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Anthrax immune globulin	Anthrax immune globulin, tradename Anthrasil, is a human immune globulin that is used in combination with antibiotics to treat anthrax. It was developed by Cangene and purchased in 2011 by the Biomedical Advanced Research and Development Authority (BARDA) under Project Bioshield. On 24 March 2015 it was granted approval by the United States Food and Drug Administration for use in treating inhalation anthrax in conjunction with antibiotics. Preparation Anthrax immune globulin is prepared from the plasma of donors who have been vaccinated against anthrax. Safety and efficacy testing Due to the ethical and feasibility concerns with testing the efficacy of anthrax immune globulin in humans, it was tested in rabbits and monkeys under the FDAs animal efficacy rule. Following efficacy testing, anthrax immune globulin was tested for safety in human volunteers, where the most common side effects were headache, back pain, nausea and infusion site pain and swelling. == References ==
Molnupiravir	Molnupiravir, sold under the brand name Lagevrio, is an antiviral medication that inhibits the replication of certain RNA viruses. It is used to treat COVID-19 in those infected by SARS-CoV-2. It is taken by mouth.Molnupiravir is a prodrug of the synthetic nucleoside derivative N4-hydroxycytidine and exerts its antiviral action by introducing copying errors during viral RNA replication.Molnupiravir was originally developed to treat influenza at Emory University by the universitys drug innovation company, Drug Innovation Ventures at Emory (DRIVE), but was reportedly abandoned for mutagenicity concerns. It was then acquired by Miami-based company Ridgeback Biotherapeutics, which later partnered with Merck & Co. to develop the drug further.Based on positive results in placebo-controlled double-blind randomized clinical trials, molnupiravir was approved for medical use in the United Kingdom in November 2021. In December 2021, the U.S. Food and Drug Administration (FDA) granted an emergency use authorization (EUA) to molnupiravir for use in certain populations where other treatments are not feasible. The emergency use authorization was only narrowly approved (13-10) because of questions about efficacy and concerns that molnupiravirs mutagenic effects could create new variants that evade immunity and prolong the COVID-19 pandemic. Medical uses Molnupiravir is indicated for the treatment of mild-to-moderate coronavirus disease (COVID-19) in adults with positive results of direct SARS-CoV-2 viral testing who are at high risk for progression to severe COVID-19 and for whom alternative FDA-authorized COVID-19 treatments are not accessible or clinically appropriate. It is the second oral medication against COVID 19 after nirmatrelvir/ritonavir, but with a lower efficacy: about 30% (95% CI, 1–51%) against hospitalization or death in unvaccinated adults with mild or moderate COVID-19 and at least one risk factor for disease progression. Contraindications Use during pregnancy is not recommended. There are no human data on use during pregnancy to assess the risk of adverse maternal or fetal outcomes. Based on animal data, the drug may cause fetal harm.In rats, bone and cartilage toxicity was observed after repeated dosing. Adverse effects Adverse reactions observed in the phase III MOVe-OUT study included diarrhea (2%), nausea (1%) and dizziness (1%), all of which were mild or moderate. Overdose The effects of overdose are unknown, treatment consists of general supportive measures such as monitoring of clinical status. Drug interactions Based on limited available data, there are no drug interactions. Mechanism of action Molnupiravir inhibits viral reproduction by promoting widespread mutations in the replication of viral RNA by RNA-directed RNA polymerase. It is metabolized into a ribonucleoside analog that resembles cytidine, β-D-N4-Hydroxycytidine 5′-triphosphate (also called EIDD-1931 5′-triphosphate or NHC-TP). During replication, the viruss enzyme incorporates NHC-TP into newly made RNA instead of using real cytidine. Molnupiravir can swap between two forms (tautomers), one of which mimics cytidine (C) and the other uridine (U). NHC-TP is not recognized as an error by the viruss proofreading exonuclease enzymes, which can replace mutated nucleotides with corrected versions. When the viral RNA polymerase attempts to copy RNA containing molnupiravir, it sometimes interprets it as C and sometimes as U. This causes more mutations in all downstream copies than the virus can survive, an effect called viral error catastrophe or lethal mutagenesis. Chemistry The first synthesis of molnupiravir was disclosed in a patent filed by Emory University in 2018.In the first step, acetone is used as a protecting group to render two of the three hydroxy groups of uridine unreactive to treatment with the acid anhydride of isobutyric acid, which converts the third hydroxy group to its ester. Treatment with 1,2,4-triazole and phosphoryl chloride produces a reactive intermediate in which the triazole portion can be replaced with hydroxylamine. Finally, removal of the protecting group using formic acid converts the material to molnupiravir.: 93–95 Alternative patented routes to molnupiravir have been reviewed. History Molnupiravir was developed at Emory University by its drug innovation company, Drug Innovation Ventures at Emory (DRIVE). In 2014, DRIVE began a screening project funded by the Defense Threat Reduction Agency to find an antiviral drug targeting Venezuelan equine encephalitis virus (VEEV), which led to the discovery of EIDD-1931. When turned into the prodrug EIDD-2801 (molnupiravir), the compound also showed activity against other RNA viruses including influenza, Ebola, chikungunya, and various coronaviruses.The international nonproprietary name of the drug was inspired by that of Thors hammer, Mjölnir. The idea is that the drug will strike down the virus like a mighty blow from the god of thunder.In 2019, the National Institute of Allergy and Infectious Diseases (NIAID) approved moving molnupiravir into Phase I clinical trials for influenza.In March 2020, the research team pivoted to studying SARS-CoV-2, and successfully used molnupiravir to treat human cells infected with the novel coronavirus. A study found that it is orally active against SARS-CoV-2 in ferrets.DRIVE then licensed molnupiravir for human clinical studies to Miami-based company Ridgeback Biotherapeutics, which later partnered with Merck & Co. to develop the drug further.The primary data supporting the U.S. Food and Drug Administration (FDA) emergency use authorization for molnupiravir are from MOVe-OUT, a randomized, double-blind, placebo-controlled clinical trial studying molnupiravir for the treatment of non-hospitalized participants with mild to moderate COVID-19 at high risk for progression to severe COVID-19 and/or hospitalization. Participants were adults 18 and older with a pre-specified chronic medical condition or at increased risk of SARS-CoV-2 infection for other reasons who had not received a COVID-19 vaccine. The main outcome measured in the trial was the percentage of people who were hospitalized or died due to any cause during 29 days of follow-up. Of the 709 people who received molnupiravir, 6.8% were hospitalized or died within this period compared to 9.7% of the 699 people who received a placebo. Society and culture Economics In September 2021, Merck signed a voluntary licensing agreement with the Medicines Patent Pool (MPP) that allows MPP to sublicense molnupiravir and supply the COVID-19 oral medication to 105 low- and middle-income countries. The cost of the U.S. governments initial purchase was about $712 per course of treatment; treatment with generics in developing countries can cost as little as $20. Legal status On 11 October 2021, Merck submitted an EUA application to the FDA, and on 30 November 2021, the FDAs Antimicrobial Drugs Advisory Committee (AMDAC) at the Center for Drug Evaluation and Research met to discuss the application. The committee narrowly voted, 13 for and 10 opposed, to recommend authorization for adults with mild to moderate illness who are at high risk of developing severe COVID-19. Concerns were expressed over the drugs low effectiveness in preventing death, which in the final trial was only 30%, as well as the increased mutation rate the drug causes, which could theoretically worsen the pandemic by driving the evolution of more dangerous variants. In December 2021, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for molnupiravir for the treatment of mild-to-moderate coronavirus disease (COVID-19) in adults with positive results of direct SARS-CoV-2 viral testing who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate.In October 2021, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) started a rolling review of molnupiravir.In November 2021, molnupiravir was approved in the U.K. by the Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of established infections of COVID-19. The MHRA issued a conditional marketing authorization applicable in the U.K., and an emergency use authorization for Northern Ireland.In November 2021, the Bangladesh Directorate General of Drug Administration (DGDA) authorized emergency use of molnupiravir.In January 2022, molnupiravir was approved for medical use in Israel. Names Molnupiravir is the international nonproprietary name (INN).Generic versions are available under the brand names Molulife (Mankind) and Molena (Emcure). Public health concerns At a November 2021 AMDAC meeting, multiple advisors raised the concern that molnupiravir could accelerate the emergence of variants of concern. Other scientists raised similar concerns both before and after the meeting. Research COVID-19 clinical trial In October 2021, preliminary results from a clinical trial (MOVe-OUT) indicated that treatment with molnupiravir may reduce the risk of hospitalization and death from COVID-19. The final analysis reported a 30% reduction in hospitalizations and deaths.As of January 2022, the Panoramic trial is testing molnupiravirs effectiveness. References Further reading Thorlund K, Sheldrick K, Meyerowitz-Katz G, Singh S, Hill A (March 2022). "Making Statistical Sense of the Molnupiravir MOVe-OUT Clinical Trial". Am J Trop Med Hyg. 106 (5): 1301–1304. doi:10.4269/ajtmh.21-1339. PMC 9128711. PMID 35276667. S2CID 247406958. External links "Molnupiravir". Drug Information Portal. U.S. National Library of Medicine.
Carbinoxamine	Carbinoxamine is an antihistamine and anticholinergic agent. It is used for hay fever, vasomotor rhinitis, mild urticaria, angioedema, dermatographism and allergic conjunctivitis. Carbinoxamine is a histamine antagonist, specifically an H1-antagonist. The maleic acid salt of the levorotatory isomer is sold as the prescription drug rotoxamine. It was patented in 1947 and came into medical use in 1953. It was first launched in the United States by the McNeil Corporation under the brand name Clistin. Carbinoxamine is available in various countries around the world by itself, combined with decongestants such as pseudoephedrine, and also with other ingredients including paracetamol, aspirin, and codeine. Society and culture In June 2006 the FDA announced that more than 120 branded pharmacy products containing carbinoxamine were being illegally marketed and demanded they be removed from the marketplace. This action was precipitated by twenty-one reported deaths in children under the age of two who had been administered carbinoxamine-containing products. Despite the fact that the drug had not been studied in this age group, a multitude of OTC preparations containing carbinoxamine were being marketed for infants and toddlers. At present, all carbinoxamine-containing formulations are approved only for adults or children ages 3 or older. Brand names Brand names include Clistin, Palgic, Rondec, Rhinopront, Ryvent. See also Carbinoxamine/pseudoephedrine Tofenacin Clemastine Captodiamine == References ==
Sarna	Sarna may refer to: Sarna (Polish surname) Sarna (Punjabi surname) Sarna (clan), a Punjabi clan of India Sarna, Warmian-Masurian Voivodeship, a village in northern Poland Särna, a locality in Dalarna County, Sweden SaRNA, small activating RNA Sarna sthal – place of worship Sarna (drug), a drug Sarna (religion) See also All pages with titles containing Sarna Sarnaism, the religious beliefs held by tribes in the state of Jharkhand, India, and other central Indian states Srna (disambiguation)Sarna.net ("Sarna" for short) is the fan wiki project for the fictional BattleTech universe, named after the equally fictional star system therein.
Heather	Heather may refer to: Plants The heather family, or Ericaceae, particularly: Common heather or ling, Calluna Various species of the genus Cassiope Various species of the genus Erica Name Heather (given name) Heather (surname) Arts and media Heathers, a 1989 film directed by Michael Lehmann Heathers: The Musical, a musical by Laurence OKeefe based on the film Heathers (TV series), a 2018 television series based on the film "Heather" (The Secret Circle), a television episode Music Heathers (band), an acoustic singing duo from Ireland "Heather" (Beatles song), an unreleased 1968 song by Paul McCartney and Donovan "Heather" (Conan Gray song), a 2020 song by American singer Conan Gray "Heather", a song from fusion drummer Billy Cobhams 1974 album Crosswinds "Heather", a 2001 song by Paul McCartney from the album Driving Rain "Heather", a song from Patent Pending by Heavens "Heather", a version of the Johnny Pearson song, "Autumn Reverie", which appeared on the Carpenters album Now & Then ”Heather”, a song from I Know Leopard’s album Love is a Landmine Places Heather, Leicestershire, a village in England Heather Preceptory, a preceptory of the Knights Hospitaller, established in the above village Heather St Johns Football Club, an English football club based in the above village Heather, Missouri, a community in the United States Heather, Washington, an unincorporated community in the United States Other uses Heather (fabric), interwoven yarns of mixed colours producing muted greyish shades with flecks of colour Heather (yacht), the original name of the yacht USS Sea Gull, built in 1902 Heather, brand name of a progestogen-only pill containing norethisterone (norethindrone) See also Heath (disambiguation) Heather Hills (disambiguation) Hurricane Heather
Cobicistat	Cobicistat, sold under the brand name Tybost, is a medication for use in the treatment of human immunodeficiency virus infection (HIV/AIDS). Its major mechanism of action is through the inhibition of human CYP3A proteins.Like ritonavir (Norvir), cobicistat is of interest for its ability to inhibit liver enzymes that metabolize other medications used to treat HIV, notably elvitegravir, an HIV integrase inhibitor. By combining cobicistat with elvitegravir, higher concentrations of the latter are achieved in the body with lower dosing, theoretically enhancing elvitegravirs viral suppression while diminishing its adverse side-effects. In contrast with ritonavir, the only other booster approved for use as a part of HAART, cobicistat has no anti-HIV activity of its own.Cobicistat is a component of three four-drug, fixed-dose combination HIV treatments. The first, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil, is marketed as Stribild and was approved by the FDA in August 2012 for use in the United States. The second, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, is marketed as Genvoya and was approved by the FDA in November 2015 for use in the United States. Both Stribild and Genvoya are owned by Gilead Sciences. The third, cobicistat, darunavir, emtricitabine, and tenofovir alafenamide, is marketed as Symtuza and was FDA approved July 17, 2018 and is owned by Janssen Pharmaceuticals.Additionally, in existence are a fixed-dose combination of cobicistat and protease inhibitor darunavir (darunavir/cobicistat; marketed as Prezcobix by Janssen Therapeutics), and a fixed-dose combination of cobicistat and protease inhibitor atazanavir (atazanavir/cobicistat; marketed as Evotaz by Bristol-Myers Squibb). Both Prezcobix and Evotaz were approved by the FDA in January 2015. Cobicistat is a potent inhibitor of cytochrome P450 3A enzymes, including the important CYP3A4 subtype. It also inhibits intestinal transport proteins, increasing the overall absorption of several HIV medications, including atazanavir, darunavir, and tenofovir alafenamide. Chemistry Cobicistat is a drug analogue of ritonavir, in which the valine moiety is exchanged for a 2-morpholinoethyl group, and the backbone hydroxyl group is removed. These changes effectively eliminate the anti-HIV activity of ritonavir while preserving its inhibitory effects on the CYP3A isozyme family of proteins. Cobicistat is therefore able to increase plasma concentration of other coadministered anti-HIV drugs without the risk of causing cobicistat-resistant mutations in the HIV virus. Synthesis Cobicistat may be synthesized from any number of commercially available starting materials. The synthesis shown below utilizes L-methionine and bromoacetic acid as starting materials. Discovery and development Cobicistat was developed through structure-activity relationship studies using ritonavir and desoxyritonavir as lead compounds. These studies were conducted by scientists at Gilead Sciences, and successfully optimized ritonavir into a potent CYP3A inhibitor lacking anti-HIV activity. Cobicistat shows potent, selective inhibition of the CYP3A isozyme family (IC50 0.15 μM) compared to some CYP1A and CYP2C isozymes. As cobicistat was discovered using structure-activity relationship studies, its CYP3A binding is still poorly understood; however, research on the protein-ligand interactions between CYP3A4 and ritonavir analogues demonstrates that CYP 3A4 residues Ile369, Ala370, Met371, as well as Arg105 and Ser119, play an important role in ritonavir analogue inhibition of CYP3A4. References External links "Cobicistat". Drug Information Portal. U.S. National Library of Medicine.
Reteplase	Reteplase, trade names include Retavase, is a thrombolytic drug, used to treat heart attacks by breaking up the clots that cause them. Reteplase is a recombinant non-glycosylated form of human tissue plasminogen activator, which has been modified to contain 357 of the 527 amino acids of the original protein. It is produced in the bacterium Escherichia coli. Reteplase was approved for use in 1996.Reteplase is similar to recombinant human tissue plasminogen activator (alteplase), but the modifications give reteplase a longer half-life of 13–16 minutes. Reteplase also binds fibrin with lower affinity than alteplase, improving its ability to penetrate into clots. As reteplase is able to penetrate inside the thrombi, an enhanced fibrinolytic activity will be achieved → rapid reperfusion → low incidence of bleeding. == References ==
Carbachol	Carbachol, also known as carbamylcholine and sold under the brand name Miostat among others, is a cholinomimetic drug that binds and activates acetylcholine receptors. Thus it is classified as a cholinergic agonist. It is primarily used for various ophthalmic purposes, such as for treating glaucoma, or for use during ophthalmic surgery. It is generally administered as an ophthalmic solution (i.e., eye drops). Carbachol produces effects comparable to those of sarin if a massive overdose is administered (as may occur following industrial and shipping accidents) and therefore it is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.It is on the World Health Organizations List of Essential Medicines. Chemistry and pharmacology Carbachol is a choline carbamate and a positively charged quaternary ammonium compound. It is not well absorbed in the gastro-intestinal tract and does not cross the blood–brain barrier. It is usually administered topical ocular or through intraocular injection. Carbachol is not easily metabolized by cholinesterase, it has a 2 to 5 minute onset of action and its duration of action is 4 to 8 hours with topical administration and 24 hours for intraocular administration. Since carbachol is poorly absorbed through topical administration, benzalkonium chloride is mixed in to promote absorption.Carbachol is a parasympathomimetic that stimulates both muscarinic and nicotinic receptors. In topical ocular and intraocular administration its principal effects are miosis and increased aqueous humour outflow.In the cat and rat, carbachol is well known for its ability to induce rapid eye movement (REM) sleep when microinjected into the pontine reticular formation. Carbachol elicits this REM sleep-like state via activation of postsynaptic muscarinic cholinergic receptors (mAChRs).A recent review indicates that carbachol is a strong promoter of ICC activity, which is mediated through the calcium-activated chloride channel, anoctamin 1. Synthesis Carbachol may be prepared in a 2 step process beginning with the reaction of 2-chloroethanol with urea to form a 2-chloroethyl-carbamate, which is then quaternised by a reaction with trimethylamine. Indications Carbachol is primarily used in the treatment of glaucoma, but it is also used during ophthalmic surgery. Carbachol eyedrops are used to decrease the pressure in the eye for people with glaucoma. It is sometimes used to constrict the pupils during cataract surgery. Topical ocular administration is used to decrease intraocular pressure in people with primary open-angle glaucoma. Intraocular administration is used to produce miosis after lens implantation during cataract surgery. Carbachol can also be used to stimulate bladder emptying to treat the condition of underactive bladder.In most countries carbachol is only available by prescription. Outside the United States, it is also indicated for urinary retention as an oral (2 mg) tablet. Contraindications Use of carbachol, as well as all other muscarinic receptor agonists, is contraindicated in patients with asthma, coronary insufficiency, gastroduodenal ulcers, and incontinence. The parasympathomimetic action of this drug will exacerbate the symptoms of these disorders. Overdose The effects of a systemic overdose will probably be similar to the effects of a nerve agent (they both act on the cholinergic system, increasing cholinergic transmission), but its toxicity is much weaker and it is easier to antagonize in overdose. When administered ocularly there is little risk of such effects, since the doses are much smaller (see topical versus systemic administration). References External links "Carbachol". Drug Information Portal. U.S. National Library of Medicine.
