg and 0.7% at 10 mg vs. 0% for placebo).Lemborexant at doses of 10, 20, and 30 mg produces drug-liking responses similar to those of zolpidem (30 mg) and suvorexant (40 mg) in recreational sedative drug users. It is a controlled substance in the United States and is considered to have a low misuse potential.
Pharmacology
Pharmacodynamics
Lemborexant is a dual antagonist of the orexin OX1 and OX2 receptors. It associates and dissociates from the orexin receptors more rapidly than certain other orexin receptor antagonists, such as suvorexant, and this may cause it to have a shorter duration of action.
Pharmacokinetics
The bioavailability of lemborexant is good and is at least 87%. The time to peak levels of lemborexant is 1 to 3 hours. A high-fat and high-calorie meal has been found to delay the time to peak levels by 2 hours. Its plasma protein binding in vitro is 94%. Lemborexant is metabolized primarily by CYP3A4 and to a lesser extent by CYP3A5. The "effective" half-life of lemborexant is 17 to 19 hours while its terminal elimination half-life is 55 hours. The medication is excreted in feces (57%) and to a lesser extent urine (29%).
Although lemborexant has a longer terminal elimination half-life than suvorexant, it appears to be more rapidly cleared than suvorexant in the earlier phases of elimination. In addition, lemborexant dissociates from the orexin receptors more rapidly than does suvorexant. These differences may allow for comparatively reduced next-day effects such as daytime somnolence with lemborexant.
History
In June 2016, Eisai initiated Phase III clinical trials in the United States, France, Germany, Italy, Japan, Poland, Spain and the UK.In December 2019, lemborexant was approved for use in the United States based on results from the SUNRISE 1 and SUNRISE 2 Phase III clinical trials.
Society and culture
Names
Lemborexant is the generic name of the drug and its INN while E-2006 was its developmental code name. Lemborexant is sold under the brand name Dayvigo.
Availability
Lemborexant is marketed in the United States, Canada, Australia, and Japan. It is not approved by the European Medicines Agency (EMA) for use in the European Union or by the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom.
Research
Lemborexant is under development for the treatment of circadian rhythm sleep disorders, sleep apnea, and chronic obstructive pulmonary disease. As of February 2022, it is in phase 2 clinical trials for circadian rhythm sleep disorders and phase 1 trials for sleep apnea and chronic obstructive pulmonary disease.
References
External links
"Lemborexant". Drug Information Portal. U.S. National Library of Medicine. |
Vonicog alfa | Vonicog alfa, sold under the brand names Vonvendi and Veyvondi, is a medication used to control bleeding in adults with von Willebrand disease (an inherited bleeding disorder). It is a recombinant von Willebrand factor.The most common adverse reactions are generalized itching, vomiting, nausea, dizziness, and vertigo.Vonicog alfa should not be used in the treatment of Hemophilia A.In the UK it is available only via a named patient access program.Vonicog alfa was approved for medical use in the United States in December 2015, in the European Union in August 2018, and in Australia in April 2020. It was granted orphan drug designations in both the United States and the European Union.
Medical uses
Vonicog alfa is indicated in adults with von Willebrand Disease (VWD), when desmopressin (DDAVP) treatment alone is ineffective or not indicated for the
Treatment of haemorrhage and surgical bleeding
Prevention of surgical bleeding.
Adverse effects
The following side effects may occur during treatment with vonicog alfa: hypersensitivity (allergic) reactions, thromboembolic events (problems due to the formation of blood clots in the blood vessels), development of inhibitors (antibodies) against von Willebrand factor, causing the medicine to stop working and resulting in a loss of bleeding control. The most common side effects with vonicog alfa (which may affect up to 1 in 10 patients) are dizziness, vertigo (a spinning sensation), dysgeusia (taste disturbances), tremor, rapid heartbeat, deep venous thrombosis (blood clot in a deep vein, usually in the leg), hypertension (high blood pressure), hot flush, vomiting, nausea (feeling sick), pruritus (itching), chest discomfort, sensations like numbness, tingling, pins and needles at the site of infusion, and an abnormal reading on the electrocardiogram (ECG).
References
Further reading
AusPAR: Vonicog alfa. Therapeutic Goods Administration (TGA) (Report). October 2020.
External links
"Vonicog alfa". Drug Information Portal. U.S. National Library of Medicine. |
Hib vaccine | The Haemophilus influenzae type B vaccine, also known as Hib vaccine, is a vaccine used to prevent Haemophilus influenzae type b (Hib) infection. In countries that include it as a routine vaccine, rates of severe Hib infections have decreased more than 90%. It has therefore resulted in a decrease in the rate of meningitis, pneumonia, and epiglottitis.It is recommended by both the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC). Two or three doses should be given before six months of age. In the United States a fourth dose is recommended between 12 and 15 months of age. The first dose is recommended around six weeks of age with at least four weeks between doses. If only two doses are used, another dose later in life is recommended. It is given by injection into a muscle.Severe side effects are extremely rare. About 20 to 25% of people develop pain at the site of injection while about 2% develop a fever. There is no clear association with severe allergic reactions. The Hib vaccine is available by itself, in combination with the diphtheria/tetanus/pertussis vaccine, and in combination with the hepatitis B vaccine, among others. All Hib vaccines that are currently used are conjugate vaccine.An initial Hib vaccine was developed in 1977, which was replaced by a more effective formulation in the 1990s. As of 2013, 184 countries include it in their routine vaccinations. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Hib conjugate vaccines have been shown to be universally effective against all manifestations of Hib disease, with a clinical efficacy among fully vaccinated children estimated to be between 95–100%. The vaccine has also been shown to be immunogenic in patients at high risk of invasive disease. Hib vaccine is not effective against non-type B Haemophilus influenzae. However, non-type B disease is rare in comparison to pre-vaccine rates of Haemophilus influenzae type B disease.
Impact
Prior to introduction of the conjugate vaccine, Hib was a leading cause of childhood meningitis, pneumonia, and epiglottitis in the United States, causing an estimated 20,000 cases a year in the early 1980s, mostly in children under five years old. Since routine vaccination began, the incidence of Hib disease has declined by greater than 99%, effectively eliminating Hib as a public health problem. Similar reductions in disease occurred after introduction of the vaccine in Western Europe and developing countries.After routine use of the vaccine in the United States from 1980 to 1990, the rate of invasive Hib disease decreased from 40–100 per 100,000 children down to fewer than 1 per 100,000.
Recommendations
The CDC and the WHO recommend that all infants be vaccinated using a polysaccharide-protein conjugate Hib vaccine, starting after the age of six weeks. The vaccination is also indicated in people without a spleen.
Side effects
Clinical trials and ongoing surveillance have shown Hib vaccine to be safe. In general, adverse reactions to the vaccine are mild. The most common reactions are mild fever, loss of appetite, transient redness, swelling, or pain at the site of injection, occurring in 5–30% of vaccine recipients. More severe reactions are extremely rare.
Mechanisms of action
Polysaccharide vaccine
Haemophilus influenzae type b is a bacterium with a polysaccharide capsule; the main component of this capsule is polyribosyl ribitol phosphate (PRP). Anti-PRP antibodies have a protective effect against Hib infections. Thus, purified PRP was considered a good candidate for a vaccine. However, the antibody response to PRP diminished rapidly after administration. This problem was due to recognition of the PRP antigen by B cells, but not T cells. In other words, even though B cell recognition was taking place, T cell recruitment (via MHC class II) was not, which compromised the immune response. This interaction with only B cells is termed T-independent (TI). This process also inhibits the formation of memory B cells, thus compromising long term immune system memory.
Conjugate vaccine
PRP covalently linked to a protein carrier was found to elicit a greater immune response than the polysaccharide form of the vaccine. This is due to the protein carrier being highly immunogenic in nature. The conjugate formulations show responses which are consistent with T-cell recruitment (namely a much stronger immune response). A memory effect (priming of the immune system against future attack by Hib) is also observed after administration; indicative that memory B cell formation is also improved over that of the polysaccharide form. Since optimal contact between B cells and T cells is required (via MHC II) to maximize antibody production, it is reasoned that the conjugate vaccine allows B cells to properly recruit T cells, this is in contrast to the polysaccharide form in which it is speculated that B cells do not interact optimally with T cells leading to the TI interaction.
Developing world
Introduction of Hib vaccine in developing countries lagged behind that in developed countries for several reasons. The expense of the vaccine was large in comparison to the standard EPI vaccines. Poor disease surveillance systems and inadequate hospital laboratories failed to detect the disease, leading many experts to believe that Hib did not exist in their countries. And health systems in many countries were struggling with the current vaccines they were trying to deliver.
GAVI and the Hib Initiative
In order to remedy these issues, the GAVI Alliance took active interest in the vaccine. GAVI offers substantial subsidization of Hib vaccine for countries interested in using the vaccine, as well as financial support for vaccine systems and safe injections. In addition, GAVI created the Hib Initiative to catalyze uptake of the vaccine. The Hib Initiative uses a combination of collecting and disseminating existing data, research, and advocacy to assist countries in the making a decision about using the Hib vaccine. Currently, 61 out of 72 low-income countries are planning on introducing the vaccine by the end of 2009.
History
Polysaccharide vaccine
The first Hib vaccine licensed was a pure polysaccharide vaccine, first marketed in the United States in 1985. Similar to other polysaccharide vaccines, immune response to the vaccine was highly age-dependent. Children under 18 months of age did not produce a positive response for this vaccine. As a result, the age group with the highest incidence of Hib disease was unprotected, limiting the usefulness of the vaccine. The vaccine was withdrawn from the market in 1988.
Conjugate vaccine
The shortcomings of the polysaccharide vaccine led to the production of the Hib polysaccharide-protein conjugate vaccine. The first such vaccine available in the United States was based on work done by American scientists John Robbins and Rachel Schneerson and was available in 1987. Attaching Hib polysaccharide to a protein carrier greatly increased the ability of the immune system of young children to recognize the polysaccharide and develop immunity. There are currently three types of conjugate vaccine, utilizing different carrier proteins for the conjugation process: inactivated tetanospasmin (also called tetanus toxoid); mutant diphtheria protein; and meningococcal group B outer membrane protein.
Combination vaccines
Multiple combinations of Hib and other vaccines have been licensed in the United States, reducing the number of injections necessary to vaccinate a child. Hib vaccine combined with diphtheria-tetanus-pertussis–polio vaccines and hepatitis B vaccines are available in the United States. The World Health Organization (WHO) has certified several Hib vaccine combinations, including a pentavalent diphtheria-pertussis-tetanus-hepatitis B-Hib, for use in developing countries. There is not yet sufficient evidence on how effective this combined pentavalent vaccine is in relation to the individual vaccines.
References
Further reading
Ramsay M, ed. (2013). "Chapter 16: Haemophilus influenzae type b (Hib)". Immunisation against infectious disease. Public Health England.
External sources
"Haemophilus Influenzae Type b (Hib) Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 10 August 2021.
"Haemophilus B Conjugate Vaccine (Meningococcal Protein Conjugate)". U.S. Food and Drug Administration (FDA). 24 April 2019.
"Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)". U.S. Food and Drug Administration (FDA). 24 April 2019.
"Hiberix". U.S. Food and Drug Administration (FDA). 3 October 2019. |
Ixazomib | Ixazomib (trade name Ninlaro) is a drug for the treatment of multiple myeloma, a type of white blood cell cancer, in combination with other drugs. It is taken by mouth in the form of capsules.
Common side effects include diarrhea, constipation and low platelet count. Like the older bortezomib (which can only be given by injection), it acts as a proteasome inhibitor, has orphan drug status in the US and Europe, and is a boronic acid derivative.
The drug was developed by Takeda. In the US, it is approved since November 2015, and in the EU since November 2016.
Medical uses
Ixazomib is used in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in adults after at least one prior therapy. There are no experiences with children and youths under 18 years of age.The study relevant for approval included 722 people. In this study, ixazomib increased the median time of progression-free survival from 14.7 months (in the placebo+lenalidomide+dexamethasone study arm including 362 people) to 20.6 months (under ixazomib+lenalidomide+dexamethasone, 360 people), which was a statistically significant effect (p = 0.012). 11.7% of patients in the ixazomib group had a complete response to the treatment, versus 6.6% in the placebo group. Overall response rate (complete plus partial) was 78.3% versus 71.5%.A phase 3 study demonstrated a significant improvement in progression-free survival (PFS) with ixazomib-lenalidomide-dexamethasone (IRd) compared with placebo. High-risk cytogenetic abnormalities were defined as del(17p), t(4;14), and/or t(14;16); additionally, patients were assessed for 1q21 amplification. Of 722 randomized patients, 552 had cytogenetic results; 137 (25%) had high-risk cytogenetic abnormalities and 172 (32%) had 1q21 amplification alone. PFS was improved with IRd versus placebo in both high-risk and standard-risk cytogenetics subgroups: in high-risk patients, with median PFS of 21.4 versus 9.7 months; in standard-risk patients, with median PFS of 20.6 versus 15.6 months. This PFS benefit was consistent across subgroups with individual high-risk cytogenetic abnormalities, including patients with del(17p). PFS was also longer with IRd versus placebo- in patients with 1q21 amplification, and in the "expanded high-risk" group, defined as those with high-risk cytogenetic abnormalities and/or 1q21 amplification. IRd demonstrated substantial benefit compared with placebo in relapsed/refractory multiple myeloma patients with high-risk and standard-risk cytogenetics, and improves the poor PFS associated with high-risk cytogenetic abnormalities.
Pregnancy and breastfeeding
Ixazomib and lenalidomide are teratogenic in animal studies. The latter is contraindicated in pregnant women, making this therapy regimen unsuitable for this group. It is not known whether ixazomib or its metabolites pass into the breast milk.
Side effects
Common side effects of the ixazomib+lenalidomide+dexamethasone study therapy included diarrhoea (42% versus 36% under placebo+lenalidomide+dexamethasone), constipation (34% versus 25%), thrombocytopenia (low platelet count; 28% versus 14%), peripheral neuropathy (28% versus 21%), nausea (26% versus 21%), peripheral oedema (swelling; 25% versus 18%), vomiting (22% versus 11%), and back pain (21% versus 16%). Serious diarrhoea or thrombocytopenia occurred in 2% of patients, respectively.Side effects of ixazomib alone were only assessed in a small number of people. Diarrhoea grade 2 or higher was found in 24% of these patients, thrombocytopenia grade 3 or higher in 28%, and fatigue grade 2 or higher in 26%.
Interactions
The drug has a low potential for interactions via cytochrome P450 (CYP) liver enzymes and transporter proteins. The only relevant finding in studies was a reduction of ixazomib blood levels when combined with the strong CYP3A4 inducer rifampicin. The Cmax was reduced by 54% and the area under the curve by 74% in this study.
Pharmacology
Mechanism of action
At therapeutic concentrations, ixazomib selectively and reversibly inhibits the protein proteasome subunit beta type-5 (PSMB5) with a dissociation half-life of 18 minutes. This mechanism is the same as of bortezomib, which has a much longer dissociation half-life of 110 minutes; the related drug carfilzomib, by contrast, blocks PSMB5 irreversibly. Proteasome subunits beta type-1 and type-2 are only inhibited at high concentrations reached in cell culture models.PSMB5 is part of the 20S proteasome complex and has enzymatic activity similar to chymotrypsin. It induces apoptosis, a type of programmed cell death, in various cancer cell lines. A synergistic effect of ixazomib and lenalidomide has been found in a large number of myeloma cell lines.
Pharmacokinetics
The medication is taken orally as a prodrug, ixazomib citrate, which is a boronic ester; this ester rapidly hydrolyzes under physiological conditions to its biologically active form, ixazomib, a boronic acid. Absolute bioavailability is 58%, and highest blood plasma concentrations of ixazomib are reached after one hour. Plasma protein binding is 99%.The substance is metabolized by many CYP enzymes (percentages in vitro, at higher than clinical concentrations: CYP3A4 42.3%, CYP1A2 26.1%, CYP2B6 16.0%, CYP2C8 6.0%, CYP2D6 4.8%, CYP2C9 4.8%, CYP2C9 <1%) as well as non-CYP enzymes, which could explain the low interaction potential. Clearance is about 1.86 litres per hour with a wide variability of 44% between individuals, and plasma half-life is 9.5 days. 62% of ixazomib and its metabolites are excreted via the urine (of which less than 3.5% in unchanged form) and 22% via the faeces.
Chemistry
Ixazomib is a boronic acid and peptide analogue like the older bortezomib. It contains a derivative of the amino acid leucine with the carboxylic acid group being replaced by a boronic acid; and the remainder of the molecule has been likened to phenylalanine. The structure has been found through a large-scale screening of boron-containing molecules.
History
The drug was developed by Takeda. It got US and European orphan drug status for multiple myeloma in 2011, and for AL amyloidosis in 2012. Takeda submitted a US new drug application for multiple myeloma in July 2015. In September 2015, the U.S. Food and Drug Administration (FDA) granted ixazomib combined with lenalidomide and dexamethasone a priority review designation for multiple myeloma. On 20 November 2015, the FDA approved this combination for second-line treatment.The request for marketing authorisation in Europe was initially refused by the European Medicines Agency (EMA) in May 2016 due to insufficient data showing a benefit of treatment. After Takeda requested a re-examination, the EMA granted a marketing authorisation on 21 November 2016 on the condition that further efficacy studies be conducted. The approval indication is the same as in the US.
Research
As of January 2017, ixazomib is also in Phase III clinical trials for the treatment of AL amyloidosis and plasmacytoma of the bones, and in Phase I/II trials for various other conditions.
References
External links
"Ixazomib". Drug Information Portal. U.S. National Library of Medicine.
"Ixazomib citrate". Drug Information Portal. U.S. National Library of Medicine. |
Adenosine | Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building blocks of RNA (and its derivative deoxyadenosine is a building block of DNA), which are essential for all life. Its derivatives include the energy carriers adenosine mono-, di-, and triphosphate, also known as AMP/ADP/ATP. Cyclic adenosine monophosphate (cAMP) is pervasive in signal transduction. Adenosine is used as an intravenous medication for some cardiac arrhythmias.
Adenosyl (abbreviated Ado or 5-dAdo) is the chemical group formed by removal of the 5′-hydroxy (OH) group. It is found in adenosylcobalamin (an active form of vitamin B12) and as a radical in radical SAM enzymes.
Medical uses
Supraventricular tachycardia
In individuals with supraventricular tachycardia (SVT), adenosine is used to help identify and convert the rhythm.Certain SVTs can be successfully terminated with adenosine. This includes any re-entrant arrhythmias that require the AV node for the re-entry, e.g., AV reentrant tachycardia (AVRT) and AV nodal reentrant tachycardia (AVNRT). In addition, atrial tachycardia can sometimes be terminated with adenosine.Fast rhythms of the heart that are confined to the atria (e.g., atrial fibrillation and atrial flutter) or ventricles (e.g., monomorphic ventricular tachycardia), and do not involve the AV node as part of the re-entrant circuit, are not typically converted by adenosine. However, the ventricular response rate is temporarily slowed with adenosine in such cases.Because of the effects of adenosine on AV node-dependent SVTs, adenosine is considered a class V antiarrhythmic agent. When adenosine is used to cardiovert an abnormal rhythm, it is normal for the heart to enter ventricular asystole for a few seconds. This can be disconcerting to a normally conscious patient, and is associated with angina-like sensations in the chest.
Nuclear stress test
Adenosine is used as an adjunct to thallium (TI 201) or technetium (Tc99m) myocardial perfusion scintigraphy (nuclear stress test) in patients unable to undergo adequate stress testing with exercise.
Dosage
When given for the evaluation or treatment of a supraventricular tachycardia (SVT), the initial dose is 6 mg to 12 mg, depending on standing orders or provider preference, given as a rapid parenteral infusion. Due to adenosines extremely short half-life, the IV line is started as proximal (near) to the heart as possible, such as the antecubital fossa. The IV push is often followed with a flush of 10–20 mL of normal saline. If this has no effect (i.e., no evidence of transient AV block), a dose of 12 mg can be given 1–2 minutes after the first dose. When given to dilate the arteries, such as in a "stress test", the dosage is typically 0.14 mg/kg/min, administered for 4 or 6 minutes, depending on the protocol.
The recommended dose may be increased in patients on theophylline since methylxanthines prevent binding of adenosine at receptor sites. The dose is often decreased in patients on dipyridamole (Persantine) and diazepam (Valium) because adenosine potentiates the effects of these drugs. The recommended dose is also reduced by half in patients presenting congestive heart failure, myocardial infarction, shock, hypoxia, and/or chronic liver disease or chronic kidney disease, and in elderly patients.
Drug interactions
Dipyridamole potentiates the action of adenosine, requiring the use of lower doses.
Methylxanthines (e.g. caffeine found in coffee, theophylline found in tea, or theobromine found in chocolate) have a purine structure and bind to some of the same receptors as adenosine. Methylxanthines act as competitive antagonists of adenosine and can blunt its pharmacological effects. Individuals taking large quantities of methylxanthines may require increased doses of adenosine.
Contraindications
Common contraindications for adenosine include
Asthma, traditionally considered an absolute contraindication. This is being contended and it is now considered a relative contraindication (however, selective adenosine antagonists are being investigated for use in treatment of asthma)
Pharmacological effects
Adenosine is an endogenous purine nucleoside that modulates many physiological processes. Cellular signaling by adenosine occurs through four known adenosine receptor subtypes (A1, A2A, A2B, and A3).Extracellular adenosine concentrations from normal cells are approximately 300 nM; however, in response to cellular damage (e.g., in inflammatory or ischemic tissue), these concentrations are quickly elevated (600–1,200 nM). Thus, in regard to stress or injury, the function of adenosine is primarily that of cytoprotection preventing tissue damage during instances of hypoxia, ischemia, and seizure activity. Activation of A2A receptors produces a constellation of responses that in general can be classified as anti-inflammatory. Enzymatic production of adenosine can be anti-inflammatory or immunosuppressive.