Cholera vaccine	Cholera vaccines are vaccines that are effective at preventing cholera. For the first six months after vaccination they provide about 85 percent protection, which decreases to 50 percent or 62 percent during the first year. After two years the level of protection decreases to less than 50 percent. When enough of the population is immunized, it may protect those who have not been immunized (known as herd immunity).The World Health Organization (WHO) recommends the use of cholera vaccines in combination with other measures among those at high risk. With the oral vaccine, two or three doses are typically recommended. The duration of protection is two years in adults and six months in children aged 2–5 years. A single dose vaccine is available for those traveling to an area where cholera is common. In 2010, in some countries an injectable cholera vaccine was available.The available types of oral vaccine are generally safe. Mild abdominal pain or diarrhea may occur. They are safe in pregnancy and in those with poor immune function. They are licensed for use in more than 60 countries. In countries where the disease is common, the vaccine appears to be cost effective.The first vaccines used against cholera were developed in the late 1800s. They were the first widely used vaccine that was made in a laboratory. Oral vaccines were first introduced in the 1990s. It is on the World Health Organizations List of Essential Medicines. Medical use In the late twentieth century, oral cholera vaccines started to be used on a massive scale, with millions of vaccinations taking place, as a tool to control cholera outbreaks in addition to the traditional interventions of improving safe water supplies, sanitation, handwashing and other means of improving hygiene. The Dukoral monovalent vaccine from Sweden, which combines formalin, heat-killed whole cells of Vibrio cholerae O1 and a recombinant cholera toxin B subunit, was licensed in 1991, mainly for travellers. Out of a million doses sold during the following decade, 63 negative side effects were reported. The Shanchol/mORCVAX bivalent vaccine, which combines the O1 and O139 serogroups, was originally licensed in Vietnam in 1997 and given in 20 million doses to children in Vietnam during the following decade. As of 2010, Vietnam continued to incorporate oral cholera vaccination in its public health programme, administering the vaccination through targeted mass vaccination of school-aged children in cholera endemic regions.The cholera vaccine is widely used by backpackers and persons visiting locations where there is a high risk of cholera infection. However, since it does not provide 100 percent immunity from the disease, food hygiene precautions are also recommended when visiting an area where there is a high risk of becoming infected with cholera. Although the protection observed has been described as "moderate", herd immunity can multiply the effectiveness of vaccination. Dukoral has been licensed for children two years of age and older, Shanchol for children one year of age and older. The administration of the vaccine to adults confers additional indirect protection (herd immunity) to children. The World Health Organization (WHO) recommends both preventive and reactive use of the vaccine, making the following key statements: WHO recommends that current available cholera vaccines be used as complements to traditional control and preventive measures in areas where the disease is endemic and should be considered in areas at risk for outbreaks. Vaccination should not disrupt the provision of other high priority health interventions to control or prevent cholera outbreaks.... Reactive vaccination might be considered in view of limiting the extent of large prolonged outbreaks, provided the local infrastructure allows it, and an in-depth analysis of past cholera data and identification of a defined target area have been performed. The WHO as of late 2013 established a revolving stockpile of two million OCV doses. The supply is increasing to six million as a South Korean companies has gone into production (2016), the old production not being able to handle WHO demand in Haiti and Sudan for 2015, nor prior years. GAVI Alliance donated $115 million to help pay for expansions. Oral The oral vaccines are generally of two forms: inactivated and attenuated. Inactivated oral vaccines provide protection in 52 percent of cases the first year following vaccination and in 62 percent of cases the second year. Two variants of the inactivated oral vaccine currently are in use: WC-rBS and BivWC. WC-rBS (marketed as "Dukoral") is a monovalent inactivated vaccine containing killed whole cells of V. cholerae O1 plus additional recombinant cholera toxin B subunit. BivWC (marketed as "Shanchol" and "mORCVAX") is a bivalent inactivated vaccine containing killed whole cells of V. cholerae O1 and V. cholerae O139. mORCVAX is only available in Vietnam. Bacterial strains of both Inaba and Ogawa serotypes and of El Tor and Classical biotypes are included in the vaccine. Dukoral is taken orally with bicarbonate buffer, which protects the antigens from the gastric acid. The vaccine acts by inducing antibodies against both the bacterial components and CTB. The antibacterial intestinal antibodies prevent the bacteria from attaching to the intestinal wall, thereby impeding colonisation of V. cholerae O1. The anti-toxin intestinal antibodies prevent the cholera toxin from binding to the intestinal mucosal surface, thereby preventing the toxin-mediated diarrhoeal symptoms.A live, attenuated oral vaccine (CVD 103-HgR or Vaxchora), derived from a serogroup O1 classical Inaba strain, was approved by the US FDA in 2016. Injectable Although rarely in use, the injected cholera vaccines are effective for people living where cholera is common. They offer some degree of protection for up to two years after a single shot, and for three to four years with annual booster. They reduce the risk of death from cholera by 50 percent in the first year after vaccination. Side effects Both of the available types of oral vaccine are generally safe. Mild abdominal pain or diarrhea may occur. They are safe in pregnancy and in those with poor immune function. They are licensed for use in more than 60 countries. In countries where the disease is common, the vaccine appears to be cost effective. History of development The first vaccines used against cholera were developed in the late 19th century. There were several pioneers in the development of the vaccine. The first cholera vaccine developed by Louis Pasteur was on chicken and other animals. They were the first widely used vaccine that was made in a laboratory. In 1884, Spanish physician Jaume Ferran i Clua developed a live vaccine he had isolated from cholera patients in Marseilles, and used it that on over 30,000 individuals in Valencia during that years epidemic. However, his vaccine and inoculation was rather controversial and was rejected by his peers and several investigation commissions. In 1892, Waldemar Haffkine developed an effective vaccine with less severe side effects, later testing it on more than 40,000 people in the Calcutta area from 1893 to 1896. His vaccine was accepted by the medical community, and is credited as the first effective human cholera vaccine. Finally, in 1896, Wilhelm Kolle introduced a heat-killed vaccine that was significantly easier to prepare than Haffkines, using it on a large scale in Japan in 1902.Oral cholera vaccines were first introduced in the 1990s. The cost to immunize against cholera is between US$0.10 and US$4.00 per vaccination.In 2016, the U.S. Food and Drug Administration (FDA) approved Vaxchora, a single-dose oral vaccine to prevent cholera for travelers. As of June 2016, Vaxchora was the only FDA-approved vaccine for the prevention of cholera. The Vaxchora vaccine can cost more than US$250. References Further reading World Health Organization (2010). The immunological basis for immunization series: module 14: cholera. World Health Organization (WHO). hdl:10665/44367. ISBN 9789241599740. Ramsay M, ed. (2013). "Chapter 14: Cholera". Immunisation against infectious disease. Public Health England. Centers for Disease Control and Prevention (2017). "Cholera". CDC Yellow Book 2020: Health Information for International Travel. New York: Oxford University Press. Cholera and enterotoxigenic escherichia coli (ETEC) travellers diarrhea vaccine: Canadian Immunization Guide. Health Canada (Report). External links "Cholera Vaccine Information Statement". Centers for Disease Control and Prevention (CDC). 23 October 2019. Cholera Vaccines at the US National Library of Medicine Medical Subject Headings (MeSH)
Amantadine	Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended due to widespread drug resistance. It acts as a nicotinic antagonist, dopamine agonist, and noncompetitive NMDA antagonist. The antiviral mechanism of action is antagonism of the influenzavirus A M2 proton channel, which prevents endosomal escape (i.e. the release of viral genetic material into the host cytoplasm).Amantadine was first used for the treatment of influenza A. After antiviral properties were initially reported in 1963, amantadine received approval for prophylaxis against the influenza virus A in 1976. However, amantadine-resistant influenza viruses were first reported during the 1980 influenza A epidemic and resistance frequency continued to rise into the early 2000s. Currently, amantadine is no longer recommended for the treatment of influenza A due to a high level of amantadine resistance among circulating influenza A viruses. In 1973, the Food and Drug Administration (FDA) approved amantadine for use in the treatment of Parkinsons disease. In 2017, the extended release formulation was approved for use in the treatment of levodopa-induced dyskinesia. Off-label uses include improvement of fatigue in multiple sclerosis and accelerating the rate of functional recovery and arousal following a brain injury.Amantadine has a mild side effect profile. Common neurological side effects include drowsiness, light headedness, dizziness, and confusion. Due to its effects on the central nervous system, it should not be combined with additional CNS stimulants or anticholinergic drugs. Amantadine is contraindicated in persons with end stage kidney disease, given that the drug is cleared by the kidneys. It should also be taken with caution in those with enlarged prostates or glaucoma, due to its anticholinergic effects. Live attenuated vaccines are contraindicated while taking amantadine, as it may limit the efficacy of the administered vaccine. Chemical structure Amantadine (brand names Gocovri, Symadine, and Symmetrel) is the organic compound 1-adamantylamine or 1-aminoadamantane, which consists of an adamantane backbone with an amino group substituted at one of the four methyne positions. Rimantadine is a closely related adamantane derivative with similar biological properties; both target the M2 proton channel of influenza A virus. Mechanism of action Parkinsons disease The mechanism of its antiparkinsonian effect is poorly understood. Amantadine is a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake. Amantadine probably does not inhibit monoamine oxidase (MAO) enzyme. Moreover, the drug has many effects in the brain, including release of dopamine and norepinephrine from nerve endings. It appears to be an anticholinergic (specifically at alpha-7 nicotinic receptors) like the similar pharmaceutical memantine.In 2004, it was discovered that amantadine and memantine bind to and act as agonists of the σ1 receptor (Ki = 7.44 μM and 2.60 μM, respectively), and that activation of the σ1 receptor is involved in the dopaminergic effects of amantadine at therapeutically relevant concentrations. These findings may also extend to the other adamantanes such as adapromine, rimantadine, and bromantane, and could explain the psychostimulant-like effects of this family of compounds. Influenza The mechanisms for amantadines antiviral and antiparkinsonian effects are unrelated. Amantadine targets the influenza A M2 ion channel protein. The M2 proteins function is to allow the intracellular virus to replicate (M2 also functions as a proton channel for hydrogen ions to cross into the vesicle), and exocytose newly formed viral proteins to the extracellular space (viral shedding). By blocking the M2 channel, the virus is unable to replicate because of impaired replication, protein synthesis, and exocytosis.Amantadine and rimantadine function in a mechanistically identical fashion, entering the barrel of the tetrameric M2 channel and blocking pore function—i.e., proton translocation.Resistance to the drug class is a consequence of mutations to the pore-lining amino acid residues of the channel, preventing both amantadine and rimantadine from binding and inhibiting the channel in their usual way. Pharmacokinetics Amantadine is well absorbed orally. The onset of action is usually within 48 hours when used for parkinsonian syndromes, including dyskinesia. As plasma concentrations of amantadine increase, there is a greater risk for toxicity.Half-life elimination averages eight days in patients with end-stage kidney disease. Amantadine is only minimally removed by hemodialysis.Amantadine is metabolized to a small extent (5-15%) by acetylation. It is mainly excreted (90%) unchanged in urine by kidney excretion. Medical uses Parkinsons disease Amantadine is used to treat Parkinsons disease-related dyskinesia and drug-induced parkinsonism syndromes. Amantadine may be used alone or in combination with another anti-Parkinsons or anticholinergic drug. The specific symptoms targeted by amantadine therapy are dyskinesia and rigidity. The extended release amantadine formulation is commonly used to treat dyskinesias in people receiving levodopa therapy for Parkinsons disease. A 2003 Cochrane review had concluded there was insufficient evidence to prove the safety or efficacy of amantadine to treat dyskinesia.In 2008, the World Health Organization reported amantadine is not effective as a stand-alone parkinsonian therapy, but recommended it could be used in combination therapy with levodopa. Influenza A Amantadine is not recommended for treatment or prophylaxis of influenza A in the United States. Amantadine has no effect preventing or treating influenza B infections. The US Centers for Disease Control and Prevention found 100% of seasonal H3N2 and 2009 pandemic flu samples were resistant to adamantanes (amantadine and rimantadine) during the 2008–2009 flu season.The U.S. Centers for Disease Control and Prevention (CDC) guidelines recommend only neuraminidase inhibitors for influenza treatment and prophylaxis. The CDC recommends against amantadine and rimantadine to treat influenza A infections.Similarly, the 2011 World Health Organization (WHO) virology report showed all tested H1N1 influenza A viruses were resistant to amantadine. WHO guidelines recommend against use of M2 inhibitors for influenza A. The continued high rate of resistance observed in laboratory testing of influenza A has reduced the priority of M2 resistance testing.A 2014 Cochrane review did not find evidence for efficacy or safety of amantadine used for the prevention or treatment of influenza A. Extra-pyramidal side effects An extended release formulation is used to treat levodopa-induced dyskinesia in patients with Parkinsons disease. The WHO recommends the use of amantadine as a combination therapy to reduce levodopa side effects. Off-label uses Fatigue in multiple sclerosis Amantadine, along with modafinil and methylphenidate, are the most commonly used medications for the treatment of multiple sclerosis (MS) related fatigue in clinical practice. A 2007 Cochrane literature review concluded that there was no overall evidence supporting the use of amantadine in treating fatigue in patients with MS. A follow up 2012 Cochrane review stated that there may be some amantadine-induced improvement in fatigue in some people with MS. Despite multiple control trials that have also demonstrated improvements in subjective and objective ratings of fatigue, there is no final conclusion regarding its effectiveness.Consensus guidelines from the German Multiple Sclerosis Society (GMSS) in 2006 state that amantadine produces moderate improvement in subjective fatigue, problem solving, memory, and concentration. Thus, GMSS guidelines strongly recommend the use of amantadine in MS-related fatigue.In the UK NICE recommends considering amantadine for MS fatigue. Awareness in patients with disorders of consciousness Disorders of consciousness (DoC) include coma, vegetative state (VS), and minimally conscious state (MCS). Amantadine has been shown to increase the rate of emergence from a MCS, defined by consistent demonstration of interactive communication and functional objective use. In traumatic brain injury patients in the intensive care unit, amantadine has also been shown in various randomized control trials to increase the rate of functional recovery and arousal, particularly in the time period immediately following an injury. There are also reports of significantly improved consciousness in patients treated for non-traumatic cases of DoC, such as in the case of a subarachnoid hemorrhage, cerebral hemorrhage, and hypoxic encephalopathy. In 2018 the American Academy of Neurology (AAN) updated treatment guidelines on the use of amantadine for patients with prolonged DoC, recommending the use of amantadine (100–200 mg bid) for adults with DoC 4–16 weeks post injury to support early functional recovery and reduce disability. Neuroplasticity and overall functional recovery in patients with brain injury In various studies, amantadine and memantine have been shown to accelerate the rate of recovery from a brain injury. The time-limited window following a brain injury is characterized by neuroplasticity, or the capacity of neurons in the brain to adapt and compensate after injury. Thus, physiatrists will often start patients on amantadine as soon as impairments are recognized. There are also case reports showing improved functional recovery with amantadine treatment occurring years after the initial brain injury. There is insufficient evidence to determine if the functional gains are a result of effects through the dopamine or norepinephrine pathways. Some patients may benefit from direct dopamine stimulation with amantadine, while others may benefit more from other stimulants that act more on the norepinephrine pathway, such as methylphenidate. It is unclear if treatment with amantadine improves long-term outcomes or simply accelerates recovery. Nonetheless, amantadine-induced acceleration of recovery reduces the burden of disability, lessens health care costs, and minimizes psychosocial stressors in patients. Adverse effects Amantadine is generally well tolerated and has a mild side-effect profile. Neurological Side effects include drowsiness (especially while driving), lightheadedness, falls, and dizziness. Patients on amantadine should avoid combination with other central nervous system (CNS) depressing agents, such as alcohol. Excessive alcohol usage may increase the potential for CNS effects such as dizziness, confusion, and light headedness.Rare severe adverse effects include neuroleptic malignant syndrome, depression, convulsions, psychosis, and suicidal ideation. It has also been associated with disinhibited actions (gambling, sexual activity, spending, other addictions) and diminished control over compulsions. Cardiovascular Amantadine may cause orthostatic hypotension, syncope, and peripheral edema. Gastrointestinal Amantadine has also been associated with dry mouth and constipation. Skin Rare cases of skin rashes, such as Stevens–Johnson syndrome and livedo reticularis have also been reported in patients treated with amantadine. Pregnancy and lactation Amantadine is Food and Drug Administration category C for pregnancy. Teratogenic effects have been observed in humans (case reports) and animal reproduction studies. Amantadine may also be present in breast milk and negatively alter breast milk production or excretion. The decision to breastfeed during amantadine therapy should consider the risk of infant exposure, the benefits of breastfeeding, and the benefits of the drug to the mother. Interactions Amantadine may affect the central nervous system due to dopaminergic and anticholinergic properties. The mechanisms of action are not fully known. Because of the CNS effects, caution is required when prescribing additional CNS stimulants or anticholinergic drugs. Thus, concurrent use of alcohol with Amantadine is not recommended due to enhanced CNS depressant effects. In addition, anti-dopaminergic drugs such as metoclopramide and typical anti-psychotics should be avoided. These interactions are likely related to opposing dopaminergic mechanisms of action, which inhibits amantadines anti-Parkinson effects. Contraindications Amantadine is contraindicated in persons with end stage kidney disease. The drug is renally cleared.Amantadine may have anticholinergic side effects. Thus, patients with an enlarged prostate or glaucoma should use with caution.Live attenuated vaccines are contraindicated while taking amantadine. It is possible that amantadine will inhibit viral replication and reduce the efficacy of administered vaccines. The U.S. Food and Drug Administration recommends avoiding amantadine for two weeks prior to vaccine administration and 48 hours afterward. History Influenza A Antiviral properties were first reported in 1963 at the University of Illinois Hospital in Chicago. In this amantadine trial study volunteer college students were exposed to a viral challenge. The group that received amantadine (100 milligrams 18 hours before viral challenge) had less Asia influenza infections than the placebo group. Amantadine received approval for the treatment of influenza virus A in adults in 1976. It was first used in West Germany in 1966. Amantadine was approved by the U.S. Food and Drug Administration in October 1968, as a prophylactic agent against Asian (H2N2) influenza and received approval for prophylactic use for influenza A in 1976.During the 1980 influenza A epidemic, the first amantadine-resistance influenza viruses were reported. The frequency of amantadine resistance among influenza A (H3N2) viruses from 1991 and 1995 was as low as 0.8%. In 2004 the resistance frequency increased to 12.3%. A year later resistance increase significantly to 96%, 72%, and 14.5% in China, South Korea, and the United States, respectively. By 2006, 90.6% of H3N2 strains and 15.6% of H1N1 were amantadine-resistant. A majority of the amantadine-resistant H3N2 isolates (98.2%) were found to contain an S31N mutation in the M2 transmembrane domain that confers resistance to amantadine. Currently, adamantane resistance is high among circulating influenza A viruses. Thus, they are no longer recommended for treatment of influenza A. Parkinsons disease An incidental finding in 1969 prompted investigations about amantadines effectiveness for treating symptoms of Parkinsons disease. A woman with Parkinsons disease was prescribed amantadine to treat her influenza infection and reported her cogwheel rigidity and tremors improved. She also reported that her symptoms worsened after she finished the course of amantadine. The published case report was not initially corroborated by any other instances by the medical literature or manufacturer data. A team of researchers looked at a group of ten patients with Parkinsons disease and gave them amantadine. Seven of the ten patients showed improvement, which was convincing evidence for the need of a clinical trial, which included 163 patients with Parkinsons disease and 66% experienced subjective or objective reduction of symptoms with a maximum daily dose of 200 mg. Additional studies followed patients for greater lengths of time and in different combinations of neurological drugs. It was found to be a safe drug that could be used over long periods of time with few side effects as monotherapy or in combination with L-dopa or anti-cholinergic drugs. By April 1973, the U.S. Food and Drug Administration approved amantadine for use in the treatment of Parkinsons disease.In 2017, the U.S. Food and Drug Administration approved the use of amantadine in an extended release formulation for the treatment of dyskinesia, an adverse effect of levodopa in people with Parkinsons disease. Veterinary misuse In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza. In Western countries and according to international livestock regulations, amantadine is approved only for use in humans. Chickens in China have received an estimated 2.6 billion doses of amantadine. Avian flu (H5N1) strains in China and southeast Asia are now resistant to amantadine, although strains circulating elsewhere still seem to be sensitive. If amantadine-resistant strains of the virus spread, the drugs of choice in an avian flu outbreak will probably be restricted to neuraminidase inhibitors oseltamivir and zanamivir which block the action of viral neuraminidase enzyme on the surface of influenza virus particles. However, there is an increasing incidence of oseltamivir resistance in circulating influenza strains (e.g., H1N1), highlighting the need for new anti-influenza therapies.In September 2015, the U.S. Food and Drug Administration announced the recall of Dingo Chip Twists "Chicken in the Middle" dog treats because the product has the potential to be contaminated with amantadine. References External links "Amantadine". Drug Information Portal. U.S. National Library of Medicine. "Amantadine hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Eteplirsen	Eteplirsen (brand name Exondys 51) is a medication to treat, but not cure, some types of Duchenne muscular dystrophy (DMD), caused by a specific mutation. Eteplirsen only targets specific mutations and can be used to treat about 14% of DMD cases. Eteplirsen is a form of antisense therapy. Eteplirsen was developed by Steve Wilton, Sue Fletcher and colleagues at the University of Western Australia and commercialized by Sarepta Therapeutics. After a controversial debate surrounding the drugs efficacy, during which two FDA review panel members resigned in protest, eteplirsen received accelerated approval from the US Food and Drug administration in late 2016. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) refused to authorize the use of eteplirsen. Adverse effects The following adverse events were observed in at least 10% of people who received eteplirsen in trials: vomiting, contusion, excoriation, arthralgia, rash, catheter site pain, and upper respiratory tract infection. Mechanism of action Duchenne muscular dystrophy is caused when a mutation in the DMD gene changes the DMD mRNA so that it no longer codes for functional dystrophin protein, usually due to a nonsense mutation that introduces a premature stop codon into the mRNA. If an exon with an appropriate number of bases lies near the mutation, by removing the defective exon the downstream reading frame can be corrected and production of partially functional dystrophin can be restored. This is the general strategy used for designing exon-skipping oligos for DMD; as there are 79 exons transcribed in the longest splice form of the dystrophin transcript, many different oligos are needed to address the range of mutations present in the population of people with DMD.Eteplirsen is a morpholino antisense oligomer which triggers excision of exon 51 during pre-mRNA splicing of the dystrophin RNA transcript. Skipping exon 51 changes the downstream reading frame of dystrophin; giving eteplirsen to a healthy person would result in production of dystrophin mRNA which would not code for functional dystrophin protein but, for DMD patients with particular nonsense mutations, giving eteplirsen can restore the reading frame of the dystrophin mRNA and result in production of functional (although modified by having an internal deletion consisting of both the patients original defect, as well as the therapeutically skipped exon) dystrophin. Eteplirsen is given by intravenous infusion for systemic treatment of DMD. Exon skipping is induced by eteplirsen, a charge-neutral, phosphorodiamidate morpholino oligomer (PMO) that selectively binds to exon 51 of dystrophin pre-mRNA, restoring the phase of the reading frame and enabling production of functional, but internally edited, dystrophin. The uncharged nature of the PMO helps make it resistant to biological degradation. This modified dystrophin protein produced by eteplirsen may cause a less severe form of dystrophinopathy, much like Becker muscular dystrophy. Eteplirsens proposed mechanism of action is to bind to dystrophin pre-mRNA and alter the exon splicing of the RNA so that more almost full-length dystrophin is made. By increasing the quantity of an abnormal, but potentially functional, dystrophin protein, the objective is to slow or prevent the progression of DMD. Nature and sequence of oligo and target Eteplirsen is a morpholino phosphorodiamidate antisense oligomer. CTCCAACATCAAGGAAGATGGCATTTCTAG (sequence source: US FDA ETEPLIRSEN BRIEFING DOCUMENT NDA 206488), 30-mer, 20% G, 43% CG, Predicted Tm: 88.9 °C at 10 μM oligo. Oligo complement CTAGAAATGCCATCTTCCTTGATGTTGGAG DMD-001 Exon 51, ENST00000357033.8 in Ensembl.org, RNA target site marked. Given that the target site is within an exon, this is likely blocking binding of an exonic splice enhancer protein and so altering splicing by interfering with splice regulation. CTCCTACTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCT CCAAA[CTAGAAATGCCATCTTCCTTGATGTTGGAG]GTACCTGCTCTGGCAGATTTCAACC GGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGATCAAGTTATAAAATCACAGA GGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAG Pharmacokinetics Following single or multiple intravenous infusions, the majority of drug elimination occurred within 24 hours of intravenous administration. Elimination half-life of eteplirsen was 3 to 4 hours. History New Drug Applications (NDA) for eteplirsen and a similar drug drisapersen were filed with the US Food and Drug Administration (FDA) in August 2015. The Prescription Drug User Fee Act (PDUFA) goal dates for these were December 27, 2015 for drisapersen and February 26, 2016, for eteplirsen. Following FDA rejection of drisapersen, the agency announced a three-month time extension for its review of eteplirsen. The FDA panel decision was controversial because the FDA staff and the panel used a stricter standard of evidence than Sarepta and patient groups used. The FDA panel said that it was required by law to apply the standard of "substantial evidence" of effectiveness. This required randomized, controlled trials showing effectiveness of a meaningful clinical outcome, such as the ability to function in daily life. Sarepta and patient groups wanted to use the standard of historical controls, personal testimonies, and the presence of altered dystrophin in the body. On April 25, 2016, the Advisory Committee Panel voted against approval;. However, in June 2016, FDA requested for additional data from Sarepta to confirm findings of dystrophin production by eteplirsen. Janet Woodcock, director of the FDAs Center for Drug Evaluation and Research, overruled the panel, and FDA Commissioner Robert Califf deferred to her decision. Eterplirsen received accelerated approval on September 19, 2016.The European Medicines Agency reviewed the molecule in 2018, and refused to approve it.Following the approval of eteplirsen, two other drugs of a similar kind, golodirsen and viltolarsen received provisional approval from the FDA for the treatment of people with a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping as well as casimersen for exon 45 skipping. Society and culture Economics The US list price of eteplirsen is US$300,000 per year of treatment. The Institute for Clinical and Economic Review has found the drug not cost effective at the list price when the cost of one Quality-adjusted life year (QALY) was equal to US$150,000. References External links "Eteplirsen". Drug Information Portal. U.S. National Library of Medicine.
Norgestimate	Norgestimate, sold under the brand names Ortho Tri-Cyclen and Previfem among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. The medication is available in combination with an estrogen and is not available alone. It is taken by mouth.Side effects of the combination of an estrogen and norgestimate include menstrual irregularities, headaches, nausea, abdominal pain, breast tenderness, mood changes, and others. Norgestimate is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has very weak androgenic activity and no other important hormonal activity. The medication is a prodrug of norelgestromin and to a lesser extent of levonorgestrel in the body.Norgestimate was patented in 1965 and introduced for medical use, specifically in birth control pills, in 1986. It was introduced for use in menopausal hormone therapy in the United States in 1999. Norgestimate is sometimes referred to as a "third-generation" progestin. It is marketed in birth control pills widely throughout the world, whereas it is available for use in menopausal hormone therapy only in the United States and Brazil. Norgestimate is available as a generic medication. In 2019, the version with ethinylestradiol was the 70th most commonly prescribed medication in the United States, with more than 10 million prescriptions. Medical uses Norgestimate is used in hormonal contraception and in menopausal hormone therapy for the treatment of menopausal symptoms. It is used in combination with ethinylestradiol in birth control pills and in combination with estradiol in menopausal hormone therapy. Available forms Norgestimate is available only in combination with the estrogens ethinylestradiol and estradiol. These formulations are for use by mouth and are indicated specifically for hormonal contraception and menopausal hormone therapy. Norgestimate is not available on its own (i.e., as a standalone medication). Contraindications Side effects Norgestimate has mostly been studied in combination with an estrogen, so the side effects of norgestimate specifically or on its own have not been well-defined.Side effects associated with the combination of ethinylestradiol and norgestimate in premenopausal women, with greater than or equal to 2% incidence over up to 24 menstrual cycles, include headache/migraine (33%), abdominal/gastrointestinal pain (7.8%), vaginal infection (8.4%), vaginal discharge (6.8%), breast issues (including breast pain, discharge, and enlargement) (6.3%), mood disorders (including depression and mood alterations) (5.0%), flatulence (3.2%), nervousness (2.9%), and rash (2.6%).Side effects associated with the combination of estradiol and norgestimate in postmenopausal women, with greater than or equal to 5% incidence over one year, include headache (23%), upper respiratory tract infection (21%), breast pain (16%), back pain (12%), abdominal pain (12%), flu-like symptoms (11%), arthralgia (9%), vaginal bleeding (9%), dysmenorrhea (8%), sinusitis (8%), vaginitis (7%), pharyngitis (7%), fatigue (6%), pain (6%), nausea (6%), viral infection (6%), flatulence (5%), tooth disorder (5%), myalgia (5%), dizziness (5%), depression (5%), and coughing (5%). Overdose Interactions Pharmacology Pharmacodynamics Norgestimate is a rapidly and completely converted prodrug, mainly of norelgestromin (17β-deacetylnorgestimate or levonorgestrel 3-oxime), but also of levonorgestrel (3-keto-17β-deacetylnorgestimate) to a lesser extent (22 ± 6% of an administered dose or about 40–70 µg) and of levonorgestrel acetate (levonorgestrel 17β-acetate) in very small amounts. Via its active metabolites, norgestimate has progestogenic activity, antigonadotropic effects, very weak androgenic activity, and no other important hormonal activity. Progestogenic activity Norgestimate is a progestogen, or an agonist of the progesterone receptor. The relative binding affinities of norgestimate and its active metabolites for the progesterone receptor compared to promegestone (100%) are 15% for norgestimate, 10% for norelgestromin, 150% for levonorgestrel, and 135% for levonorgestrel acetate. Because of their low concentrations, norgestimate and levonorgestrel acetate are not thought to contribute significantly to the biological activity of norgestimate. In addition, although levonorgestrel binds to the progesterone receptor with much higher affinity than norelgestromin, levonorgestrel has high affinity for sex hormone-binding globulin (SHBG) (87% of that of testosterone), which may limit its activity, whereas norelgestromin does not bind to SHBG. The ovulation-inhibiting dosage of norgestimate is 200 µg/day. Androgenic activity In addition to its progestogenic activity, norgestimate has weak androgenic activity. However, the medication shows less androgenic activity than related 19-nortestosterone progestins like levonorgestrel and norethisterone. Norgestimate and norelgestromin have negligible affinity for the androgen receptor (both 0% of the affinity of metribolone), while levonorgestrel has considerable affinity for the androgen receptor (45% of that of metribolone). In addition to their lack of affinity for the androgen receptor, norgestimate and norelgestromin have virtually no affinity for SHBG, and therefore do not displace testosterone from this carrier protein (although levonorgestrel does still bind with high affinity to SHBG and hence could increase free testosterone levels via occupation of SHBG). In accordance, clinical trials of norgestimate have observed minimal androgenic side effects in women treated with the medication. As an example, clinical studies have found that norgestimate does not appreciably inhibit the increase in SHBG levels produced by ethinylestradiol. This is of interest because estrogens increase and androgens decrease liver production of SHBG and by extension circulating levels of SHBG.The relative binding affinity of norgestimate and its metabolite norelgestromin for the rat prostatic androgen receptor (AR) are 0.3% and 1.3% of those of dihydrotestosterone (DHT), respectively, whereas the respective values for levonorgestrel and gestodene are 22% and 15%. Based on these findings, the ratios of AR to PR binding are 219 for norgestimate and 48 for norelgestromin, whereas the ratios for progesterone, levonorgestrel, and gestodene are 93, 11, and 28, respectively. As such, norgestimate and norelgestromin would appear to have much lower androgenic potency than other 19-nortestosterone progestins. However, levonorgestrel is an important metabolite of both norgestimate and norelgestromin, and it may serve to increase their androgenic potency to some degree.When norgestimate is combined with ethinylestradiol, which is potently antiandrogenic, there are only antiandrogenic effects overall and the combination is suitable for treatment of hyperandrogenism. Other activities Norgestimate and its active metabolites do not bind to other steroid hormone receptors besides the progesterone and androgen receptors and hence have no other off-target hormonal activity. This includes estrogenic, glucocorticoid, antimineralocorticoid, and neurosteroid activity. However, levonorgestrel has been found to inhibit 5α-reductase and hepatic cytochrome P450 enzymes in vitro to some extent. Pharmacokinetics Norgestimate is rapidly and almost completely metabolized into its active metabolites, mainly norelgestromin (the primary active metabolite) and to a lesser extent levonorgestrel, upon oral ingestion. As a result, only very low concentrations (70 pg/mL) of norgestimate itself are detectable in the circulation, and only for about 6 hours after an oral dose. The oral bioavailability of norgestimate is unknown. This is due to the rapid and extensive metabolism of norgestimate, which makes determination of overall bioavailability difficult and necessitates methods other than area-under-the-curve (AUC) to do so. Peak levels of norelgestromin (3,500 pg/mL) are reached at approximately 2 hours following administration of norgestimate. Co-administration of norgestimate with a high-fat meal has been found to significantly decrease peak levels of norelgestromin, although the area-under-the-curve levels of norelgestromin are not significantly altered by food. Steady-state levels of norelgestromin and levonorgestrel are reached within 21 days of treatment with norgestimate. There is an approximate 2-fold accumulation in levels of norelgestromin and a non-linear approximate 8-fold accumulation in levels of levonorgestrel with continuous administration of norgestimate. The accumulation of levonorgestrel is thought to be a result of its high affinity for SHBG, which limits its biological activity. The plasma protein binding of norelgestromin is approximately 99% and it is bound to albumin but not to SHBG. Conversely, levonorgestrel is approximately 98% bound to plasma proteins and is bound to both albumin and SHBG.Norgestimate is extensively metabolized into its active metabolites during first-pass metabolism in the liver and intestines. The major metabolite of norgestimate is norelgestromin and is formed from norgestimate via deacetylation in the liver and intestines. A more minor metabolite of norgestimate is levonorgestrel, which accounts for 20 to 25% (22 ± 6%) of an administered dose or about 40 to 70 µg norgestimate, and a very minor metabolite of norgestimate is levonorgestrel 17β-acetate. Both of these metabolites are active similarly to norgelstromin. With a typical oral contraceptive dosage of norgestimate of 200 to 250 µg/day, an amount of 50 to 60 µg/day levonorgestrel may be produced. This is similar to the ovulation-inhibiting dosage of levonorgestrel, and suggests that norgestimate may act in considerable part as a prodrug specifically of levonorgestrel. Following their formation, the active metabolites of norgestimate are inactivated via reduction, hydroxylation, and conjugation into levonorgestrel metabolites. The terminal half-life of norelgestromin is between 17 and 37 hours and of levonorgestrel is between 24 and 32 hours. The metabolites of norgestimate are eliminated 47% in urine and 37% in feces. Unchanged norgestimate is undetectable in urine. Chemistry Norgestimate, also known as 17α-ethynyl-18-methyl-19-nortestosterone 3-oxime 17β-acetate or as 17α-ethynyl-18-methylestr-4-en-17β-ol-3-one 3-oxime 17β-acetate, is a synthetic estrane steroid and a derivative of testosterone. It is a racemic mixture of E and Z isomers. Norgestimate is more specifically a derivative of norethisterone (17α-ethynyl-19-nortestosterone) and is a member of the gonane (18-methylestrane) subgroup of the 19-nortestosterone family of progestins. It is the C3 oxime and C17β acetate ester of levonorgestrel and is also known as levonorgestrel acetate oxime. A related compound is norethisterone acetate oxime (norethisterone-3-oxime 17β-acetate). History Norgestimate was introduced as a component of combined oral contraceptives in 1986. Based on its year of introduction, norgestimate is sometimes described as a "third-generation" progestin. Norgestimate was approved in combination with estradiol for use in menopausal hormone therapy in 1999 in the United States, and a generic version of this preparation became available in this country in 2005. Society and culture Generic names Norgestimate is the generic name of the drug and its INN, USAN, USP, BAN, and DCF. It is also known by its developmental code name ORF-10131. Brand names Norgestimate is marketed in combination with ethinylestradiol as a birth control pill under the brand names Amicette, Cilest, Cyclen, Edelsin, Effiprev, Estarylla, MonoNessa, Orlon, Ortho Tri-Cyclen, Ortho Tri-Cyclen Lo, Ortho-Cyclen, Pramino, Previfem, Sprintec, Triafemi, TriCilest, Tri-Cyclen, Tri-Cyclen LO, Tridette, Tri-Estarylla, Tri-Linyah, TriNessa, Tri-Previfem, and Tri-Sprintec. It is marketed in combination with estradiol for menopausal hormone therapy under the brand name Prefest only. Availability Norgestimate in combination with ethinylestradiol is marketed widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere throughout Europe, South Africa, Latin America, and Asia. It is not listed as being marketed in Australia, New Zealand, Japan, South Korea, China, India, or certain other countries. Unlike the combined birth control pills of norgestimate with ethinylestradiol, the combination of norgestimate with estradiol, sold under the brand name Prefest for menopausal hormone therapy, is reportedly only marketed currently in the United States and Brazil. Research A 2017 study found that norgestimate inhibits staphylococcal biofilm formation and resensitizes methicillin-resistant Staphylococcus aureus to β-lactam antibiotics. In contrast, norelgestromin showed much weaker activity, indicating that the acetyl group of norgestimate is important for the activity. It was suggested by the researchers that norgestimate may be a promising lead compound for the development of new antibiotics. References Further reading Henzl MR (July 2001). "Norgestimate. From the laboratory to three clinical indications". J Reprod Med. 46 (7): 647–61. PMID 11499185. Curran MP, Wagstaff AJ (2001). "Estradiol and norgestimate: a review of their combined use as hormone replacement therapy in postmenopausal women". Drugs Aging. 18 (11): 863–85. doi:10.2165/00002512-200118110-00007. PMID 11772126. S2CID 22720686. Curran MP, Wagstaff AJ (2002). "Spotlight on estradiol and norgestimate as hormone replacement therapy in postmenopausal women". Treat Endocrinol. 1 (2): 127–9. doi:10.2165/00024677-200201020-00006. PMID 15765628. S2CID 1936039. External links "Norgestimate". Drug Information Portal. U.S. National Library of Medicine. "Ethinyl estradiol mixture with norgestimate". Drug Information Portal. U.S. National Library of Medicine. "Estradiol mixture with norgestimate". Drug Information Portal. U.S. National Library of Medicine.
Sulconazole	Sulconazole (trade name Exelderm) is an antifungal medication of the imidazole class. It is available as a cream or solution to treat skin infections such as athletes foot, ringworm, jock itch, and sun fungus. Although not used commercially for insect control, sulconazole nitrate exhibits a strong anti-feeding effect on the keratin-digesting Australian carpet beetle larvae Anthrenocerus australis. == References ==
Ferric maltol	Ferric maltol, sold under the brand names Accrufer (US) and Feraccru (EU), is an iron containing medication for the treatment of adults with low iron stores. It is taken by mouth. Contraindications The drug is contraindicated in people with hereditary hemochromatosis and other kinds of iron overload, as well as those repeatedly receiving blood transfusions and are therefore also at risk of developing iron overload. Side effects The most common side effects are flatulence (in 5% of people taking the drug), diarrhea (4%), constipation (4%), stool color change (4%), nausea (3%), vomiting (3%), and abdominal discomfort, bloating and pain (1%). Ferric maltol may cause serious side effects including increased risk of inflammatory bowel disease flare and iron overload in the body. Interactions No systematic interaction studies with ferric maltol have been conducted. Food reduces its uptake from the gut, as do calcium and magnesium salts and tetracycline antibiotics. Conversely, iron inhibits the uptake of many drugs, such as bisphosphonates, tetracycline antibiotics, quinolone antibiotics, levothyroxin, and levodopa. Combining the drug with intravenous iron can result in fast release of iron into the blood, potentially leading to low blood pressure or even collapse.Dimercaprol in combination with iron is toxic for the kidneys. The antibiotic chloramphenicol interferes with incorporation of iron into red blood cells and with iron excretion. Furthermore, iron can reduce the blood pressure lowering effects of methyldopa.Maltol is metabolized by the enzyme UGT1A6. It is not known whether inhibitors of this enzyme increase maltol concentrations in the body. Pharmacology Mechanism of action Ferric maltol acts as a source of iron, which is essential for oxygen transport in the blood and other processes in the human body. Pharmacokinetics The substance is a complex of iron with maltol, which is absorbed from the gut and then dissociates, releasing iron and maltol separately into the bloodstream. Iron is bound to transferrin and reaches its highest concentrations in the blood plasma one to three hours after ingestion. It is also bound to ferritin for storage. Maltol reaches its highest plasma concentrations after 1 to 1.5 hours. It is quickly metabolized to the glucuronide by UGT1A6 and eliminated via the urine with a biological half-life of 0.7 hours. 40–60% are excreted in the glucuronidized form. History Ferric maltol was approved for medical use in the European Union in February 2016.Ferric maltol was approved for medical use in the United States in July 2019, based on evidence from three clinical trials (trial 1, trial 2, and trial 3). All 295 participants had low iron stores in the body and consequent iron deficiency anemia. In the first two trials low iron was caused by participants inflammatory bowel disease (IBD) and in the last trial, by long standing (chronic) kidney disease.Trials were conducted at 79 sites in Europe and the United States. References External links "Ferric maltol". Drug Information Portal. U.S. National Library of Medicine (NLM).
Eplerenone	Eplerenone, sold under the brand name Inspra, is an aldosterone antagonist type of potassium-sparing diuretic that is used to treat chronic heart failure and high blood pressure, particularly for patients with resistant hypertension due to elevated aldosterone. It is a steroidal antimineralocorticoid of the spirolactone group and a selective aldosterone receptor antagonist (SARA). Eplerenone is more selective than spironolactone at the mineralocorticoid receptor relative to binding at androgen, progestogen, glucocorticoid, or estrogen receptors. Medical uses Heart failure Eplerenone reduces risk of death in patients with heart failure, particularly in patients with recent myocardial infarction (heart attack). Hypertension Eplerenone lowers blood pressure in patients with primary hypertension. Eplerenone also reduces arterial stiffness and vascular endothelial dysfunction.For persons with resistant hypertension, eplerenone is safe and effective for reducing blood pressure, particularly in persons with resistant hypertension due to hyperaldosteronism. Central serous chorioretinopathy Eplerenone is often prescribed for people with central serous chorioretinopathy (CSC). However, the most recent and largest randomized controlled trial showed that eplerenone has no significant effect on chronic CSC. Adverse effects Common adverse drug reactions (ADRs) associated with the use of eplerenone include: hyperkalaemia, hypotension, dizziness, and reduced renal clearance. Eplerenone may have a lower incidence than spironolactone of sexual side effects such as feminization, gynecomastia, impotence, low sex drive and reduction of size of male genitalia. This is because other antimineralocorticoids have structural elements of the progesterone molecule, causing progestogenic and antiandrogenic outcomes. When considering taking these medicines, it is important to note the variations in their ability to offset the nongenomic effects of aldosterone.Currently, there is not enough evidence available from the randomized controlled trials on side effects of eplerenone to do a benefit versus risk assessment in people with primary hypertension. Interactions Eplerenone is primarily metabolized by the cytochrome P450 enzyme CYP3A4. Thus the potential exists for adverse drug interactions with other drugs that induce or inhibit CYP3A4. Specifically, the concomitant use of the CYP3A4 potent inhibitors ketoconazole and itraconazole is contraindicated. Other CYP3A4 inhibitors including erythromycin, saquinavir, and verapamil should be used with caution. Other drugs that increase potassium concentrations may increase the risk of hyperkalemia associated with eplerenone therapy, including salt substitutes, potassium supplements and other potassium-sparing diuretics. Pharmacology Eplerenone is an antimineralocorticoid, or an antagonist of the mineralocorticoid receptor (MR). Eplerenone is also known chemically as 9,11α-epoxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21,17-carbolactone and "was derived from spironolactone by the introduction of a 9α,11α-epoxy bridge and by substitution of the 17α-thoacetyl group of spironolactone with a carbomethoxy group." The drug controls high blood pressure by blocking the binding of aldosterone to the mineralocorticoid receptor (MR) in epithelial tissues, such as the kidney. Blocking the action of aldosterone decreases blood volume and lowers blood pressure. It has 10- to 20-fold lower affinity for the MR relative to spironolactone, and is less potent in vivo as an antimineralocorticoid. However, in contrast to spironolactone, eplerenone has little affinity for the androgen, progesterone, and glucocorticoid receptors. It also has more consistently observed non-genomic antimineralocorticoid effects relative to spironolactone (see membrane mineralocorticoid receptor). Eplerenone differs from spironolactone in its extensive metabolism, with a short half-life and inactive metabolites.Eplerenone seems to be about 50 to 75% as potent as spironolactone as an antimineralocorticoid. Hence, 25 mg/day spironolactone may be equivalent to approximately 50 mg/day eplerenone. Regulatory and Patent History Eplerenone was patented in 1983 and approved for medical use in the United States in 2002. Eplerenone is currently approved for sale in Canada, the US, EU, Netherlands and Japan. Eplerenone costs an estimated $2.93 per day when treating congestive heart failure and $5.86 per day when treating hypertension. See also Finerenone Mexrenone == References ==
Retinyl palmitate	Retinyl palmitate, or vitamin A palmitate, is the ester of retinol (vitamin A) and palmitic acid, with formula C36H60O2. It is the most abundant form of vitamin A storage in animals.An alternate spelling, retinol palmitate, which violates the -yl organic chemical naming convention for esters, is also frequently seen. Biology Animals use long-chain esters of vitamin A, most abundantly the palmitate form, as a form of vitamin A storage. The storage reaction is catalyzed by LRAT, and the inverse is catalyzed by REH. The esters are also intermediates in the visual cycle: RPE65 isomerizes the retinyl part to 11-cis-retinal. Uses Vitamin A palmitate is a common vitamin supplement, available in both oral and injectable forms for treatment of vitamin A deficiency, under the brand names Aquasol A, Palmitate A and many others. It is a constituent of intra ocular treatment for dry eyes at a concentration of 138 μg/g (VitA-Pos) by Ursapharm. It is a pre-formed version of vitamin A; therefore, the intake should not exceed the Recommended Dietary Allowance (RDA). Overdosing preformed Vitamin A forms such as retinyl palmitate leads to adverse physiological reactions (hypervitaminosis A).Retinyl palmitate is used as an antioxidant and a source of vitamin A added to low fat milk and other dairy products to replace the vitamin content lost through the removal of milk fat. Palmitate is attached to the alcohol form of vitamin A, retinol, in order to make vitamin A stable in milk.Retinyl palmitate is also a constituent of some topically applied skin care products. After its absorption into the skin, retinyl palmitate is converted to retinol, and ultimately to retinoic acid (the active form of vitamin A present in Retin-A), though neither its skin absorption nor its conversion is very effective. Carcinogenicity controversy New York Senator Chuck Schumer has called attention to the fact that high doses of topical retinyl palmitate were shown to accelerate cancer in lab animals, fueling the sunscreen controversy in the popular press. One toxicological analysis determined that "there is no convincing evidence to support the notion that [retinyl palmitate] in sunscreens is carcinogenic." A technical report issued thereafter by the National Toxicology Program concluded that diisopropyl adipate increased incidence of skin tumors in mice, and the addition of either retinoic acid or retinyl palmitate both exacerbated the rate and frequency of tumors. Teratogenicity World Health Organization recommendation on Maternal Supplementation During Pregnancy states that "health benefits are expected for the mother and her developing fetus with little risk of detriment to either, from a daily supplement not exceeding 10,000 IU [preformed] vitamin A (3000 μg RE) at any time during pregnancy." Preformed Vitamin A refers to retinyl palmitate and retinyl acetate. See also Vitamin A Retinyl acetate Vitamin supplement == References ==
Phenytoin	Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The intravenous form, fosphenytoin, is used for status epilepticus that does not improve with benzodiazepines. It may also be used for certain heart arrhythmias or neuropathic pain. It can be taken intravenously or by mouth. The intravenous form generally begins working within 30 minutes and is effective for roughly 24 hours. Blood levels can be measured to determine the proper dose.Common side effects include nausea, stomach pain, loss of appetite, poor coordination, increased hair growth, and enlargement of the gums. Potentially serious side effects include sleepiness, self harm, liver problems, bone marrow suppression, low blood pressure, and toxic epidermal necrolysis. There is evidence that use during pregnancy results in abnormalities in the baby. It appears to be safe to use when breastfeeding. Alcohol may interfere with the medications effects.Phenytoin was first made in 1908 by the German chemist Heinrich Biltz and found useful for seizures in 1936. It is on the World Health Organizations List of Essential Medicines. Phenytoin is available as a generic medication. In 2017, it was the 221st most commonly prescribed medication in the United States, with more than two million prescriptions. Medical uses Seizures Tonic-clonic seizures: Mainly used in the prophylactic management of tonic-clonic seizures with complex symptomatology (psychomotor seizures). A period of 5–10 days of dosing may be required to achieve anticonvulsant effects. Focal seizures: Mainly used to protect against the development of focal seizures with complex symptomatology (psychomotor and temporal lobe seizures). Also effective in controlling focal seizures with autonomic symptoms. Absence seizures: Not used in treatment of pure absence seizures due to risk for increasing frequency of seizures. However, can be used in combination with other anticonvulsants during combined absence and tonic-clonic seizures. Seizures during surgery: A 2018 meta-analysis found that early antiepileptic treatment with either phenytoin or phenobarbital reduced the risk of seizure in the first week after neurosurgery for brain tumors. Status epilepticus: Considered after failed treatment using a benzodiazepine due to slow onset of action. Other Abnormal heart rhythms: may be used in the treatment of ventricular tachycardia and sudden episodes of atrial tachycardia after other antiarrhythmic medications or cardioversion has failed. It is a class 1b antiarrhythmic. Digoxin toxicity: Intravenous formulation is drug of choice for arrhythmias caused by cardiac glycoside toxicity. Trigeminal neuralgia: Second choice drug to carbamazepine. Special considerations Phenytoin has a narrow therapeutic index. Its therapeutic range for an anticonvulsant effect is 10–20 μg/mL and for an antiarrhythmic effect 10–20 μg/mL. The most common cause of phenytoin intoxication is self‑medication, which accounts for more than thirty percent of the cases. Avoid giving intramuscular formulation unless necessary due to skin cell death and local tissue destruction. Elderly patients may show earlier signs of toxicity. In the obese, ideal body weight should be used for dosing calculations. Pregnancy: Pregnancy category D due to risk of fetal hydantoin syndrome and fetal bleeding. However, optimal seizure control is very important during pregnancy so drug may be continued if benefits outweigh the risks. Due to decreased drug concentrations as a result of plasma volume expansion during pregnancy, dose of phenytoin may need to be increased if only option for seizure control. Breastfeeding: The manufacturer does not recommend breastfeeding since low concentrations of phenytoin are excreted in breast milk. Liver disease: Do not use oral loading dose. Consider using decreased maintenance dose. Kidney disease: Do not use oral loading dose. Can begin with standard maintenance dose and adjust as needed. Intravenous use is contraindicated in patients with sinus bradycardia, sinoatrial block, second- or third-degree atrioventricular block, Stokes-Adams syndrome, or hypersensitivity to phenytoin, other hydantoins or any ingredient in the respective formulation. Side effects Common side effects include nausea, stomach pain, loss of appetite, poor coordination, increased hair growth, and enlargement of the gums. Potentially serious side effects include sleepiness, self harm, liver problems, bone marrow suppression, low blood pressure, and toxic epidermal necrolysis. There is evidence that use during pregnancy results in abnormalities in the baby. Its use appears to be safe during breastfeeding. Alcohol may interfere with the medications effects. Heart and blood vessels Severe low blood pressure and abnormal heart rhythms can be seen with rapid infusion of IV phenytoin. IV infusion should not exceed 50 mg/min in adults or 1–3 mg/kg/min (or 50 mg/min, whichever is slower) in children. Heart monitoring should occur during and after IV infusion. Due to these risks, oral phenytoin should be used if possible. Neurological At therapeutic doses, phenytoin may produce nystagmus on lateral gaze. At toxic doses, patients experience vertical nystagmus, double vision, sedation, slurred speech, cerebellar ataxia, and tremor. If phenytoin is stopped abruptly, this may result in increased seizure frequency, including status epilepticus.Phenytoin may accumulate in the cerebral cortex over long periods of time which can cause atrophy of the cerebellum. The degree of atrophy is related to the duration of phenytoin treatment and is not related to dosage of the medication.Phenytoin is known to be a causal factor in the development of peripheral neuropathy. Blood Folate is present in food in a polyglutamate form, which is then converted into monoglutamates by intestinal conjugase to be absorbed by the jejunum. Phenytoin acts by inhibiting this enzyme, thereby causing folate deficiency, and thus megaloblastic anemia. Other side effects may include: agranulocytosis, aplastic anemia, decreased white blood cell count, and a low platelet count. Pregnancy Phenytoin is a known teratogen, since children exposed to phenytoin are at a higher risk of birth defects than children born to women without epilepsy and to women with untreated epilepsy. The birth defects, which occur in approximately 6% of exposed children, include neural tube defects, heart defects and craniofacial abnormalities, including broad nasal bridge, cleft lip and palate, and smaller than normal head. The effect on IQ cannot be determined as no study involves phenytoin as monotherapy, however poorer language abilities and delayed motor development may have been associated with maternal use of phenytoin during pregnancy. This syndrome resembles the well-described fetal alcohol syndrome and has been referred to as "fetal hydantoin syndrome". Some recommend avoiding polytherapy and maintaining the minimal dose possible during pregnancy, but acknowledge that current data fails to demonstrate a dose effect on the risk of birth defects. Data now being collected by the Epilepsy and Antiepileptic Drug Pregnancy Registry may one day answer this question definitively. Cancer There is no good evidence to suggest that phenytoin is a human carcinogen. Mouth Phenytoin has been associated with drug-induced gingival enlargement (overgrowth of the gums), probably due to above-mentioned folate deficiency; indeed, evidence from a randomized controlled trial suggests that folic acid supplementation can prevent gingival enlargement in children who take phenytoin. Plasma concentrations needed to induce gingival lesions have not been clearly defined. Effects consist of the following: bleeding upon probing, increased gingival exudate, pronounced gingival inflammatory response to plaque levels, associated in some instances with bone loss but without tooth detachment. Skin Hypertrichosis, Stevens–Johnson syndrome, purple glove syndrome, rash, exfoliative dermatitis, itching, excessive hairiness, and coarsening of facial features can be seen in those taking phenytoin. Phenytoin therapy has been linked to the life-threatening skin reactions Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These conditions are significantly more common in patients with a particular HLA-B allele, HLA-B1502. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians. Phenytoin is primarily metabolized to its inactive form by the enzyme CYP2C9. Variations within the CYP2C9 gene that result in decreased enzymatic activity have been associated with increased phenytoin concentrations, as well as reports of drug toxicities due to these increased concentrations. The U.S. Food and Drug Administration (FDA) notes on the phenytoin drug label that since strong evidence exists linking HLA-B1502 with the risk of developing SJS or TEN in patients taking carbamazepine, consideration should be given to avoiding phenytoin as an alternative to carbamazepine in patients carrying this allele. Immune system Phenytoin has been known to cause drug-induced lupus.Phenytoin is also associated with induction of reversible IgA deficiency. Psychological Phenytoin may increase risk of suicidal thoughts or behavior. People on phenytoin should be monitored for any changes in mood, the development or worsening depression, and/or any thoughts or behavior of suicide. Some case reports of acute phenytoin psychosis were already described. Bones Chronic phenytoin use has been associated with decreased bone density and increased bone fractures. Phenytoin induces metabolizing enzymes in the liver. This leads to increased metabolism of vitamin D, thus decreased vitamin D levels. Vitamin D deficiency, as well as low calcium and phosphate in the blood cause decreased bone mineral density. Interactions Phenytoin is an inducer of the CYP3A4 and CYP2C9 families of the P450 enzyme responsible for the livers degradation of various drugs.A 1981 study by the National Institutes of Health showed that antacids administered concomitantly with phenytoin "altered not only the extent of absorption but also appeared to alter the rate of absorption. Antacids administered in a peptic ulcer regimen may decrease the AUC of a single dose of phenytoin. Patients should be cautioned against concomitant use of antacids and phenytoin."Warfarin and trimethoprim increase serum phenytoin levels and prolong the serum half-life of phenytoin by inhibiting its metabolism. Consider using other options if possible. Pharmacology Mechanism of action Phenytoin is believed to protect against seizures by causing voltage-dependent block of voltage gated sodium channels. This blocks sustained high frequency repetitive firing of action potentials. This is accomplished by reducing the amplitude of sodium-dependent action potentials through enhancing steady-state inactivation. Sodium channels exist in three main conformations: the resting state, the open state, and the inactive state. Phenytoin binds preferentially to the inactive form of the sodium channel. Because it takes time for the bound drug to dissociate from the inactive channel, there is a time-dependent block of the channel. Since the fraction of inactive channels is increased by membrane depolarization as well as by repetitive firing, the binding to the inactive state by phenytoin sodium can produce voltage-dependent, use-dependent and time-dependent block of sodium-dependent action potentials.The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses which prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures. Pharmacokinetics Phenytoin elimination kinetics show mixed-order, non-linear elimination behaviour at therapeutic concentrations. Where phenytoin is at low concentration it is cleared by first order kinetics, and at high concentrations by zero order kinetics. A small increase in dose may lead to a large increase in drug concentration as elimination becomes saturated. The time to reach steady state is often longer than 2 weeks. History Phenytoin (diphenylhydantoin) was first synthesized by German chemist Heinrich Biltz in 1908. Biltz sold his discovery to Parke-Davis, which did not find an immediate use for it. In 1938, outside people including H. Houston Merritt and Tracy Putnam discovered phenytoins usefulness for controlling seizures, without the sedative effects associated with phenobarbital. According to Goodman and Gilmans Pharmacological Basis of Therapeutics: In contrast to the earlier accidental discovery of the antiseizure properties of potassium bromide and phenobarbital, phenytoin was the product of a search among nonsedative structural relatives of phenobarbital for agents capable of suppressing electroshock convulsions in laboratory animals. It was approved by the FDA in 1953 for use in seizures. Jack Dreyfus, founder of the Dreyfus Fund, became a major proponent of phenytoin as a means to control nervousness and depression when he received a prescription for Dilantin in 1966. He has claimed to have supplied large amounts of the drug to Richard Nixon throughout the late 1960s and early 1970s, although this is disputed by former White House aides and Presidential historians. Dreyfus experience with phenytoin is outlined in his book, A Remarkable Medicine Has Been Overlooked. Despite more than $70 million in personal financing, his push to see phenytoin evaluated for alternative uses has had little lasting effect on the medical community. This was partially because Parke-Davis was reluctant to invest in a drug nearing the end of its patent life, and partially due to mixed results from various studies. In 2008, the drug was put on the FDAs Potential Signals of Serious Risks List to be further evaluated for approval. The list identifies medications that the FDA has identified a potential safety issue, but does not mean that FDA has identified a causal relationship between the drug and the listed risk. To address this concern, the Warnings and Precautions section of the labeling for Dilantin injection was updated to include additional information about purple glove syndrome in November 2011. Society and culture Economics Phenytoin is available as a generic medication.Since September 2012, the marketing licence in the UK has been held by Flynn Pharma Ltd, of Dublin, Ireland, and the product, although identical, has been called Phenytoin Sodium xxmg Flynn Hard Capsules. (The xxmg in the name refers to the strength—for example "Phenytoin sodium 25 mg Flynn Hard Capsules"). The capsules are still made by Pfizers Goedecke subsidiarys plant in Freiburg, Germany and they still have Epanutin printed on them. After Pfizers sale of the UK marketing licence to Flynn Pharma, the price of a 28-pack of 25 mg phenytoin sodium capsules marked Epanutin rose from 66p (about $0.88) to £15.74 (about $25.06). Capsules of other strengths also went up in price by the same factor—2,384%, costing the UKs National Health Service an extra £43 million (about $68.44 million) a year. The companies were referred to the Competition and Markets Authority (CMA) who found that they had exploited their dominant position in the market to charge "excessive and unfair" prices.The CMA imposed a record £84.2 million fine on the manufacturer Pfizer, and a £5.2 million fine on the distributor Flynn Pharma and ordered the companies to reduce their prices. Trade names Phenytoin is marketed under many brand names worldwide. Research Tentative evidence suggests that topical phenytoin is useful in wound healing in people with chronic skin wounds. A meta-analysis also supported the use of phenytoin in managing various ulcers.Some clinical trials have explored whether phenytoin can be used as neuroprotector in multiple sclerosis. References Further reading Dean L (2016). "Phenytoin Therapy and HLA-B*15:02 and CYP2C9 Genotypes". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520374. Bookshelf ID: NBK385287. External links "Phenytoin". Drug Information Portal. U.S. National Library of Medicine. English translation of 1908 German article on phenytoin synthesis by Heinrich Biltz
Phenylephrine	Phenylephrine is a medication primarily used as a decongestant, to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids. It was long maintained that when taken orally as a decongestant, it relieves nasal congestion due to colds and hay fever. Phenylephrine can be taken by mouth, as a nasal spray, given by injection into a vein or muscle, or applied to the skin.Common side effects when taken by mouth or injected include nausea, vomiting, headache, and anxiety. Use on hemorrhoids is generally well tolerated. Severe side effects may include a slow heart rate, intestinal ischemia, chest pain, kidney failure, and tissue death at the site of injection. It is unclear if use during pregnancy or breastfeeding is safe. Phenylephrine is a selective α1-adrenergic receptor agonist which results in the constriction of both arteries and veins.Phenylephrine was patented in 1927 and came into medical use in 1938. It is available as a generic medication. Unlike pseudoephedrine, abuse of phenylephrine is very uncommon.As of 2022, there is push back on the effectiveness of phenylephrine as a decongestant, often fused with the supposition that phenylephrine is coasting on its historical status within the Food and Drug Administrations regulatory sphere as an established substitute for the proven use of pseudoephedrine as a decongestant, whose availability has been restricted by law due to its use in the illicit synthesis of methamphetamine. Medical uses Decongestant Phenylephrine is used as a decongestant sold as an oral medicine or as a nasal spray. It is a common ingredient in over-the-counter decongestants in the United States.Phenylephrine is used as an alternative for pseudoephedrine in decongestant medicines due to pseudoephedrines use in the illicit manufacture of methamphetamine. Its efficacy as an oral decongestant has been questioned, with several independent studies finding that it provided no more relief to sinus congestion than a placebo.A 2007 meta-analysis concluded that the evidence for its effectiveness is insufficient, though another meta-analysis published shortly thereafter by researchers from GlaxoSmithKline found the standard 10-mg dose to be more effective than a placebo; however, the fact that GSK markets many products containing phenylephrine has raised some speculation regarding selective publishing and other controversial techniques. A 2007 study by Wyeth Consumer Healthcare notes that 7 studies available in 1976 support the efficacy of phenylephrine at a 10 mg dosage.Two studies published in 2009, examined the effects of phenylephrine on symptoms of allergic rhinitis by exposing people to pollen in a controlled, indoor environment. Neither study was able to distinguish between the effects of phenylephrine or a placebo. Pseudoephedrine and loratadine–montelukast therapy were found to be significantly more effective than both phenylephrine and placebo.The Food and Drug Administration withdrew the indication "for the temporary relief of nasal congestion associated with sinusitis" in 2007.Pseudoephedrine was previously much more commonly available in the United States, however, provisions of the Combat Methamphetamine Epidemic Act of 2005 placed restrictions on the sale of pseudoephedrine products to prevent the clandestine manufacture of methamphetamine. Since 2004, phenylephrine has been increasingly marketed as a substitute for pseudoephedrine; some manufacturers have changed the active ingredients of products to avoid the restrictions on sales. Phenylephrine has been off patent for some time, and many generic brands are available. Hemorrhoids Hemorrhoids are caused by swollen veins in the rectal area. Phenylephrine can be used topically to prevent symptoms of hemorrhoids. Phenylephrine causes the constriction of vascular smooth muscle and is often used in the treatment of hemorrhoids presumably to narrow the swollen veins and relieve the attendant pain. However, veins—unlike arteries—contain less vascular smooth muscle in their walls so the mechanism by which pain relief is achieved is likely related to something other than vascular change alone. Products for treatment may also include substances that will form a protective barrier over the inflamed area, resulting in less pain when feces are passed. Pupil dilation Phenylephrine is used as an eye drop to dilate the pupil to facilitate visualization of the retina. It is often used in combination with tropicamide as a synergist when tropicamide alone is not sufficient. Narrow-angle glaucoma is a contraindication to phenylephrine use. As a mydriatic, it is available in 2.5% and 10% minims. Phenylephrine eye drops are applied to the eye after a topical anesthetic is applied. Intraocular bleeding Phenylephrine has been used as an intracameral injection into the anterior chamber of the eye to arrest intraocular bleeding occurring during cataract and glaucoma surgery. Vasopressor Phenylephrine is commonly used as a vasopressor to increase the blood pressure in unstable patients with hypotension, especially resulting from septic shock. Such use is common in anesthesia or critical-care practices; it is especially useful in counteracting the hypotensive effect of epidural and subarachnoid anesthetics, as well as the vasodilating effect of bacterial toxins and the inflammatory response in sepsis and systemic inflammatory response syndrome. The elimination half life of phenylephrine is about 2.5 to 3.0 hours. The clinical effects of a single intravenous bolus dose of phenylephrine are short lived and needs to be repeated every 10–15 minutes. Commonly the drug is given as a carefully titrated intravenous infusion with a syringe pump or volumetric pump. Because of its vasoconstrictive effect, phenylephrine can cause severe necrosis if it infiltrates the surrounding tissues. Because of this, it should be given through a central line if at all possible. Damage may be prevented or mitigated by infiltrating the tissue with the alpha blocker phentolamine by subcutaneous injection.Phenylephrine hydrochloride at 0.25% is used as a vasoconstrictor in some suppository formulations.Recently, Phenylephrine has been used to treat conditions of orthostatic intolerance such as postural orthostatic tachycardia syndrome - where by activation of venous alpha 1 adrenoreceptors increases venous return and stroke volume which improves symptoms. Priapism Phenylephrine is used to treat priapism. It is diluted with normal saline and injected directly into the corpora cavernosa. The mechanism of action is to cause constriction of the blood vessels entering into the penis, thus causing decreased blood flow and relieving the priapism. An injection is given every 3–5 minutes. If priapism is not resolved in one hour, another form of therapy is considered. Side effects Phenylephrine may cause side effects such as headache, reflex bradycardia, excitability, restlessness and cardiac arrhythmias. Phenylephrine is not suggested for use in people with hypertension. Heart The primary side effect of phenylephrine is high blood pressure. People with high blood pressure are typically advised to avoid products containing it. Because this medication is a sympathomimetic amine without beta-adrenergic activity, it does not increase contractility force and output of the cardiac muscle. It may increase blood pressure resulting in a slow heart rate through stimulation of vascular (likely carotid) baroreceptors. A common side effect during IV administration is reflex bradycardia. The low concentration eye drops do not cause blood pressure changes and the changes with the higher dose drops do not last long. Other Prostatic hyperplasia can also be worsened by use, and chronic use can lead to rebound hyperemia. People with a history of anxiety or panic disorders, or on anticonvulsant medication for epilepsy should not take this substance. The drug interaction might produce seizures. Some patients have been shown to have an upset stomach, severe abdominal cramping, and vomiting issues connected to taking this drug.Phenylephrine is pregnancy category C. Due to the lack of studies done in animals and in humans, it is not known whether there is harm to the fetus. Phenylephrine should only be given to pregnant women who have a clear need.Extended use may cause rhinitis medicamentosa, a condition of rebound nasal congestion. Interactions The increase in blood pressure effect of phenylephrine may be increased by drugs such as monoamine oxidase inhibitors, tricyclic antidepressants, and hydrocortisone. Patients taking these medications may need a lower dose of phenylephrine to achieve a similar increase in blood pressure. Drugs that may decrease the effects of phenylephrine may include calcium channel blockers, ACE inhibitors and benzodiazepines. Patients taking these medications may need a higher dose of phenylephrine to achieve a comparable increase in blood pressure. Pharmacology Pharmacodynamics Phenylephrine is a sympathomimetic drug, which means that it mimics the actions of epinephrine (commonly known as adrenaline) or norepinephrine. Phenylephrine selectively binds to alpha-1 receptors which cause blood vessels to constrict.Whereas pseudoephedrine causes both vasoconstriction and increase of mucociliary clearance through its nonspecific adrenergic activity, phenylephrines selective α-adrenergic agonism causes vasoconstriction alone, creating a difference in their methods of action. Pharmacokinetics Oral phenylephrine is extensively metabolized by monoamine oxidase, an enzyme that is present on the mitochondrial membrane of cells throughout the body. Compared to intravenous pseudoephedrine, phenylephrine has a reduced and variable bioavailability; only up to 38%. References External links "Phenylephrine". U.S. National Library of Medicine: Drug Information Portal.
Kaopectate	Kaopectate is an orally taken medication from Arcadia Consumer Healthcare for the treatment of mild diarrhea. It is also sometimes used to treat indigestion, nausea, and stomach ulcers. The active ingredients have varied over time, and are different between the United States and Canada. The original active ingredients were kaolinite and pectin. In the US, the active ingredient is now bismuth subsalicylate (the same as in Pepto-Bismol). In Switzerland, attapulgite is used. Ingredients The active ingredient in Kaopectate has changed since its original creation. Originally, kaolinite was used as the adsorbent and pectin as the emollient. Attapulgite (a type of absorbent clay) replaced the kaolinite in the 1980s, but was banned by the U.S. Food and Drug Administration in a ruling made in April 2003. As a consequence, since 2004, bismuth subsalicylate has been used as the active ingredient in U.S. marketed products. In Canada, McNeil Consumer Healthcare continues to market Kaopectate using attapulgite as the active ingredient. However, Kaopectate was recalled in July 2021 in Canada because it may contain arsenic and lead beyond acceptable limits.As of 2020, the US rights to Kaopectate are owned by Arcadia Consumer Healthcare (formerly Kramer Laboratories). Other animals The U.S. Food and Drug Administration (FDA) does not have a clear stance on the administration of Kaopectate products on animals such as dogs and cats suffering from diarrhea. However, the Journal of the American Veterinary Medical Association Journal news article noted in 2003 that the new salicylate formulation might be harmful to cats. Kaolin-pectate, the original compound, was approved by the OTA (Organic Trade Association) for use in animals being produced for food. Notes External links Official website
Mifepristone	Mifepristone, also known as RU-486, is a medication typically used in combination with misoprostol to bring about a medical abortion during pregnancy and manage early miscarriage. This combination is 97% effective during the first 63 days of pregnancy. It is also effective in the second trimester of pregnancy. Effectiveness should be verified two weeks after use. It is taken by mouth.Common side effects include abdominal pain, feeling tired, and vaginal bleeding. Serious side effects may include heavy vaginal bleeding, bacterial infection, and birth defects if the pregnancy does not end. If used, appropriate follow up care needs to be available. Mifepristone is an antiprogestogen. It works by blocking the effects of progesterone, making both the cervix and uterine vessels dilate and causing uterine contraction.Mifepristone was developed in 1980 and came into use in France in 1987. It became available in the United States in 2000. It is on the World Health Organizations List of Essential Medicines. Mifepristone was approved by Health Canada in 2015 and became available in Canada in January 2017. Cost and availability limits access in many parts of the developing world. Medical uses Abortion Mifepristone followed by a prostaglandin analog (misoprostol or gemeprost) is used for medical abortion. Medical organizations have found this combination to be safe and effective. Guidelines from the Royal College of Obstetricians and Gynaecologists describe medication abortion using mifepristone and misoprostol as effective and appropriate at any gestational age. The World Health Organization and the American Congress of Obstetricians and Gynecologists recommend mifepristone followed by misoprostol for first- and second-trimester medical abortion. Mifepristone alone is less effective, resulting in abortion within 1–2 weeks in anywhere from 54% to 92% of pregnancies, according to review of 13 studies. Cushings syndrome Mifepristone is used for the medical treatment of high blood sugar caused by high cortisol levels in the blood (hypercortisolism) in adults with endogenous Cushings syndrome who also have type 2 diabetes mellitus or glucose intolerance and have failed surgery or cannot have surgery. Other Mifepristone at low doses has been used for emergency contraception. It may also be used together with misoprostol for early pregnancy loss. Mifepristone has also been used to treat symptomatic leiomyoma (uterine fibroids) and endometriosis. Side effects Serious complications with mifepristone are rare with about 0.04%–0.9% requiring hospitalization and 0.05% requiring blood transfusion.Nearly all women using the mifepristone/misoprostol regimen experienced abdominal pain, uterine cramping, and vaginal bleeding or spotting for an average of 9–16 days. For most women, the most severe cramps after use of misoprostol last for less than 6 hours and can generally be managed with ibuprofen. Up to 8% of women experienced some type of bleeding for 30 days or more. Other less common side effects included nausea, vomiting, diarrhea, dizziness, fatigue, and fever. Pelvic inflammatory disease is a very rare but serious complication. Excessive bleeding and incomplete termination of a pregnancy require further intervention by a doctor (such as a repeat dose of misoprostol or a vacuum aspiration). Mifepristone is contraindicated in the presence of adrenal failure, long-term oral corticosteroid therapy (although inhaled and topical steroids are fine), hemorrhagic disorders, inherited porphyria, and hemophilia or anticoagulant use. Women with an intrauterine device in their uterus should remove the IUD prior to medication abortion to avoid unnecessary cramping. Mifepristone is not effective in treating ectopic pregnancy. A postmarketing summary found, of about 1.52 million women who had received mifepristone until April 2011 in the United States, 14 were reported to have died after application. Eight of these cases were associated with sepsis; the other six had various causes such as drug abuse and suspected murder. Other incidents reported to the FDA included 612 nonlethal hospitalizations, 339 blood transfusions, 48 severe infections, and 2,207 (0.15%) adverse events altogether. Cancer No long-term studies to evaluate the carcinogenic potential of mifepristone have been performed. This is in accord with ICH guidelines, which do not require carcinogenicity testing in nongenotoxic drugs intended for administration for less than six months. Pregnancy Mifepristone alone results in abortion within 1–2 weeks in 54% to 92% of pregnancies. The effectiveness increases to greater than 90% if misoprostol is given after the mifepristone. There is no evidence that the effects of mifepristone can be reversed, although some anti-abortion groups claim that it can be reversed by giving progesterone. Researchers in the United States initiated a trial of the so-called "reversal" regimen in 2019, but stopped prematurely due to serious safety concerns about using mifepristone without follow-up misoprostol. Giving progesterone has not been shown to halt medication abortion, and not completing the combination regimen of mifepristone and misoprostol may cause serious bleeding.In those who continue pregnancy after use of mifepristone together with misoprostol for termination, birth defects may occur. Exposure to a single large dose of mifepristone in newborn rats was not associated with any reproductive problems, although chronic low-dose exposure of newborn rats to mifepristone was associated with structural and functional reproductive abnormalities. Studies in mice, rats, and rabbits revealed developmental abnormalities for rabbits, but not rats or mice. Pharmacology Pharmacodynamics Mifepristone is a steroidal antiprogestogen (IC50 = 0.025 nM for the PR), as well as an antiglucocorticoid (IC50 = 2.2 nM for the GR) and antiandrogen (IC50 = 10 nM for the AR) to a much lesser extent. It antagonizes cortisol action competitively at the receptor level.In the presence of progesterone, mifepristone acts as a competitive progesterone receptor antagonist (in the absence of progesterone, mifepristone acts as a partial agonist). Mifepristone is a 19-nor steroid with a bulky p-(dimethylamino) phenyl substituent above the plane of the molecule at the 11β-position responsible for inducing or stabilizing an inactive receptor conformation and a hydrophobic 1-propynyl substituent below the plane of the molecule at the 17α-position that increases its progesterone receptor binding affinity.In addition to being an antiprogestogen, mifepristone is also an antiglucocorticoid and a weak antiandrogen. Mifepristones relative binding affinity at the progesterone receptor is more than twice that of progesterone, its relative binding affinity at the glucocorticoid receptor is more than three times that of dexamethasone and more than ten times that of cortisol. Its relative binding affinity at the androgen receptor is less than one-third that of testosterone, and it does not bind to the estrogen receptor or the mineralocorticoid receptor.Mifepristone as a regular contraceptive at 2 mg daily prevents ovulation (1 mg daily does not). A single preovulatory 10-mg dose of mifepristone delays ovulation by three to four days and is as effective an emergency contraceptive as a single 1.5-mg dose of the progestin levonorgestrel.In women, mifepristone at doses greater or equal to 1 mg/kg antagonizes the endometrial and myometrial effects of progesterone. In humans, an antiglucocorticoid effect of mifepristone is manifested at doses greater or equal to 4.5 mg/kg by a compensatory increase in ACTH and cortisol. In animals, a weak antiandrogenic effect is seen with prolonged administration of very high doses of 10 to 100 mg/kg.In medication abortion regimens, mifepristone blockade of progesterone receptors directly causes endometrial decidual degeneration, cervical softening and dilatation, release of endogenous prostaglandins, and an increase in the sensitivity of the myometrium to the contractile effects of prostaglandins. Mifepristone-induced decidual breakdown indirectly leads to trophoblast detachment, resulting in decreased syncytiotrophoblast production of hCG, which in turn causes decreased production of progesterone by the corpus luteum (pregnancy is dependent on progesterone production by the corpus luteum through the first nine weeks of gestation—until placental progesterone production has increased enough to take the place of corpus luteum progesterone production). When followed sequentially by a prostaglandin, mifepristone 200 mg is (100 mg may be, but 50 mg is not) as effective as 600 mg in producing a medical abortion.Contragestion is a term promoted by Étienne-Émile Baulieu in the context of his advocacy of mifepristone, defining it as inclusive of some hypothesized mechanisms of action of some contraceptives and those of mifepristone to induce abortion. Baulieus definition of a contragestive included any birth control method that could possibly act after fertilization and before nine-weeks gestational age. Pharmacokinetics The elimination half-life is complex; according to the label: "After a distribution phase, elimination is at first slow, the concentration decreasing by a half between about 12 and 72 hours, and then more rapid, giving an elimination half-life of 18 hours. With radio receptor assay techniques, the terminal half-life is of up to 90 hours, including all metabolites of mifepristone able to bind to progesterone receptors." Metapristone is the major metabolite of mifepristone. Chemistry Mifepristone, also known as 11β-(4-(dimethylamino)phenyl)-17α-(1-propynyl)estra-4,9-dien-17β-ol-3-one, is a synthetic estrane steroid and a derivative of steroid hormones like progesterone, cortisol, and testosterone. It has substitutions at the C11β and C17α positions and double bonds at the C4(5) and C9(10) positions. History 1980–1987 In April 1980, as part of a formal research project at the French pharmaceutical company Roussel-Uclaf for the development of glucocorticoid receptor antagonists, endocrinologist Étienne-Émile Baulieu and chemist Georges Teutsch synthesized mifepristone (RU-38486, the 38,486th compound synthesized by Roussel-Uclaf from 1949 to 1980; shortened to RU-486), which was discovered to also be a progesterone receptor antagonist. In October 1981, Étienne-Émile Baulieu, a consultant to Roussel-Uclaf, arranged tests of its use for medical abortion in 11 women in Switzerland by gynecologist Walter Herrmann at the University of Genevas Cantonal Hospital, with successful results announced on 19 April 1982. On 9 October 1987, following worldwide clinical trials in 20,000 women of mifepristone with a prostaglandin analogue (initially sulprostone or gemeprost, later misoprostol) for medical abortion, Roussel-Uclaf sought approval in France for their use for medical abortion, with approval announced on 23 September 1988. 