Adenosine receptors
All adenosine receptor subtypes (A1, A2A, A2B, and A3) are G-protein-coupled receptors. The four receptor subtypes are further classified based on their ability to either stimulate or inhibit adenylate cyclase activity. The A1 receptors couple to Gi/o and decreases cAMP levels, while the A2 adenosine receptors couple to Gs, which stimulates adenylate cyclase activity. In addition, A1 receptors couple to Go, which has been reported to mediate adenosine inhibition of Ca2+ conductance, whereas A2B and A3 receptors also couple to Gq and stimulate phospholipase activity.
Researchers at Cornell University have recently shown adenosine receptors to be key in opening the blood-brain barrier (BBB).
Mice dosed with adenosine have shown increased transport across the BBB of amyloid plaque antibodies and prodrugs associated with Parkinsons disease, Alzheimers, multiple sclerosis, and cancers of the central nervous system.
Ghrelin/growth hormone secretagogue receptor
Adenosine is an endogenous agonist of the ghrelin/growth hormone secretagogue receptor. However, while it is able to increase appetite, unlike other agonists of this receptor, adenosine is unable to induce the secretion of growth hormone and increase its plasma levels.
Mechanism of action
When it is administered intravenously, adenosine causes transient heart block in the atrioventricular (AV) node. This is mediated via the A1 receptor, inhibiting adenylyl cyclase, reducing cAMP and so causing cell hyperpolarization by increasing K+ efflux via inward rectifier K+ channels, subsequently inhibiting Ca2+ current. It also causes endothelial-dependent relaxation of smooth muscle as is found inside the artery walls. This causes dilation of the "normal" segments of arteries, i.e. where the endothelium is not separated from the tunica media by atherosclerotic plaque. This feature allows physicians to use adenosine to test for blockages in the coronary arteries, by exaggerating the difference between the normal and abnormal segments.
The administration of adenosine also reduces blood flow to coronary arteries past the occlusion. Other coronary arteries dilate when adenosine is administered while the segment past the occlusion is already maximally dilated, which is a process called coronary steal. This leads to less blood reaching the ischemic tissue, which in turn produces the characteristic chest pain.
Metabolism
Adenosine used as a second messenger can be the result of de novo purine biosynthesis via adenosine monophosphate (AMP), though it is possible other pathways exist.When adenosine enters the circulation, it is broken down by adenosine deaminase, which is present in red blood cells and the vessel wall.
Dipyridamole, an inhibitor of adenosine nucleoside transporter, allows adenosine to accumulate in the blood stream. This causes an increase in coronary vasodilatation.
Adenosine deaminase deficiency is a known cause of immunodeficiency.
Research
Viruses
The adenosine analog NITD008 has been reported to directly inhibit the recombinant RNA-dependent RNA polymerase of the dengue virus by terminating its RNA chain synthesis. This interaction suppresses peak viremia and rise in cytokines and prevents lethality in infected animals, raising the possibility of a new treatment for this flavivirus. The 7-deaza-adenosine analog has been shown to inhibit the replication of the hepatitis C virus. BCX4430 is protective against Ebola and Marburg viruses. Such adenosine analogs are potentially clinically useful since they can be taken orally.
Anti-inflammatory properties
Adenosine is believed to be an anti-inflammatory agent at the A2A receptor. Topical treatment of adenosine to foot wounds in diabetes mellitus has been shown in lab animals to drastically increase tissue repair and reconstruction. Topical administration of adenosine for use in wound-healing deficiencies and diabetes mellitus in humans is currently under clinical investigation.
Methotrexates anti-inflammatory effect may be due to its stimulation of adenosine release.
Central nervous system
In general, adenosine has an inhibitory effect in the central nervous system (CNS).
Caffeines stimulatory effects are credited primarily (although not entirely) to its capacity to block adenosine receptors, thereby reducing the inhibitory tonus of adenosine in the CNS. This reduction in adenosine activity leads to increased activity of the neurotransmitters dopamine and glutamate. Experimental evidence suggests that adenosine and adenosine agonists can activate Trk receptor phosphorylation through a mechanism that requires the adenosine A2A receptor.
Hair
Adenosine has been shown to promote thickening of hair on people with thinning hair. A 2013 study compared topical adenosine with minoxidil in male androgenetic alopecia, finding it was as potent as minoxidil (in overall treatment outcomes) but with higher satisfaction rate with patients due to “faster prevention of hair loss and appearance of the newly grown hairs” (further trials were called for to clarify the findings).
Sleep
The principal component of cannabis delta-9-tetrahydrocannabinol (THC) and the endocannabinoid anandamide (AEA) induce sleep in rats by increasing adenosine levels in the basal forebrain. They also significantly increase slow-wave sleep during the third hour, mediated by CB1 receptor activation. These findings identify a potential therapeutic use of cannabinoids to induce sleep in conditions where sleep may be severely attenuated.
Vasodilation
It also plays a role in regulation of blood flow to various organs through vasodilation.
See also
Adenosine receptor
Adenosine reuptake inhibitor
List of growth hormone secretagogues
== References == |
Nelfinavir | Nelfinavir, sold under the brand name Viracept, is an antiretroviral medication used in the treatment of HIV/AIDS. Nelfinavir belongs to the class of drugs known as protease inhibitors (PIs) and like other PIs is almost always used in combination with other antiretroviral drugs.
Nelfinavir is an orally bioavailable human immunodeficiency virus HIV-1 protease inhibitor (Ki = 2 nM) and is widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection.It was patented in 1992 and approved for medical use in 1997.
Toxicity
Common (>1%) side effects include insulin resistance, hyperglycemia and lipodystrophy.Nelfinavir can produce a range of adverse side effects. Flatulence, diarrhea, or abdominal pain are common (i.e. experienced by more than one in one hundred patients). Fatigue, urination, rash, mouth ulcers, or hepatitis are less frequent effects (experienced by one in one thousand to one in one hundred patients). Nephrolithiasis, arthralgia, leukopenia, pancreatitis, or allergic reactions may occur, but are rare (less than one in one thousand patients) .
Other bioactivity
Antiviral
Nelfinavir inhibits maturation and export of the herpes simplex 1 virus and the Kaposis sarcoma virus.
Anti-virulence activity
Nelfinavir and simple derivatives have been found to inhibit the production of the virulence factor streptolysin S, a cytolysin produced by the human pathogen Streptococcus pyogenes. Nelfinavir and these related molecules did not exhibit detectable antibiotic activity, but did also inhibit the production of other biologically active molecules, including plantazolicin (antibiotic), listeriolysin S (cytolysin), and clostridiolysin S (cytolysin), by other bacteria.
Interactions
Nelfinavirs interaction profile is similar to that of other protease inhibitors. Most interactions occur at the level of the Cytochrome P450 isozymes 3A4 and CYP2C19, by which nelfinavir is metabolised.
Pharmacology
Nelfinavir should be taken with food. Taking the drug with food decreases the risk of diarrhea as a side effect.
Mechanism of action
Nelfinavir is a protease inhibitor: it inhibits HIV-1 and HIV-2 proteases. HIV protease is an aspartate protease which splits viral protein molecules into smaller fragments, and it is vital to both the replication of the virus within the cell, and also to the release of mature viral particles from an infected cell. Nelfinavir is a competitive inhibitor (2 nM) which is designed to bind tightly and is not cleaved due to the presence of a hydroxyl group as opposed to a keto group in the middle amino acid residue mimic, which would be otherwise S-phenylcysteine. All protease inhibitors bind to the protease, the precise mode of binding determines how the molecule inhibits the protease. The way Nelfinavir binds the enzyme may be sufficiently unique to reduce cross-resistance between it and other PIs. Also, not all PIs inhibit both HIV-1 and HIV-2 proteases.
History
Nelfinavir was developed by Agouron Pharmaceuticals as part of a joint venture with Eli Lilly and Company. Agouron Pharmaceuticals was acquired by Warner Lambert in 1999 and is now a subsidiary of Pfizer. It is marketed in Europe by Hoffman-La Roche and elsewhere by ViiV Healthcare.
The U.S. Food and Drug Administration (FDA) approved it for therapeutic use on March 14, 1997, making it the twelfth approved antiretroviral. The initial product launched proved to be the largest "biotech launch" in the history of the pharmaceutical industry, achieving first full year sales exceeding $US335M. Agourons patent on the drug expired in 2014.
On the 6 June 2007, both the Medicines and Healthcare products Regulatory Agency and the European Medicines Agency put out an alert requesting the recall of any of the drug in circulation, because some batches may have been contaminated with potentially cancer-causing chemicals.
Research
Since 2009, nelfinavir has been under investigation for potential use as an anti-cancer agent. When applied to cancer cells in culture (in vitro), it can inhibit the growth of a variety of cancer types and can trigger cell death (apoptosis). When Nelfinavir was given to laboratory mice with tumors of the prostate or of the brain, it could suppress tumor growth in these animals. At the cellular level, nelfinavir exerts multiple effects to inhibit cancer growth; the two main ones appear to be inhibition of the Akt/PKB signaling pathway and activation of endoplasmic reticulum stress with subsequent unfolded protein response.In the United States, about three dozen clinical trials are being conducted (or have been completed) in order to determine whether nelfinavir is effective as a cancer therapeutic agent in humans. In some of these trials, nelfinavir is used alone in monotherapy fashion, whereas in others it is combined with other modes of cancer therapy, such as well-established chemotherapeutic agents or radiation therapy.
As of April 2022, nelfinavir is being studied as a radiosensitizing agent as part of treatment of advanced cervical cancer.
References
Further reading
Pai, VB; Nahata, MC (March 1999). "Nelfinavir mesylate: a protease inhibitor". The Annals of Pharmacotherapy. 33 (3): 325–39. doi:10.1345/aph.18089. PMID 10200859. S2CID 24066955.
Bardsley-Elliot, A; Plosker, GL (March 2000). "Nelfinavir: an update on its use in HIV infection". Drugs. 59 (3): 581–620. doi:10.2165/00003495-200059030-00014. PMID 10776836.
External links
"Nelfinavir". Drug Information Portal. U.S. National Library of Medicine. |
Terbinafine | Terbinafine, sold under the brand name Lamisil among others, is an antifungal medication used to treat pityriasis versicolor, fungal nail infections, and ringworm including jock itch and athletes foot. It is either taken by mouth or applied to the skin as a cream or ointment. The cream and ointment are not effective for nail infections.Common side effects when taken by mouth include nausea, diarrhea, headache, cough, rash, and elevated liver enzymes. Severe side effects include liver problems and allergic reactions. Liver injury is, however, unusual. Use during pregnancy is not typically recommended. The cream and ointment may result in itchiness but are generally well tolerated. Terbinafine is in the allylamines family of medications. It works by decreasing the ability of fungi to synthesize sterols. It appears to result in fungal cell death.Terbinafine was discovered in 1991. It is on the World Health Organizations List of Essential Medicines. In 2017, it was the 307th most commonly prescribed medication in the United States, with more than one million prescriptions.
Medical uses
Terbinafine is mainly effective on fungi of the group Onygenales and some yeasts in the genus Candida (e.g. Candida glabrata)
As a cream or powder, it is used topically for superficial skin infections such as jock itch (tinea cruris), athletes foot (tinea pedis), and other types of ringworm (tinea corporis).Tablets by mouth are often prescribed for the treatment of onychomycosis, a fungal nail infection, typically by a dermatophyte or Candida species. Fungal nail infections are located deep under the nail in the cuticle to which topically applied treatments are unable to penetrate in sufficient amounts. The tablets may, rarely, cause hepatotoxicity, so patients are warned of this and may be monitored with liver function tests. Alternatives to oral administration have been studied.
Terbinafine may induce or exacerbate subacute cutaneous lupus erythematosus. Persons with lupus erythematosus should first discuss possible risks with their doctor before initiation of therapy.
Side effects
Many side effects and adverse drug reactions have been reported with oral terbinafine hydrochloride possibly due to its extensive biodistribution and the often extended durations involved in antifungal treatment (longer than two months). A comprehensive list of adverse events associated with terbinafine use includes:
Gastrointestinal problems: Diarrhea, constipation, nausea, fullness, abdominal pain, indigestion, dyspepsia, gastritis, cholestasis, flatulence, altered stool colour, abdominal muscular pain
Central nervous system or neurological problems: Headaches, dizziness, vertigo, light-headedness, decreased concentration levels, paraesthesia (pins and needles)
Hepatic problems: Raised liver enzyme levels, liver inflammation (hepatitis), liver damage, liver failure
Immune system problems: Decreased white blood cell counts including pancytopenia, leukopenia, lymphopenia, thrombocytopenia, agranulocytosis, and neutropenia, autoimmune reactions such as lupus erythematosus
Psychological problems: Depression, anxiety, insomnia, increased or unusual dream activity, malaise
Sensory problems: Complete loss of taste (ageusia), decreased taste (hypogeusia) and distorted taste (dysgeusia), often involving a metallic taste sensation and dry mouth, visual disturbances including blurred vision, green vision and double vision. In extremely rare cases, the loss or impairment of taste is permanent
Skin problems: Rashes, hives (urticaria), skin irritation, itching, jaundice, Stevens–Johnson syndrome
Other side effects: Fatigue, increased heart rate (tachycardia), hair loss (alopecia), decreased red blood cell count (anemia), muscle pain (myalgia), joint pain (arthralgia)In 2015 physicians reported that a patient with an MTHFR enzyme mutation (specifically the C677T variant) had developed an adverse reaction to Lamisil (headache, fatigue, and dizziness). Genetic testing revealed the MTHFR C677T mutation. It was noted that Lamisil interferes with the methylation cycle and that this can cause side effects in individuals with the MTHFR C677T mutation.
Pharmacology
Like other allylamines, terbinafine inhibits ergosterol synthesis by inhibiting squalene epoxidase, an enzyme that catalyzes the conversion of squalene to lanosterol. In fungi, lanosterol is then converted to ergosterol; in humans, lanosterol becomes cholesterol. However, as fungi and animals diverged around 1.1 billion years ago - there is enough difference in this enzyme that terbinafine preferentially binds fungal squalene epoxidase, making it selective for inhibiting ergosterol production in fungi without significantly affecting cholesterol production in mammals. This is thought to fatally disrupt the fungal cell membrane.
Terbinafine is highly lipophilic and tends to accumulate in hair, skin, nails, and fat cells.
This accumulation results in therapeutic levels of terbinafine even after 80 days following one week treatment of 250 mg/day. Different dosing schedules have been proposed such as 500 mg/day for one week or 250 mg/day for two weeks each followed by a drug-free period of three or two weeks, totaling 3 months of treatment including the drug-free periods. Such intermittent dosing schedules appear to be as effective as continuous regimes.
Chemistry
Terbinafine hydrochloride is a white crystalline powder that is freely soluble in methanol and dichloromethane, soluble in ethanol, and slightly soluble in water.Terbinafine is produced from olefin metathesis of 1,3-dichloropropene and neohexene followed by reaction with N-methyl-1-naphthalenemethanamine.Despite its name it does not contain terbium.
History
Terbinafine first became available in Europe in 1991 and in the United States in 1996. The U.S. Food and Drug Administration has approved the first generic versions of prescription Lamisil (terbinafine hydrochloride) tablets. The remaining patent or exclusivity for Lamisil expired on June 30, 2007.
On September 28, 2007, the FDA stated that terbinafine is a new treatment approved for use by children age four and up. The antifungal granules can be sprinkled on a childs food to treat ringworm of the scalp, tinea capitis.In the United States the price in 1999 was $547 for a 12-week course; this fell to $10 by 2015, after the patent had expired.
Society and culture
Brand names
Terbinafine is sold in India as Terboderm by Omega Pharma and Tyza (Abbott Healthcare).
Lamisil in Argentina, Australia, Bangladesh, Belgium, Brazil, Canada, Chile, Colombia, Croatia, Egypt, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Mexico, the Netherlands, New Zealand, Norway, Pakistan (لیمسل), Peru, the Philippines, Romania, Russia, Slovakia, Slovenia, South Africa, Sweden, Thailand, the United Kingdom, the United States, and Venezuela
Corbinal and Terbisil in Turkey, Pakistan, Undofen in Poland, and Terbistad (Stada Arzneimittel).
As a generic oral medication, it is sold as Sebifin, Tinasil, Terbisil, Terbicor, and Tamsil in Australia, whilst the generic topical medication is sold there as SolvEasyTinea and Tamsil.
It is also available as a generic medication in the United States, the United Kingdom, Belgium, Switzerland, Brazil, Mexico, Canada and France.
In India, terbinafine hydrochloride is available in topical form under the brand names Triabin by Medley Pharmaceuticals, Sebifin (Sun Pharma), Zimig (GSK Pharma) and mycoCeaze (Progreś Laboratories). MycoVa, developed by Apricus Biosciences, is a topical nail solution of terbinafine and DDAIP, which has completed three phase-III studies for the treatment of onychomycosis.
Other names include Terbinaforce (Mankind Pharma) and Tafine (Deurali Janta Pharmaceuticals Pvt Ltd.) Turbo (Apex Pharmaceuticals Pvt Ltd) in Nepal.
The topical form is sold as Lamisil AT in the United States.
References
External links
"Terbinafine". Drug Information Portal. U.S. National Library of Medicine. |
Idarubicin | Idarubicin or 4-demethoxydaunorubicin is an anthracycline antileukemic drug. It inserts itself into DNA and prevents DNA unwinding by interfering with the enzyme topoisomerase II. It is an analog of daunorubicin, but the absence of a methoxy group increases its fat solubility and cellular uptake.
Similar to other anthracyclines, it also induces histone eviction from chromatin.It belongs to the family of drugs called antitumor antibiotics.
It is currently combined with cytosine arabinoside as a first line treatment of acute myeloid leukemia.
It is used for treatment of acute lymphoblastic leukemia and chronic myelogenous leukemia in blast crisis.It is distributed under the trade names Zavedos (UK) and Idamycin (USA).
Side effects
Diarrhea, stomach cramps, nausea and vomiting are common among patients treated with idarubicin.
References
External links
Idarubicin bound to proteins in the PDB |
Fremanezumab | Fremanezumab, sold under the brand name Ajovy, is a medication used to prevent migraines in adults. It is given by injection under the skin.The most common side effect is pain and redness at the site of injection. Other side effects include allergic reactions. It is in the calcitonin gene-related peptide antagonist class of medications.It was approved for medical use in the United States in 2018, the European Union in 2019 and the UK in 2020.
Medical uses
Fremanezumab was shown to be effective in adults with four or more attacks per month.
Adverse effects
The most common adverse effects are reactions at the injection site, which occurred in 43 to 45% of people in studies (as compared to 38% under placebo). Hypersensitivity reactions occurred in fewer than 1% of patients.
Interactions
Fremanezumab does not interact with other antimigraine drugs such as triptans, ergot alkaloids and analgesics. It is expected to generally have a low potential for interactions because it is not metabolized by cytochrome P450 enzymes.
Pharmacology
Mechanism of action
Fremanezumab is a fully humanized monoclonal antibody directed against calcitonin gene-related peptides (CGRP) alpha and beta. The precise mechanism of action is unknown. It can be given with a quarterly interval.
Pharmacokinetics
After subcutaneous injection, fremanezumab has a bioavailability of 55–66%. Highest concentrations in the body are reached after five to seven days. Like other proteins, the substance is degraded by proteolysis to small peptides and amino acids, which are reused or excreted via the kidney. The elimination half-life is estimated to be 30 to 31 days.
History
Fremanezumab was discovered and developed by Rinat Neuroscience, was acquired by Pfizer in 2006, and was then licensed to Teva. It was approved by the US Food and Drug Administration in September 2018. In March 2019, fremanezumab was approved for marketing and use in the European Union.The drug has been and is still being evaluated for diseases other than migraine, where the endogenous substance CGRP has been implicated in the pathology. Teva is still developing it for episodic cluster headache but stopped development of fremanezumab for the treatment of chronic cluster headache in 2018 after the primary endpoint of a Phase III trial was not met.
Chemistry
Fremanezumab is a humanized monoclonal antibody. It is produced using recombinant DNA in Chinese hamster ovary cells.
References
External links
"Fremanezumab". Drug Information Portal. U.S. National Library of Medicine. |
Nisoldipine | Nisoldipine is a pharmaceutical drug used for the treatment of chronic angina pectoris and hypertension. It is a calcium channel blocker of the dihydropyridine class. It is sold in the United States under the proprietary name Sular. Nisoldipine has tropism for cardiac blood vessels.It was patented in 1975 and approved for medical use in 1990.
Contraindications
Nisoldipine is contraindicated in people with cardiogenic shock, unstable angina, myocardial infarction, and during pregnancy and lactation.
Adverse effects
Common side effects are headache, confusion, fast heartbeat, and edema. Hypersensitivity reactions are rare and include angioedema.
Interactions
The substance is metabolized by the liver enzyme CYP3A4. Consequently, CYP3A4 inducers such as rifampicin or carbamazepine could reduce the effectiveness of nisoldipine, while CYP3A4 inhibitors such as ketoconazole increase the amount of nisoldipine in the body more than 20-fold. Grapefruit juice also increases nisoldipine concentrations by inhibiting CYP3A4.
Pharmacology
Mechanism of action
Nisoldipine is a calcium channel blocker that selectively inhibits L-type calcium channels.
References
External links
Diseases Database (DDB): 30009
Mielcarek J, Grobelny P, Szamburska O (2005). "The effect of beta-carotene on the photostability of nisoldipine". Methods Find Exp Clin Pharmacol. 27 (3): 167–71. doi:10.1358/mf.2005.27.3.890873. PMID 15834448.
Missan S, Zhabyeyev P, Dyachok O, Jones SE, McDonald TF (November 2003). "Block of cardiac delayed-rectifier and inward-rectifier K+ currents by nisoldipine". Br. J. Pharmacol. 140 (5): 863–70. doi:10.1038/sj.bjp.0705518. PMC 1574108. PMID 14530219.