1988–1990 On 21 October 1988, in response to antiabortion protests and concerns of majority (54.5%) owner Hoechst AG of Germany, Roussel-Uclafs executives and board of directors voted 16 to 4 to stop distribution of mifepristone, which they announced on 26 October 1988. Two days later, the French government ordered Roussel-Uclaf to distribute mifepristone in the interests of public health. French Health Minister Claude Évin explained: "I could not permit the abortion debate to deprive women of a product that represents medical progress. From the moment Government approval for the drug was granted, RU-486 became the moral property of women, not just the property of a drug company." Following use by 34,000 women in France from April 1988 to February 1990 of mifepristone distributed free of charge, Roussel-Uclaf began selling Mifegyne (mifepristone) to hospitals in France in February 1990 at a price (negotiated with the French government) of US$48 (equivalent to $99.56 in 2021) per 600-mg dose.Aside from "did not want to get in the middle of the national battle over abortion" in the United States, Hoechst had another reason cited by The New York Post: "During World War II, Hoechst was called I.G. Farben, the firm that manufactured" the poison gas that killed so many in the concentration camps. 1991–1996 Mifegyne was subsequently approved in Great Britain on 1 July 1991, and in Sweden in September 1992, but until his retirement in late April 1994, Hoechst AG chairman Wolfgang Hilger, a devout Roman Catholic, blocked any further expansion in availability. On 16 May 1994, Roussel-Uclaf announced it was donating without remuneration all rights for medical uses of mifepristone in the United States to the Population Council, which subsequently licensed mifepristone to Danco Laboratories, a new single-product company immune to antiabortion boycotts, which won FDA approval as Mifeprex on 28 September 2000. 1997–1999 On 8 April 1997, after buying the remaining 43.5% of Roussel-Uclaf stock in early 1997, Hoechst AG (US$30 (equivalent to $51.83 in 2021) billion annual revenue) announced the end of its manufacture and sale of Mifegyne (US$3.44 (equivalent to $5.94 in 2021) million annual revenue) and the transfer of all rights for medical uses of mifepristone outside of the United States to Exelgyn S.A., a new single-product company immune to antiabortion boycotts, whose CEO was former Roussel-Uclaf CEO Édouard Sakiz. In 1999, Exelgyn won approval of Mifegyne in 11 additional countries, and in 28 more countries over the following decade. Society and culture Mifepristone is on the World Health Organizations List of Essential Medicines. Since 2019 it has been included on the core list, with misoprostol, with a special note "where permitted under national law and where culturally acceptable". Frequency of use United States Medication abortions voluntarily reported by 33 U.S. states to the Centers for Disease Control and Prevention (CDC) have increased as a percentage of total abortions every year since the approval of mifepristone: 1.0% in 2000, 2.9% in 2001, 5.2% in 2002, 7.9% in 2003, 9.3% in 2004, 9.9% in 2005, 10.6% in 2006, and 13.1% in 2007 (20.3% of those at less than 9 weeks gestation).A Guttmacher Institute survey of abortion providers estimated that medication abortions accounted for 17% of all abortions and slightly over 25% of abortions before 9 weeks gestation in the United States in 2008 (94% of nonhospital medication abortions used mifepristone and misoprostol, 6% used methotrexate and misoprostol). Medication abortions accounted for 32% of first trimester abortions at Planned Parenthood clinics in the United States in 2008. Considering abortions performed in non-hospital facilities, medication abortions accounted for 24% in 2011 and 31% in 2014. In 2014, facilities that provided a relatively small number of abortions (fewer than 400 procedures per year) were more likely to perform them with medication. Medication abortions accounted for 39% of all U.S. abortions in 2017, and 54% in 2020. Europe In France, the percentage of medication abortions of all abortions continues to increase: 38% in 2003, 42% in 2004, 44% in 2005, 46% in 2006, 49% in 2007 (vs. 18% in 1996). In England and Wales, 52% of early abortions (less than 9 weeks gestation) in 2009 were medication-based; the percentage of all abortions that are medication-based has increased every year for the past 14 years (from 5% in 1995 to 40% in 2009) and has more than doubled in the last five years. In Scotland, 81.2% of early abortions in 2009 were medication-based (up from 55.8% in 1992 when medication abortion was introduced); the percentage of all abortions that are medication-based has increased every year for the past 17 years (from 16.4% in 1992 to 69.9% in 2009). In Sweden, 85.6% of early abortions and 73.2% of abortions before the end of the 12th week of gestation in 2009 were medication-based; 68.2% of all abortions in 2009 were medication-based. In Great Britain and Sweden, mifepristone is licensed for use with vaginal gemeprost or oral misoprostol. As of 2000, more than 620,000 women in Europe had had medication abortions using a mifepristone regimen. In Denmark, mifepristone was used in between 3,000 and 4,000 of just over 15,000 abortions in 2005. Legal status United States Mifepristone was approved for abortion in the United States by the FDA in September 2000. It is legal and available in all 50 states, Washington, D.C., Guam, and Puerto Rico. It is a prescription drug, but was not initially available to the public through pharmacies; its distribution is primarily restricted to specially qualified licensed physicians, sold by Danco Laboratories under the trade name Mifeprex. As of September 2021, in 32 states, the drug could only be provided by a licensed physician, and in 19 states, the prescribing clinician was required to be physically in the room with the patient while they are taking the drug.Roussel Uclaf did not seek U.S. approval, so in the United States legal availability was not initially possible. The United States banned importation of mifepristone for personal use in 1989, a decision supported by Roussel Uclaf. In 1994, Roussel Uclaf gave the U.S. drug rights to the Population Council in exchange for immunity from any product liability claims. The Population Council sponsored clinical trials in the United States. The drug went on approvable status from 1996. Production was intended to begin through the Danco Group in 1996, but they withdrew briefly in 1997 due to a corrupt business partner, delaying availability again.In 2016, the US Food and Drug Administration approved mifepristone, to end a pregnancy through 70 days gestation (70 days or less since the first day of a womans last menstrual period). The approved dosing regimen is 200 mg of mifepristone taken by mouth (swallowed). 24 to 48 hours after taking mifepristone, 800 mcg (micrograms) of misoprostol is taken buccally (in the cheek pouch), at a location appropriate for the patient.Mifepristone tablets have a marketing authorization in the United States for the treatment of high blood sugar caused by high cortisol levels in the blood (hypercortisolism) in adults with endogenous Cushings syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or cannot have surgery.In 2019, the first generic form of mifepristone in the United States became available, manufactured by GenBioPro.Due to the COVID-19 pandemic, safe access to mifepristone was a concern, and the American College of Obstetricians and Gynecologists among other groups filed a lawsuit to relax the FDAs rule as to allow mifepristone to be acquired from mail-order and retail pharmacies. While the Fourth Circuit had granted a preliminary injunction to allow this distribution, the Supreme Court of the United States issued a stay order in January 2021 to retain the FDAs rule pending the results of the ongoing litigation.On 16 December 2021, the FDA voluntarily adopted a new rule permanently relaxing the requirement that the pill be obtained in person, allowing it to be sent through the mail. A prescription is still required, so that a doctor can screen for risk factors that would make taking the pill unsafe for the mother. Subsection H Some drugs are approved by the FDA under subsection H, which has two subparts. The first sets forth ways to rush experimental drugs, such as aggressive HIV and cancer treatments, to market when speedy approval is deemed vital to the health of potential patients. The second part of subsection H applies to drugs that not only must meet restrictions for use due to safety requirements, but also are required to meet postmarketing surveillance to establish that the safety results shown in clinical trials are seconded by use in a much wider population. Until December 2021, Mifepristone was approved under the second part of subsection H. The result is that women could not pick the drug up at a pharmacy, but were required to receive it directly from a doctor. Due to the possibility of adverse reactions such as excessive bleeding, which may require a blood transfusion, and incomplete abortion, which may require surgical intervention, the drug was only considered safe if a physician who is capable of administering a blood transfusion or a surgical abortion is available to the patient in the event of such emergencies. The approval of mifepristone under subsection H included a black box warning. Europe Outside the United States, mifepristone is marketed and distributed by Exelgyn Laboratories under the tradename Mifegyne. It was approved for use in France in 1988 (initial marketing in 1989), the United Kingdom in 1991, Sweden in 1992, then Austria, Belgium, Denmark, Finland, Germany, Greece, Luxembourg, the Netherlands, Spain, and Switzerland in 1999. In 2000, it was approved in Norway, Russia and Ukraine. Serbia and Montenegro approved it in 2001, Belarus and Latvia in 2002, Estonia in 2003, Moldova in 2004, Albania and Hungary in 2005, Portugal in 2007, Romania in 2008, Bulgaria, Czech Republic and Slovenia in 2013. In Italy, clinical trials have been constrained by protocols requiring women be hospitalized for three days, but the drug was finally approved on 30 July 2009 (officialized later in the year), despite strong opposition from the Vatican. In Italy, the pill must be prescribed and used in a clinical structure and is not sold at chemists. It was approved in Hungary in 2005, but as of 2005 had not been released on the market yet, and was the target of protests. Mifepristone is currently licensed in Ireland for use of abortions up to 12 weeks since it was legalised in 2018. Mifepristone is not available in Poland, where abortion is highly restricted.Mifepristone 200 mg tablets (Mifegyne, Mifepristone Linepharma, Medabon) have marketing authorizations in the European Economic Area from the European Medicines Agency (EMA) for: Early first trimester medication abortion when followed by a prostaglandin analog (misoprostol or gemeprost) through 63 days gestational age Second trimester medication abortion when followed by a prostaglandin analog Cervical softening and dilation prior to first trimester surgical abortion Induction of labor after fetal death in utero when prostaglandin analogs and oxytocin are contraindicated Other countries Mifepristone was banned in Australia in 1996. In late 2005, a private members bill was introduced to the Australian Senate to lift the ban and transfer the power of approval to the Therapeutic Goods Administration (TGA). The move caused much debate in the Australian media and among politicians. The bill passed the Senate on 10 February 2006, and mifepristone is now legal in Australia. It is provided regularly at several specialized abortion clinics per state. Mifepristone 200 mg tablets have marketing authorizations in Australia from the TGA for early first trimester medication abortion when followed by the prostaglandin analog misoprostol through 63 days gestational age and second trimester medication abortion when followed by a prostaglandin analog.In New Zealand, pro-abortion rights doctors established an import company, Istar, and submitted a request for approval to Medsafe, the New Zealand pharmaceutical regulatory agency. After a court case brought by Right to Life New Zealand failed, use of mifepristone was permitted.Mifepristone was approved in Israel in 1999.Clinical trials of mifepristone in China began in 1985. In October 1988, China became the first country in the world to approve mifepristone. Chinese organizations tried to purchase mifepristone from Roussel Uclaf, which refused to sell it to them, so in 1992 China began its own domestic production of mifepristone. In 2000, the cost of medication abortion with mifepristone was higher than surgical abortion and the percentage of medication abortions varied greatly, ranging from 30% to 70% in cities to being almost nonexistent in rural areas. A report from the United States Embassy in Beijing in 2000 said mifepristone had been widely used in Chinese cities for about two years, and that according to press reports, a black market had developed with many women starting to buy it illegally (without a prescription) from private clinics and drugstores for about US$15 (equivalent to $23.6 in 2021), causing Chinese authorities to worry about medical complications from use without physician supervision.In 2001, mifepristone was approved in Taiwan. Vietnam included mifepristone in the National Reproductive Health program in 2002.Mifepristone is approved in only one sub-Saharan African country—South Africa, where it was approved in 2001. It is also approved in one north African country—Tunisia, also in 2001.Mifepristone was approved for use in India in 2002, where medication abortion is referred to as "medical termination of pregnancy". It is only available under medical supervision, not by prescription, due to adverse reactions such as excessive bleeding, and criminal penalties are given for buying or selling it on the black market or over-the-counter at pharmacies.medication abortion used to be available in Canada but on a limited basis using methotrexate and misoprostol. Clinical trials were done in 2000 in various Canadian cities comparing methotrexate to mifepristone, after approbation by the federal government. While both drugs had overall similar results, mifepristone was found to act faster.
Mifepristone	Health Canada gave approval to mifepristone in July 2015. Initially, its use was limited to seven weeks into a pregnancy, but this was changed to nine weeks in 2017. The previous requirement of written consent from the woman was also ended at the same time. It can be dispensed directly to a patient by a pharmacist or a prescribing health professional. Women are required to have an ultrasound to ensure the pregnancy is not ectopic.Mifepristone was registered for use in Azerbaijan, Georgia, and Uzbekistan in 2002, in Guyana and Moldova in 2004, in Mongolia in 2005, and in Armenia in 2007.Low dose mifepristone tablets (Bi Yun, Fu Nai Er, Hou Ding Nuo, Hua Dian, Si Mi An) for emergency contraception are available directly from a pharmacist without a prescription and with a prescription in China.Low dose mifepristone tablets for emergency contraception are available by prescription in Armenia (Gynepriston), Russia (Agesta, Gynepriston, Mifepristone 72, Negele), Ukraine (Gynepriston), and Vietnam (Mifestad 10, Ciel EC). Controversy Many anti-abortion groups in the United States actively campaigned against the approval of mifepristone and continue to actively campaign for its withdrawal. They cite either ethical issues with abortion or safety concerns regarding the drug and the adverse reactions associated with it. In March 2022, during a debate in the Kentucky House of Representatives about anti-abortion legislation, Republican representative Danny Bentley made several false claims, including the assertion that mifepristone had originally been called Zyklon B and had been developed by the Nazis during World War Two. After several Jewish advocacy groups including the American Jewish Committee complained about Bentleys comments, he later apologized for any harm he had caused, stating that he "clearly should have been more sensitive with (his) comments", but failed to correct the false statement regarding the development of the drug.Religious and anti-abortion groups outside the United States have also protested mifepristone, especially in Germany and Australia. Research The original target for the research group was the discovery and development of compounds with antiglucocorticoid properties. These antiglucocorticoid properties are of great interest in the treatment of severe mood disorders and psychosis, although a review of published articles was inconclusive on their efficacy, and considered the use of these drugs in mood disorders at proof of concept stage.Use of mifepristone as a cervical ripening agent has been described. The medication has been studied as an antiandrogen in the treatment of prostate cancer. Mifepristone showed no detectable anti-HIV activity in clinical trials.Mifepristone showed initial promise in psychotic major depression, a difficult-to-treat form of depression, but a phase-III clinical trial was terminated early due to lack of efficacy. It has been studied in bipolar disorder, post traumatic stress disorder, and anorexia nervosa. References External links "Mifepristone". Drug Information Portal. U.S. National Library of Medicine.
Sodium nitroprusside	Sodium nitroprusside (SNP), sold under the brand name Nitropress among others, is a medication used to lower blood pressure. This may be done if the blood pressure is very high and resulting in symptoms, in certain types of heart failure, and during surgery to decrease bleeding. It is used by continuous injection into a vein. Onset is nearly immediate and effects last for up to ten minutes. It has been known to cause reflex tachycardia. It is often used as the vasodilator of choice in acute, emergency situations. The pharmacological activation is in relation to the release of nitric oxide which occurs from sodium nitroprusside which serves to activate Sodium Guanylyl Cyclase. Common side effects include low blood pressure and cyanide toxicity. Other serious side effects include methemoglobinemia. It is not generally recommended during pregnancy due to concerns of side effects. High doses are not recommended for more than ten minutes. It works by increasing nitric oxide levels in the blood, which increases cGMP levels in cells, and causes dilation of blood vessels.Sodium nitroprusside was discovered as early as 1850 and found to be useful in medicine in 1928. It is on the World Health Organizations List of Essential Medicines. Sodium nitroprusside is light sensitive, so it needs to be shielded from light to prevent degradation. Medical use Sodium nitroprusside is intravenously infused in cases of acute hypertensive crises. Its effects are usually seen within a few minutes.Nitric oxide reduces both total peripheral resistance and venous return, thus decreasing both preload and afterload. So, it can be used in severe congestive heart failure where this combination of effects can act to increase cardiac output. In situations where cardiac output is normal, the effect is to reduce blood pressure. It is sometimes also used to induce hypotension (to reduce bleeding) for surgical procedures (for which it is also FDA, TGA, and MHRA labelled).The medication is extremely beneficial for use in medical patients because the effects of the medication will directly stop the second that it stops being infused. This is due to the metabolism of the drug, and the rapid inactivation to thiocyanin once conversion of the drug stops. This compound has also been used as a treatment for aortic valve stenosis, oesophageal varices, myocardial infarction, pulmonary hypertension, respiratory distress syndrome in the newborn, shock, and ergot toxicity. Adverse effects Adverse effects by incidence and severityCommon Unknown frequency Serious Ileus Reduced platelet aggregation Haemorrhage Increased intracranial pressure Metabolic acidosis Methaemoglobinaemia Cyanide poisoning Thiocyanate toxicity Contraindications Sodium nitroprusside should not be used for compensatory hypertension (e.g. due to an arteriovenous stent or coarctation of the aorta). It should not be used in patients with inadequate cerebral circulation or in patients who are near death. It should not be used in patients with vitamin B12 deficiency, anaemia, severe renal disease, or hypovolaemia. Patients with conditions associated with a higher cyanide/thiocyanate ratio (e.g. congenital (Lebers) optic atrophy, tobacco amblyopia) should only be treated with sodium nitroprusside with great caution. Its use in patients with acute congestive heart failure associated with reduced peripheral resistance is also not recommended. Its use in hepatically impaired individuals is also not recommended, as is its use in cases of pre-existing hypothyroidism.Its use in pregnant women is advised against, although the available evidence suggests it may be safe, provided maternal pH and cyanide levels are closely monitored. Some evidence suggests sodium nitroprusside use in critically ill children may be safe, even without monitoring of cyanide level. Interactions The only known drug interactions are pharmacodynamic in nature, that is it is possible for other antihypertensive drugs to reduce the threshold for dangerous hypotensive effects to be seen. Overdose Due to its cyanogenic nature, overdose may be particularly dangerous. Treatment of sodium nitroprusside overdose includes the following: Discontinuing sodium nitroprusside administration Buffering the cyanide by using sodium nitrite to convert haemoglobin to methaemoglobin as much as the patient can safely tolerate Infusing sodium thiosulfate to convert the cyanide to thiocyanate.Haemodialysis is ineffective for removing cyanide from the body but it can be used to remove most of the thiocyanate produced from the above procedure. Toxicology The cyanide can be detoxified by reaction with a sulfur-donor such as thiosulfate, catalysed by the enzyme rhodanese. In the absence of sufficient thiosulfate, cyanide ions can quickly reach toxic levels. Hydroxocobalamin can be administered to reduce the risk of thiocyanate toxicity induced by nitroprusside. Mechanism of action As a result of its breakdown to nitric oxide (NO), sodium nitroprusside has potent vasodilating effects on arterioles and venules (arterial more than venous), whereas other nitrates exhibit more selectivity for veins (e.g. nitroglycerin).Sodium nitroprusside breaks down in circulation to release nitric oxide (NO). It does this by binding to oxyhaemoglobin to release cyanide, methaemoglobin and nitric oxide. NO activates guanylate cyclase in vascular smooth muscle and increases intracellular production of cGMP. cGMP activates protein kinase G which activates phosphatases which inactivate myosin light chains. Myosin light chains are involved in smooth muscle contraction. The result is vascular smooth muscle relaxation, which allow vessels to dilate. This mechanism is similar to that of phosphodiesterase 5 (PDE5) inhibitors such as sildenafil (Viagra) and tadalafil (Cialis), which elevate cGMP concentration by inhibiting its degradation by PDE5.A role for NO in various common psychiatric disorders including schizophrenia, bipolar disorder and major depressive disorder has been proposed and supported by several clinical findings. These findings may also implicate the potential of drugs that alter NO signalling such as SNP in their treatment. Such a role is also supported by the findings of the recent SNP clinical trial. Structure and properties Nitroprusside is an inorganic compound with the formula Na2[Fe(CN)5NO], usually encountered as the dihydrate, Na2[Fe(CN)5NO]·2H2O. This red-colored sodium salt dissolves in water or ethanol to give solutions containing the free complex dianion [Fe(CN)5NO]2−. Nitroprusside is a complex anion that features an octahedral iron(II) centre surrounded by five tightly bound cyanide ligands and one linear nitric oxide ligand (Fe-N-O angle = 176.2 °). The anion possesses idealized C4vsymmetry. Due to the linear Fe-N-O angle, the relatively short N-O distance of 113 pm and the relatively high stretching frequency of 1947 cm−1, the complex is formulated as containing an NO+ ligand. Consequently, iron is assigned an oxidation state of 2+. The iron center has a diamagnetic low-spin d6 electron configuration, although a paramagnetic long-lived metastable state has been observed by EPR spectroscopy.The chemical reactions of sodium nitroprusside are mainly associated with the NO ligand. For example, addition of S2− ion to [Fe(CN)5(NO)]2− produces the violet colour[Fe(CN)5(NOS)]4− ion, which is the basis for a sensitive test for S2− ions. An analogous reaction also exists with OH− ions, giving [Fe(CN)5(NO2)]4−. Roussins red salt (K2[Fe2S2(NO)4]) and Roussins black salt (NaFe4S3(NO)7) are related iron nitrosyl complexes. The former was first prepared by treating nitroprusside with sulfur. Preparation Sodium nitroprusside can be synthesized by digesting a solution of potassium ferrocyanide in water with nitric acid, followed by neutralization with sodium carbonate: K 4 [ Fe ( CN ) 6 ] + 6 HNO 3 ⟶ H 2 [ Fe ( CN ) 5 ( NO ) ] + CO 2 + NH 4 NO 3 + 4 KNO 3 {\textstyle {\ce {K4[Fe(CN)6] + 6 HNO3 -> H2[Fe(CN)5(NO)] + CO2 + NH4NO3 + 4 KNO3}}} H 2 [ Fe ( CN ) 5 NO ] + Na 2 CO 3 ⟶ Na 2 [ Fe ( CN ) 5 ( NO ) ] + CO 2 + H 2 O {\textstyle {\ce {H2[Fe(CN)5NO] + Na2CO3 -> Na2[Fe(CN)5(NO)] + CO2 + H2O}}} Alternatively, the nitrosyl ligand can be introduced using nitrite: [ Fe ( CN ) 6 ] 4 − + H 2 O + NO 2 − ⟶ [ Fe ( CN ) 5 ( NO ) ] 2 − + CN − + 2 OH − {\textstyle {\ce {[Fe(CN)6]^4- + H2O + NO_2^- -> [Fe(CN)5(NO)]^2- + CN- + 2OH-}}} Other uses Sodium nitroprusside is often used as a reference compound for the calibration of Mössbauer spectrometers. Sodium nitroprusside crystals are also of interest for optical storage. For this application, sodium nitroprusside can be reversibly promoted to a metastable excited state by blue-green light, and de-excited by heat or red light.In physiology research, sodium nitroprusside is frequently used to test endothelium-independent vasodilation. Iontophoresis, for example, allows local administration of the drug, preventing the systemic effects listed above but still inducing local microvascular vasodilation. Sodium nitroprusside is also used in microbiology, where it has been linked with the dispersal of Pseudomonas aeruginosa biofilms by acting as a nitric oxide donor. Analytical reagent Sodium nitroprusside is also used as an analytical reagent under the name sodium nitroferricyanide for the detection of methyl ketones, amines, and thiols. It is also used as a catalyst in the quantitative determination of Ammonia in water samples via the Phenate Method. Ketones The nitroprusside reaction is used for the identification of ketones in urine testing. Sodium nitroprusside was found to give a reaction with acetone or creatine under basic conditions in 1882. Rothera refined this method by the use of ammonia in place of sodium or potassium hydroxide. The reaction was now specific for methyl ketones. Addition of ammonium salts (e.g. ammonium sulfate) improved the sensitivity of the test, too.In this test, known as Rotheras test, methyl ketones (CH3C(=O)-) under alkaline conditions give bright red coloration (see also iodoform test). Rotheras test was initially applied to detecting ketonuria (a symptom of diabetes) in urine samples. This reaction is now exploited in the form of urine test strips (e.g. "Ketostix"). Thiols and cysteine The nitroprusside reaction is a chemical test used to detect the presence of thiol groups of cysteine in proteins. Proteins with the free thiol group give a red colour when added to a solution of sodium nitroprusside in aqueous ammonia. Some proteins test positive when denatured, indicating that thiol groups are liberated.Sodium nitroprusside is used in a separate urinalysis test known as the cyanide nitroprusside test or Brands test. In this test, sodium cyanide is added first to urine and let stand for about 10 minutes. In this time, disulfide bonds will be broken by the released cyanide. The destruction of disulfide bonds liberates cysteine from cystine as well as homocysteine from homocystine. Next, sodium nitroprusside is added to the solution and it reacts with the newly freed sulfhydryl groups. The test will turn a red/purple colour if the test is positive, indicating significant amounts of amino acids were in the urine (aminoaciduria). Cysteine, cystine, homocysteine, and homocystine all react when present in the urine when this test is performed. This test can indicate inborn errors of amino acid transporters such as cystinuria, which results from pathology in the transport of dibasic amino acids. Amines Sodium nitroprusside is also used to detect amines, including those in illicit drugs. This compound is thus used as a stain to indicate amines in thin layer chromatography. Sodium nitroprusside is similarly used as a presumptive test for the presence of alkaloids (amine-containing natural products) common in illicit substances. The test, called Simons test, is performed by adding 1 volume of a solution of sodium nitroprusside and acetaldehyde in deionized water to a suspected drug, followed by the addition of 2 volumes of an aqueous sodium carbonate solution. The test turns blue for some secondary amines. The most common secondary amines encountered in forensic chemistry include 3,4-methylenedioxymethamphetamine (MDMA, the main component in Ecstasy) and phenethylamines such as methamphetamine. Sodium nitroprusside is also useful in the identification the mercaptans (thiol groups) in the nitroprusside reaction. History Sodium nitroprusside is primarily used as a vasodilator. It was first used in human medicine in 1928. By 1955, data on its safety during short-term use in people with severe hypertension had become available. Despite this, due to difficulties in its chemical preparation, it was not finally approved by the US FDA until 1974 for the treatment of severe hypertension. By 1993, its popularity had grown such that total sales in the US had totalled US$2 million. == References ==