Hamilton S, Houle L, Thadani U (1999). "Rapid-release and coat-core formulations of nisoldipine in treatment of hypertension, angina, and heart failure". Heart Dis. 1 (5): 279–88. PMID 11720635. |
Tivozanib | Tivozanib, sold under the brand name Fotivda, is a medication used for the treatment of relapsed or refractory advanced renal cell carcinoma (RCC). It is an oral VEGF receptor tyrosine kinase inhibitor.The most common side effects include fatigue, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis.Tivozanib was approved for medical use in the European Union in August 2017, and in the United States in March 2021.
Medical uses
Tivozanib is used for the treatment of adults with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies.
Contraindications
Tivozanib must not be combined with St. Johns Wort, an inducer of the liver enzyme CYP3A4 (see interactions below). It should not be taken during pregnancy as it is teratogenic, embryotoxic and fetotoxic in rats.
Adverse effects
The most common side effects in studies were hypertension (high blood pressure, in 48% of patients), dysphonia (hoarse voice, 27%), fatigue and diarrhoea (both 26%). A hypertensive crisis occurred in 1% of patients.
Interactions
Administration of a single dose of tivozanib with rifampicin, a strong inducer of the enzyme CYP3A4, cuts the biological half-life and total exposure (AUC) of tivozanib in half, but has no relevant influence on highest concentrations in the blood. Combination with ketoconazole, a strong CYP3A4 inhibitor, has no relevant effects. The clinical significance of these findings is not known.
Pharmacology
Mechanism of action
A quinoline urea derivative, tivozanib suppresses angiogenesis by being selectively inhibitory against vascular endothelial growth factor (VEGF). It is designed to inhibit all three VEGF receptors.
Pharmacokinetics
After tivozanib is taken by mouth, highest blood serum levels are reached after 2 to 24 hours. The total AUC is independent of food intake. When in the bloodstream, over 99% of the substance are bound to plasma proteins, predominantly albumin. Although the enzymes CYP3A4 and CYP1A1 and several UGTs are capable of metabolising the drug, over 90% circulate in unchanged form. The metabolites are demethylation, hydroxylation and N-oxidation products and glucuronides.The biological half-life is 4.5 to 5.1 days; 79% being excreted via the faeces, mostly unchanged, and 12% via the urine, completely unchanged.
Chemistry
Tivozanib is used in form of the hydrochloride monohydrate, which is a white to light brown powder. It is practically insoluble in water and has low solubility in aqueous acids, ethanol and methanol. It is not hygroscopic and not optically active.
History
It was discovered by Kyowa Kirin and developed by AVEO Pharmaceuticals.
Clinical trials
Phase III results on advanced renal cell carcinoma suggested a 30% or 3 months improvement in median progression-free survival compared to sorafenib but showed an inferior overall survival rate of the experimental arm versus the control arm. The Food and Drug Administrations Oncologic Drugs Advisory Committee voted in May 2013 13 to 1 against recommending approval of tivozanib for renal cell carcinoma. The committee felt the drug failed to show a favorable risk-benefit ratio and questioned the equipose of the trial design, which allowed control arm patients who used sorafenib to transition to tivozanib following progression disease but not those on the experimental arm using tivozanib to transition to sorafenib. The application was formally rejected by the FDA in June 2013, saying that approval would require additional clinical studies.In 2016, AVEO Oncology published data in conjunction with the ASCO meeting showing a geographical location effect on overall survival in the Phase III trial.In 2016, AVEO Oncology announced the start of a second Phase III clinical study in third line advanced RCC patients.In 2016, EUSA Pharma and AVEO Oncology announced that tivozanib had been submitted to the European Medicines Agency for review under the centralised procedure.In June 2017, the EMA Scientific Committee recommended tivozanib for approval in Europe, with approval expected in September.In August 2017, the European Commission (EC) formally approved tivozanib in Europe.
References
External links
"Tivozanib". Drug Information Portal. U.S. National Library of Medicine. |
Gemifloxacin | Gemifloxacin mesylate (trade name Factive, Oscient Pharmaceuticals) is an oral broad-spectrum quinolone antibacterial agent used in the treatment of acute bacterial exacerbation of chronic bronchitis and mild-to-moderate pneumonia. Vansen Pharma Inc. has licensed the active ingredient from LG Life Sciences of Korea.
Indications
Gemifloxacin is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below.
Acute bacterial exacerbation of chronic bronchitis caused by S. pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis
Community-acquired pneumonia (of mild to moderate severity) caused by S. pneumoniae (including multi-drug resistant strains, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae, or Klebsiella pneumoniae
Microbiology
Gemifloxacin has been shown to be active against most strains of the following microorganisms:
Aerobic gram-positive microorganisms – Streptococcus pneumoniaeincluding multi-drug resistant Streptococcus pneumoniae (MDRSP). MDRSP includes isolates previously known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are strains resistant to two or more of the following antibiotics: penicillin, 2nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
Staphylococcus aureus and Streptococcus pyogenesAerobic gram-negative microorganisms – Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae (many strains are moderately susceptible), Moraxella catarrhalis, Acinetobacter lwoffii, Klebsiella oxytoca, Legionella pneumophila, Proteus vulgaris.
Other microorganisms – Chlamydia pneumoniae, Mycoplasma pneumoniae
Adverse effects
Fluoroquinolones are generally well tolerated with most side effects being mild and serious adverse effects being rarely. Some of the serious adverse effects which occur more commonly with fluoroquinolones than with other antibiotic drug classes include CNS and tendon toxicity. The currently marketed quinolones have safety profiles similar to that of other antimicrobial classes.The serious events may occur with therapeutic or with acute overdose. At therapeutic doses they include: central nervous system toxicity, cardiovascular toxicity, tendon / articular toxicity, and rarely hepatic toxicity. Events that may occur in acute overdose are rare and include: renal failure and seizure. Children and the elderly are at greater risk. Tendon damage may manifest during, as well as up to a year after fluoroquinolone therapy.The FDA ordered a black box warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.On August 15, 2013 the FDA issued a Safety Announcement where they described that they are requiring the medication guides and drug labels for all fluoroquinolones to be updated and better describe the risk for peripheral neuropathy. The peripheral neuropathy may occur very quickly, and may be irreversible. This warning applies to fluoroquinolones taken by mouth and injection, but does not apply to fluoroquinolones taken topically.
Current findings
One recent study showed that Gemifloxacin possess anti-metastatic activities against breast cancer in vitro and in vivo (in mice).
See also
Fluoroquinolone
== References == |
RID | RID may refer to:
Isaiah ben Mali di Trani (the Elder), an Italian Talmudist
Radial immunodiffusion, a scientific technique for measuring the quantity of an antigen
Radionuclide identification device, a hand-held instrument for the detection and identification of radioactive sources
Refractive index detector, a type of chromatography detector
Registry of Interpreters for the Deaf, an American Sign Language interpreters organization
Relative identifier, a component of Microsoft Windows NT security
RID (insect repellent), an Australian brand
Rivista Italiana Difesa, an Italian magazine related to military and geo-strategic issues
Robots in Disguise, an English electro band
Royal Institute Dictionary, a prescriptive dictionary of Thailand
Real-time Inter-network Defense, a reporting method for sharing incident-handling data between networks |
Modicon | Modicon can mean:
Modicon PLC, the first programmable logic controller
Ethinylestradiol/norethisterone, an oral contraceptive formulation |
Cevimeline | Cevimeline (trade name Evoxac) is a synthetic analog of the natural alkaloid muscarine with a particular agonistic effect on M1 and M3 receptors. It is used in the treatment of dry mouth and Sjögrens syndrome.
Medical uses
Cevimeline is used in the treatment of xerostomia (dry mouth), and Sjögrens syndrome. It increases the production of saliva.
Side effects
Known side effects include nausea, vomiting, diarrhea, excessive sweating, rash, headache, runny nose, cough, drowsiness, hot flashes, blurred vision, and difficulty sleeping.Contraindications include asthma and angle closure glaucoma.
Mechanism of action
Cevimeline is a cholinergic agonist. It has a particular effect on M1 and M3 receptors. By activating the M3 receptors of the parasympathetic nervous system, cevimeline stimulates secretion by the salivary glands, thereby alleviating dry mouth.
See also
Pilocarpine — a similar parasympathomimetic medication for dry mouth (xerostomia)
Bethanechol — a similar muscarinic parasympathomimetic with longer-lasting effect
References
External links
Evoxac (cevimeline HCl hydrate capsules) Full Prescribing Information |
Levomilnacipran | Levomilnacipran (brand name Fetzima) is an antidepressant which was approved in the United States in 2013 for the treatment of major depressive disorder (MDD) in adults. It is the levorotatory enantiomer of milnacipran, and has similar effects and pharmacology, acting as a serotonin–norepinephrine reuptake inhibitor (SNRI).
Medical uses
Depression
The FDA approved levomilnacipran for the treatment of major depressive disorder based on the results of one 10-week phase II and four 8-week phase III clinical trials. Four of the five trials demonstrated a statistically significant superiority to placebo as measured by the Montgomery–Åsberg Depression Rating Scale. Superiority to placebo was also demonstrated by improvement in the Sheehan Disability Scale.
Side effects
Side effects seen more often with levomilnacipran than with placebo in clinical trials included nausea, dizziness, sweating, constipation, insomnia, increased heart rate and blood pressure, urinary hesitancy, erectile dysfunction and delayed ejaculation in males, vomiting, tachycardia, and palpitations.
Pharmacology
Pharmacodynamics
Relative to other SNRIs, levomilnacipran, as well as milnacipran, differ in that they are much more balanced reuptake inhibitors of serotonin and norepinephrine. To demonstrate, the serotonin:norepinephrine ratios of SNRIs are as follows: venlafaxine = 30:1, duloxetine = 10:1, desvenlafaxine = 14:1, milnacipran = 1.6:1, and levomilnacipran = 1:2. The clinical implications of more balanced elevations of serotonin and norepinephrine are unclear, but may include improved effectiveness, though also increased side effects.Levomilnacipran is selective for the serotonin and norepinephrine transporters, lacking significant affinity for over 23 off-target sites. However, it does show some affinity for the dizocilpine (MK-801/PCP) site of the NMDA receptor (Ki = 1.7 μM), and has been found to inhibit NR2A and NR2B subunit-containing NMDA receptors with respective IC50 values of 5.62 and 4.57 μM. As such, levomilnacipran is an NMDA receptor antagonist at high concentrations.Levomilnacipran has recently been found to act as an inhibitor of beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1), which is responsible for β-amyloid plaque formation, and hence may be a potentially useful drug in the treatment of Alzheimers disease.
Pharmacokinetics
Levomilnacipran has a high oral bioavailability of 92% and a low plasma protein binding of 22%. It is metabolized in the liver by the cytochrome P450 enzyme CYP3A4, thereby making the medication susceptible to grapefruit-drug interactions. The drug has an elimination half-life of approximately 12 hours, allowing for once-daily administration. Levomilnacipran is excreted in urine.
History
Levomilnacipran was developed by Forest Laboratories and Pierre Fabre Group, and was approved by the Food and Drug Administration in July 2013.
References
External links
Media related to Levomilnacipran at Wikimedia Commons
"Levomilnacipran". Drug Information Portal. U.S. National Library of Medicine. |
Radium-223 | Radium-223 (223Ra, Ra-223) is an isotope of radium with an 11.4-day half-life. It was discovered in 1905 by T. Godlewski, a Polish chemist from Kraków, and was historically known as actinium X (AcX). Radium-223 dichloride is an alpha particle-emitting radiotherapy drug that mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover. The principal use of radium-223, as a radiopharmaceutical to treat metastatic cancers in bone, takes advantage of its chemical similarity to calcium, and the short range of the alpha radiation it emits.
Origin and preparation
Although radium-223 is naturally formed in trace amounts by the decay of uranium-235, it is generally made artificially, by exposing natural radium-226 to neutrons to produce radium-227, which decays with a 42-minute half-life to actinium-227. Actinium-227 (half-life 21.8 years) in turn decays via thorium-227 (half-life 18.7 days) to radium-223. This decay path makes it convenient to prepare radium-223 by "milking" it from an actinium-227 containing generator or "cow", similar to the moly cows widely used to prepare the medically important isotope technetium-99m.223Ra itself decays to 219Rn (half-life 3.96 s), a short-lived gaseous radon isotope, by emitting an alpha particle of 5.979 MeV.
Medical use
The pharmaceutical product and medical use of radium-223 against skeletal metastases was invented by Roy H. Larsen, Gjermund Henriksen and Øyvind S. Bruland and has been developed by the former Norwegian company Algeta ASA, in a partnership with Bayer, under the trade name Xofigo (formerly Alpharadin), and is distributed as a solution containing radium-223 chloride (1100 kBq/ml), sodium chloride, and other ingredients for intravenous injection. Algeta ASA was later acquired by Bayer who is now the sole owner of Xofigo. The recommended regimen is six treatments of 55 kBq/kg (1.5 μCi/kg), repeated at 4-week intervals.
Mechanism of action
The use of radium-223 to treat metastatic bone cancer relies on the ability of alpha radiation from radium-223 and its short-lived decay products to kill cancer cells. Radium is preferentially absorbed by bone by virtue of its chemical similarity to calcium, with most radium-223 that is not taken up by the bone being cleared, primarily via the gut, and excreted. Although radium-223 and its decay products also emit beta and gamma radiation, over 95% of the decay energy is in the form of alpha radiation. Alpha radiation has a very short range in tissues compared to beta or gamma radiation: around 2-10 cells. This reduces damage to surrounding healthy tissues, producing an even more localized effect than the beta-emitter strontium-89, also used to treat bone cancer. Taking account of its preferential uptake by bone and the alpha particles short range, radium-223 is estimated to give targeted osteogenic cells a radiation dose at least eight times higher than other non-targeted tissues.
Clinical trials and FDA and EMA approval
The phase II study of radium-223 in castration-resistant prostate cancer (CRPC) patients with bone metastases showed minimum myelotoxicity and good tolerance for the treatment.223Ra successfully met the primary endpoint of overall survival in the phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer patients) study for bone metastases resulting from CRPC in 922 patients.The ALSYMPCA study was stopped early after a pre-planned efficacy interim analysis, following a recommendation from an Independent Data Monitoring Committee, on the basis of achieving a statistically significant improvement in overall survival (two-sided p-value = 0.0022, HR = 0.699, the median overall survival was 14.0 months for 223Ra and 11.2 months for placebo). Earlier phase II of the trial showed a median increased survival of 18.9 weeks (around 4.4 months). The lower figure of 2.8 months increased survival in interim phase III results is a probable result of stopping the trial; median survival time for patients still alive could not be calculated. A 2014 update indicates a median increased survival of 3.6 months.In May 2013, 223Ra received marketing approval from the U.S. Food and Drug Administration (FDA) as a treatment for CRPC with bone metastases in patients with symptomatic bone metastases and without known visceral disease. 223Ra received priority review as a treatment for an unmet medical need, based on its ability to extend overall survival as shown its Phase III trial.This study also led to approval in the European Union on 19 September 2013 The European Medicines Agency subsequently recommended restricting its use to patients who have had two previous treatments for metastatic prostate cancer or who cannot receive other treatments. The medicine must also not be used with abiraterone acetate, prednisone or prednisolone and its use is not recommended in patients with a low number of osteoblastic bone metastases.223Ra also showed promising preliminary results in a phase IIa trial enrolling 23 women with bone metastases resulting from breast cancer that no longer responds to endocrine therapy. 223Ra treatment reduced the levels of bone alkaline phosphatase (bALP) and urine N-telopeptide (uNTX), key markers of bone turnover associated with bone metastases in breast cancer, diminished bone pain slightly though consistently, and was well tolerated. Another single-arm, open-label Phase II trial reported possible efficacy of 223Ra combined with endocrine therapy in hormone-receptor-positive, bone-dominant breast cancer metastasis.
Side effects
The most common side effects reported during clinical trials in men receiving 223Ra were nausea, diarrhea, vomiting and swelling of the leg, ankle or foot. The most common abnormalities detected during blood testing were anemia, lymphocytopenia, leukopenia, thrombocytopenia and neutropenia.
Other radium-223-based compounds
Although radium does not easily form stable molecular complexes, data has been presented on methods to increase and customize its specificity for particular cancers by linking it to monoclonal antibodies, by enclosing the 223Ra in liposomes bearing the antibodies on their surface.
See also
Actinium-225
Actinium series
Bismuth-213
Isotopes of radium
Radium chloride
References
External links
"Radium-223". Drug Information Portal. U.S. National Library of Medicine.
"FDA approves new drug for advanced prostate cancer" (Press release). US FDA. Archived from the original on 4 June 2013. Retrieved 16 December 2019. |
Darifenacin | Darifenacin (trade name Enablex in United States and Canada, Emselex in the European Union) is a medication used to treat urinary incontinence due to an overactive bladder. It was discovered by scientists at the Pfizer research site in Sandwich, UK under the identifier UK-88,525 and used to be marketed by Novartis. In 2010, the US rights were sold to Warner Chilcott for US$400 million.
Adverse effects
Darifenacin should not be used in people with urinary retention. Anticholinergic agents, such as darifenacin, may also produce constipation and blurred vision. Heat prostration (due to decreased sweating) can occur when anticholinergics such as darifenacin are used in a hot environment.
Medical uses
Darifenacin is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency in adults. It may also be recommended with an alpha blocker to help provide symptomatic benefit for overactive bladder and obstructive symptoms such as likely associated with benign prostatic hypertrophy.
Mechanism of action
Darifenacin works by blocking the M3 muscarinic acetylcholine receptor, which is primarily responsible for bladder muscle contractions. It thereby decreases the urgency to urinate. It is not known whether this selectivity for the M3 receptor translates into any clinical advantage when treating symptoms of overactive bladder syndrome.
References
External links
"Darifenacin". Drug Information Portal. U.S. National Library of Medicine.
"Darifenacin hydrobromide". Drug Information Portal. U.S. National Library of Medicine. |
Hydrometallurgy | Hydrometallurgy is a technique within the field of extractive metallurgy, the obtaining of metals from their ores. Hydrometallurgy involve the use of aqueous solutions for the recovery of metals from ores, concentrates, and recycled or residual materials. Processing techniques that complement hydrometallurgy are pyrometallurgy, vapour metallurgy, and molten salt electrometallurgy. Hydrometallurgy is typically divided into three general areas:
Leaching
Solution concentration and purification
Metal or metal compound recovery
Leaching
Leaching involves the use of aqueous solutions to extract metal from metal bearing materials which is brought into contact with a material containing a valuable metal. The first examples come from 11-12th centuries China where it was applied to extraction of copper and accounted for a significant share of total copper production. In the 17th century it was used for the same purposes in Germany and Spain.The lixiviant solution conditions vary in terms of pH, oxidation-reduction potential, presence of chelating agents and temperature, to optimize the rate, extent and selectivity of dissolution of the desired metal component into the aqueous phase. Through the use of chelating agents, one can selectively extract certain metals. Such chelating agents are typically amines of schiff bases.The five basic leaching reactor configurations are in-situ, heap, vat, tank and autoclave.
In-situ leaching
In-situ leaching is also called "solution mining." This process initially involves drilling of holes into the ore deposit. Explosives or hydraulic fracturing are used to create open pathways within the deposit for solution to penetrate into. Leaching solution is pumped into the deposit where it makes contact with the ore. The solution is then collected and processed. The Beverley uranium deposit is an example of in-situ leaching and also Trojan Mine in Zimbabwe.
Heap leaching
In heap leaching processes, crushed (and sometimes agglomerated) ore is piled in a heap which is lined with an impervious layer. Leach solution is sprayed over the top of the heap, and allowed to percolate downward through the heap. The heap design usually incorporates collection sumps, which allow the "pregnant" leach solution (i.e. solution with dissolved valuable metals) to be pumped for further processing. An example is gold cyanidation, where pulverized ores are extracted with a solution of sodium cyanide, which, in the presence of air, dissolves the gold, leaving behind the nonprecious residue.
Vat leaching
Vat leaching involves contacting material, which has usually undergone size reduction and classification, with leach solution in large vats.
Tank leaching
Stirred tank, also called agitation leaching, involves contacting material, which has usually undergone size reduction and classification, with leach solution in agitated tanks. The agitation can enhance reaction kinetics by enhancing mass transfer. Tanks are often configured as reactors in series.
Autoclave leaching
Autoclave reactors are used for reactions at higher temperatures, which can enhance the rate of the reaction. Similarly, autoclaves enable the use of gaseous reagents in the system.
Solution concentration and purification
After leaching, the leach liquor must normally undergo concentration of the metal ions that are to be recovered. Additionally, undesirable metal ions sometimes require removal.
Precipitation is the selective removal of a compound of the targeted metal or removal of a major impurity by precipitation of one of its compounds. Copper is precipitated as its sulfide as a means to purify nickel leachates.
Cementation is the conversion of the metal ion to the metal by a redox reaction. A typical application involves addition of scrap iron to a solution of copper ions. Iron dissolves and copper metal is deposited.
Solvent Extraction
Ion Exchange
Gas reduction. Treating a solution of nickel and ammonia with hydrogen affords nickel metal as its powder.
Electrowinning is a particularly selective if expensive electrolysis process applied to the isolation of precious metals. Gold can be electroplated from its solutions.
Solvent extraction
In the solvent extraction a mixture of an extractant in a diluent is used to extract a metal from one phase to another. In solvent extraction this mixture is often referred to as the "organic" because the main constituent (diluent) is some type of oil.
The PLS (pregnant leach solution) is mixed to emulsification with the stripped organic and allowed to separate. The metal will be exchanged from the PLS to the organic they are modified. The resulting streams will be a loaded organic and a raffinate. When dealing with electrowinning, the loaded organic is then mixed to emulsification with a lean electrolyte and allowed to separate. The metal will be exchanged from the organic to the electrolyte. The resulting streams will be a stripped organic and a rich electrolyte. The organic stream is recycled through the solvent extraction process while the aqueous streams cycle through leaching and electrowinning processes respectively.
Ion exchange
Chelating agents, natural zeolite, activated carbon, resins, and liquid organics impregnated with chelating agents are all used to exchange cations or anions with the solution. Selectivity and recovery are a function of the reagents used and the contaminants present.
Metal recovery
Metal recovery is the final step in a hydrometallurgical process. Metals suitable for sale as raw materials are often directly produced in the metal recovery step. Sometimes, however, further refining is required if ultra-high purity metals are to be produced. The primary types of metal recovery processes are electrolysis, gaseous reduction, and precipitation. For example, a major target of hydrometallurgy is copper, which is conveniently obtained by electrolysis. Cu2+ ions reduce at mild potentials, leaving behind other contaminating metals such as Fe2+ and Zn2+.
Electrolysis
Electrowinning and electrorefining respectively involve the recovery and purification of metals using electrodeposition of metals at the cathode, and either metal dissolution or a competing oxidation reaction at the anode.
Precipitation
Precipitation in hydrometallurgy involves the chemical precipitation of either metals and their compounds or of the contaminants from aqueous solutions. Precipitation will proceed when, through reagent addition, evaporation, pH change or temperature manipulation, any given species exceeds its limit of solubility.
References
External links
Hydrometallurgy, BioMineWiki |
Ulipristal acetate | Ulipristal acetate, sold under the brand name Ella among others, is a medication used for emergency contraception (birth control) and uterine fibroids. As emergency contraception it should be used within 120 hours of vaginally penetrating intercourse. For fibroids it may be taken for up to six months. It is taken by mouth.Common side effects include headache, nausea, feeling tired, and abdominal pain. It should not be used in women who are already pregnant. It is in the selective progesterone receptor modulator (SPRM) class of medications. It works by preventing the effects of progesterone, therefore preventing ovulation but not affecting fertilization or implantation.Ulipristal acetate was approved for medical use in the United States in 2010. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Emergency contraception
For emergency contraception a 30 mg tablet is used within 120 hours (5 days) after unprotected intercourse or contraceptive failure. It has been shown to prevent about 62–85% of expected pregnancies, and prevents more pregnancies than emergency contraception with levonorgestrel. Ulipristal acetate is available by prescription for emergency contraception in over 50 countries, with access through pharmacists without a prescription being tested in the United Kingdom. In November 2014, the European Medicines Agency (EMA) recommended availability of ellaOne emergency contraceptive without prescription in the European Union. In January 2015 the European Commission issued an implementing decision amending accordingly the marketing authorization of EllaOne in the EU. Since July 2016, it is available without prescription in Israel.
Uterine fibroids
Ulipristal acetate is used for pre-operative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age. The use of ulipristal acetate to treat fibroids was suspended in the European Union in March 2020.In November 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended that ulipristal acetate be used only to treat uterine fibroids in premenopausal women for whom surgical procedures (including uterine fibroid embolization) are not appropriate or have not worked. In addition, the committee stated that ulipristal acetate must not be used for controlling symptoms of uterine fibroids while awaiting surgical treatment.Treatment of uterine fibroids with ulipristal acetate for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids.Two intermittent 3-months treatment courses of ulipristal acetate 10 mg resulted in amenorrhea at the end of the first treatment course in 79.5%, at the end of the second course in 88.5% of subjects. Mean myoma volume reduction observed during the first treatment course (−41.9%) was maintained during the second one (−43.7%). After two to four 3-months courses of treatment, UPA-treated fibroids shown about -70% in volume reduction.Volume reduction of uterine fibroid induced by ulipristal acetate was tentatively explained by the combination of multifactorial events involving control of proliferation of the tumor cells, induction of apoptosis and remodeling of the extracellular matrix under the action of matrix metalloproteinases.In May 2018, the European Medicines Agency (EMA) recommended measures to minimize the risk of rare but serious liver injury with ulipristal, including contraindication in women with known liver problems; liver tests before, during and after stopping treatment; a card for women to inform them about the need for liver monitoring and to contact their doctor should they develop symptoms of liver injury. In addition, use of the medicine for more than one treatment course has been restricted to women who are not eligible for surgery.
Contraindications
Ulipristal acetate should not be taken by women with severe liver diseases because of its CYP mediated metabolism. It has not been studied in women under the age of 18.It is also not recommended for women with severe asthma receiving glucocorticoid treatment because it has shown antiglucocorticoid effects in animal studies.
Pregnancy
Unlike levonorgestrel, and like mifepristone, ulipristal acetate is embryotoxic in animal studies. Before taking the drug, a pregnancy must be excluded. The EMA proposed to avoid any allusion to a possible use as an abortifacient in the package insert to avert off-label use. It is unlikely that ulipristal acetate could effectively be used as an abortifacient, since it is used in much lower doses (30 mg) than the roughly equipotent mifepristone (600 mg), and since mifepristone has to be combined with a prostaglandin for the induction of abortion. However, data on embryotoxicity in humans are very limited, and it is not clear what the risk for an abortion or for teratogenicity (birth defects) is. Of the 29 women studied who became pregnant despite taking ulipristal acetate, 16 had induced abortions, six had spontaneous abortions, six continued the pregnancies, and one was lost to follow-up.
Lactation
It is not recommended to breast feed within seven days of taking the drug since ulipristal acetate is excreted into the breast milk, and possible effects on the infant have not been studied.
Side effects
The most common side effects include headache, nausea (feeling sick), abdominal pain (stomach ache), and dysmenorrhea (period pains).
Interactions
Ulipristal acetate is metabolized by CYP3A4 in vitro. Ulipristal acetate is likely to interact with substrates of CYP3A4, like rifampicin, phenytoin, St Johns wort, carbamazepine or ritonavir, therefore concomitant use with these agents is not recommended. It might also interact with hormonal contraceptives and progestogens such as levonorgestrel and other substrates of the progesterone receptor, as well as with glucocorticoids.
Pharmacology
Pharmacodynamics
As an SPRM, ulipristal acetate has partial agonistic as well as antagonistic effects on the progesterone receptor. Ulipristal acetate exhibits similar potency to antagonize progesterone receptor as mifepristone in vitro. It also binds to the androgen receptor and the glucocorticoid receptor, but is only a weak antiandrogen and antiglucocorticoid relative to flutamide and mifepristone, respectively. Ulipristal acetate has no relevant affinity to the estrogen and mineralocorticoid receptors. Phase II clinical trials suggest that the mechanism might consist of blocking or delaying ovulation and of delaying the maturation of the endometrium.
Pharmacokinetics
In animal studies, the drug was quickly and nearly completely absorbed from the gut. Intake of food delays absorption, but it is not known whether this is clinically relevant.Ulipristal acetate is metabolized in the liver, most likely by CYP3A4, and to a small extent by CYP1A2 and CYP2D6. The two main metabolites have been shown to be pharmacologically active, but less than the original drug. The main excretion route is via the feces.
History
Ulipristal acetate was granted marketing authorization by the European Medicines Agency (EMA) in May 2009. In 2014, the EMA recommended ulipristal be made available without a prescription in the European Union.The U.S. Food and Drug Administration (FDA) approved the drug for use in the United States on 13 August 2010, following the FDA advisory committees recommendation. Watson Pharmaceuticals announced the availability of ulipristal acetate in the United States on 1 December 2010, in retail pharmacies, clinics, and one on-line pharmacy, KwikMed.
Society and culture
Brand names
Ulipristal acetate is marketed in the United States under the brand name Ella and in Canada under the brand name Fibristal. It is also marketed under the brand names EllaOne and Esmya in many countries including the United Kingdom and Ireland. A few less-widely used brand names also exist.
References
External links
"Ulipristal acetate". Drug Information Portal. U.S. National Library of Medicine. |
Miconazole | Miconazole, sold under the brand name Monistat among others, is an antifungal medication used to treat ring worm, pityriasis versicolor, and yeast infections of the skin or vagina. It is used for ring worm of the body, groin (jock itch), and feet (athletes foot). It is applied to the skin or vagina as a cream or ointment.Common side effects include itchiness or irritation of the area in which it was applied. Use in pregnancy is believed to be safe for the baby. Miconazole is in the imidazole family of medications. It works by decreasing the ability of fungi to make ergosterol, an important part of their cell membrane.Miconazole was patented in 1968 and approved for medical use in 1971. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Miconazole is mainly used externally for the treatment of ringworm including jock itch and athletes foot. Internal application is used for oral or vaginal thrush (yeast infection). This oral gel may also be used for the lip disorder angular cheilitis and other associated systems.
In the UK, miconazole may be used to treat neonatal oral thrush, while the alternative nystatin is only licensed for patients over the age of one month, but drug interactions are possible.
Side effects
Miconazole is generally well tolerated. The oral gel can cause dry mouth, nausea and an unpleasant taste in about 1–10% of people. Anaphylactic reactions are rare. The drug prolongs the QT interval.
Interactions
The substance is partly absorbed in the intestinal tract when used orally, as with the oral gel, and possibly when used vaginally. This can lead to increased concentrations of drugs that are metabolized by the liver enzymes CYP3A4 and CYP2C9, because miconazole inhibits these enzymes. Such interactions occur for example with anticoagulants of the warfarin type, phenytoin, some newer atypical antipsychotics, ciclosporin, and most statins used to treat hypercholesterolemia.These interactions are not relevant for miconazole that is applied to the skin.
Contraindications
Miconazole is contraindicated for people who use certain drugs that are metabolized by CYP3A4, for the reasons mentioned above:
drugs that also prolong the QT interval because of potential problems with the heart rhythm
ergot alkaloids
statins
triazolam and oral midazolam
sulfonamides with a potential to cause hypoglycaemia (low blood sugar)
Pharmacology
Mechanism of action
Miconazole inhibits the fungal enzyme 14α-sterol demethylase, resulting in a reduced production of ergosterol. In addition to its antifungal actions, miconazole, similarly to ketoconazole, is known to act as an antagonist of the glucocorticoid receptor.
Pharmacokinetics
After application to the skin, miconazole can be measured in the skin for up to four days, but less than 1% is absorbed into the bloodstream. When applied to the oral mucosa (and possibly also for vaginal use), it is significantly absorbed. In the bloodstream, 88.2% are bound to plasma proteins and 10.6% to blood cells. The substance is partly metabolized via the liver enzyme CYP3A4 and mainly eliminated via the faeces.
Chemistry
The solubilities of miconazole nitrate powder are 0.03% in water, 0.76% in ethanol and up to 4% in acetic acid. Miconazole crystallises as colourless prisms in the monoclinic space group P21/c.
Other uses
Miconazole is also used in Ektachrome film developing in the final rinse of the Kodak E-6 process and similar Fuji CR-56 process, replacing formaldehyde. Fuji Hunt also includes miconazole as a final rinse additive in their formulation of the C-41RA rapid access color negative developing process.
Brands and formulations
Oral treatment: (brand names Daktarin in UK, Fungimin Oral Gel in Bangladesh):
Oral gel 24 mg/ml (20 mg/g)
Oravig 50 mg once daily buccal tablet:In 2010, the U.S. Food and Drug Administration approved Oravig (miconazole) buccal tablets once daily for the local treatment of oropharyngeal candidiasis, more commonly known as thrush, in adults and children age 16 and older. Oravig is the only local, oral prescription formulation of miconazole approved for this use in the U.S.External skin treatment (brand names Desenex and Zeasorb in US and Canada, Micatin, Monistat-Derm, Daktarin in India, UK, Australia, Belgium and the Philippines, Daktar in Norway, Fungidal in Bangladesh, Decocort in Malaysia)
Topical cream: 2-5%
Combination: hydrocortisone/miconazole cream with 1% and 2%, respectively (Daktacort in UK, Daktodor in Greece)
Dusting powder: 2% powder with chlorhexidine hydrochloride (mycoDust)Vaginal treatment (brand names Miconazex, Monistat, Femizol or Gyno-Daktarin in UK):
Pessaries: 200 or 100 mg
Vaginal cream: 2% (7-day treatment), 4% (3-day treatment)
Combination: 2% cream with either 100 or 200 mg
References
External links
Kodak process E6 Ektachrome (color transparency) processing manual Z-119
Kodak process E6 Q-LAB processing manual Z-6 (more details than processing manual Z119 above)
"Miconazole". Drug Information Portal. U.S. National Library of Medicine. |
Regadenoson | Regadenoson, sold under the brand name Lexiscan among others, is an A2A adenosine receptor agonist that is a coronary vasodilator that is commonly used in pharmacologic stress testing. It produces hyperemia quickly and maintains it for a duration that is useful for radionuclide myocardial perfusion imaging. The selective nature of the drug makes it preferable to other stress agents such as adenosine, which are less selective and therefore cause more side-effects.
Regadenoson was approved by the United States Food and Drug Administration on April 10, 2008, and is marketed by Astellas Pharma under the tradename Lexiscan. It is approved for use in the European Union and under the name of Rapiscan. It is marketed by GE Healthcare and is sold in both the United Kingdom and Germany. Regadenoson was approved for use in the European Union in September 2010.Regadenoson has a 2 to 3 minute biological half-life, as compared with adenosines 10-second half-life. As a result, regadenoson stress protocols use a single bolus, instead of a 4-6 minute continuous infusion, which was needed with adenosine. Another difference is that adenosine infusion is weight based (140mcg/kg/minute), while with regadenoson, a 0.4 mg/5mL preloaded syringe dose is standard for all weights. Regadenoson stress tests are not affected by the presence of beta blockers, as regadenoson vasodilates via the adenosine pathway without stimulating beta adrenergic receptors.One side effect of regadenoson is that it can temporarily disrupt the integrity of the blood-brain barrier by inhibiting P-glycoprotein function.
References
External links
"Regadenoson". Drug Information Portal. U.S. National Library of Medicine.
"FDA warns of rare but serious risk of heart attack and death with cardiac nuclear stress test drugs Lexiscan (regadenoson) and Adenoscan (adenosine)". U.S. Food and Drug Administration (FDA). 12 January 2017. |
Rasagiline | Rasagiline (Azilect, Azipron) is an irreversible inhibitor of monoamine oxidase-B used as a monotherapy to treat symptoms in early Parkinsons disease or as an adjunct therapy in more advanced cases.The racemic form of the drug was invented by Aspro Nicholas in the early 1970s. Moussa B.H. Youdim identified it as a potential drug for Parkinsons disease, and working with collaborators at Technion – Israel Institute of Technology in Israel and the drug company, Teva Pharmaceuticals, identified the R-isomer as the active form of the drug. Teva brought it to market in partnership with Lundbeck in Europe and Eisai in the US and elsewhere. It was approved in Europe in 2005 and in the US in 2006.
Rasagiline is used to treat symptoms of Parkinsons disease both alone and in combination with other drugs. It has shown efficacy in both early and advanced Parkinsons, and appears to be especially useful in dealing with non-motor symptoms like fatigue.Rasagiline has not been tested in pregnant women and is Pregnancy Category C in the US.
Side effects
The FDA label contains warnings that rasagiline may cause severe hypertension or hypotension, may make people sleepy, may make motor control worse in some people, may cause hallucinations and psychotic-like behavior, may cause impulse control disorder, may increase the risk of melanoma, and upon withdrawal may cause high fever or confusion.Side effects when the drug is taken alone include flu-like symptoms, joint pain, depression, stomach upset, headache, dizziness, and insomnia. When taken with L-DOPA, side effects include increased movement problems, accidental injury, sudden drops in blood pressure, joint pain and swelling, dry mouth, rash, abnormal dreams and digestive problems including vomiting, loss of appetite, weight loss, abdominal pain, nausea, constipation. When taken with Parkinsons drugs other than L-DOPA, side effects include peripheral edema, fall, joint pain, cough, and insomnia.
Interactions
People who are taking meperidine, tramadol, methadone, propoxyphene, dextromethorphan, St. John’s wort, cyclobenzaprine, or another MAO inhibitor should not take rasagiline.The FDA drug label carries a warning of the risk of serotonin syndrome when rasagiline is used with antidepressants or with meperidine. However the risk appears to be low, based on a multicenter retrospective study in 1504 people, which looked for serotonin syndrome in people with PD who were treated with rasagiline plus antidepressants, rasagiline without antidepressants, or antidepressants plus Parkinsons drugs other than either rasagiline or selegiline; no cases were identified.There is a risk of psychosis or bizarre behavior if rasagiline is used with dextromethorphan and there is a risk of non-selective MAO inhibition and hypertensive crisis if rasagiline is used with other MAO inhibitors.
Chemistry
Rasagiline is molecularly a propargylamine derivative. The form brought to market by Teva and its partners is the mesylate salt, and was designated chemically as: 1H-Inden-1-amine-2,3-dihydro-N-2-propynyl-(1R)-methanesulfonate.
Pharmacology
Mechanism of action
Parkinsons disease is characterized by the death of cells that produce dopamine, a neurotransmitter. An enzyme called monoamine oxidase (MAO) breaks down neurotransmitters. MAO has two forms, MAO-A and MAO-B. MAO-B is generally believed to break down dopamine; however, recent evidence suggests that MAO-A may mostly or entirely be responsible for dopamine metabolism. Rasagiline prevents the breakdown of dopamine by irreversibly binding to MAO-B. Dopamine is therefore more available, somewhat compensating for the diminished quantities made in the brains of people with Parkinsons.Selegiline was the first selective MAO-B inhibitor. It is partly metabolized to levomethamphetamine (l-methamphetamine), one of the two enantiomers of methamphetamine, in vivo. While these metabolites may contribute to selegilines ability to inhibit reuptake of the neurotransmitters dopamine and norepinephrine, they have also been associated with orthostatic hypotension and hallucinations in some people. Rasagiline metabolizes into 1(R)-aminoindan which has no amphetamine-like characteristics and has neuroprotective properties in cells and in animal models.It is selective for MAO type B over type A by a factor of fourteen.
Metabolism
Rasagiline is broken down via CYP1A2, part of the cytochrome P450 metabolic path in the liver. It is contraindicated in patients with hepatic insufficiency and its use should be monitored carefully in patients taking other drugs that alter the normal effectiveness of this metabolic path.
History
Racemic rasagiline was discovered and patented by Aspro Nicholas in the 1970s as a drug candidate for treatment of hypertension.Moussa B. H. Youdim, a biochemist, had been involved in developing selegiline as a drug for Parkinsons, in collaboration with Peter Reiderer. He wanted to find a similar compound that would have fewer side effects, and around 1977, at about the same time he moved from London to Haifa to join the faculty of Technion, he noticed that rasagiline could potentially be such a compound. He called that compound, AGN 1135.In 1996 Youdim, in collaboration with scientists from Technion and the US National Institutes of Health, and using compounds developed with Teva Pharmaceuticals, published a paper in which the authors wrote that they were inspired by the racemic nature of deprenyl and the greater activity of one of its stereoisomers, L-deprenyl, which became selegiline, to explore the qualities of the isomers of the Aspro compound, and they found that the R-isomer had almost all the activity; this is the compound that became rasagiline. They called the mesylate salt of the R-isomer TVP-1012 and the hydrochloride salt, TVP-101.Teva and Technion filed patent applications for this racemically pure compound, methods to make it, and methods to use it to treat Parkinsons and other disorders, and Technion eventually assigned its rights to Teva.Teva began development of rasagiline, and by 1999 was in Phase III trials, and entered into a partnership with Lundbeck in which Lundbeck agreed to share the costs and obtained the joint right to market the drug in Europe. In 2003 Teva partnered with Eisai, giving Eisai the right to jointly market the drug for Parkinsons in the US, and to co-develop and co-market the drug for Alzheimers and other neurological diseases.It was approved by the European Medicines Agency for Parkinsons in 2005 and in the US in 2006.: 255
Research
Rasagiline was tested for efficacy in people with multiple system atrophy in a large randomized, placebo-controlled, double-blind disease-modification trial; the drug failed.Teva conducted clinical trials attempting to prove that rasagiline did not just treat symptoms, but was a disease-modifying drug - that it actually prevented the death of the dopaminergic neurons that characterize Parkinsons disease and slowed disease progression. They conducted two clinical trials, called TEMPO and ADAGIO, to try to prove this. The FDA advisory committee rejected their claim in 2011, saying that the clinical trial results did not prove that rasagiline was neuroprotective. The main reason was that in one of the trials, the lower dose was effective at slowing progression, but the higher dose was not, and this made no sense in light of standard dose-response pharmacology.
See also
Selegiline
Ladostigil
References
External links
"Rasagiline". Drug Information Portal. U.S. National Library of Medicine.
"Rasagiline mesylate". Drug Information Portal. U.S. National Library of Medicine. |
Labetalol | Labetalol is a medication used to treat high blood pressure and in long term management of angina. This includes essential hypertension, hypertensive emergencies, and hypertension of pregnancy. In essential hypertension it is generally less preferred than a number of other blood pressure medications. It can be given by mouth or by injection into a vein.Common side effects include low blood pressure with standing, dizziness, feeling tired, and nausea. Serious side effects may include low blood pressure, liver problems, heart failure, and bronchospasm. Use appears safe in the latter part of pregnancy and it is not expected to cause problems during breastfeeding. It works by blocking the activation of β-receptors and α-receptors.Labetalol was patented in 1966 and came into medical use in 1977. It is available as a generic medication. In 2019, it was the 198th most commonly prescribed medication in the United States, with more than 2 million prescriptions.
Medical uses
Labetalol is effective in the management of hypertensive emergencies, postoperative hypertension, pheochromocytoma-associated hypertension, and rebound hypertension from beta blocker withdrawal.It has a particular indication in the treatment of pregnancy-induced hypertension which is commonly associated with pre-eclampsia.It is also used as an alternative in the treatment of severe hypertension.