Acamprosate	Acamprosate, sold under the brand name Campral, is a medication used along with counselling to treat alcohol use disorder.Acamprosate is thought to stabilize chemical signaling in the brain that would otherwise be disrupted by alcohol withdrawal. When used alone, acamprosate is not an effective therapy for alcohol use disorder in most individuals; studies have found that acamprosate works best when used in combination with psychosocial support since the drug facilitates a reduction in alcohol consumption as well as full abstinence.Serious side effects include allergic reactions, abnormal heart rhythms, and low or high blood pressure, while less serious side effects include headaches, insomnia, and impotence. Diarrhea is the most common side-effect. Acamprosate should not be taken by people with kidney problems or allergies to the drug.Until it became generic in the United States, Campral was manufactured and marketed in the United States by Forest Laboratories, while Merck KGaA markets it outside the US. Medical uses Acamprosate is useful when used along with counseling in the treatment of alcohol use disorder. Over three to twelve months it increases the number of people who do not drink at all and the number of days without alcohol. It appears to work as well as naltrexone for maintenance of abstinence from alcohol, however naltrexone works slightly better for reducing alcohol cravings and heavy drinking, and acamprosate tends to work more poorly outside of Europe where treatment services are less robust. Contraindications Acamprosate is primarily removed by the kidneys and should not be given to people with severely impaired kidneys (creatinine clearance less than 30 mL/min). A dose reduction is suggested in those with moderately impaired kidneys (creatinine clearance between 30 mL/min and 50 mL/min). It is also contraindicated in those who have a strong allergic reaction to acamprosate calcium or any of its components. Adverse effects The US label carries warnings about increases of suicidal behavior, major depressive disorder, and kidney failure.Adverse effects that caused people to stop taking the drug in clinical trials included diarrhea, nausea, depression, and anxiety.Potential adverse effects include headache, stomach pain, back pain, muscle pain, joint pain, chest pain, infections, flu-like symptoms, chills, heart palpitations, high blood pressure, fainting, vomiting, upset stomach, constipation, increased appetite, weight gain, edema, sleepiness, decreased sex drive, impotence, forgetfulness, abnormal thinking, abnormal vision, distorted sense of taste, tremors, runny nose, coughing, difficulty breathing, sore throat, bronchitis, and rashes. Pharmacology Pharmacodynamics The pharmacodynamics of acamprosate are complex and not fully understood; however, it is believed to act as an NMDA receptor antagonist and positive allosteric modulator of GABAA receptors.Its activity on those receptors is indirect, unlike that of most other agents used in this context. An inhibition of the GABA-B system is believed to cause indirect enhancement of GABAA receptors. The effects on the NMDA complex are dose-dependent; the product appears to enhance receptor activation at low concentrations, while inhibiting it when consumed in higher amounts, which counters the excessive activation of NMDA receptors in the context of alcohol withdrawal.The product also increases the endogenous production of taurine.Ethanol and benzodiazepines act on the central nervous system by binding to the GABAA receptor, increasing the effects of the inhibitory neurotransmitter GABA (i.e., they act as positive allosteric modulators at these receptors). In alcohol use disorder, one of the main mechanisms of tolerance is attributed to GABAA receptors becoming downregulated (i.e. these receptors become less sensitive to GABA). When alcohol is no longer consumed, these down-regulated GABAA receptor complexes are so insensitive to GABA that the typical amount of GABA produced has little effect, leading to physical withdrawal symptoms; since GABA normally inhibits neural firing, GABAA receptor desensitization results in unopposed excitatory neurotransmission (i.e., fewer inhibitory postsynaptic potentials occur through GABAA receptors), leading to neuronal over-excitation (i.e., more action potentials in the postsynaptic neuron). One of acamprosates mechanisms of action is the enhancement of GABA signaling at GABAA receptors via positive allosteric receptor modulation. It has been purported to open the chloride ion channel in a novel way as it does not require GABA as a cofactor, making it less liable for dependence than benzodiazepines. Acamprosate has been successfully used to control tinnitus, hyperacusis, ear pain, and inner ear pressure during alcohol use due to spasms of the tensor tympani muscle.In addition, alcohol also inhibits the activity of N-methyl-D-aspartate receptors (NMDARs). Chronic alcohol consumption leads to the overproduction (upregulation) of these receptors. Thereafter, sudden alcohol abstinence causes the excessive numbers of NMDARs to be more active than normal and to contribute to the symptoms of delirium tremens and excitotoxic neuronal death. Withdrawal from alcohol induces a surge in release of excitatory neurotransmitters like glutamate, which activates NMDARs. Acamprosate reduces this glutamate surge. The drug also protects cultured cells from excitotoxicity induced by ethanol withdrawal and from glutamate exposure combined with ethanol withdrawal.The substance also helps re-establish a standard sleep architecture by normalizing stage 3 and REM sleep phases, which is believed to be an important aspect of its pharmacological activity. Pharmacokinetics Acamprosate is not metabolized by the human body. Acamprosates absolute bioavailability from oral administration is approximately 11%, and its bioavailability is decreased when taken with food. Following administration and absorption of acamprosate, it is excreted unchanged (i.e., as acamprosate) via the kidneys.Its absorption and elimination are very slow, with a Tmax of 6 hours and an elimination half life of over 30 hours. History Acamprosate was developed by Lipha, a subsidiary of Merck KGaA. and was approved for marketing in Europe in 1989.In October 2001 Forest Laboratories acquired the rights to market the drug in the US.It was approved by the FDA in July 2004.The first generic versions of acamprosate were launched in the US in 2013.As of 2015 acamprosate was in development by Confluence Pharmaceuticals as a potential treatment for fragile X syndrome. The drug was granted orphan status for this use by the FDA in 2013 and by the EMA in 2014. Society and culture "Acamprosate" is the INN and BAN for this substance. "Acamprosate calcium" is the USAN and JAN. It is also technically known as N-acetylhomotaurine or as calcium acetylhomotaurinate. It is sold under the brand name Campral. Research In addition to its apparent ability to help patients refrain from drinking, some evidence suggests that acamprosate is neuroprotective (that is, it protects neurons from damage and death caused by the effects of alcohol withdrawal, and possibly other causes of neurotoxicity). See also Homotaurine (tramiprosate) List of investigational anxiolytics List of investigational antidepressants == References ==
Gonadotropin preparations	Gonadotropin preparations are drugs that mimic the physiological effects of gonadotropins, used therapeutically mainly as fertility medication for ovarian hyperstimulation and ovulation induction. For example, the so-called menotropins consist of LH and FSH extracted from human urine from menopausal women. There are also recombinant variants. FSH and LH preparations hMG (human Menopausal Gonadotrophins), FSH and LH prepared from human urine collected from postmenopausal women. First extracted in 1953. Injected intra-muscularily (IM) or subcutaneously (SC). Generic menotropins for injections, USPBrands Menopur, 5 mL vials containing 75 IU FSH and 75 IU LH. Repronex, vials containing either 75 IU FSH and 75 IU LH, or 150 IU FSH and 150 IU LH.The more common side effects of preparations containing FSH and LH are: Mild bloating Pain, swelling, or irritation injection site Rash at injection site or other part of body Stomach pain or pelvic pain FSH preparations Preparations of follicle-stimulating hormone (FSH) mainly include those derived from the urine of menopausal women, as well as recombinant preparations. The recombinant preparations are more pure and more easily administered, but they are more expensive. The urinary preparations are equally effective and less expensive, but are not as convenient to administer as they are available in vials versus injection pens. One study reported that users of the purified urinary FSH preparation Bravelle experienced less injection site pain compared to the recombinant preparation Follistim. Urinary preparations Purified urinary FSH (75 IU FSH and ≤ 2 IU of LH)Generic urofollitropin for injection, purified.Brands Bravelle, U.S., (≤ 2 IU LH) Metrodin, U.S. and Canada, (≤ 1 IU LH) Fertinorm Hp, (Canada)Highly purified urinary FSH (75 IU FSH and ≤ 0.1 IU LH/1000 IU FSH)Generic urofollitropin for injection, (highly) purified.Dosage typically 75 - 300, but as high as 600 IU / dayBrands Fertinex (≤ 0.1 IU LH/1000 IU FSH) Recombinant preparations Follitropin alfaGeneric Follitropin alfa injectionBrandsGonal-f Cinnal-f Fertilex Ovaleap BemfolaFollitropin betaGeneric follitropin beta injectionBrands Follistim AQ PuregonFollitropin deltaGeneric follitropin delta injectionBrands RekovelleThe package insert for Gonal-f states that based on physio-chemical tests and bioassays that follitropin beta and follitropin alfa are indistinguishable. Two studies showed no difference. However, a more recent study showed there may be a slight clinical difference, with the alfa form tending towards a higher pregnancy rate and the beta form tending towards a lower pregnancy rate, but with significantly higher estradiol (E2) levels.The package insert for Puregon states that structural analysis shows that the amino acid sequence of follitropin beta is identical to that of natural human follicle stimulating hormone (hFSH). Further, the ogliosaccharide side chains are very similar, but not completely identical to that of natural hFSH. However, these small differences do not affect the bioactivity compared to natural hFSH. Gonal-f was approved for medical use in the European Union in October 1995.Puregon was approved for medical use in the European Union in February 1996.Rekovelle was approved for medical use in the European Union in December 2016. Biosimilars Ovaleap was approved for medical use in the European Union in September 2013. It was approved for medical use in Australia in March 2021.Bemfola was approved for medical use in the European Union in March 2014. Side effects of FSH preparations Side effects of FSH preparations include: Local irritation at the injection site Feeling of fullness, bloating, and tenderness in the lower abdomen due to increasing size of the ovaries. Mood swings Fatigue FSH analogues Corifollitropin alfa Merck received approval on February 15, 2010, from the European Commission for ELONVA (corifollitropin alfa) a long lasting single injection fusion protein lacking LH activity. Only one injection is required for the first seven days, replacing the first seven daily injections of conventional FSH. Initial results demonstrates similar pregnancy rates as daily recombinant FSH injections. LH (Luteinizing hormone) preparations Prepared from recombinant DNA. Generic lutropin alfa for injection Brands Luveris hCG preparations Human chorionic gonadotropin (hCG) can be recovered from the urine of pregnant women or be produced from recombinant DNA. It acts similarly to LH, but the larger supply makes it less costly; it also has a longer half-life. In veterinary medicine, equine chorionic gonadotropin (eCG) extracted from pregnant mare serum is used instead on a variety of mammals, sometimes eliciting an immune response in non-horse species.In Women: Used to induce final maturation of follicle and subsequent ovulation. Also used for luteal phase support. Typically a single injection of 10,000 international units is used to induce ovulation. In men: Used to treat select cases of Hypogonadotropic Hypogonadism in adult males. Typical dosages are 500-1000IU three times weekly, or 4,000IU three times weekly for 6–9 months until atrophy is reversed and the dose is reduced to 2,000IU three times weekly. These doses are starting guidelines for treatment, and variable depending on individual response. In off-label use, some urologists prescribe hCG in low doses in combination with Testosterone replacement to preserve fertility.In male children: Also used to treat prepubertal cryptorchidism not due to anatomical obstruction. therapy is usually administered between ages 4 and 9. Urinary preparations Derived from the urine of pregnant women. Generic (human) chorionic gonadotropin for injection, USPBrands Pregnyl (Merck/Schering-Plough) Follutein Profasi Novarel Recombinant preparations Generic choriogonadotropin alfa for injection (recombinant human Chorionic Gonadotropin, r-hCG). Brands Ovidrel == References ==
Inclisiran	Inclisiran, sold under the brand name Leqvio, is a medication for the treatment of people with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk-equivalents, and heterozygous familial hypercholesterolemia (HeFH). It is a small interfering RNA (siRNA) that acts as an inhibitor of a proprotein convertase, specifically, inhibiting translation of the protein PCSK9.Inclisiran was approved for use in the European Union in December 2020. In August 2021, it received NICE approval for use by the National Health Service in the UK. In December 2021, it was approved for medical use in the United States. Medical uses In the European Union, inclisiran is indicated in adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet in combination with a statin or statin with other lipid-lowering therapies in people unable to reach LDL-C goals with the maximum tolerated dose of a statin, or alone or in combination with other lipid-lowering therapies in people who are statin-intolerant, or for whom a statin is contraindicated.In the United States, it is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of low- density lipoprotein cholesterol (LDL-C). Discovery and mechanism of action Inclisiran is a small interfering RNA that acts as an inhibitor of a proprotein convertase, specifically, inhibiting translation of the protein termed proprotein convertase subtilisin/kexin type 9 (PCSK9). Small interfering RNA molecules (siRNAs) are designed to intervene in the pathway of RNA interference (RNAi), a naturally operating mechanism, wherein they bind to a complex within the cell termed the RNA-induced silencing complex (RISC); after binding, the RISC structure in the siRNA-RISC complex is altered, allowing it to cleave specific messenger RNA molecules (mRNAs). The siRNA-RISC complex is catalytic, and thus can cleave multiple copies of the mRNA that it targets; cleaved mRNAs are not translated into proteins, and thus the concentration of the protein targeted by the siRNA design is decreased.The proprotein convertase, PCSK9, is a liver-produced and -secreted serine protease whose binding and action on LDL receptors results in their increased lysosomal degradation in hepatocytes, a consequence of which is an increase in the level of circulating LDL cholesterol (and inhibition of which, the decrease in this level). Studies of PCSK9 genetics supported the conclusion that decreases in circulating LDL cholesterol accomplished in this way would result in "diminished cardiovascular risk... with no apparent negative health consequences", and long term administration of antibodies with short in vivo half-lives, 1-2 times a month, reduced circulating PCSK9 and LDL cholesterol levels, with the result of a "lower incidence of cardiovascular events than placebo". Together, these results contributed to the validation of PCSK9-targeting siRNAs for development as a new therapeutic for use in LDL cholesterol–lowering therapy; specifically, small interfering RNA (siRNA) molecules of appropriate sequence and structure were sought and discovered as a means of decreasing PCSK9 levels, and the development of a clinical candidate ensued thereafter. Clinical study history In 2019, The Medicines Company announced positive results from pivotal phase III study (all primary and secondary endpoints were met with efficacy consistent with Phase I and II studies). The company anticipated regulatory submissions in the U.S. in the fourth quarter of 2019, and in Europe in the first quarter of 2020. Inclisiran is being developed by The Medicines Company, a subsidiary of Novartis, which licensed the rights to inclisiran from Alnylam Pharmaceuticals.The effectiveness of inclisiran was studied in three randomized, double-blind, placebo-controlled trials that enrolled 3,457 adults with HeFH or clinical ASCVD. Enrolled participants were taking maximally tolerated statin therapy but required additional LDL-C lowering based on their risk for cardiovascular events. In all three studies, the main effectiveness outcome measure was the percent change in LDL-C from the beginning of the trial to day 510 (month 17). In each trial, participants received under-the-skin injections of either 284 mg inclisiran or a placebo on four separate days: day 1, day 90 (month 3), day 270 (month 9), and day 450 (month 15).Study 1 enrolled 1,561 adults with ASCVD. At day 510, the inclisiran group had an average LDL-C decrease of 51% whereas the placebo group had an average LDL-C increase of 1%. Study 2 enrolled 1,414 adults with ASCVD. At day 510, the inclisiran group had an average LDL-C decrease of 46% whereas the placebo group had an average LDL-C increase of 4%. Study 3 enrolled 482 adults with HeFH. At day 510, the inclisiran group had an average LDL-C decrease of 40% whereas the placebo group had an average LDL-C increase of 8%.The effect of inclisiran on cardiovascular morbidity (suffering from a disease) and mortality (death) has not been determined. References Further reading Ray KK, Landmesser U, Leiter LA, et al. (April 2017). "Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol" (PDF). N. Engl. J. Med. 376 (15): 1430–1440. doi:10.1056/NEJMoa1615758. hdl:10044/1/45416. PMID 28306389. S2CID 205101529. Ray KK, Wright RS, Kallend D, et al. (March 2020). "Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol". N. Engl. J. Med. 382 (16): 1507–1519. doi:10.1056/NEJMoa1912387. PMID 32187462. External links "Inclisiran". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03399370 for "Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol (ORION-10)" at ClinicalTrials.gov Clinical trial number NCT03400800 for "Inclisiran for Subjects With ACSVD or ACSVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol (ORION-11)" at ClinicalTrials.gov Clinical trial number NCT03397121 for "Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH) (ORION-9)" at ClinicalTrials.gov
Ocella (butterfly)	"Ocella" is also a generic brand of oral drospirenone contraceptive. Ocella is a genus of skippers in the family Hesperiidae. References Natural History Museum Lepidoptera genus database
Fluconazole	Fluconazole is an antifungal medication used for a number of fungal infections. This includes candidiasis, blastomycosis, coccidiodomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and pityriasis versicolor. It is also used to prevent candidiasis in those who are at high risk such as following organ transplantation, low birth weight babies, and those with low blood neutrophil counts. It is given either by mouth or by injection into a vein.Common side effects include vomiting, diarrhea, rash, and increased liver enzymes. Serious side effects may include liver problems, QT prolongation, and seizures. During pregnancy it may increase the risk of miscarriage while large doses may cause birth defects. Fluconazole is in the azole antifungal family of medication. It is believed to work by affecting the fungal cellular membrane.Fluconazole was patented in 1981 and came into commercial use in 1988. It is on the World Health Organizations List of Essential Medicines. Fluconazole is available as a generic medication. In 2019, it was the 133rd most commonly prescribed medication in the United States, with more than 5 million prescriptions. Medical uses Fluconazole is a first-generation triazole antifungal medication. It differs from earlier azole antifungals (such as ketoconazole) in that its structure contains a triazole ring instead of an imidazole ring. While the imidazole antifungals are mainly used topically, fluconazole and certain other triazole antifungals are preferred when systemic treatment is required because of their improved safety and predictable absorption when administered orally.Fluconazoles spectrum of activity includes most Candida species (but not Candida krusei or Candida glabrata), Cryptococcus neoformans, some dimorphic fungi, and dermatophytes, among others. Common uses include: The treatment of non-systemic Candida infections of the vagina ("yeast infections"), throat, and mouth. Certain systemic Candida infections in people with healthy immune systems, including infections of the bloodstream, kidney, or joints. Other antifungals are usually preferred when the infection is in the heart or central nervous system, and for the treatment of active infections in people with weak immune systems. The prevention of Candida infections in people with weak immune systems, such as those neutropenic due to cancer chemotherapy, those with advanced HIV infections, transplant patients, and premature infants. As a second-line agent for the treatment of cryptococcal meningoencephalitis, a fungal infection of the central nervous system. Resistance Fungal resistance to drugs in the azole class tends to occur gradually over the course of prolonged drug therapy, resulting in clinical failure in immunocompromised patients (e.g., patients with advanced HIV receiving treatment for thrush or esophageal Candida infection).In C. albicans, resistance occurs by way of mutations in the ERG11 gene, which codes for 14α-demethylase. These mutations prevent the azole drug from binding, while still allowing binding of the enzymes natural substrate, lanosterol. Development of resistance to one azole in this way will confer resistance to all drugs in the class. Another resistance mechanism employed by both C. albicans and C. glabrata is increasing the rate of efflux of the azole drug from the cell, by both ATP-binding cassette and major facilitator superfamily transporters. Other gene mutations are also known to contribute to development of resistance. C. glabrata develops resistance by up regulating CDR genes, and resistance in C. krusei is mediated by reduced sensitivity of the target enzyme to inhibition by the agent.The full spectrum of fungal susceptibility and resistance to fluconazole can be found in the TOKU-Es product data sheet. According to the United States Centers for Disease Control, fluconazole resistance among Candida strains in the U.S. is about 7%. Contraindications Fluconazole is contraindicated in patients who: Drink alcohol have known hypersensitivity to other azole medicines such as ketoconazole; are taking terfenadine, if 400 mg per day multidose of fluconazole is administered; concomitant administration of fluconazole and quinidine, especially when fluconazole is administered in high dosages; take SSRIs such as fluoxetine or sertraline. Side effects Adverse drug reactions associated with fluconazole therapy include: Common (≥1% of patients): rash, headache, dizziness, nausea, vomiting, abdominal pain, diarrhea, and/or elevated liver enzymes Infrequent (0.1–1% of patients): anorexia, fatigue, constipation Rare (<0.1% of patients): oliguria, hypokalaemia, paraesthesia, seizures, alopecia, Stevens–Johnson syndrome, thrombocytopenia, other blood dyscrasias, serious hepatotoxicity including liver failure, anaphylactic/anaphylactoid reactions Very rare: prolonged QT interval, torsades de pointes FDA is now saying treatment with chronic, high doses of fluconazole during the first trimester of pregnancy may be associated with a rare and distinct set of birth defects in infants.If taken during pregnancy it may result in harm. These cases of harm, however, were only in women who took large doses for most of the first trimester.Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of fluconazole in lactating mothers is not recommended.Fluconazole therapy has been associated with QT interval prolongation, which may lead to serious cardiac arrhythmias. Thus, it is used with caution in patients with risk factors for prolonged QT interval, such as electrolyte imbalance or use of other drugs that may prolong the QT interval (particularly cisapride and pimozide).Fluconazole has also rarely been associated with severe or lethal hepatotoxicity, so liver function tests are usually performed regularly during prolonged fluconazole therapy. In addition, it is used with caution in patients with pre-existing liver disease.Some people are allergic to azoles, so those allergic to other azole drugs might be allergic to fluconazole. That is, some azole drugs have adverse side-effects. Some azole drugs may disrupt estrogen production in pregnancy, affecting pregnancy outcome. Fluconazole taken at low doses is in FDA pregnancy category C. However, high doses have been associated with a rare and distinct set of birth defects in infants. If taken at these doses, the pregnancy category is changed from category C to category D. Pregnancy category D means there is positive evidence of human fetal risk based on human data. In some cases, the potential benefits from use of the drug in pregnant women with serious or life-threatening conditions may be acceptable despite its risks. Fluconazole should not be taken during pregnancy or if one could become pregnant during treatment without first consulting a doctor. Oral fluconazole is not associated with a significantly increased risk of birth defects overall, although it does increase the odds ratio of tetralogy of Fallot, but the absolute risk is still low. Women using fluconazole during pregnancy have a 50% higher risk of spontaneous abortion.Fluconazole should not be taken with cisapride (Propulsid) due to the possibility of serious, even fatal, heart problems. In rare cases, severe allergic reactions including anaphylaxis may occur.Powder for oral suspension contains sucrose and should not be used in patients with hereditary fructose, glucose/galactose malabsorption or sucrase-isomaltase deficiency. Capsules contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption Interactions Fluconazole is an inhibitor of the human cytochrome P450 system, particularly the isozyme CYP2C19 (CYP3A4 and CYP2C9 to lesser extent) In theory, therefore, fluconazole decreases the metabolism and increases the concentration of any drug metabolised by these enzymes. In addition, its potential effect on QT interval increases the risk of cardiac arrhythmia if used concurrently with other drugs that prolong the QT interval. Berberine has been shown to exert synergistic effects with fluconazole even in drug-resistant Candida albicans infections. Fluconazole may increase the serum concentration of Erythromycin (Risk X: avoid combination). Pharmacology Pharmacodynamics Like other imidazole- and triazole-class antifungals, fluconazole inhibits the fungal cytochrome P450 enzyme 14α-demethylase. Mammalian demethylase activity is much less sensitive to fluconazole than fungal demethylase. This inhibition prevents the conversion of lanosterol to ergosterol, an essential component of the fungal cytoplasmic membrane, and subsequent accumulation of 14α-methyl sterols. Fluconazole is primarily fungistatic; however, it may be fungicidal against certain organisms in a dose-dependent manner, specifically Cryptococcus. Pharmacokinetics Following oral dosing, fluconazole is almost completely absorbed within two hours. Bioavailability is not significantly affected by the absence of stomach acid. Concentrations measured in the urine, tears, and skin are approximately 10 times the plasma concentration, whereas saliva, sputum, and vaginal fluid concentrations are approximately equal to the plasma concentration, following a standard dose range of between 100 mg and 400 mg per day. The elimination half-life of fluconazole follows zero order, and only 10% of elimination is due to metabolism, the remainder being excreted in urine and sweat. Patients with impaired renal function will be at risk of overdose.In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. History Fluconazole was patented by Pfizer in 1981 in the United Kingdom and came into commercial use in 1988. Patent expirations occurred in 2004 and 2005. References External links "Fluconazole". Drug Information Portal. U.S. National Library of Medicine. Doi : Evolution of Fluconazole-Resistant Candida albicans Strains by Drug-Induced Mating Competence and Parasexual Recombination
Chlorambucil	Chlorambucil, sold under the brand name Leukeran among others, is a chemotherapy medication used to treat chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, and non-Hodgkin lymphoma. For CLL it is a preferred treatment. It is given by mouth.Common side effects include bone marrow suppression. Other serious side effects include an increased long term risk of further cancer, infertility, and allergic reactions. Use during pregnancy often results in harm to the baby. Chlorambucil is in the alkylating agent family of medications. It works by blocking the formation of DNA and RNA.Chlorambucil was approved for medical use in the United States in 1957. It is on the World Health Organizations List of Essential Medicines. It was originally made from nitrogen mustard. Medical uses Chlorambucils current use is mainly in chronic lymphocytic leukemia, as it is well tolerated by most patients, though chlorambucil has been largely replaced by fludarabine as first-line treatment in younger patients. It can be used for treating some types of non-Hodgkin lymphoma, Waldenström macroglobulinemia, polycythemia vera, trophoblastic neoplasms, and ovarian carcinoma. Moreover, it also has been used as an immunosuppressive drug for various autoimmune and inflammatory conditions, such as nephrotic syndrome. Side effects Bone marrow suppression (anemia, neutropenia, thrombocytopenia) is the most commonly occurring side effect of chlorambucil. Withdrawn from the drug, this side effect is typically reversible. Like many alkylating agents, chlorambucil has been associated with the development of other forms of cancer. Less commonly occurring side effects include: Gastrointestinal Distress (nausea, vomiting, diarrhea, and oral ulcerations). Central Nervous System: Seizures, tremors, muscular twitching, confusion, agitation, ataxia, and hallucinations. Skin reactions Hepatotoxicity Infertility Hair Loss Pharmacology Mechanism of action Chlorambucil produces its anti-cancer effects by interfering with DNA replication and damaging the DNA in a cell. The DNA damage induces cell cycle arrest and cellular apoptosis via the accumulation of cytosolic p53 and subsequent activation of Bcl-2-associated X protein, an apoptosis promoter.Chlorambucil alkylates and cross-links DNA during all phases of the cell cycle, inducing DNA damage via three different methods of covalent adduct generation with double-helical DNA: Attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA. DNA damage via the formation of cross-links which prevents DNA from being separated for synthesis or transcription. Induction of mispairing of the nucleotides leading to mutations.The precise mechanisms by which chlorambucil acts to kill tumor cells are not yet completely understood. Limitations to bioavailability A recent study has shown Chlorambucil to be detoxified by human glutathione transferase Pi (GST P1-1), an enzyme that is often found over-expressed in cancer tissues.This is important since chlorambucil, as an electrophile, is made less reactive by conjugation with glutathione, thereby making the drug less toxic to the cell. Shown above, chlorambucil reacts with glutathione as catalyzed by hGSTA 1-1 leading to the formation of the monoglutathionyl derivative of chlorambucil. Chemistry Chlorambucil is a white to pale beige crystalline or granular powder with a slight odor. When heated to decomposition it emits very toxic fumes of hydrogen chloride and nitrogen oxides. History Nitrogen mustards arose from the derivatization of sulphur mustard gas after military personnel exposed to it during World War I were observed to have decreased white blood cell counts. Since the sulphur mustard gas was too toxic to be used in humans, Gilman hypothesized that by reducing the electrophilicity of the agent, which made it highly chemically reactive towards electron-rich groups, then less toxic drugs could be obtained. To this end, he made analogues that were less electrophilic by exchanging the sulphur with a nitrogen, leading to the nitrogen mustards.With an acceptable therapeutic index in humans, nitrogen mustards were first introduced in the clinic in 1946. Aliphatic mustards were developed first, such as mechlorethamine hydrochloride (mustine hydrochloride), which is still used in the clinic today. In the 1950s, aromatic mustards like chlorambucil were introduced as less toxic alkylating agents than the aliphatic nitrogen mustards, proving to be less electrophilic and react with DNA more slowly. Additionally, these agent can be administered orally, a significant advantage. Chlorambucil was first synthesized by Everett et al. References External links Leukeran (manufacturers website) "Chlorambucil". Drug Information Portal. U.S. National Library of Medicine.