Special populations
Pregnancy: studies in lab animals showed no harm to the baby. However, a comparable well-controlled study has not been performed in pregnant women.Nursing: breast milk has been shown to contain small amounts of labetalol (0.004% original dose). Prescribers should be cautious in the use of labetalol for nursing mothers.Pediatric: no studies have established safety or usefulness in this population.Geriatric: the elderly are more likely to experience dizziness when taking labetalol. Labetalol should be dosed with caution in the elderly and counseled on this side effect.
Side effects
Common
Neurologic: headache (2%), dizziness (11%)
Gastrointestinal: nausea (6%), dyspepsia (3%)
Cholinergic: nasal congestion (3%), ejaculation failure (2%)
Respiratory: dyspnea (2%)
Other: fatigue (5%), vertigo (2%), orthostatic hypotensionLow blood pressure with standing is more severe and more common with IV formulation (58% vs 1%) and is often the reason larger doses of the oral formulation cannot be used.
Rare
Fever
Muscle cramps
Dry eyes
Heart block
Hyperkalemia
Hepatotoxicity
Drug eruption similar to lichen planus
Hypersensitivity - which may result in a lethal respiratory distress
Contraindications
Labetalol is contraindicated in people with overt cardiac failure, greater-than-first-degree heart block, severe bradycardia, cardiogenic shock, severe hypotension, anyone with a history of obstructive airway disease including asthma, and those with hypersensitivity to the drug.
Chemistry
The minimum requirement for adrenergic agents is a primary or secondary amine separated from a substituted benzene ring by one or two carbons. This configuration results in strong agonist activity. As the size of the substituent attached to the amine becomes greater, particularly with respect to a t-butyl group, then the molecule typically is found to have receptor affinity without intrinsic activity, and is, therefore, an antagonist. Labetalol, with its 1-methyl-3-phenylpropyl substituted amine, is greater in size relative to a t-butyl group and therefore acts predominantly as an antagonist. The overall structure of labetalol is very polar. This was created by substituting the isopropyl group in the standard beta-blocker structure with an aralkyl group, including a carboxamide group on the meta position, and by adding a hydroxyl group on the para position.Labetalol has two chiral carbons and consequently exists as four stereoisomers. Two of these isomers, the (S,S)- and (R,S)- forms are inactive. The third, the (S,R)-isomer, is a powerful α1 blocker. The fourth isomer, the (R,R)-isomer which is also known as dilevalol, is a mixed nonselective β blocker and selective α1 blocker. Labetalol is typically given as a racemic mixture to achieve both alpha and beta receptor blocking activity.
Labetalol acts by blocking alpha and beta adrenergic receptors, resulting in decreased peripheral vascular resistance without significant alteration of heart rate or cardiac output.
The β:α antagonism of labetalol is approximately 3:1.It is chemically designated in International Union of Pure and Applied Chemistry (IUPAC) nomenclature as 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide monohydrochloride.
Pharmacology
Mechanism of action
Labetalols dual alpha and beta adrenergic antagonism has different physiological effects in short- and long-term situations. In short-term, acute situations, labetalol decreases blood pressure by decreasing systemic vascular resistance with little effect on stroke volume, heart rate and cardiac output. During long-term use, labetalol can reduce heart rate during exercise while maintaining cardiac output by an increase in stroke volume.Labetalol is a dual alpha (α1) and beta (β1/β2) adrenergic receptor blocker and competes with other Catecholamines for binding to these sites. Its action on these receptors are potent and reversible. Labetalol is highly selective for postsynaptic alpha1- adrenergic, and non-selective for beta-adrenergic receptors. It is about equipotent in blocking beta1- and beta2- receptors.The amount of alpha to beta blockade depends on whether labetalol is administered orally or intravenously (IV). Orally, the ratio of alpha to β blockade is 1:3. Intravenously, alpha to β blockade ratio is 1:7. Thus, the labetalol can be thought to be a beta-blocker with some alpha-blocking effects. By comparison, labetalol is a weaker β-blocker than propranolol, and has a weaker affinity for alpha-receptors compared to Phentolamine.Labetalol possesses intrinsic sympathomimetic activity. In particular, it is a partial agonist at beta2- receptors located in the vascular smooth muscle. Labetalol relaxes vascular smooth muscle by a combination of this partial beta2- agonism and through alpha1- blockade. Overall, this vasodilatory effect can decrease blood pressure.Similar to local anesthetics and sodium channel blocking antiarrhythmics, labetalol also has membrane stabilizing activity. By decreasing sodium entry, labetalol decreases action potential firing and thus has local anesthetic activity.
Physiological action
The physiological effects of labetalol when administered acutely (intravenously) are not predictable solely by their receptor blocking effect, i.e. blocking beta1- receptors should decrease heart rate, but labetalol does not. When labetalol is given in acute situations, it decreases the peripheral vascular resistance and systemic blood pressure while having little effect on the heart rate, cardiac output and stroke volume, despite its alpha1-, beta1- and beta2- blocking mechanism. These effects are mainly seen when the person is in the upright position.Long term labetalol use also has different effects from other beta-blocking drugs. Other beta-blockers, such as propranolol, persistently reduce cardiac output during exercise. The peripheral vascular resistance decreases when labetalol is first administered. Continuous labetalol use further decreases peripheral vascular resistance. However, during exercise, cardiac output remains the same due to a compensatory mechanism that increases stroke volume. Thus, labetalol is able to reduce heart rate during exercise while maintaining cardiac output by the increase in stroke volume.
Pharmacokinetics
Labetalol, in animal models, was found to cross the blood-brain-barrier in only negligible amounts.
History
Labetalol was the first drug created that combined both alpha- and beta- adrenergic receptor blocking properties. It was created to potentially fix the compensatory reflex issue that occurred when blocking a single receptor subtype, i.e. vasoconstriction after blocking beta-receptors or tachycardia after blocking alpha receptors. Because the reflex from blocking the single receptor subtypes acted to prevent the lowering of blood pressure, it was postulated that weak blocking of both alpha- and beta- receptors could work together to decrease blood pressure.
References
External links
"Labetalol". Drug Information Portal. U.S. National Library of Medicine.
"Labetalol hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Belatacept | Belatacept, sold under the brand name Nulojix, is a fusion protein composed of the Fc fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4, which is a molecule crucial in the regulation of T cell costimulation, selectively blocking the process of T-cell activation. It is intended to provide extended graft and transplant survival while limiting the toxicity generated by standard immune suppressing regimens, such as calcineurin inhibitors. It differs from abatacept (Orencia) by only two amino acids.Belatacept was developed by Bristol-Myers-Squibb and approved by the U.S. Food and Drug Administration (FDA) on June 15, 2011.
References
External links
"Belatacept". Drug Information Portal. U.S. National Library of Medicine. |
Lovastatin | Lovastatin, sold under the brand name Mevacor among others, is a statin medication, to treat high blood cholesterol and reduce the risk of cardiovascular disease. Its use is recommended together with lifestyle changes. It is taken by mouth.Common side effects include diarrhea, constipation, headache, muscles pains, rash, and trouble sleeping. Serious side effects may include liver problems, muscle breakdown, and kidney failure. Use during pregnancy may harm the baby and use during breastfeeding is not recommended. It works by decreasing the livers ability to produce cholesterol by blocking the enzyme HMG-CoA reductase.Lovastatin was patented in 1979 and approved for medical use in 1987. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 95th most commonly prescribed medication in the United States, with more than 8 million prescriptions.
Medical uses
The primary uses of lovastatin is for the treatment of dyslipidemia and the prevention of cardiovascular disease. It is recommended to be used only after other measures, such as diet, exercise, and weight reduction, have not improved cholesterol levels.
Side effects
Lovastatin is usually well tolerated, with the most common side effects being, in approximately descending order of frequency: creatine phosphokinase elevation, flatulence, abdominal pain, constipation, diarrhoea, muscle aches or pains, nausea, indigestion, weakness, blurred vision, rash, dizziness and muscle cramps. As with all statin drugs, it can rarely cause myopathy, hepatotoxicity (liver damage), dermatomyositis or rhabdomyolysis. This can be life-threatening if not recognised and treated in time, so any unexplained muscle pain or weakness whilst on lovastatin should be promptly mentioned to the prescribing doctor. Other uncommon side effects that should be promptly mentioned to either the prescribing doctor or an emergency medical service include:
These less serious side effects should still be reported if they persist or increase in severity:
Contraindications
Contraindications, conditions that warrant withholding treatment with lovastatin, include pregnancy, breast feeding, and liver disease. Lovastatin is contraindicated during pregnancy (Pregnancy Category X); it may cause birth defects such as skeletal deformities or learning disabilities. Owing to its potential to disrupt infant lipid metabolism, lovastatin should not be taken while breastfeeding. Patients with liver disease should not take lovastatin.
Interactions
As with atorvastatin, simvastatin, and other statin drugs metabolized via CYP3A4, drinking grapefruit juice during lovastatin therapy may increase the risk of side effects. Components of grapefruit juice, the flavonoid naringin, or the furanocoumarin bergamottin inhibit CYP3A4 in vitro, and may account for the in vivo effect of grapefruit juice concentrate decreasing the metabolic clearance of lovastatin, and increasing its plasma concentrations.
Mechanism of action
Lovastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), an enzyme that catalyzes the conversion of HMG-CoA to mevalonate.
Mevalonate is a required building block for cholesterol biosynthesis and lovastatin interferes with its production by acting as a reversible competitive inhibitor for HMG-CoA, which binds to the HMG-CoA reductase. Lovastatin is a prodrug, an inactive lactone in its native form, the gamma-lactone closed ring form in which it is administered, is hydrolysed in vivo to the β-hydroxy acid open ring form; which is the active form.
Lovastatin and other statins have been studied for their chemopreventive and chemotherapeutic effects. No such effects were seen in the early studies. More recent investigations revealed some chemopreventive and therapeutic effects, for certain types of cancer, especially in combination of statins with other anticancer drugs. It is likely that these effect are mediated by the properties of statins to reduce proteasome activity, leading to an accumulation of cyclin-dependent kinase inhibitors p21 and p27, and to subsequent G1-phase arrest, as seen in cells of different cancer lines.
History
Compactin and lovastatin, natural products with a powerful inhibitory effect on HMG-CoA reductase, were discovered in the 1970s, and taken into clinical development as potential drugs for lowering LDL cholesterol.In 1982, some small-scale clinical investigations of lovastatin, a polyketide-derived natural product isolated from Aspergillus terreus, in very high-risk patients were undertaken, in which dramatic reductions in LDL cholesterol were observed, with very few adverse effects. After the additional animal safety studies with lovastatin revealed no toxicity of the type thought to be associated with compactin, clinical studies continued.
Large-scale trials confirmed the effectiveness of lovastatin. Observed tolerability continued to be excellent, and lovastatin was approved by the US FDA in 1987. It was the first statin approved by the FDA.Lovastatin is also naturally produced by certain higher fungi, such as Pleurotus ostreatus (oyster mushroom) and closely related Pleurotus spp. Research into the effect of oyster mushroom and its extracts on the cholesterol levels of laboratory animals has been extensive, although the effect has been demonstrated in a very limited number of human subjects.In 1998, the FDA placed a ban on the sale of dietary supplements derived from red yeast rice, which naturally contains lovastatin, arguing that products containing prescription agents require drug approval. Judge Dale A. Kimball of the United States District Court for the District of Utah, granted a motion by Cholestins manufacturer, Pharmanex, that the agencys ban was illegal under the 1994 Dietary Supplement Health and Education Act because the product was marketed as a dietary supplement, not a drug.
The objective is to decrease excess levels of cholesterol to an amount consistent with maintenance of normal body function. Cholesterol is biosynthesized in a series of more than 25 separate enzymatic reactions that initially involves three successive condensations of acetyl-CoA units to form the six-carbon compound 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA). This is reduced to mevalonate and then converted in a series of reactions to the isoprenes that are building-blocks of squalene, the immediate precursor to sterols, which cyclizes to lanosterol (a methylated sterol) and further metabolized to cholesterol. A number of early attempts to block the synthesis of cholesterol resulted in agents that inhibited late in the biosynthetic pathway between lanosterol and cholesterol. A major rate-limiting step in the pathway is at the level of the microsomal enzyme that catalyzes the conversion of HMG CoA to mevalonic acid, and that has been considered to be a prime target for pharmacologic intervention for several years.HMG CoA reductase occurs early in the biosynthetic pathway and is among the first committed steps to cholesterol formulation. Inhibition of this enzyme could lead to accumulation of HMG CoA, a water-soluble intermediate that is, then, capable of being readily metabolized to simpler molecules. This inhibition of reductase would lead to accumulation of lipophylic intermediates with a formal sterol ring.
Lovastatin was the first specific inhibitor of HMG CoA reductase to receive approval for the treatment of hypercholesterolemia. The first breakthrough in efforts to find a potent, specific, competitive inhibitor of HMG CoA reductase occurred in 1976, when Endo et al. reported the discovery of mevastatin, a highly functionalized fungal metabolite, isolated from cultures of Penicillium citrium.
Biosynthesis
The biosynthesis of lovastatin occurs via an iterative type I polyketide synthase (PKS) pathway. The six genes that encode enzymes that are essential for the biosynthesis of lovastatin are lovB, lovC, lovA, lovD, lovG, and lovF . The synthesis of dihydromonacolin L requires a total of 9-malonyl Coa . It proceeds in the PKS pathway until it reaches (E) a hexaketide, where it undergoes a Diels-Alder cycloaddition to form the fused rings. After cyclization it continues through the PKS pathway until it reaches (I) a nonaketide, which then undergoes release from LovB through the thioesterase encoded by LovG. Dihydromonacolin L, (J), then undergoes oxidation and dehydration via a cytochrome P450 oxygenase encoded by LovA to obtain monacolin J, (L).
The MT domain from lovB is active in the conversion of (B) to (C) when it transfers a methyl group from S-adenosyl-L-methionine (SAM) to the tetraketide (C) . Owing to the fact that LovB contains an inactive ER domain, LovC is required at specific steps to obtain fully reduced products. The domain organization of LovB, LovC, LovG and LovF is shown in Figure 2. The inactive ER domain of lovB is shown with an oval and where LovC acts in trans to LovB is shown with a red box.
In a parallel pathway, the diketide side chain of lovastatin is synthesized by another highly reducing type I polyketide synthase enzyme encoded by LovF . Lastly, the side chain, 2-methylbutyrate (M) is covalently attached to C-8 hydroxy group of monacolin J (L) by a transesterase encoded by LovD to form lovastatin.
Total synthesis
A major bulk of work in the synthesis of lovastatin was done by M. Hirama in the 1980s.
Hirama synthesized compactin and used one of the intermediates to follow a different path to get to lovastatin. The synthetic sequence is shown in the schemes below. The γ-lactone was synthesized using Yamada methodology starting with glutamic acid. Lactone opening was done using lithium methoxide in methanol and then silylation to give a separable mixture of the starting lactone and the silyl ether. The silyl ether on hydrogenolysis followed by Collins oxidation gave the aldehyde. Stereoselective preparation of (E,E)-diene was accomplished by addition of trans-crotyl phenyl sulfone anion, followed by quenching with Ac2O and subsequent reductive elimination of sulfone acetate. Condensation of this with lithium anion of dimethyl methylphosphonate gave compound 1. Compound 2 was synthesized as shown in the scheme in the synthetic procedure. Compounds 1 and 2 were then combined using 1.3 eq sodium hydride in THF followed by reflux in chlorobenzene for 82 hr under nitrogen to get the enone 3.
Simple organic reactions were used to get to lovastatin as shown in the scheme.
Society and culture
Natural sources
Lovastatin is a naturally occurring compound found in low concentrations in food such as oyster mushrooms, red yeast rice, and Pu-erh.
Brand names
Mevacor, Advicor (as a combination with niacin), Altocor, Altoprev
Other applications
In plant physiology, lovastatin has occasionally been used as inhibitor of cytokinin biosynthesis.
See also
Medicinal fungi
References
External links
Media related to Lovastatin at Wikimedia Commons
"Lovastatin". Drug Information Portal. U.S. National Library of Medicine. |
Eribulin | Eribulin, sold under the brand name Halaven, is an anticancer medication used to treat breast cancer and liposarcoma.The most common side effects include fatigue, nausea, hair loss (alopecia), constipation, certain nerve damage causing weakness or numbness in the hands and feet (peripheral neuropathy), abdominal pain and fever (pyrexia). Eribulin may also cause low levels of infection-fighting white blood cells (neutropenia) or decreased levels of potassium or calcium.
Approvals and indications
Eribulin was approved for medical use in the European Union in March 2011, and it is indicated for the treatment of:
people with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimens for advanced disease. Prior therapy should have included an anthracycline and a taxane unless the people were not suitable for these treatments.
adults with unresectable liposarcoma who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease.
Breast cancer
The mesylate salt was approved by the U.S. Food and Drug Administration (FDA) on November 15, 2010, with an indication to treat people with metastatic breast cancer who have received at least two prior chemotherapy regimens for late-stage disease, including both anthracycline- and taxane-based chemotherapies. It was approved by Health Canada on December 14, 2011, with an indication for the treatment of people with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Metastatic breast cancer impacts about 150,000 people in the U.S. and due to the small patient population, Eisai was able to file a New Drug Application (NDA) under the orphan and rare disease designation.
Liposarcoma
On January 28, 2016, the U.S. Food and Drug Administration (FDA) approved eribulin for the treatment of inoperable liposarcoma in people who received prior chemotherapy that contained an anthracycline drug. A Phase III trial reported: With eribulin the median overall survival for participants with liposarcoma was 15.6 months, compared to 8.4 months for participants treated with dacarbazine.
Adverse effects
Serious side effects may include anaemia; decrease in white blood cell count, which can increase the risk of serious infections that could lead to death; , hair loss; cancer-related fatigue; numbness, tingling or burning in the hands and feet (neuropathy); harm to a developing fetus; as well as changes in heartbeat (QTc prolongation), that may also lead to death.
Structure and mechanism
Eribulin is a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin B, the parent molecule being a naturally occurring, potent mitotic inhibitor with a unique mechanism of action. The parent molecule was originally found in the sponge Halichondria okadai.Eribulin is a mechanistically unique inhibitor of microtubule dynamics, binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules.
Eribulin has both cytotoxic and non-cytotoxic mechanisms of action. Its cytotoxic effects are related to its antimitotic activities, wherein apoptosis of cancer cells is induced following prolonged and irreversible mitotic blockade. In addition to its cytotoxic, antimitotic-based mechanisms, preclinical studies in human breast cancer models have shown that eribulin also exerts complex effects on the biology of surviving cancer cells and residual tumors that appear unrelated to its antimitotic effects. These non-mitotic mechanisms include vascular remodeling that leads to increased tumor perfusion and mitigation of tumor hypoxia, phenotypic changes consistent with reversal of epithelial-mesenchymal transition (EMT), and decreased capacity for migration and invasion leading to reduced metastatic capacity as measured in a preclinical experimental metastasis model. In other studies, eribulin treatment of leiomyosarcoma and liposarcoma cells leads to increased expression of smooth muscle and adipocyte differentiation antigens, respectively. Taxane-resistant cancers are often unresponsive to eribulin. A recent study found that this resistance is due to expression of multidrug resistance protein 1 (MDR1). Fluorescently labeled eribulin has been used to study the pharmacokinetics and pharmacodynamics at single cell level in vivo.The synthesis of eribulin was first published in 2001; a new synthetic route to the drug was published in 2009.
Clinical trials
Eribulin is being investigated for use in a variety of other solid tumors, including breast cancer, non-small cell lung cancer, prostate cancer, brain cancer, cervical cancer, urothelial cancer, melanoma, solitary fibrous tumors, and various sarcomas.
Research and development
Two new eribulin based products are in the research and development phase; a liposomal formulation and antibody drug combination therapy, both are for the treatment of solid tumors. The liposomal formulation of eribulin, E7389 liposomal, is currently in Phase I clinical trials. Preliminary in vivo experiments show a decrease in C(max) and a longer half-life with the liposomal formulation. The drug antibody eribulin combination therapy is a joint venture between Eisai and Merck. The clinical trials combine eribulin and pembrolizumab, a PD-1 inhibitor, for the treatment of breast cancer and other advanced cancers.
Intellectual Property
Currently there are five active patents in the United States that are associated with the Halaven drug application, N201532. The first one expired on June 16, 2019, the last one (USRE46965) expires on January 8, 2027.
References
External links
"Eribulin". Drug Information Portal. U.S. National Library of Medicine.
"Eribulin mesylate". Drug Information Portal. U.S. National Library of Medicine. |
Doxorubicin | Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposis sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used together with other chemotherapy agents. Doxorubicin is given by injection into a vein.Common side effects include hair loss, bone marrow suppression, vomiting, rash, and inflammation of the mouth. Other serious side effects may include allergic reactions such as anaphylaxis, heart damage, tissue damage at the site of injection, radiation recall, and treatment-related leukemia. People often experience red discoloration of the urine for a few days. Doxorubicin is in the anthracycline and antitumor antibiotic family of medications. It works in part by interfering with the function of DNA.Doxorubicin was approved for medical use in the United States in 1974. It is on the World Health Organizations List of Essential Medicines. Versions that are pegylated and in liposomes are also available; however, they are more expensive. Doxorubicin was originally made from the bacterium Streptomyces peucetius.
Medical uses
In the EU doxorubicin pegylated liposomal (as Caelyx) is indicated to treat breast cancer, ovarian cancer, and AIDS-related Kaposis sarcoma. It is indicated to treat multiple myeloma in combination with bortezomib. Doxorubicin hydrochloride (as Myocet liposomal) is indicated to treat breast cancer in combination with cyclophosphamide.Doxorubicin is commonly used to treat some leukemias and Hodgkins lymphoma, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, soft tissue sarcoma, multiple myeloma, and others. Commonly used doxorubicin-containing regimens are AC (Adriamycin, cyclophosphamide), TAC (taxotere, AC), ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), BEACOPP, CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) and FAC (5-fluorouracil, adriamycin, cyclophosphamide).Doxil (see below) is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after platinum-based chemotherapy, or for the treatment of AIDS-related Kaposis sarcoma.
Side effects
Cardiotoxicity
The most dangerous side effect of doxorubicin is dilated cardiomyopathy, leading to congestive heart failure. The rate of cardiomyopathy is dependent on its cumulative dose, with an incidence about 4% when the dose of doxorubicin is 500–550 mg/m2, 18% when the dose is 551–600 mg/m2 and 36% when the dose exceeds 600 mg/m2. There are several ways in which doxorubicin is believed to cause cardiomyopathy, including oxidative stress, downregulation of genes for contractile proteins, and p53-mediated apoptosis.Doxorubicin-induced cardiomyopathy typically results in dilated cardiomyopathy, with all four cardiac chambers being enlarged. This results in both systolic and diastolic dysfunction. Eventually, heart failure can result, which carries a 50% mortality rate. There is no effective treatment against established cardiomyopathy caused by the drug as of 2010. The drug dexrazoxane may be used to decrease the risk of doxorubicins cardiotoxicity in certain cases.
Other
Another common and potentially fatal complication of doxorubicin is typhlitis, an acute life-threatening inflammation of the bowel. Additionally, some people may develop PPE, characterized by skin eruptions on the palms of the hand or soles of the feet, swelling, pain, and erythema. Due to these side effects and its red color, doxorubicin has earned the nickname "red devil" or "red death."Chemotherapy can cause reactivation of hepatitis B, and doxorubicin-containing regimens are no exception.Doxorubicin and several chemotherapeutic drugs (including cyclophosphamide) can cause a loss of skin pigmentation.
Liposomal formulations
There is a pegylated (polyethylene glycol coated) liposome-encapsulated form of doxorubicin, developed to treat Kaposis sarcoma The polyethylene glycol coating results in preferential concentration of doxorubicin in the skin. However, this also results in a side effect called palmar plantar erythrodysesthesia (PPE), more commonly known as hand-foot syndrome.
Following administration of this form of doxorubicin, small amounts of the drug can leak from capillaries in the palms of the hands and soles of the feet. The result of this leakage is redness, tenderness, and peeling of the skin that can be uncomfortable and even painful. In clinical testing at 50 mg/m2 dosing every 4 weeks, half of people developed hand-foot syndrome. The rate of this side effect limits the dose of this formulation that can be given as compared with plain doxorubicin in the same treatment regimen, thereby limiting potential substitution. Substitution would be desirable because liposome-encapsulated doxorubicin is less cardiotoxic than unencapsulated doxorubicin. This liposome-encapsulated form is also approved by the FDA for treatment of ovarian cancer and multiple myeloma.A non-pegylated liposomal doxorubicin, called Myocet, is approved in the European Union and in Canada for the treatment of metastatic breast cancer in combination with cyclophosphamide, but it has not been approved by the FDA for use in the United States. Unlike Doxil, the Myocet liposome does not have a polyethylene glycol coating, and therefore does not result in the same rate of PPE. The minimization of this side effect may allow for one-for-one (1:1) substitution with doxorubicin in the same treatment regimen, thereby improving safety with no loss of efficacy. Like Doxil, the liposomal encapsulation of the doxorubicin limits the cardiotoxicity. In theory, by limiting the cardiotoxicity of doxorubicin through liposomal encapsulation, it can be used safely in concurrent combination with other cardiotoxic chemotherapy drugs, such as trastuzumab. There is an FDA black box warning that trastuzumab cannot be used in concurrent combination with doxorubicin, only in sequential combination. Though concurrent combination of trastuzumab and doxorubicin in clinical studies found superior tumor response, the combination resulted in unacceptable cardiotoxicity, including risk of cardiac failure manifesting as congestive heart failure (CHF). Published phase II study results have shown that Myocet, trastuzumab, and paclitaxel can safely be used concurrently without the cardiac risk, as measured by reduction in LVEF function, while still achieving superior tumor response. This finding is the basis for the ongoing phase III trial for FDA approval.
Biosynthesis
Doxorubicin (DXR) is a 14-hydroxylated version of daunorubicin, the immediate precursor of DXR in its biosynthetic pathway.
Daunorubicin is more abundantly found as a natural product because it is produced by a number of different wild type strains of Streptomyces. In contrast, only one known non-wild type species, Streptomyces peucetius subspecies cesius ATCC 27952, was initially found to be capable of producing the more widely used doxorubicin. This strain was created by Arcamone et al. in 1969 by mutating a strain producing daunorubicin, but not DXR, at least in detectable quantities. Subsequently, Hutchinsons group showed that under special environmental conditions, or by the introduction of genetic modifications, other strains of Streptomyces can produce doxorubicin. His group also cloned many of the genes required for DXR production, although not all of them have been fully characterized. In 1996, Strohls group discovered, isolated and characterized dox A, the gene encoding the enzyme that converts daunorubicin into DXR.By 1999, they produced recombinant dox A, a cytochrome P450 oxidase, and found that it catalyzes multiple steps in DXR biosynthesis, including steps leading to daunorubicin. This was significant because it became clear that all daunorubicin-producing strains have the necessary genes to produce DXR, the much more therapeutically important of the two. Hutchinsons group went on to develop methods to improve the yield of DXR, from the fermentation process used in its commercial production, not only by introducing dox A encoding plasmids, but also by introducing mutations to deactivate enzymes that shunt DXR precursors to less useful products, for example baumycin-like glycosides. Some triple mutants, that also over-expressed dox A, were able to double the yield of DXR. This is of more than academic interest, because at that time DXR cost about $1.37 million per kg and current production in 1999 was 225 kg per annum.More efficient production techniques have brought the price down to $1.1 million per kg for the nonliposomal formulation. Although DXR can be produced semi-synthetically from daunorubicin, the process involves electrophilic bromination and multiple steps, and the yield is poor. Since daunorubicin is produced by fermentation, it would be ideal if the bacteria could complete DXR synthesis more effectively.
Mechanism of action
Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis. This inhibits the progression of topoisomerase II, an enzyme which relaxes supercoils in DNA for transcription. Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being released and thereby stopping the process of replication. It may also increase quinone type free radical production, hence contributing to its cytotoxicity.The planar aromatic chromophore portion of the molecule intercalates between two base pairs of the DNA, while the six-membered daunosamine sugar sits in the minor groove and interacts with flanking base pairs immediately adjacent to the intercalation site, as evidenced by several crystal structures.By intercalation, doxorubicin can also induce histone eviction from transcriptionally active chromatin. As a result, DNA damage response, epigenome and transcriptome are deregulated in doxorubicin-exposed cells.
History
In the 1950s, an Italian research company, Farmitalia Research Laboratories, began an organized effort to find anticancer compounds from soil-based microbes. A soil sample was isolated from the area surrounding the Castel del Monte, a 13th-century castle. A new strain of Streptomyces peucetius, which produced a red pigment, was isolated, and an antibiotic from this bacterium was effective against tumors in mice. Since a group of French researchers discovered the same compound at about the same time, the two teams named the compound daunorubicin, combining the name Dauni, a pre-Roman tribe that occupied the area of Italy where the compound was isolated, with the French word for ruby, rubis, describing the color. Clinical trials began in the 1960s, and the drug was successful in treating acute leukemia and lymphoma. However, by 1967, it was recognized that daunorubicin could lead to fatal cardiac toxicity.Researchers at Farmitalia soon discovered that changes in biological activity could be made by minor changes in the structure of the compound. A strain of Streptomyces was mutated using N-nitroso-N-methyl urethane, and this new strain produced a different, red-colored antibiotic. They named this new compound Adriamycin, after the Adriatic Sea, and the name was later changed to doxorubicin to conform to the established naming convention. Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. It also showed a higher therapeutic index, yet the cardiotoxicity remained.Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. Subsequent research has led to many other anthracycline antibiotics, or analogs, and there are now over 2,000 known analogs of doxorubicin. By 1991, 553 of them had been evaluated in the screening program at the National Cancer Institute (NCI). In 2016 GPX-150 was granted orphan drug designation by US FDA.
Society and culture
Legal status
On 24 March 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Zolsketil pegylated liposomal, intended for the treatment of metastatic breast cancer, advanced ovarian cancer, progressive multiple myeloma and AIDS-related Kaposis sarcoma. The applicant for this medicinal product is Accord Healthcare S.L.U. Zolsketil pegylated liposomal is a hybrid medicine of Adriamycin. It contains the same active substance as Adriamycin, but is available in a pegylated liposomal formulation. Zolsketil pegylated liposomal was approved for medical use in the European Union in May 2022.On 21 July 2022, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Celdoxome pegylated liposomal, intended for the treatment of metastatic breast cancer, advanced ovarian cancer, progressive multiple myeloma and AIDS-related Kaposis sarcoma. The applicant for this medicinal product is YES Pharmaceutical Development Services GmbH. Celdoxome pegylated liposomal is a hybrid medicine of Adriamycin which has been authorized in the EU since 24 October 1979. Celdoxome pegylated liposomal contains the same active substance as Adriamycin, but is available in a pegylated liposomal formulation.
Names
It is also known as hydroxydaunorubicin and hydroxydaunomycin.It is sold under a number of different brand names, including Adriamycin PFS, Adriamycin RDF, or Rubex.
Formulations
Doxorubicin is photosensitive, and containers are often covered by an aluminum bag and/or brown wax paper to prevent light from affecting it. Doxorubicin is also available in liposome-encapsulated forms as Doxil (pegylated form), Myocet (nonpegylated form), and Caelyx, which are also given by intravenous injection.The FDA approved the first generic version of Doxil, made by Sun, in February 2013.
Research
Combination therapy experiments with sirolimus (rapamycin) and doxorubicin have shown promise in treating Akt-positive lymphomas in mice.Further, the release of photo-activated adriamycin with the aid of nanoporous optical antenna resulted in significant anti-cancer effect in MCF-7 breast cancer cells.
In 2006, animal research coupling a murine monoclonal antibody with doxorubicin created an immunoconjugate that was able to eliminate HIV-1 infection in mice.
Antimalarial activity
There is some evidence for antimalarial activity for doxorubicin and similar compounds. In 2009, a compound similar in structure to doxorubicin was found to inhibit plasmepsin II, an enzyme unique to the malarial parasite Plasmodium falciparum. The pharmaceutical company GlaxoSmithKline (GSK) later identified doxorubicin in a set of compounds that inhibit parasite growth
Fluorescence
Doxorubicin is also known to be fluorescent. This has often been used to characterize doxorubicin concentrations, and has opened the possibility of using the molecule as a theranostic agent. However, there are significant limitations, as doxorubicins fluorescence spectrum is known to depend on a variety of factors, including the pH of the environment, solvent dielectric constant and others. Doxorubicin fluorescence is quenched by binding to DNA, and shielded by micelle encapsulation. It is also known to self-quench at high concentrations. In contrast, histone binding amplifies fluorescence.
References
External links
Media related to Doxorubicin at Wikimedia Commons
"Doxorubicin". Drug Information Portal. U.S. National Library of Medicine.
"Doxorubicin hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Darolutamide | Darolutamide, sold under the brand name Nubeqa, is an antiandrogen medication which is used in the treatment of non-metastatic castration-resistant prostate cancer in men. It is specifically approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration. The medication is taken by mouth twice per day with food.Side effects of darolutamide added to castration may include fatigue, asthenia, pain in the arms and legs, and rash. Darolutamide is a nonsteroidal antiandrogen (NSAA), and acts as a selective antagonist of the androgen receptor (AR). It has been referred to as a second- or third-generation NSAA.Darolutamide was patented in 2011 and was approved for medical use in USA in July 2019, in the European Union in March 2020 and in Australia in July 2020.
Medical uses
Darolutamide is approved for use concurrently with a gonadotropin-releasing hormone (GnRH) agonist or antagonist or bilateral orchiectomy in the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) in men. It is used at a dosage of 600 mg orally twice per day (1,200 mg/day total) with food. In individuals with severe renal impairment or moderate hepatic impairment, darolutamide is used at a dosage of 300 mg orally twice per day (600 mg/day total) with food. No dosage adjustment is needed for mild to moderate renal impairment or mild hepatic impairment, whereas appropriate dosage adjustment for end-stage kidney disease and severe hepatic impairment is unknown.Two 2020 meta-analyses reported that enzalutamide and apalutamide seemed to be more effective than darolutamide in improving metastasis-free survival (MFS), however 2021 matched adjusted indirect comparison showed no significant differences between drugs in terms of MFS. According to 2021 meta-analysis darolutamide was ranked first in terms of improving overall survival (OS). Also, darolutamide showed significantly lower rate of grade 3-5 adverse events (AE) compared to both enzalutamide and apalutamide.
Available forms
Darolutamide is provided in the form of 300 mg oral film-coated tablets.
Contraindications
Darolutamide has no contraindications in men. However, the medication may have teratogenic effects in male fetuses due to its antiandrogenic effects and hence should not be used by women who are pregnant.
Side effects
The most common side effects of darolutamide in clinical trials (≥2% incidence) in castrated men included fatigue and asthenia (16% vs. 11% for placebo), pain in extremities (6% vs. 3% for placebo), and rash (3% vs. 1% for placebo). Darolutamide was also associated with higher incidences of ischemic heart disease (4.0% vs. 3.4% for placebo) and heart failure (2.1% vs. 0.9% for placebo). In terms of laboratory test abnormalities, darolutamide was associated with decreased neutrophil count (20% vs. 9% for placebo), increased aspartate aminotransferase (AST) (23% vs. 14% for placebo; Grade 3–4: 0.5% vs. 0.2% for placebo), and increased bilirubin (16% vs. 7% for placebo). In the clinical studies, 88% of patients treated with darolutamide were age 65 years or older.No seizures have been observed with darolutamide in clinical trials. Darolutamide is an expected teratogen and has a theoretical risk of birth defects in male infants if taken by women during pregnancy. It may impair male fertility. When used as a monotherapy (i.e., without surgical or medical castration) in men, NSAAs are known to produce feminizing breast changes including breast tenderness and gynecomastia.
Overdose
Darolutamide has been studied at a dosage of up to 1,800 mg/day in clinical trials. There were no dose-limiting toxicities seen at this dosage. Due to its saturable absorption and lack of acute toxicity, overdose of darolutamide is not expected to result in systemic toxicity in people with intact hepatic and renal function. There is no specific antidote for overdose of darolutamide. In the event of darolutamide overdose, if there is no toxicity, treatment can be continued as normal. If there is suspicion of toxicity, general supportive measures should be undertaken until clinical toxicity has decreased or resolved and then treatment may be continued.
Interactions
Combined P-glycoprotein and strong or moderate CYP3A4 inducers such as rifampicin may decrease exposure to darolutamide, while combined P-glycoprotein and strong CYP3A4 inhibitors such as itraconazole may increase exposure to darolutamide. Darolutamide is an inhibitor of the breast cancer resistance protein (BCRP) transporter and can increase exposure to substrates for this protein such as rosuvastatin. It has been found to increase exposure to rosuvastatin by approximately 5-fold.
Pharmacology
Pharmacodynamics
Darolutamide is a second- or third-generation nonsteroidal antiandrogen (NSAA). It acts as a selective competitive silent antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). Its affinity (Ki) for the AR is 11 nM and its functional inhibition (IC50) of the AR is 26 nM. The major metabolite of darolutamide, ketodarolutamide, has similar antiandrogenic activity relative to darolutamide (Ki = 8 nM; IC50 = 38 nM). In addition to its actions as an AR antagonist, darolutamide has been found to act as a silent antagonist of the progesterone receptor (PR), with approximately 1% of the potency of its AR antagonism.A dosage of darolutamide of 1,200 mg/day has been found to result in a mean decrease in prostate specific antigen (PSA) levels of more than 90% in men with prostate cancer. The addition of darolutamide to castration has been found to decrease PSA levels by more than 50% in about 50% of men at 200 mg/day, 69% of men at 400 mg/day, 83% of men at 1,200 mg/day, and 86% of men at 1,400 mg/day.Darolutamide shows some advantages in comparison to enzalutamide and apalutamide, two other second-generation NSAAs. It appears to negligibly cross the blood–brain barrier, and hence has reduced risk of seizures and other central side effects from off-target GABAA receptor inhibition. In accordance with its diminished central penetration, darolutamide does not appear to increase testosterone levels. Darolutamide has been found to block the activity of all tested/well-known mutant ARs in prostate cancer, including the recently identified clinically-relevant F876L mutation that produces resistance to enzalutamide and apalutamide. The medication shows higher affinity and inhibitory potency at the AR relative to enzalutamide and apalutamide in vitro (Ki = 11 nM relative to 86 nM for enzalutamide and 93 nM for apalutamide; IC50 = 26 nM relative to 219 nM for enzalutamide and 200 nM for apalutamide).Darolutamide inhibits the organic anion transporting polypeptide (OATP) transporters OATP1B1 and OATP1B3 in vitro. It shows no inhibition or induction of cytochrome P450 enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4) at clinically relevant concentrations. Similarly, darolutamide shows no inhibition of a variety of other transporters (P-glycoprotein, MRP2, BSEP, OATs, OCTs, MATEs, OATP2B1, NTCP) at therapeutic concentrations.
Pharmacokinetics
Absorption
The absolute bioavailability of darolutamide with oral administration of a single 300-mg dose without food is approximately 30%. The bioavailability of darolutamide is increased by about 2- to 2.5-fold when administered with food, with a similar increase in exposure occurring for ketodarolutamide. Exposure to darolutamide and ketodarolutamide increases in a nearly linear or dose-proportional manner across a dose range of 100 to 700 mg (or about 0.17- to 1.17-fold the recommended 600-mg dosage). No further increase in exposure to darolutamide was observed at a dosage of darolutamide of 900 mg twice per day (or 1.5 times the recommended 600-mg dosage), indicating a saturation of absorption at doses above 700 mg. Following a single 600-mg dose of darolutamide, peak levels of darolutamide occur after approximately 4 hours. Steady-state levels of darolutamide occur after 2 to 5 days of continuous administration with food, during which time an approximate 2-fold accumulation in darolutamide levels occurs. At steady state with 600 mg/day darolutamide, mean levels of darolutamide are 4.79 μg/mL and area-under-the-curve levels of darolutamide over time 0 to 12 hours (AUC0–12) are 52.82 h•μg/mL. Total exposure to ketodarolutamide is approximately 1.7-fold that of darolutamide.
Distribution
The volume of distribution of darolutamide with intravenous administration is 119 L. The plasma protein binding of darolutamide is 92%, with 8% circulating freely, and of ketodarolutamide is 99.8%, with 0.2% circulating unbound. As such, free levels of darolutamide in the circulation are about 40-fold higher than those of ketodarolutamide. Both darolutamide and ketodarolutamide are bound mainly to albumin. Darolutamide and ketodarolutamide appear to negligibly cross the blood–brain barrier both in mice and humans. Darolutamide is a known substrate of P-glycoprotein and the breast cancer resistance protein (BCRP). P-Glycoprotein is known to play a major role in excluding drugs from the brain due to efflux back across the blood–brain barrier.
Metabolism
Darolutamide is primarily metabolized into ketodarolutamide via dehydrogenation by CYP3A4 in the liver. The medication is also conjugated via glucuronidation by UGT1A9 and UGT1A1. The elimination half-life of darolutamide and ketodarolutamide has been reported to be approximately 20 hours. A clinical study found that the elimination half-lives of darolutamide and ketodarolutamide at steady-state were 15.8 hours and 10.0 hours, respectively, with these half-lives being independent of dosage across a dose range of darolutamide of 200 to 1,800 mg/day. The elimination half-life of darolutamide is far shorter than that of enzalutamide (e.g., 1.6 hours vs. 18.3 hours in mice). The clearance of darolutamide following intravenous administration is 116 mL/min.
Excretion
After a single oral dose of darolutamide, more than 95% of the dose is excreted in urine and feces within one week following administration. A total of 63.4% darolutamide-related material is recovered in urine (about 7% as unchanged darolutamide) and a total of 32.4% darolutamide-related material (about 30% as unchanged darolutamide) is recovered in feces.
Variability
No clinically significant differences in the pharmacokinetics of darolutamide have been observed in men with nmCRPC on the basis of age (48 to 95 years), race (white, Asian, black), mild-to-moderate renal impairment, or mild hepatic impairment. In non-nmCRPC individuals with severe renal impairment not on dialysis, exposure to darolutamide was increased by about 2.5-fold relative to healthy people. In non-nmCRPC individuals with moderate hepatic impairment, darolutamide exposure was increased by about 1.9-fold compared to healthy controls. The pharmacokinetics of darolutamide have not been assessed in end-stage kidney disease or severe hepatic impairment.
Chemistry
Darolutamide is a nonsteroidal compound and is structurally distinct from other marketed NSAAs, including enzalutamide and apalutamide.
History
Darolutamide was developed by Orion Corporation and Bayer HealthCare. Orion Corporation applied for a patent on darolutamide in October 2010, and this patent was published in May 2011. Darolutamide entered phase I clinical trials in April 2011, with the results of the first clinical study of darolutamide initially published in 2012. The U.S. Food and Drug Administration (FDA) approved darolutamide in July 2019, under the agencys priority review designation.Approval was based on ARAMIS, a multicenter, double-blind, placebo-controlled clinical trial in 1,509 patients with non-metastatic castration resistant prostate cancer. Patients were randomized (2:1) to receive either 600 mg darolutamide orally twice daily (n=955) or matching placebo (n=554). All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm.The primary endpoint was metastasis free survival (MFS), defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first. The median MFS was 40.4 months (95% CI: 34.3, not reached) for patients treated with darolutamide compared with 18.4 months (95% CI: 15.5, 22.3) for those receiving placebo (hazard ratio 0.41; 95% CI: 0.34, 0.50; p<0.0001).