Magnesium sulfate	Magnesium sulfate or magnesium sulphate (in English-speaking countries other than the US) is a chemical compound, a salt with the formula MgSO4, consisting of magnesium cations Mg2+ (20.19% by mass) and sulfate anions SO2−4. It is a white crystalline solid, soluble in water but not in ethanol. Magnesium sulfate is usually encountered in the form of a hydrate MgSO4·nH2O, for various values of n between 1 and 11. The most common is the heptahydrate MgSO4·7H2O, known as Epsom salt, which is a household chemical with many traditional uses, including bath salts.The main use of magnesium sulfate is in agriculture, to correct soils deficient in magnesium (an essential plant nutrient because of the role of magnesium in chlorophyll and photosynthesis). The monohydrate is favored for this use; by the mid 1970s, its production was 2.3 million tons per year. The anhydrous form and several hydrates occur in nature as minerals, and the salt is a significant component of the water from some springs. Hydrates Magnesium sulfate can crystallize as several hydrates, including: Anhydrous, MgSO4; unstable in nature, hydrates to form epsomite. Monohydrate, MgSO4·H2O; kieserite, monoclinic. MgSO4·1.25H2O or 4MgSO4·5H2O. Dihydrate, MgSO4·2H2O; orthorhombic. MgSO4·2.5H2O or 2MgSO4·5H2O. Trihydrate, MgSO4·3H2O. Tetrahydrate, MgSO4·4H2O; starkeyite, monoclinic. Pentahydrate, MgSO4·5H2O; pentahydrite, triclinic. Hexahydrate, MgSO4·6H2O; hexahydrite, monoclinic. Heptahydrate, MgSO4·7H2O ("Epsom salt"); epsomite, orthorhombic. Enneahydrate, MgSO4·9H2O, monoclinic. Decahydrate, MgSO4·10H2O. Undecahydrate, MgSO4·11H2O; meridianiite, triclinic.As of 2017, the existence of the decahydrate apparently has not been confirmed.All the hydrates lose water upon heating. Above 320 °C, only the anhydrous form is stable. It decomposes without melting at 1124 °C into magnesium oxide (MgO) and sulfur trioxide (SO3). Heptahydrate The heptahydrate takes its common name "Epsom salt" from a bitter saline spring in Epsom in Surrey, England, where the salt was produced from the springs that arise where the porous chalk of the North Downs meets the impervious London clay. The heptahydrate readily loses one equivalent of water to form the hexahydrate. It is a natural source of both magnesium and sulphur. Epsom salts are commonly used in bath salts, exfoliants, muscle relaxers and pain relievers. However, these are different from Epsom salts that are used for gardening, as they contain aromas and perfumes not suitable for plants. Monohydrate Magnesium sulfate monohydrate, or kieserite, can be prepared by heating the heptahydrate to 120 °C. Further heating to 250 °C gives anhydrous magnesium sulfate. Undecahydrate The undecahydrate MgSO4·11H2O, meridianiite, is stable at atmospheric pressure only below 2 °C. Above that temperature, it liquefies into a mix of solid heptahydrate and a saturated solution. It has a eutectic point with water at −3.9 °C and 17.3% (mass) of MgSO4. Large crystals can be obtained from solutions of the proper concentration kept at 0 °C for a few days.At pressures of about 0.9 GPa and at 240 K, meridianiite decomposes into a mixture of ice VI and the enneahydrate MgSO4·9H2O. Enneahydrate The enneahydrate MgSO4·9H2O was identified and characterized only recently, even though it seems easy to produce (by cooling a solution of MgSO4 and sodium sulfate Na2SO4 in suitable proportions). The structure is monoclinic, with unit-cell parameters at 250 K: a = 0.675 nm, b = 1.195 nm, c = 1.465 nm, β = 95.1°, V = 1.177 nm3 with Z = 4. The most probable space group is P21/c. Magnesium selenate also forms an enneahydrate MgSeO4·9H2O, but with a different crystal structure. Natural occurrence As Mg2+ and SO2−4 ions are respectively the second cation and the second anion present in seawater after Na+ and Cl−, magnesium sulfates are common minerals in geological environments. Their occurrence is mostly connected with supergene processes. Some of them are also important constituents of evaporitic potassium-magnesium (K-Mg) salts deposits. Bright spots observed by the Dawn Spacecraft in Occator Crater on the dwarf planet Ceres are most consistent with reflected light from magnesium sulfate hexahydrate.Almost all known mineralogical forms of MgSO4 are hydrates. Epsomite is the natural analogue of "Epsom salt". Meridianiite, MgSO4·11H2O, has been observed on the surface of frozen lakes and is thought to also occur on Mars. Hexahydrite is the next lower hydrate. Three next lower hydrates – pentahydrite, starkeyite, and especially sanderite – are rare. Kieserite is a monohydrate and is common among evaporitic deposits. Anhydrous magnesium sulfate was reported from some burning coal dumps. Preparation Magnesium sulfate is usually obtained directly from dry lake beds and other natural sources. It can also be prepared by reacting magnesite (magnesium carbonate, MgCO3) or magnesia (oxide, MgO) with sulfuric acid (H2SO4). Another possible method is to treat seawater or magnesium-containing industrial wastes so as to precipitate magnesium hydroxide and react the precipitate with sulfuric acid. Also, magnesium sulfate heptahydrate (epsomite, MgSO4·7H2O) is manufactured by dissolution of magnesium sulfate monohydrate (kieserite, MgSO4·H2O) in water and subsequent crystallization of the heptahydrate. Physical properties Magnesium sulfate relaxation is the primary mechanism that causes the absorption of sound in seawater at frequencies above 10 kHz (acoustic energy is converted to thermal energy). Lower frequencies are less absorbed by the salt, so that low frequency sound travels farther in the ocean. Boric acid and magnesium carbonate also contribute to absorption. Uses Medical Magnesium sulfate is used both externally (as Epsom salt) and internally. The main external use is the formulation as bath salts, especially for foot baths to soothe sore feet. Such baths have been claimed to also soothe and hasten recovery from muscle pain, soreness, or injury. Potential health effects of magnesium sulfate are reflected in medical studies on the impact of magnesium on resistant depression and as an analgesic for migraine and chronic pain. Magnesium sulfate has been studied in the treatment of asthma, preeclampsia and eclampsia.Magnesium sulfate is the usual component of the concentrated salt solution used in isolation tanks to increase its specific gravity to approximately 1.25–1.26. This high density allows an individual to float effortlessly on the surface of water in the closed tank, eliminating as many of the external senses as possible. In the UK, a medication containing magnesium sulfate and phenol, called "drawing paste", is useful for small boils or localized infections and removing splinters.Internally, magnesium sulfate may be administered by oral, respiratory, or intravenous routes. Internal uses include replacement therapy for magnesium deficiency, treatment of acute and severe arrhythmias, as a bronchodilator in the treatment of asthma, preventing eclampsia, a tocolytic agent, and as an anticonvulsant.It also may be used as laxative. Agriculture In agriculture, magnesium sulfate is used to increase magnesium or sulfur content in soil. It is most commonly applied to potted plants, or to magnesium-hungry crops such as potatoes, tomatoes, carrots, peppers, lemons, and roses. The advantage of magnesium sulfate over other magnesium soil amendments (such as dolomitic lime) is its high solubility, which also allows the option of foliar feeding. Solutions of magnesium sulfate are also nearly pH neutral, compared with the slightly alkaline salts of magnesium as found in limestone; therefore, the use of magnesium sulfate as a magnesium source for soil does not significantly change the soil pH. Contrary to the popular belief that magnesium sulfate is able to control pests and slugs, helps seeds germination, produce more flowers, improve nutrient uptake, and is environmentally friendly, it does none of the purported claims except for correcting magnesium deficiency in soils. Magnesium sulfate can even pollute water if used in excessive amounts.Magnesium sulfate was historically used as a treatment for lead poisoning prior to the development of chelation therapy, as it was hoped that any lead ingested would be precipitated out by the magnesium sulfate and subsequently purged from the digestive system. This application saw particularly widespread use among veterinarians during the early-to-mid 20th century; Epsom salt was already available on many farms for agricultural use, and it was often prescribed in the treatment of farm animals that inadvertently ingested lead. Food preparation Magnesium sulfate is used as Brewing salt in making beer. coagulant for making tofu. Salt substitute. Chemistry Anhydrous magnesium sulfate is commonly used as a desiccant in organic synthesis owing to its affinity for water and compatibility with most organic compounds. During work-up, an organic phase is treated with anhydrous magnesium sulfate. The hydrated solid is then removed by filtration, decantation, or by distillation (if the boiling point is low enough). Other inorganic sulfate salts such as sodium sulfate and calcium sulfate may be used in the same way. Construction Magnesium sulfate is used to prepare specific cements by the reaction between magnesium oxide and magnesium sulfate solution, which are of good binding ability and more resistance than Portland cement. This cement is mainly adopted in the production of lightweight insulation panels. Weakness in water resistance limits its usage. Magnesium (or sodium) sulfate is also used for testing aggregates for soundness in accordance with ASTM C88 standard, when there are no service records of the material exposed to actual weathering conditions. The test is accomplished by repeated immersion in saturated solutions followed by oven drying to dehydrate the salt precipitated in permeable pore spaces. The internal expansive force, derived from the rehydration of the salt upon re-immersion, simulates the expansion of water on freezing. Magnesium sulfate is also used to test the resistance of concrete to external sulfate attack (ESA). Aquaria Magnesium sulfate heptahydrate is also used to maintain the magnesium concentration in marine aquaria which contain large amounts of stony corals, as it is slowly depleted in their calcification process. In a magnesium-deficient marine aquarium, calcium and alkalinity concentrations are very difficult to control because not enough magnesium is present to stabilize these ions in the saltwater and prevent their spontaneous precipitation into calcium carbonate. Double salts Double salts containing magnesium sulfate exist. There are several known as sodium magnesium sulfates and potassium magnesium sulfates. A mixed copper-magnesium sulfate heptahydrate (Mg,Cu)SO4·7H2O was recently found to occur in mine tailings and has been given the mineral name alpersite. See also Calcium sulfate Magnesium chloride References External links International Chemical Safety Cards—Magnesium Sulfate
Estradiol valerate	Estradiol valerate (EV), sold for use by mouth under the brand name Progynova and Primiwal E4 and for use by injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen medication. It is used in hormone therapy for menopausal symptoms and low estrogen levels, hormone therapy for transgender people, and in hormonal birth control. It is also used in the treatment of prostate cancer. The medication is taken by mouth or by injection into muscle or fat once every 1 to 4 weeks.Side effects of estradiol valerate include breast tenderness, breast enlargement, nausea, headache, and fluid retention. Estradiol valerate is an estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol. It is an estrogen ester and a prodrug of estradiol in the body. Because of this, it is considered to be a natural and bioidentical form of estrogen.Estradiol valerate was first described in 1940 and was introduced for medical use in 1954. Along with estradiol cypionate, it is one of the most widely used esters of estradiol. Estradiol valerate is used in the United States, Canada, Europe, and throughout much of the rest of the world. It is available as a generic medication. Medical uses The medical uses of estradiol valerate are the same as those of estradiol and other estrogens. Examples of indications for the medication include hormone therapy and hormonal contraception. In regard to the latter, estradiol valerate is available in combination with a progestin as a combined estradiol-containing oral contraceptive (with dienogest) and as a combined injectable contraceptive. Along with estradiol cypionate, estradiol undecylate, and estradiol benzoate, estradiol valerate is used as a form of high-dose estrogen therapy in feminizing hormone therapy for transgender women. It is also used as a form of high-dose estrogen therapy in the treatment of prostate cancer in men. Low-dose oral estradiol valerate (2–6 mg/day) has been used in the treatment of breast cancer in women who were previously treated with and benefited from but acquired resistance to aromatase inhibitors as well. Injectable estradiol valerate has been used to suppress sex drive in sex offenders.In the United States, the approved indications of estradiol valerate injections include the treatment of moderate to severe hot flashes and vaginal atrophy associated with menopause in women, the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure in women, and the palliative treatment of advanced prostate cancer in men. Elsewhere in the world, oral estradiol valerate is similarly approved for the treatment of symptoms associated with menopause or hypoestrogenism due to castration in women. Such symptoms may include hot flashes, outbreaks of sweat, sleep disturbances, depressive moods, irritability, headaches, and dizziness.Estradiol valerate by intramuscular injection is usually used at a dosage of 10 to 20 mg every 4 weeks in the treatment of menopausal symptoms and hypoestrogenism due to hypogonadism, castration, or primary ovarian failure in women. In the past, it was used at even higher doses of 10 to 40 every 1 to 4 weeks for estrogen replacement. Estradiol valerate is usually used in the treatment of advanced prostate cancer in men at a dosage of 30 mg or more every 1 to 2 weeks by intramuscular injection. In transgender women, estradiol valerate given by intramuscular injection is usually used at a dosage of 5 to 20 mg, but up to 30 to 40 mg, once every 2 weeks. Estradiol valerate has also been used at a dose of 10 to 40 mg by intramuscular injection to limit bleeding in women with hemorrhage due to dysfunctional uterine bleeding.: 318 : 60 Available forms Estradiol valerate is and has been available in the form of vials and ampoules of oil solution for intramuscular injection in concentrations of 4, 5, 10, 20, and 40 mg/mL and in the form of oral tablets at doses of 0.5, 1, 2, and 4 mg per tablet. In the United States, it is specifically available in formulations of 10, 20, and 40 mg/mL in oil solution (as Delestrogen, as well as generics). Aside from estradiol valerate, the only other injectable estrogen formulations that remain available in the United States are estradiol cypionate (5 mg/mL in oil solution) and conjugated estrogens (25 mg/vial in solution). Some or all oral estradiol valerate tablets are micronized, similarly to oral estradiol tablets.In addition to single-drug formulations, oral estradiol valerate is available in combination with the progestin dienogest as a combined oral contraceptive and intramuscular estradiol valerate is marketed at a concentration of 5 mg/mL in combination with the progestin hydroxyprogesterone caproate and with the progestin norethisterone enantate as combined injectable contraceptives. Intramuscular estradiol valerate is also marketed at a concentration of 4 mg/mL in combination with the weak androgen and neurosteroid prasterone enanthate (DHEA enanthate) and with the androgen testosterone enantate for use in menopausal hormone therapy, but the latter formulation has been discontinued. The availability of estradiol valerate-containing products varies throughout the world. Contraindications Contraindications of estrogens include coagulation problems, cardiovascular diseases, liver disease, and certain hormone-sensitive cancers such as breast cancer and endometrial cancer, among others. Side effects The side effects of estradiol valerate are the same as those of estradiol. Examples of such side effects include breast tenderness and enlargement, nausea, bloating, edema, headache, and melasma. High-dose estrogen therapy with estradiol valerate injections may also cause an increased risk of thromboembolism, changes in blood lipid profile, increased insulin resistance, and increased levels of prolactin. Overdose Estradiol valerate has been used at very high doses of 40 to 100 mg once per week in women and men, without overt signs of acute toxicity observed. Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and leg cramps. These side effects can be diminished by reducing the estrogen dosage. Interactions Inhibitors and inducers of cytochrome P450 may influence the metabolism of estradiol and by extension circulating estradiol levels. Pharmacology Pharmacodynamics Estradiol valerate is an estradiol ester, or a prodrug of estradiol. As such, it is an estrogen, or an agonist of the estrogen receptors. The affinity of estradiol valerate for the estrogen receptor is approximately 50 times lower than that of estradiol. In addition, estradiol valerate is rapidly cleaved into estradiol and is unable to reach target tissues in concentrations of significance, if at all. As such, estradiol valerate is essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol. The molecular weight of estradiol valerate is about 131% of that of estradiol due to the presence of its C17β valerate ester, and hence estradiol valerate contains about 76% of the amount of estradiol of an equal dose of estradiol. Aside from dose adjustment to account for the difference in molecular weight, oral estradiol valerate is considered to be equivalent to oral estradiol. Because estradiol valerate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen. Effects on liver protein synthesis The influence of 2 mg/day oral estradiol valerate on coagulation factors is less than that of 10 μg/day oral ethinylestradiol. Oral ethinylestradiol at 10 μg/day has been found to have about 1.5- to 2.5-fold the impact of 2 mg/day oral estradiol valerate on HDL cholesterol and triglycerides. The influence of 20 or 50 μg/day oral ethinylestradiol on coagulation factors and HDL cholesterol is markedly greater than that of 2 mg/day oral estradiol valerate.Estradiol-containing birth control pills, which contain 1 to 3 mg/day estradiol or estradiol valerate, have been found to increase sex hormone-binding globulin (SHBG) levels by 1.5-fold. Oral estradiol valerate at 6 mg/day has been found to increase SHBG levels by 2.5- to 3-fold in transgender women. For comparison, combined birth control pills containing ethinylestradiol and a progestin with minimal androgenic or antiandrogenic activity have been found to increase SHBG levels by about 3- to 4-fold. Pharmacokinetics Regardless of the route of administration, estradiol valerate behaves as a prodrug of estradiol via cleavage by esterases into estradiol and the natural fatty acid valeric acid. This cleavage occurs not only in the liver, but also in the blood and in tissues, and the hydrolysis of estradiol valerate into estradiol and valeric acid is complete regardless of whether the medication is administered orally or parenterally. High levels of circulating estradiol are found after an intravenous injection of estradiol valerate, and this indicates very rapid cleavage of the medication upon entering circulation. Oral administration Esterification of the C17β position of estradiol as in estradiol valerate reduces the metabolism of estradiol valerate by 17β-hydroxysteroid dehydrogenase (17β-HSD). As approximately 80% of estradiol is metabolized into estrone (and estrone sulfate) by 17β-HSD during first-pass metabolism, this improves the metabolic stability and hence bioavailability of estradiol valerate. However, estradiol valerate is hydrolyzed into estradiol and valeric acid in the intestines, and hence, is still subject to extensive first-pass metabolism. As such, the oral bioavailability of estradiol valerate is only around 3 to 5%, and is similar to that of oral estradiol. All oral tablets in the cases of both estradiol and estradiol valerate seem to be micronized. Due to its nature as a rapidly converted prodrug of estradiol, the pharmacokinetics of oral estradiol valerate are similar to those of oral estradiol. Moreover, the pharmacodynamics and potency (after differences in molecular weight are taken into account) of oral estradiol valerate are considered to be equivalent to those of oral estradiol. This is also notably true for effects on hepatic protein synthesis (e.g., of SHBG), again after differences in molecular weight between the two compounds are considered.A dosage of 1 mg/day oral estradiol valerate has been found to produce approximate circulating concentrations of 50 pg/mL estradiol and 160 pg/mL estrone, while a dosage of 2 mg/day results in circulating levels of 60 pg/mL estradiol and 300 pg/mL estrone. These concentrations of estradiol and estrone are comparable to those observed with 1 and 2 mg/day oral estradiol. A review of selected studies reported a range of mean peak estradiol levels of 24 to 140 pg/mL occurring 1 to 12 hours after administration of 2 mg oral estradiol valerate. A study found that, in accordance with their differences in molecular weights, oral estradiol produced higher levels of estradiol than oral estradiol valerate. Likewise, other studies found that levels of estradiol and estrone are very similar after oral administration of roughly equimolar doses of estradiol (1.5 mg) and estradiol valerate (2 mg). A study of high-dose oral estradiol valerate found levels of estradiol of about 250 pg/mL after a single 10-mg dose in three women. Sublingual administration Estradiol valerate has been studied by sublingual administration in premenopausal women for the purpose of cycle control and ovulation suppression in egg donation and surrogacy. It has been investigated for this indication, along with vaginal and transdermal estradiol, because oral estradiol valerate is sometimes unable to achieve adequate estradiol levels and hence proper cycle control in this situation. Sublingual administration of estradiol valerate bypasses the first pass that occurs with the oral route and results in higher levels of estradiol and improved cycle control. Sublingual estradiol valerate is also used in hormone therapy for transgender women.The administration of 2 mg oral micronized estradiol valerate tablets (Progynova, Schering) sublingually 3 or 4 times per day has been found to result in circulating estradiol levels of about 290 pg/mL to 460 pg/mL in premenopausal women (time of measurements not given). Steady-state levels of estradiol were achieved within about 2 or 3 days. Levels of progesterone, luteinizing hormone, and follicle-stimulating hormone were all considerably suppressed, and ovulation, as well as the associated mid-cycle hormonal surges, were prevented. Similarly to oral administration of estradiol, but in contrast to the vaginal and transdermal routes, the ratio of estradiol to estrone is decreased with sublingual administration of either estradiol valerate or estradiol. Intramuscular injection In contrast to oral administration, the bioavailability of estradiol valerate is complete (i.e., 100%) via intramuscular injection. Due to the far greater bioavailability of intramuscular estradiol valerate relative to oral, the former is substantially stronger (in terms of potency) than the latter. As an example, a single 4 mg intramuscular injection is said to be approximately equivalent to 2 mg/day of the medication administered orally over the course of 3 weeks. Estradiol valerate, when given intramuscularly in oil, has a relatively long duration due to the formation of an intramuscular depot from which the medication is slowly released and absorbed. Upon intramuscular injection of estradiol valerate in an oil solution, the solvent (i.e., oil) is absorbed, and a primary microcrystalline depot is formed within the muscle at the site of injection. In addition, a secondary depot may also be formed in adipose