Darolutamide was associated with greater benefits than placebo for all secondary end points, including overall survival (hazard ratio 0.69; 95% CI: 0.53-0.88; P=0.003), time to pain progression (median 40.3 months vs. 25.4 months; hazard ratio 0.65; 95% CI: 0.53-0.79; P<0.001), time to cytotoxic chemotherapy (hazard ratio 0.43; 95% CI: 0.31-0.60), and time to a symptomatic skeletal event (hazard ratio 0.43; 95% CI: 0.22-0.84).
Society and culture
Generic names
Darolutamide is the generic name of the medication and its INN and USAN. It is also known by its developmental code names ODM-201 and BAY-1841788.
Brand names
Darolutamide is marketed under the brand name Nubeqa.
Availability
Darolutamide is available in the United States and the European Union.
Research
Darolutamide monotherapy is being studied in comparison to androgen deprivation therapy with GnRH agonist or antagonist monotherapy in men with treatment-naive prostate cancer. As of 2018, it is entering a phase II clinical trial for this indication. This study is expected for completion in 2021 or 2022.Darolutamide is being studied for the treatment of breast cancer in women. As of November 2019, it is in phase II clinical trials for this indication.
References
External links
"Darolutamide". Drug Information Portal. U.S. National Library of Medicine. |
Ethylenediaminetetraacetic acid | Ethylenediaminetetraacetic acid (EDTA) is an aminopolycarboxylic acid with the formula [CH2N(CH2CO2H)2]2. This white, water-soluble solid is widely used to bind to iron (Fe2+/Fe3+) and calcium ions (Ca2+), forming water-soluble complexes even at neutral pH. It is thus used to remove (dissolve) Fe- and Ca-containing scale as well as to delivery Fe ions under conditions where its oxides are insoluble. EDTA is available as several salts, notably disodium EDTA, sodium calcium edetate, and tetrasodium EDTA, but these all function similarly.
Uses
Textile industry
In industry, EDTA is mainly used to sequester (bind or confine) metal ions in aqueous solution. In the textile industry, it prevents metal ion impurities from modifying colours of dyed products. In the pulp and paper industry, EDTA inhibits the ability of metal ions, especially Mn2+, from catalysing the disproportionation of hydrogen peroxide, which is used in chlorine-free bleaching. In a similar manner, EDTA is added to some food as a preservative or stabiliser to prevent catalytic oxidative decolouration, which is catalysed by metal ions.In soft drinks containing ascorbic acid and sodium benzoate, EDTA mitigates formation of benzene (a carcinogen).
Water softener
The reduction of water hardness in laundry applications and the dissolution of scale in boilers both rely on EDTA and related complexants to bind Ca2+, Mg2+, as well as other metal ions. Once bound to EDTA, these metal complexes are less likely to form precipitates or to interfere with the action of the soaps and detergents. For similar reasons, cleaning solutions often contain EDTA. In a similar manner EDTA is used in the cement industry for the determination of free lime and free magnesia in cement and clinkers.The solubilisation of Fe3+ ions at or below near neutral pH can be accomplished using EDTA. This property is useful in agriculture including hydroponics. However, given the pH dependence of ligand formation, EDTA is not helpful for improving iron solubility in above neutral soils. Otherwise, at near-neutral pH and above, iron(III) forms insoluble salts, which are less bioavailable to susceptible plant species.
Scrubbing
Aqueous [Fe(EDTA)]− is used for removing ("scrubbing") hydrogen sulfide from gas streams. This conversion is achieved by oxidising the hydrogen sulfide to elemental sulfur, which is non-volatile:
2 [Fe(EDTA)]− + H2S → 2 [Fe(EDTA)]2− + S + 2 H+In this application, the iron(III) centre is reduced to its iron(II) derivative, which can then be reoxidised by air. In similar manner, nitrogen oxides are removed from gas streams using [Fe(EDTA)]2−.
The oxidising properties of [Fe(EDTA)]− are also exploited in photography, where it is used to solubilise silver particles.
Ion-exchange chromatography
EDTA was used in separation of the lanthanide metals by ion-exchange chromatography. Perfected by F. H. Spedding et al. in 1954, the method relies on the steady increase in stability constant of the lanthanide EDTA complexes with atomic number. Using sulfonated polystyrene beads and Cu2+ as a retaining ion, EDTA causes the lanthanides to migrate down the column of resin while separating into bands of pure lanthanides. The lanthanides elute in order of decreasing atomic number. Due to the expense of this method, relative to countercurrent solvent extraction, ion exchange is now used only to obtain the highest purities of lanthanides (typically greater than 99.99%).
Medicine
Sodium calcium edetate, an EDTA derivative, is used to bind metal ions in the practice of chelation therapy, such as for treating mercury and lead poisoning. It is used in a similar manner to remove excess iron from the body. This therapy is used to treat the complication of repeated blood transfusions, as would be applied to treat thalassaemia.
Dentistry
Dentists and endodontists use EDTA solutions to remove inorganic debris (smear layer) and lubricate the root canals in endodontics. This procedure helps prepare root canals for obturation. Furthermore, EDTA solutions with the addition of a surfactant loosen up calcifications inside a root canal and allow instrumentation (canal shaping) and facilitate apical advancement of a file in a tight or calcified root canal towards the apex.
Eyedrops
It serves as a preservative (usually to enhance the action of another preservative such as benzalkonium chloride or thiomersal) in ocular preparations and eyedrops.
Analysis
In evaluating kidney function, the chromium(III) complex [Cr(EDTA)]− (as radioactive chromium-51 (51Cr)) is administered intravenously and its filtration into the urine is monitored. This method is useful for evaluating glomerular filtration rate (GFR) in nuclear medicine.EDTA is used extensively in the analysis of blood. It is an anticoagulant for blood samples for CBC/FBCs, where the EDTA chelates the calcium present in the blood specimen, arresting the coagulation process and preserving blood cell morphology. Tubes containing EDTA are marked with lavender (purple) or pink tops. EDTA is also in tan top tubes for lead testing and can be used in royal blue top tubes for trace metal testing.EDTA is a slime dispersant, and has been found to be highly effective in reducing bacterial growth during implantation of intraocular lenses (IOLs).
Alternative medicine
Some alternative practitioners believe EDTA acts as an antioxidant, preventing free radicals from injuring blood vessel walls, therefore reducing atherosclerosis. These ideas are unsupported by scientific studies, and seem to contradict some currently accepted principles. The U.S. FDA has not approved it for the treatment of atherosclerosis.
Cosmetics
In shampoos, cleaners, and other personal care products, EDTA salts are used as a sequestering agent to improve their stability in air.
Laboratory applications
In the laboratory, EDTA is widely used for scavenging metal ions: In biochemistry and molecular biology, ion depletion is commonly used to deactivate metal-dependent enzymes, either as an assay for their reactivity or to suppress damage to DNA, proteins, and polysaccharides. EDTA also acts as a selective inhibitor against dNTP hydrolyzing enzymes (Taq polymerase, dUTPase, MutT), liver arginase and horseradish peroxidase independently of metal ion chelation. These findings urge the rethinking of the utilisation of EDTA as a biochemically inactive metal ion scavenger in enzymatic experiments. In analytical chemistry, EDTA is used in complexometric titrations and analysis of water hardness or as a masking agent to sequester metal ions that would interfere with the analyses.
EDTA finds many specialised uses in the biomedical labs, such as in veterinary ophthalmology as an anticollagenase to prevent the worsening of corneal ulcers in animals. In tissue culture EDTA is used as a chelating agent that binds to calcium and prevents joining of cadherins between cells, preventing clumping of cells grown in liquid suspension, or detaching adherent cells for passaging. In histopathology, EDTA can be used as a decalcifying agent making it possible to cut sections using a microtome once the tissue sample is demineralised.
EDTA is also known to inhibit a range of metallopeptidases, the method of inhibition occurs via the chelation of the metal ion required for catalytic activity. EDTA can also be used to test for bioavailability of heavy metals in sediments. However, it may influence the bioavailability of metals in solution, which may pose concerns regarding its effects in the environment, especially given its widespread uses and applications.
EDTA is also used to remove crud (corroded metals) from fuel rods in nuclear reactors.
Side effects
EDTA exhibits low acute toxicity with LD50 (rat) of 2.0 g/kg to 2.2 g/kg. It has been found to be both cytotoxic and weakly genotoxic in laboratory animals. Oral exposures have been noted to cause reproductive and developmental effects. The same study also found that both dermal exposure to EDTA in most cosmetic formulations and inhalation exposure to EDTA in aerosolised cosmetic formulations would produce exposure levels below those seen to be toxic in oral dosing studies.
Synthesis
The compound was first described in 1935 by Ferdinand Münz, who prepared the compound from ethylenediamine and chloroacetic acid. Today, EDTA is mainly synthesised from ethylenediamine (1,2-diaminoethane), formaldehyde, and sodium cyanide. This route yields the tetrasodium EDTA, which is converted in a subsequent step into the acid forms:
H2NCH2CH2NH2 + 4 CH2O + 4 NaCN + 4 H2O → (NaO2CCH2)2NCH2CH2N(CH2CO2Na)2 + 4 NH3(NaO2CCH2)2NCH2CH2N(CH2CO2Na)2 + 4 HCl → (HO2CCH2)2NCH2CH2N(CH2CO2H)2 + 4 NaClThis process is used to produce about 80,000 tonnes of EDTA each year. Impurities cogenerated by this route include glycine and nitrilotriacetic acid; they arise from reactions of the ammonia coproduct.
Nomenclature
To describe EDTA and its various protonated forms, chemists distinguish between EDTA4−, the conjugate base that is the ligand, and H4EDTA, the precursor to that ligand. At very low pH (very acidic conditions) the fully protonated H6EDTA2+ form predominates, whereas at very high pH or very basic condition, the fully deprotonated EDTA4− form is prevalent. In this article, the term EDTA is used to mean H4−xEDTAx−, whereas in its complexes EDTA4− stands for the tetraanion ligand.
Coordination chemistry principles
In coordination chemistry, EDTA4− is a member of the aminopolycarboxylic acid family of ligands. EDTA4− usually binds to a metal cation through its two amines and four carboxylates, i.e., it is It a hexadentate ("six-toothed") chelating agent. Many of the resulting coordination compounds adopt octahedral geometry. Although of little consequence for its applications, these octahedral complexes are chiral. The cobalt(III) anion [Co(EDTA)]− has been resolved into enantiomers. Many complexes of EDTA4− adopt more complex structures due to either the formation of an additional bond to water, i.e. seven-coordinate complexes, or the displacement of one carboxylate arm by water. The iron(III) complex of EDTA is seven-coordinate. Early work on the development of EDTA was undertaken by Gerold Schwarzenbach in the 1940s. EDTA forms especially strong complexes with Mn(II), Cu(II), Fe(III), Pb(II) and Co(III).Several features of EDTAs complexes are relevant to its applications. First, because of its high denticity, this ligand has a high affinity for metal cations:
[Fe(H2O)6]3+ + H4EDTA ⇌ [Fe(EDTA)]− + 6 H2O + 4 H+ Keq = 1025.1Written in this way, the equilibrium quotient shows that metal ions compete with protons for binding to EDTA. Because metal ions are extensively enveloped by EDTA, their catalytic properties are often suppressed. Finally, since complexes of EDTA4− are anionic, they tend to be highly soluble in water. For this reason, EDTA is able to dissolve deposits of metal oxides and carbonates.
The pKa values of free EDTA are 0, 1.5, 2, 2.66 (deprotonation of the four carboxyl groups) and 6.16, 10.24 (deprotonation of the two amino groups).
Environmental fate
Abiotic degradation
EDTA is in such widespread use that questions have been raised whether it is a persistent organic pollutant. While EDTA serves many positive functions in different industrial, pharmaceutical and other avenues, the longevity of EDTA can pose serious issues in the environment. The degradation of EDTA is slow. It mainly occurs abiotically in the presence of sunlight.The most important process for the elimination of EDTA from surface waters is direct photolysis at wavelengths below 400 nm. Depending on the light conditions, the photolysis half-lives of iron(III) EDTA in surface waters can range as low as 11.3 minutes up to more than 100 hours. Degradation of FeEDTA, but not EDTA itself, produces iron complexes of the triacetate (ED3A), diacetate (EDDA), and monoacetate (EDMA) – 92% of EDDA and EDMA biodegrades in 20 hours while ED3A displays significantly higher resistance. Many environmentally-abundant EDTA species (such as Mg2+ and Ca2+) are more persistent.
Biodegradation
In many industrial wastewater treatment plants, EDTA elimination can be achieved at about 80% using microorganisms. Resulting byproducts are ED3A and iminodiacetic acid (IDA) – suggesting that both the backbone and acetyl groups were attacked. Some microorganisms have even been discovered to form nitrates out of EDTA, but they function optimally at moderately alkaline conditions of pH 9.0–9.5.Several bacterial strains isolated from sewage treatment plants efficiently degrade EDTA. Specific strains include Agrobacterium radiobacter ATCC 55002 and the sub-branches of Pseudomonadota like BNC1, BNC2, and strain DSM 9103. The three strains share similar properties of aerobic respiration and are classified as gram-negative bacteria. Unlike photolysis, the chelated species is not exclusive to iron(III) in order to be degraded. Rather, each strain uniquely consumes varying metal–EDTA complexes through several enzymatic pathways. Agrobacterium radiobacter only degrades Fe(III) EDTA while BNC1 and DSM 9103 are not capable of degrading iron(III) EDTA and are more suited for calcium, barium, magnesium and manganese(II) complexes. EDTA complexes require dissociation before degradation.
Alternatives to EDTA
Interest in environmental safety has raised concerns about biodegradability of aminopolycarboxylates such as EDTA. These concerns incentivize the investigation of alternative aminopolycarboxylates. Candidate chelating agents include nitrilotriacetic acid (NTA), iminodisuccinic acid (IDS), polyaspartic acid, S,S-ethylenediamine-N,N′-disuccinic acid (EDDS), methylglycinediacetic acid (MGDA), and L-Glutamic acid N,N-diacetic acid, tetrasodium salt (GLDA).
Iminodisuccinic acid (IDS)
Commercially used since 1998, iminodisuccinic acid (IDS) biodegrades by about 80% after only 7 days. IDS binds to calcium exceptionally well and forms stable compounds with other heavy metal ions. In addition to having a lower toxicity after chelation, IDS is degraded by Agrobacterium tumefaciens (BY6), which can be harvested on a large scale. The enzymes involved, IDS epimerase and C−N lyase, do not require any cofactors.
Polyaspartic acid
Polyaspartic acid, like IDS, binds to calcium and other heavy metal ions. It has many practical applications including corrosion inhibitors, wastewater additives, and agricultural polymers. A Polyaspartic acid-based laundry detergent was the first laundry detergent in the world to receive the EU flower ecolabel. Calcium binding ability of polyaspartic acid has been exploited for targeting of drug-loaded nanocarriers to bone. Preparation of hydrogels based on polyaspartic acid, in a variety of physical forms ranging from fiber to particle, can potentially enable facile separation of the chelated ions from a solution. Therefore, despite being weaker than EDTA, polyaspartic acid can still be regarded as a viable alternative due to these features as well as biocompatibility, and biodegradability.
S,S-Ethylenediamine-N,N′-disuccinic acid (EDDS)
A structural isomer of EDTA, ethylenediamine-N,N′-disuccinic acid (EDDS) is readily biodegradable at high rate in its S,S form.
Methylglycinediacetic acid (MGDA)
Trisodium dicarboxymethyl alaninate, also known as methylglycinediacetic acid (MGDA), has a high rate of biodegradation at over 68%, but unlike many other chelating agents can degrade without the assistance of adapted bacteria. Additionally, unlike EDDS or IDS, MGDA can withstand higher temperatures while maintaining a high stability as well as the entire pH range. MGDA has been shown to be an effective chelating agent, with a capacity for mobilization comparable with that of nitrilotriacetic acid (NTA), with application to water for industrial use and for the removal of calcium oxalate from urine from patients with kidney stones.
Methods of detection and analysis
The most sensitive method of detecting and measuring EDTA in biological samples is selected reaction monitoring capillary electrophoresis mass spectrometry (SRM-CE/MS), which has a detection limit of 7.3 ng/mL in human plasma and a quantitation limit of 15 ng/mL. This method works with sample volumes as small as 7–8 nL.EDTA has also been measured in non-alcoholic beverages using high performance liquid chromatography (HPLC) at a level of 2.0 μg/mL.
In popular culture
In the movie Blade (1998), EDTA is used as a weapon to kill vampires, exploding when in contact with vampire blood.
References
External links
EDTA: Molecule of the Month
EDTA Determination of Total Water Hardness
Oviedo, Claudia; Rodríguez, Jaime (2003). "EDTA: The chelating agent under environmental scrutiny". Química Nova. 26 (6): 901–905. doi:10.1590/S0100-40422003000600020. |
Calcium chloride | Calcium chloride is an inorganic compound, a salt with the chemical formula CaCl2. It is a white crystalline solid at room temperature, and it is highly soluble in water. It can be created by neutralising hydrochloric acid with calcium hydroxide.
Calcium chloride is commonly encountered as a hydrated solid with generic formula CaCl2·nH2O, where n = 0, 1, 2, 4, and 6. These compounds are mainly used for de-icing and dust control. Because the anhydrous salt is hydroscopic and deliquescent, it is used as a desiccant.
Uses
De-icing and freezing-point depression
By depressing the freezing point of water, calcium chloride is used to prevent ice formation and is used to de-ice. This application consumes the greatest amount of calcium chloride. Calcium chloride is relatively harmless to plants and soil. As a deicing agent, it is much more effective at lower temperatures than sodium chloride. When distributed for this use, it usually takes the form of small, white spheres a few millimeters in diameter, called prills. Solutions of calcium chloride can prevent freezing at temperatures as low as −52 °C (−62 °F), making it ideal for filling agricultural implement tires as a liquid ballast, aiding traction in cold climates.It is also used in domestic and industrial chemical air dehumidifiers.
Road surfacing
The second largest application of calcium chloride exploits its hygroscopic nature and the tackiness of its hydrates; calcium chloride is highly hygroscopic and its hydration is an exothermic process. A concentrated solution keeps a liquid layer on the surface of dirt roads, which suppresses the formation of dust. It keeps the finer dust particles on the road, providing a cushioning layer. If these are allowed to blow away, the large aggregate begins to shift around and the road breaks down. Using calcium chloride reduces the need for grading by as much as 50% and the need for fill-in materials as much as 80%.
Food
The average intake of calcium chloride as food additives has been estimated to be 160–345 mg/day. Calcium chloride is permitted as a food additive in the European Union for use as a sequestrant and firming agent with the E number E509. It is considered as generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. Its use in organic crop production is generally prohibited under the US National Organic Program.In marine aquariums, calcium chloride is one way to introduce bioavailable calcium for calcium carbonate-shelled animals such as mollusks and some cnidarians. Calcium hydroxide (limewater) or a calcium reactor can also be used.
As a firming agent, calcium chloride is used in canned vegetables, in firming soybean curds into tofu and in producing a caviar substitute from vegetable or fruit juices. It is commonly used as an electrolyte in sports drinks and other beverages, including bottled water. The extremely salty taste of calcium chloride is used to flavor pickles without increasing the foods sodium content. Calcium chlorides freezing-point depression properties are used to slow the freezing of the caramel in caramel-filled chocolate bars. Also, it is frequently added to sliced apples to maintain texture.
In brewing beer, calcium chloride is sometimes used to correct mineral deficiencies in the brewing water. It affects flavor and chemical reactions during the brewing process, and can also affect yeast function during fermentation.
In cheesemaking, calcium chloride is sometimes added to processed (pasteurized/homogenized) milk to restore the natural balance between calcium and protein in casein. It is added before the coagulant.
Calcium chloride is used to prevent cork spot and bitter pit on apples by spraying on the tree during the late growing season.
Laboratory and related drying operations
Drying tubes are frequently packed with calcium chloride. Kelp is dried with calcium chloride for use in producing sodium carbonate. Anhydrous calcium chloride has been approved by the FDA as a packaging aid to ensure dryness (CPG 7117.02).The hydrated salt can be dried for re-use but will dissolve in its own water of hydration if heated quickly and form a hard amalgamated solid when cooled.
Other applications
Calcium chloride is used in concrete mixes to accelerate the initial setting, but chloride ions lead to corrosion of steel rebar, so it should not be used in reinforced concrete. The anhydrous form of calcium chloride may also be used for this purpose and can provide a measure of the moisture in concrete.Calcium chloride is included as an additive in plastics and in fire extinguishers, in blast furnaces as an additive to control scaffolding (clumping and adhesion of materials that prevent the furnace charge from descending), and in fabric softener as a thinner.
The exothermic dissolution of calcium chloride is used in self-heating cans and heating pads.
In the oil industry, calcium chloride is used to increase the density of solids-free brines. It is also used to provide inhibition of swelling clays in the water phase of invert emulsion drilling fluids.
CaCl2 acts as flux material, decreasing the melting point, in the Davy process for the industrial production of sodium metal through the electrolysis of molten NaCl.
Calcium chloride is also used in the production of activated charcoal.
Calcium chloride can be used to precipitate fluoride ions from water as insoluble CaF2.
Calcium chloride is also an ingredient used in ceramic slipware. It suspends clay particles so that they float within the solution, making it easier to use in a variety of slipcasting techniques.
Calcium chloride dihydrate (20 percent by weight) dissolved in ethanol (95 percent ABV) has been used as a sterilant for male animals. The solution is injected into the testes of the animal. Within one month, necrosis of testicular tissue results in sterilization.Cocaine producers in Colombia import tons of calcium chloride to recover solvents that are on the INCB Red List and are more tightly controlled.
Metal reduction flux
Similarly, CaCl2 is used as a flux and electrolyte in the FFC Cambridge electrolysis process for titanium production, where it ensures the proper exchange of calcium and oxygen ions between the electrodes.
Hazards
Although non-toxic in small quantities when wet, the strongly hygroscopic properties of the non-hydrated salt present some hazards. Calcium chloride can act as an irritant by desiccating moist skin. Solid calcium chloride dissolves exothermically, and burns can result in the mouth and esophagus if it is ingested. Ingestion of concentrated solutions or solid products may cause gastrointestinal irritation or ulceration.Consumption of calcium chloride can lead to hypercalcemia.
Properties
Calcium chloride dissolves in water, producing chloride and the aquo complex [Ca(H2O)6]2+. In this way, these solutions are sources of "free" calcium and free chloride ions. This description is illustrated by the fact that these solutions react with phosphate sources to give a solid precipitate of calcium phosphate:
3 CaCl2 + 2 PO3−4 → Ca3(PO4)2 + 6 Cl−Calcium chloride has a very high enthalpy change of solution, indicated by considerable temperature rise accompanying dissolution of the anhydrous salt in water. This property is the basis for its largest-scale application.
Molten calcium chloride can be electrolysed to give calcium metal and chlorine gas:
CaCl2 → Ca + Cl2
Preparation
In much of the world, calcium chloride is derived from limestone as a by-product of the Solvay process, which follows the net reaction below:
2 NaCl + CaCO3 → Na2CO3 + CaCl2North American consumption in 2002 was 1,529,000 tonnes (3.37 billion pounds).In the US, most of calcium chloride is obtained by purification from brine.As with most bulk commodity salt products, trace amounts of other cations from the alkali metals and alkaline earth metals (groups 1 and 2) and other anions from the halogens (group 17) typically occur, but the concentrations are trifling.
Occurrence
Calcium chloride occurs as the rare evaporite minerals sinjarite (dihydrate) and antarcticite (hexahydrate). Another natural hydrate known is ghiaraite – a tetrahydrate. The related minerals chlorocalcite (potassium calcium chloride, KCaCl3) and tachyhydrite (calcium magnesium chloride, CaMg2Cl6·12H2O) are also very rare. So is true for rorisite, CaClF (calcium chloride fluoride).
See also
Calcium(I) chloride
Calcium chloride transformation
Magnesium chloride
References
Greenwood, Norman N.; Earnshaw, Alan (1997). Chemistry of the Elements (2nd ed.). Butterworth-Heinemann. ISBN 978-0-08-037941-8.
External links
International Chemical Safety Card 1184
Product and Application Information (Formerly Dow Chemical Calcium Chloride division)
Report on steel corrosion by chloride including CaCl2
Collection of calcium chloride reports and articles
Calcium chloride, Anhydrous MSDS
Difusivity of calcium chloride
Centers for Disease Control and Prevention, National Institutes of Occupational Safety and Health, "Calcium Chloride (anhydrous)" |
Sodium calcium edetate | Sodium calcium edetate (sodium calcium EDTA), also known as edetate calcium disodium among other names, is a medication primarily used to treat lead poisoning, including both short-term and long-term lead poisoning. Sodium calcium edetate came into medical use in the United States in 1953.
Chelation agent
Sodium calcium edetate is in the chelating agent family of medication. It is a salt of edetate with two sodium and one calcium atoms.
It works by binding to a number of heavy metals, which renders them almost inert and allows them to leave the body in the urine.Edetate disodium is a different formulation which does not have the same effects.
Medical use
Sodium calcium edetates primary use is to treat lead poisoning,
for which it is an alternative to succimer.
It is given by slow injection into a vein or into a muscle.For lead encephalopathy sodium calcium edetate is typically used together with dimercaprol.
It may also be used to treat plutonium poisoning.
It does not appear to be useful for poisoning by tetra-ethyl lead.
Side effects
Common side effects include pain at the site of injection. Other side effects may include kidney problems, diarrhea, fever, muscle pains, and low blood pressure. Benefits when needed in pregnancy are likely greater than the risks.
History
Sodium calcium edetate came into medical use in the United States in 1953. It is on the World Health Organizations List of Essential Medicines.
References
External links
"Sodium calcium edetate". U.S. National Library of Medicine. Drug Information Portal. U.S. National Institutes of Health. |
Argatroban | Argatroban is an anticoagulant that is a small molecule direct thrombin inhibitor. In 2000, argatroban was licensed by the Food and Drug Administration (FDA) for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). In 2002, it was approved for use during percutaneous coronary interventions in patients who have HIT or are at risk for developing it. In 2012, it was approved by the MHRA in the UK for anticoagulation in patients with heparin-induced thrombocytopenia Type II (HIT) who require parenteral antithrombotic therapy.Argatroban is given intravenously and drug plasma concentrations reach steady state in 1–3 hours. Argatroban is metabolized in the liver and has a half-life of about 50 minutes. It is monitored by PTT. Because of its hepatic metabolism, it may be used in patients with renal dysfunction. (This is in contrast to lepirudin, a direct thrombin inhibitor that is primarily renally cleared).
Transitioning to warfarin in individuals with heparin-induced thrombocytopenia
Argatroban is used as an anticoagulant in individuals with thrombosis and heparin-induced thrombocytopenia. Often these individuals require long-term anticoagulation. If warfarin is chosen as the long-term anticoagulant, this poses particular challenges due to the falsely elevated prothrombin time and INR caused by argatroban. The combination of argatroban and warfarin may raise the INR to greater than 5.0 without a significant increased risk of bleeding complications. One solution to this problem is to measure the chromogenic factor X level. A level < 40-45% typically indicates that the INR will be therapeutic (2-3) when the argatroban is discontinued.
References
External links
"Argatroban". Drug Information Portal. U.S. National Library of Medicine. |
Intron | An intron is any nucleotide sequence within a gene that is removed by RNA processing during production of the final RNA product. The word intron is derived from the term intragenic region, i.e. a region inside a gene. The term intron refers to both the DNA sequence within a gene and the corresponding RNA sequence in RNA transcripts. The non-intron sequences that become joined by this RNA processing to form the mature RNA are called exons.Introns are found in the genes of most organisms and many viruses and they can be located in both protein-coding genes and genes that function as RNA (noncoding genes). There are four main types of introns: tRNA introns, group I introns, group II introns, and spliceosomal introns (see below). Introns are rare in Bacteria and Archaea (prokaryotes), but most eukaryotic genes contain multiple splicesomal introns.
Discovery and etymology
Introns were first discovered in protein-coding genes of adenovirus, and were subsequently identified in genes encoding transfer RNA and ribosomal RNA genes. Introns are now known to occur within a wide variety of genes throughout organisms, bacteria, and viruses within all of the biological kingdoms.
The fact that genes were split or interrupted by introns was discovered independently in 1977 by Phillip Allen Sharp and Richard J. Roberts, for which they shared the Nobel Prize in Physiology or Medicine in 1993. The term intron was introduced by American biochemist Walter Gilbert:
"The notion of the cistron [i.e., gene] ... must be replaced by that of a transcription unit containing regions which will be lost from the mature messenger – which I suggest we call introns (for intragenic regions) – alternating with regions which will be expressed – exons." (Gilbert 1978)
The term intron also refers to intracistron, i.e., an additional piece of DNA that arises within a cistron.Although introns are sometimes called intervening sequences, the term "intervening sequence" can refer to any of several families of internal nucleic acid sequences that are not present in the final gene product, including inteins, untranslated regions (UTR), and nucleotides removed by RNA editing, in addition to introns.
Distribution
The frequency of introns within different genomes is observed to vary widely across the spectrum of biological organisms. For example, introns are extremely common within the nuclear genome of jawed vertebrates (e.g. humans and mice), where protein-coding genes almost always contain multiple introns, while introns are rare within the nuclear genes of some eukaryotic microorganisms, for example bakers/brewers yeast (Saccharomyces cerevisiae). In contrast, the mitochondrial genomes of vertebrates are entirely devoid of introns, while those of eukaryotic microorganisms may contain many introns.
A particularly extreme case is the Drosophila dhc7 gene containing a ≥3.6 megabase (Mb) intron, which takes roughly three days to transcribe. On the other extreme, a 2015 study suggests that the shortest known metazoan intron length is 30 base pairs (bp) belonging to the human MST1L gene. The shortest known introns belong to the heterotrich ciliates, such as Stentor coeruleus, in which most (> 95%) introns are 15 or 16 bp long.
Classification
Splicing of all intron-containing RNA molecules is superficially similar, as described above. However, different types of introns were identified through the examination of intron structure by DNA sequence analysis, together with genetic and biochemical analysis of RNA splicing reactions.At least four distinct classes of introns have been identified:
Introns in nuclear protein-coding genes that are removed by spliceosomes (spliceosomal introns)
Introns in nuclear and archaeal transfer RNA genes that are removed by proteins (tRNA introns)
Self-splicing group I introns that are removed by RNA catalysis
Self-splicing group II introns that are removed by RNA catalysisGroup III introns are proposed to be a fifth family, but little is known about the biochemical apparatus that mediates their splicing. They appear to be related to group II introns, and possibly to spliceosomal introns.
Spliceosomal introns
Nuclear pre-mRNA introns (spliceosomal introns) are characterized by specific intron sequences located at the boundaries between introns and exons. These sequences are recognized by spliceosomal RNA molecules when the splicing reactions are initiated. In addition, they contain a branch point, a particular nucleotide sequence near the 3 end of the intron that becomes covalently linked to the 5 end of the intron during the splicing process, generating a branched (lariat) intron. Apart from these three short conserved elements, nuclear pre-mRNA intron sequences are highly variable. Nuclear pre-mRNA introns are often much longer than their surrounding exons.
tRNA introns
Transfer RNA introns that depend upon proteins for removal occur at a specific location within the anticodon loop of unspliced tRNA precursors, and are removed by a tRNA splicing endonuclease. The exons are then linked together by a second protein, the tRNA splicing ligase. Note that self-splicing introns are also sometimes found within tRNA genes.
Group I and group II introns
Group I and group II introns are found in genes encoding proteins (messenger RNA), transfer RNA and ribosomal RNA in a very wide range of living organisms. Following transcription into RNA, group I and group II introns also make extensive internal interactions that allow them to fold into a specific, complex three-dimensional architecture. These complex architectures allow some group I and group II introns to be self-splicing, that is, the intron-containing RNA molecule can rearrange its own covalent structure so as to precisely remove the intron and link the exons together in the correct order. In some cases, particular intron-binding proteins are involved in splicing, acting in such a way that they assist the intron in folding into the three-dimensional structure that is necessary for self-splicing activity. Group I and group II introns are distinguished by different sets of internal conserved sequences and folded structures, and by the fact that splicing of RNA molecules containing group II introns generates branched introns (like those of spliceosomal RNAs), while group I introns use a non-encoded guanosine nucleotide (typically GTP) to initiate splicing, adding it on to the 5-end of the excised intron.
On the accuracy of splicing
The spliceosome is a very complex structure containing up to one hundred proteins and five different RNAs. The substrate of the reaction is a long RNA molecule and the transesterification reactions catalyzed by the spliceosome require the bringing together of sites that may be thousands of nucleotides apart. All biochemical reactions are associated with known error rates and the more complicated the reaction the higher the error rate. Therefore, it is not surprising that the splicing reaction catalyzed by the spliceosome has a significant error rate even though there are spliceosome accessory factors that suppress the accidental cleavage of cryptic splice sites.Under ideal circumstances, the splicing reaction is likely to be 99.999% accurate (error rate of 10−5) and the correct exons will be joined and the correct intron will be deleted. However, these ideal conditions require very close matches to the best splice site sequences and the absence of any competing cryptic splice site sequences within the introns and those conditions are rarely met in large eukaryotic genes that may cover more than 40 kilobase pairs. Recent studies have shown that the actual error rate can be considerably higher than 10−5 and may be as high as 2% or 3% errors (error rate of 2 or 3 x 10−2) per gene. Additional studies suggest that the error rate is no less that 0.1% per intron. This relatively high level of splicing errors explains why most splice variants are rapidly degraded by nonsense-mediated decay.The presence of sloppy binding sites within genes causes splicing errors and it may seem strange that these sites havent been eliminated by natural selection. The argument for their persistence is similar to the argument for junk DNA.
Although mutations which create or disrupt binding sites may be slightly deleterious, the large number of possible such mutations makes it inevitable that some will reach fixation in a population. This is particularly relevant in species, such as humans, with relatively small long-term effective population sizes. It is plausible, then, that the human genome carries a substantial load of suboptimal sequences which cause the generation of aberrant transcript isoforms. In this study, we present direct evidence that this is indeed the case.
While the catalytic reaction may be accurate enough for effective processing most of the time, the overall error rate may be partly limited by the fidelity of transcription because transcription errors will introduce mutations that create cryptic splice sites. In addition, the transcription error rate of 10−5 - 10−6 is high enough that one in every 25,000 transcribed exons will have an incorporation error in one of the splice sites leading to a skipped intron or a skipped exon. Almost all multi-exon genes will produce incorrectly spliced transcripts but the frequency of this background noise will depend on the size of the genes, the number of introns, and the quality of the splice site sequences.In some cases, splice variants will be produced by mutations in the gene (DNA). These can be SNP polymorphisms that create a cryptic splice site or mutate a functional site. They can also be somatic cell mutations that affect splicing in a particular tissue or a cell line. When the mutant allele is in a heterozygous state this will result in production of two abundant splice variants; one functional and one non-functional. In the homozygous state the mutant alleles may cause a genetic disease such as the hemophilia found in descendants of Queen Victoria where a mutation in one of the introns in a blood clotting factor gene creates a cryptic 3 splice site resulting in aberrant splicing. A significant fraction of human deaths by disease may be caused by mutations that interfere with normal splicing; mostly by creating cryptic splice sites.Incorrectly spliced transcripts can easily be detected and their sequences entered into the online databases. They are usually described as "alternatively spliced" transcripts, which can be confusing because the term does not distinguish between real, biologically relevant, alternative splicing and processing noise due to splicing errors. One of the central issues in the field of alternative splicing is working out the differences between these two possibilities. Many scientists have argued that the null hypothesis should be splicing noise, putting the burden of proof on those who claim biologically relevant alternative splicing. According to those scientists, the claim of function must be accompanied by convincing evidence that multiple functional products are produced from the same gene.
Biological functions and evolution
While introns do not encode protein products, they are integral to gene expression regulation. Some introns themselves encode functional RNAs through further processing after splicing to generate noncoding RNA molecules. Alternative splicing is widely used to generate multiple proteins from a single gene. Furthermore, some introns play essential roles in a wide range of gene expression regulatory functions such as nonsense-mediated decay and mRNA export.The biological origins of introns are obscure. After the initial discovery of introns in protein-coding genes of the eukaryotic nucleus, there was significant debate as to whether introns in modern-day organisms were inherited from a common ancient ancestor (termed the introns-early hypothesis), or whether they appeared in genes rather recently in the evolutionary process (termed the introns-late hypothesis). Another theory is that the spliceosome and the intron-exon structure of genes is a relic of the RNA world (the introns-first hypothesis). There is still considerable debate about the extent to which of these hypotheses is most correct. The popular consensus at the moment is that introns arose within the eukaryote lineage as selfish elements.Early studies of genomic DNA sequences from a wide range of organisms show that the intron-exon structure of homologous genes in different organisms can vary widely. More recent studies of entire eukaryotic genomes have now shown that the lengths and density (introns/gene) of introns varies considerably between related species. For example, while the human genome contains an average of 8.4 introns/gene (139,418 in the genome), the unicellular fungus Encephalitozoon cuniculi contains only 0.0075 introns/gene (15 introns in the genome). Since eukaryotes arose from a common ancestor (common descent), there must have been extensive gain or loss of introns during evolutionary time. This process is thought to be subject to selection, with a tendency towards intron gain in larger species due to their smaller population sizes, and the converse in smaller (particularly unicellular) species. Biological factors also influence which genes in a genome lose or accumulate introns.Alternative splicing of exons within a gene after intron excision acts to introduce greater variability of protein sequences translated from a single gene, allowing multiple related proteins to be generated from a single gene and a single precursor mRNA transcript. The control of alternative RNA splicing is performed by a complex network of signaling molecules that respond to a wide range of intracellular and extracellular signals.
Introns contain several short sequences that are important for efficient splicing, such as acceptor and donor sites at either end of the intron as well as a branch point site, which are required for proper splicing by the spliceosome. Some introns are known to enhance the expression of the gene that they are contained in by a process known as intron-mediated enhancement (IME).
Actively transcribed regions of DNA frequently form R-loops that are vulnerable to DNA damage. In highly expressed yeast genes, introns inhibit R-loop formation and the occurrence of DNA damage. Genome-wide analysis in both yeast and humans revealed that intron-containing genes have decreased R-loop levels and decreased DNA damage compared to intronless genes of similar expression. Insertion of an intron within an R-loop prone gene can also suppress R-loop formation and recombination. Bonnet et al. (2017) speculated that the function of introns in maintaining genetic stability may explain their evolutionary maintenance at certain locations, particularly in highly expressed genes.
Starvation adaptation
The physical presence of introns promotes cellular resistance to starvation via intron enhanced repression of ribosomal protein genes of nutrient-sensing pathways.
As mobile genetic elements
Introns may be lost or gained over evolutionary time, as shown by many comparative studies of orthologous genes. Subsequent analyses have identified thousands of examples of intron loss and gain events, and it has been proposed that the emergence of eukaryotes, or the initial stages of eukaryotic evolution, involved an intron invasion. Two definitive mechanisms of intron loss, reverse transcriptase-mediated intron loss (RTMIL) and genomic deletions, have been identified, and are known to occur. The definitive mechanisms of intron gain, however, remain elusive and controversial. At least seven mechanisms of intron gain have been reported thus far: intron transposition, transposon insertion, tandem genomic duplication, intron transfer, intron gain during double-strand break repair (DSBR), insertion of a group II intron, and intronization. In theory it should be easiest to deduce the origin of recently gained introns due to the lack of host-induced mutations, yet even introns gained recently did not arise from any of the aforementioned mechanisms. These findings thus raise the question of whether or not the proposed mechanisms of intron gain fail to describe the mechanistic origin of many novel introns because they are not accurate mechanisms of intron gain, or if there are other, yet to be discovered, processes generating novel introns.In intron transposition, the most commonly purported intron gain mechanism, a spliced intron is thought to reverse splice into either its own mRNA or another mRNA at a previously intron-less position. This intron-containing mRNA is then reverse transcribed and the resulting intron-containing cDNA may then cause intron gain via complete or partial recombination with its original genomic locus. Transposon insertions can also result in intron creation. Such an insertion could intronize the transposon without disrupting the coding sequence when a transposon inserts into the sequence AGGT, resulting in the duplication of this sequence on each side of the transposon. It is not yet understood why these elements are spliced, whether by chance, or by some preferential action by the transposon. In tandem genomic duplication, due to the similarity between consensus donor and acceptor splice sites, which both closely resemble AGGT, the tandem genomic duplication of an exonic segment harboring an AGGT sequence generates two potential splice sites. When recognized by the spliceosome, the sequence between the original and duplicated AGGT will be spliced, resulting in the creation of an intron without alteration of the coding sequence of the gene. Double-stranded break repair via non-homologous end joining was recently identified as a source of intron gain when researchers identified short direct repeats flanking 43% of gained introns in Daphnia. These numbers must be compared to the number of conserved introns flanked by repeats in other organisms, though, for statistical relevance. For group II intron insertion, the retrohoming of a group II intron into a nuclear gene was proposed to cause recent spliceosomal intron gain.
Intron transfer has been hypothesized to result in intron gain when a paralog or pseudogene gains an intron and then transfers this intron via recombination to an intron-absent location in its sister paralog. Intronization is the process by which mutations create novel introns from formerly exonic sequence. Thus, unlike other proposed mechanisms of intron gain, this mechanism does not require the insertion or generation of DNA to create a novel intron.The only hypothesized mechanism of recent intron gain lacking any direct evidence is that of group II intron insertion, which when demonstrated in vivo, abolishes gene expression. Group II introns are therefore likely the presumed ancestors of spliceosomal introns, acting as site-specific retroelements, and are no longer responsible for intron gain. Tandem genomic duplication is the only proposed mechanism with supporting in vivo experimental evidence: a short intragenic tandem duplication can insert a novel intron into a protein-coding gene, leaving the corresponding peptide sequence unchanged. This mechanism also has extensive indirect evidence lending support to the idea that tandem genomic duplication is a prevalent mechanism for intron gain. The testing of other proposed mechanisms in vivo, particularly intron gain during DSBR, intron transfer, and intronization, is possible, although these mechanisms must be demonstrated in vivo to solidify them as actual mechanisms of intron gain. Further genomic analyses, especially when executed at the population level, may then quantify the relative contribution of each mechanism, possibly identifying species-specific biases that may shed light on varied rates of intron gain amongst different species.
See also
Structure:
Exon
mRNA
Eukaryotic chromosome fine structure
Small t intronSplicing:
Alternative splicing
Exitron
Minor spliceosome
OutronFunction
MicroRNAOthers:
Exon shuffling
Intein
Interrupted gene
Noncoding DNA
Noncoding RNA
Selfish DNA
Twintron
Exon-intron database
References
External links
A search engine for exon/intron sequences defined by NCBI
Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter Molecular Biology of the Cell, 2007, ISBN 978-0-8153-4105-5. Fourth edition is available online through the NCBI Bookshelf: link
Jeremy M Berg, John L Tymoczko, and Lubert Stryer, Biochemistry 5th edition, 2002, W H Freeman. Available online through the NCBI Bookshelf: link
Intron finding tool for plant genomic sequences
Exon-intron graphic maker |
Subsets and Splits
No saved queries yet
Save your SQL queries to embed, download, and access them later. Queries will appear here once saved.