tissue. The slow release of estradiol valerate is caused by the increased lipophilicity of the medication, which in turn is due to its long fatty acid valeric acid ester moiety. The elimination half-life of estradiol valerate in oil by intramuscular injection (brand names Estradiol-Depot 10 mg, Progynon Depot-10) is about 3.5 days, with a range of 1.2 days to 7.2 days in different individuals. Α couple of older studies from the 1980s with sample sizes of only 2 or 3 individuals reported an elimination half-life of 4 to 5 days.A single intramuscular injection of 4 mg estradiol valerate has been found to result in maximal circulating levels of estradiol of about 390 pg/mL within 3 days of administration, with levels declining to 100 pg/mL (baseline, in the study) by 12 to 13 days. Studies in general have found that a single intramuscular injection of 4 mg estradiol valerate results in peak levels of estradiol of 240 to 540 pg/mL after 1 to 5 days following administration. A study found that a single intramuscular injection of 5 mg estradiol valerate resulted in peak circulating levels of 667 pg/mL estradiol and 324 pg/mL estrone within approximately 2 and 3 days, respectively. The duration of estradiol valerate at this dose and in this study was considered to be 7 to 8 days. Other studies have found that larger doses of intramuscular estradiol valerate exceeding 20 mg have a duration of more than 15 days. A third study, in contrast to the preceding study, found that a single 10 mg intramuscular injection of estradiol valerate resulted in maximal estradiol levels of 506 to 544 pg/mL and maximal estrone levels of 205 to 219 pg/mL in postmenopausal women.With intramuscular injections of estradiol valerate, it has been reported that a dose of 5 mg has a duration of 7 to 8 days, 10 mg a duration of 10 to 14 days, 40 mg a duration of 2 to 3 weeks (14 to 21 days), and 100 mg a duration of 3 to 4 weeks (21 to 28 days).A study of pseudopregnancy with intramuscular injections of 40 mg/week estradiol valerate and 250 mg/week hydroxyprogesterone caproate in women with estrogen deficiency observed estradiol levels of about 3,100 pg/mL at 3 months of therapy and 2,500 pg/mL at 6 months of therapy. Subcutaneous injection Estradiol esters like estradiol valerate and estradiol cypionate can be given by subcutaneous injection instead of intramuscular injection. Intravenous injection The administration of estradiol valerate by intravenous injection has been studied. It has been found to be very rapidly cleaved into estradiol. The bioavailability and metabolism of estradiol valerate does not differ with intravenous versus intramuscular injection. Conversely, intravenous injection of estradiol valerate has a very short duration, whereas intramuscular injection has a long duration and elimination half-life. Chemistry Estradiol valerate is a synthetic estrane steroid and the C17β valerate (pentanoate) fatty acid ester of estradiol. It is also known as estradiol 17β-valerate or as estra-1,3,5(10)-triene-3,17β-diol 17β-pentanoate. Other common esters of estradiol in use include estradiol cypionate, estradiol enantate, and estradiol acetate, the former two of which are C17β esters of estradiol similarly to estradiol valerate and the latter of which is the C3 acetate ester of estradiol.The experimental log octanol/water partition coefficient (log P) of estradiol valerate is 5.6. History Estradiol valerate was patented by Ciba in 1940 and 1941, with a priority date of 1936. It was synthesized and studied, along with a variety of other estradiol esters, by Karl Junkmann of Schering AG in 1953. The medication was first introduced for medical use via intramuscular injection in 1954 by Schering in Europe under the brand name Progynon Depot and by Squibb in the United States under the brand name Delestrogen. In 1966, oral estradiol valerate was introduced by Schering for medical use in Europe under the brand name Progynova. A report of its metabolism was published in 1967. Esterification of estradiol, as in estradiol valerate, has been claimed to improve its metabolic stability with oral administration. In 1968, micronized preparations of oral estradiol valerate were first introduced under the brand names Progynova 21 and Progynova 21 mite. Along with estradiol benzoate (1933) and estradiol cypionate (1952), estradiol valerate is one of the most widely used esters of estradiol. Society and culture Generic names Estradiol valerate is the generic name of the drug and its INN, USAN, BANM, and JAN, while oestradiol valerate was formerly its BANM. Brand names Estradiol valerate has been marketed under the brand names Altadiol, Androtardyl-Oestradiol, Ardefem, Climaval, Cyclabil, Cyclocur, Deladiol, Delahormone Unimatic, Delestrogen, Delestrogen 4X, Depogen, Diol-20, Dioval, Ditate, Dura-Estate, Dura-Estradiol, Duratrad, Duragen, Estate, Estra-L, Estradiol Depot, Estraval, Estraval Depot, Estraval PA, Estravel, Femogen, Femogex, Gynogen L.A., Gynokadin, Lastrogen, Menaval, Merimono, Neofollin, Nuvelle, Oestrogynal, Ostrin Depo, Pelanin, Pharlon, Postoval, Primogyna, Primogyn, Primogyn Depot, Progynon, Progynon Depot, Progynova, Repestrogen, Repo-Estra, Reposo-E, Retestrin, Ronfase, Span-Est, Testaval, and Valergen, among others. Neofollin is an oil solution of estradiol valerate. Availability Oral estradiol valerate is used primarily in Europe, under the brand name Progynova. Although oral estradiol valerate was previously available in the United States, it is no longer available in this country except in combination with dienogest as a combined oral contraceptive (under the brand name Natazia). Estradiol valerate by intramuscular injection is available under the brand name Delestrogen in the United States and Canada and under the brand name Progynon Depot in Europe and elsewhere in the world. Research SH-834 was a combination of 90 mg estradiol valerate and 300 mg gestonorone caproate for weekly intramuscular injection that was developed by Schering in the 1970s. It was investigated clinically as a treatment for breast cancer and was found to be effective, but was never marketed. See also Estradiol valerate/hydroxyprogesterone caproate Estradiol valerate/norethisterone enantate Estradiol valerate/prasterone enanthate Estradiol valerate/testosterone enanthate References Further reading Vermeulen A (1975). "Longacting steroid preparations". Acta Clin Belg. 30 (1): 48–55. doi:10.1080/17843286.1975.11716973. PMID 1231448. Düsterberg B, Nishino Y (1982). "Pharmacokinetic and pharmacological features of oestradiol valerate". Maturitas. 4 (4): 315–24. doi:10.1016/0378-5122(82)90064-0. PMID 7169965. Sang GW (1994). "Pharmacodynamic effects of once-a-month combined injectable contraceptives". Contraception. 49 (4): 361–85. doi:10.1016/0010-7824(94)90033-7. PMID 8013220. OConnell MB (1995). "Pharmacokinetic and pharmacologic variation between different estrogen products". J Clin Pharmacol. 35 (9 Suppl): 18S–24S. doi:10.1002/j.1552-4604.1995.tb04143.x. PMID 8530713. S2CID 10159196. Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947. S2CID 24616324. Stanczyk, Frank Z.; Archer, David F.; Bhavnani, Bhagu R. (2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception. 87 (6): 706–727. doi:10.1016/j.contraception.2012.12.011. ISSN 0010-7824. PMID 23375353.
Losartan/hydrochlorothiazide	Losartan/hydrochlorothiazide, sold under the brand name Hyzaar among others, is a combination medication used to treat high blood pressure when losartan is not sufficient. It consists of losartan (an angiotensin II receptor antagonist) and hydrochlorothiazide (a diuretic). It is taken by mouth.Common side effects include dizziness, back pain, and upper respiratory tract infections. Serious side effects may include low blood pressure, kidney problems, allergic reactions, and electrolyte problems. Use in pregnancy and breastfeeding is not recommended. Losartan works by blocking the effects of angiotensin II while hydrochlorothiazide works by decreasing the ability of the kidneys to absorb electrolytes. Interactions include with lithium, agents which increase potassium, and NSAIDs.The combination was approved for medical use in the United States in 1995. It is available as a generic medication. In 2019, it was the 73rd most commonly prescribed medication in the United States, with more than 10 million prescriptions. Medical uses It is used for high blood pressure (hypertension) once a day. Based on the initial blood pressure response and/or losartan-hydrochlorothiazide side effects, the dosage may be increased or decreased. With each change in dosage, it may take up to a month to see the full effect. Side Effects Common side effects include dizziness, headache, back pain, rash, fever, diarrhea, cough, and upper respiratory tract infections. Serious side effects may include low blood pressure, kidney problems, allergic reactions, and electrolyte problems. Drug interactions Drug interactions to be aware of include lithium, agents increasing serum levels of potassium, and the use of hydrochlorothiazide with antidiabetic drugs both oral agents and insulin. Mechanisms Losartan works by blocking the effects of angiotensin II by preventing it from binding to the angiotensin I receptor while hydrochlorothiazide works by decreasing the ability of the kidneys to absorb electrolytes. The effects of hydrochlorothiazide indirectly lower the levels of serum potassium. However, with coadministration of losartan which is an angiotensin II receptor antagonist, the low levels of potassium are reversed. Brand names The losartan/hydrochlorothiazide combination preparation is marketed by Merck under the brand name Hyzaar and by Xeno Pharmaceuticals under the name Anzaplus. Merck, Sharp & Dohme market it as Ocsaar Plus in Israel. It is marketed as Cozaar comp in Sweden and South Africa. References External links "Hydrochlorothiazide mixture with Losartan". Drug Information Portal. U.S. National Library of Medicine.
Peanut allergen powder	Peanut (Arachis hypogaea) Allergen Powder, sold under the brand name Palforzia, is an oral medication for the treatment of allergic reactions, including anaphylaxis, in children typically aged between four and 17 years of age who have confirmed cases of peanut allergy. It is taken by mouth.Peanut (Arachis hypogaea) allergen powder is a powder that is manufactured from peanuts and packaged in pull-apart color-coded capsules for dose escalation and up-dosing, and in a sachet for maintenance treatment. The powder is emptied from the capsules or sachet and mixed with a small amount of semisolid food, such as applesauce, yogurt, or pudding for consumption.The most common side effects of peanut (Arachis hypogaea) allergen powder are abdominal pain, vomiting, nausea, tingling in the mouth, itching (including in the mouth and ears), cough, runny nose, throat irritation and tightness, hives, wheezing and shortness of breath and anaphylaxis. Peanut (Arachis hypogaea) allergen powder should not be administered to those with uncontrolled asthma.To mitigate the risk of anaphylaxis associated with peanut (Arachis hypogaea) allergen powder, the U.S. Food and Drug Administration (FDA) requires a Risk Evaluation and Mitigation Strategy (REMS). Peanut (Arachis hypogaea) allergen powder is only available through specially certified healthcare providers, health care settings, and pharmacies to those who are enrolled in the REMS program. The FDA is requiring that healthcare providers who prescribe peanut (Arachis hypogaea) allergen powder - and healthcare settings that dispense and administer peanut (Arachis hypogaea) allergen powder - are educated on the risk of anaphylaxis associated with its use. In addition, the Initial Dose Escalation phase and first dose of each Up-Dosing level must only be administered to patients in a certified healthcare setting equipped to monitor patients and to identify and manage anaphylaxis. Patients or their parents or caregivers must also be counseled on the need for the patients to have injectable epinephrine available for immediate use at all times, the need for continued dietary peanut avoidance, and how to recognize the signs and symptoms of anaphylaxis.In January 2020, the FDA approved the drug to Aimmune Therapeutics for mitigating "allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanuts." It is the first drug approved for peanut allergies. It will not make allergic people to be able to eat normal amounts of peanuts, but will prevent allergies due to accidental eating. History The effectiveness of peanut (Arachis hypogaea) allergen powder is supported by a randomized, double-blind, placebo-controlled study conducted in the U.S., Canada and Europe in approximately 500 peanut-allergic individuals. Effectiveness was assessed by evaluating the percentage of study participants tolerating an oral challenge with a single 600 mg dose of peanut protein (twice the daily maintenance dose of peanut (Arachis hypogaea) allergen powder) with no more than mild allergic symptoms after six months of maintenance treatment. The results showed that 67.2% of peanut (Arachis hypogaea) allergen powder recipients tolerated a 600 mg dose of peanut protein in the challenge, compared to 4.0% of placebo recipients.The safety of peanut (Arachis hypogaea) allergen powder was assessed in two double-blind, placebo-controlled studies in approximately 700 peanut-allergic individuals.On 21 December 2018, Aimmune Therapeutics applied Biologics License Application for Peanut (Arachis hypogaea) Allergen Powder-dnfp to the U.S. Food and Drug Administration. On 13 September 2019, the FDA Allergenic Products Advisory Committee decided seven to two in favour of the approval. The final approval was issued on 31 January 2020.On 15 October 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 Palforzia, intended for desensitizing children and adolescents to peanut allergy. It was approved for medical use in the European Union in December 2020. Controversy Although the FDA had decided the approval of Palforzia in 2019, the Institute for Clinical and Economic Review (ICER) reported that the clinical evidence is still insufficient. A 2019 systematic review and meta-analysis of 12 clinical trials consisting of 1041 cases questioned the safety of oral peanut allergen treatment. The study concluded that the treatments "increase allergic and anaphylactic reactions over avoidance or placebo, despite effectively inducing desensitisation." References Further reading The PALISADE Group of Clinical Investigators (November 2018). "AR101 Oral Immunotherapy for Peanut Allergy". New England Journal of Medicine. 379 (21): 1991–2001. doi:10.1056/nejmoa1812856. ISSN 0028-4793. PMID 30449234. Bird JA, Spergel JM, Jones SM, et al. (2018). "Efficacy and Safety of AR101 in Oral Immunotherapy for Peanut Allergy: Results of ARC001, a Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial". J Allergy Clin Immunol Pract. 6 (2): 476–485.e3. doi:10.1016/j.jaip.2017.09.016. PMID 29092786. Allergenic Products Advisory Committee September 13, 2019 Meeting Transcript (PDF) (Report). U.S. Food and Drug Administration. Dufresne É, Poder TG, Bégin P (October 2019). "The value of oral immunotherapy". Allergy. Wiley. 75 (6): 1291–93. doi:10.1111/all.14072. ISSN 0105-4538. PMID 31579934. External links "Peanut allergy". Drug Information Portal. U.S. National Library of Medicine.
Idursulfase	Idursulfase (brand name Elaprase), manufactured by Takeda, is a drug used to treat Hunter syndrome (also called MPS-II). It is a purified form of the lysosomal enzyme iduronate-2-sulfatase and is produced by recombinant DNA technology in a human cell line. It is one of the most expensive drugs ever produced, costing US$567,412 per patient per year. References External links idursulfase at the US National Library of Medicine Medical Subject Headings (MeSH)
Ty21a	Ty21a is a live attenuated bacterial vaccine that protects against typhoid. First licensed in Europe in 1983 and in the United States in 1989, it is an orally administered, live-attenuated Ty2 strain of S. Typhi in which multiple genes, including the genes responsible for the production of Vi, have been deleted so as to render it harmless but nevertheless immunogenic. It is one of the three typhoid vaccines currently recommended by the World Health Organization (the other two being the Typhoid Conjugate Vaccine (TCV) and Vi capsular polysaccharide vaccine).The vaccine is given by mouth. The vaccine is presented either as enteric coated capsules or as a liquid suspension. The vaccine must be stored at 2 to 8 °C, but will retain its potency for 14 days at 25 °C. Medical uses The vaccine offers a statistically significant protection for the first seven years. The vaccine is most commonly used to protect travelers to endemic countries, but some agencies claim that the vaccine could be used in large scale public prevention programs.The Vi polysaccharide vaccine is also effective at preventing typhoid fever. Dosing The recommended dose varies according to country and preparation. At least three doses are required for protection.In the US and Canada, an initial course of 4 doses on alternate days is recommended. Full protection is achieved 7 days after the last dose. In the US, a booster dose is recommended after 5 years. In Canada, a booster dose is recommended after 7 years.In Australia and Europe, an initial course of 3 doses on alternate days is recommended. Protection is achieved 7 days after the last dose. A booster dose is recommended every 3 years for people living in endemic areas, but every year for people traveling from non-endemic to endemic areas. Side effects Side effects of this vaccine are mild and rare. Trade names Vivotif (manufactured by PaxVax) Research Ty21a may also provide some degree of protection against paratyphoid fever A and B. This cross-protection by a typhoid vaccine is most likely due to O antigens shared between different S. enterica serotypes.A newer Vi-rEPA vaccine is being tested for preventing typhoid fever. It has a similar level of protection, but the protection may last longer with this newer vaccine. References External links Manufacturers Product Page
Goserelin	Goserelin, sold under the brand name Zoladex among others, is a medication which is used to suppress production of the sex hormones (testosterone and estrogen), particularly in the treatment of breast and prostate cancer. It is an injectable gonadotropin releasing hormone agonist (GnRH agonist). Structurally, it is a decapeptide. It is the natural GnRH decapeptide with two substitutions to inhibit rapid degradation. Goserelin stimulates the production of the sex hormones testosterone and estrogen in a non-pulsatile (non-physiological) manner. This causes the disruption of the endogenous hormonal feedback systems, resulting in the down-regulation of testosterone and estrogen production. It was patented in 1976 and approved for medical use in 1987. It is on the World Health Organizations List of Essential Medicines. Medical uses Goserelin is used to treat hormone-sensitive cancers of the breast (in pre- and peri-menopausal women) and prostate, and some benign gynaecological disorders (endometriosis, uterine fibroids and endometrial thinning). In addition, goserelin is used in assisted reproduction and in the treatment of precocious puberty. It may also be used in the treatment of male-to-female transgender people and is favoured above other anti-androgens in some countries, such as the UK. It is available as a 1-month depot and a long-acting 3-month depot. Goserelin is administered by subcutaneous injection as an implant every 28 days for the duration of treatment. Side effects Goserelin may cause a temporary increase in bone pain and symptoms of prostatic cancer during the first few weeks of treatment. This is known as the tumour flare effect, and is the result of an initial increase in luteinizing hormone production, before the receptors are desensitised and hormonal production is inhibited. The symptoms will disappear, with hormonal inhibition. It is therefore advisable to co-treat with an antiandrogen during the first 2–3 weeks of goserelin treatment, particularly in patients with pre-existing bone symptoms.Goserelin may cause bone pain, hot flushes, headache, stomach upset, depression, difficulty urinating (isolated cases), weight gain, swelling and tenderness of breasts (infrequent), decreased erections and reduced sexual desire. Bone pain can be managed symptomatically, and erectile dysfunction can be treated by vardenafil (Levitra) or other similar oral therapies, although they will not treat the reduced sexual desire. The rates of gynecomastia with goserelin have been found to range from 1 to 5%.Short-term memory impairment has also been reported in women and may in some cases be severe, but this effect disappears gradually once treatment is discontinued. Pharmacology Goserelin is a synthetic analogue of a naturally occurring gonadotropin-releasing hormone (GnRH). Bioavailability is almost complete by injection. Goserelin is poorly protein-bound and has a serum elimination half-life of two to four hours in patients with normal renal function. The half-life increases with patients with impaired renal function. There is no significant change in pharmacokinetics in subjects with liver failure. After administration, peak serum concentrations are reached in about two hours. It rapidly binds to the GnRH receptor cells in the pituitary gland thus leading to an initial increase in production of luteinizing hormone and thus leading to an initial increase in the production of corresponding sex hormones. This initial flare may be treated by co-prescribing/co-administering an androgen receptor antagonist such as bicalutamide (Casodex). Eventually, after a period of about 14–21 days, production of LH is greatly reduced due to receptor downregulation, and sex hormones are generally reduced to castrate levels. Chemistry Goserelin is a GnRH analogue and decapeptide. It is provided as the acetate salt. Society and culture Generic names Goserelin is the generic name of the drug and its INN, USAN, and BAN. References External links "Goserelin acetate". Drug Information Portal. U.S. National Library of Medicine.
Emedastine	Emedastine (trade name Emadine) is a second generation antihistamine used in eye drops to alleviate the symptoms of allergic conjunctivitis. It acts as a H1 receptor antagonist. It works by blocking the action of histamine that causes allergic symptoms. It is used in form of the difumarate. The emedastine difumarate is a white, crystalline, water-soluble fine powder. Emedastine eye drops is usually applied twice a day to the affected eye. When the patients with allergic conjunctivitis were treated with 0.05% emedastine difumarate ophthalmic solution for six weeks, the signs and symptoms such as redness, itching and swelling of the eyes were relieved. Emedastine appears to be devoid of effects on adrenergic, dopaminergic and serotonin receptors. This drug was developed by Alcon, which is global medical company specializing in eye care products. Pharmacodynamics Emedastine is significantly selective to H1 histamine receptors (Ki = 1.3 nM), whereas its affinities for other histamine receptors were low (H2: Ki = 49067 nM and H3: Ki = 12430 nM) ub in vitro study. Topical ocular administration of emedastine inhibits histamine-stimulated vascular permeability in the conjunctiva as a concentration-dependent manner in in vitro study. Pharmacokinetics The human oral bioavailability is approximately 50% and maximum plasma concentration was achieved within 1–2 hours after dosing. Emedastine is mainly metabolized by the liver. There are two primary metabolites: 5-hydroxyemedastine and 6-hydroxyemedastine. They are excreted in the urine as both free and conjugated forms. The 5-oxoanalogs of 5-hydroxyemedastine, 6-hydroxyemedastine and the N-oxide are also formed as minor metabolites. The elimination half-life of oral emedastine in plasma is 3–4 hours, whereas that of topical emedastine is 10 hours. Approximately 44% of the oral dose is recovered in the urine over 24 hours with only 3.6% of the dose excreted as parent drug. Contraindications Emedastine should not be used in patients who are hypersensitive to emedastine or any other excipients of the preparation. Benzalkonium chloride contained in the bottle of emedastine solution can discolor soft contact lenses, so people who wear contact lenses should be careful using it. Adverse events The most common adverse effect was headache (11%). The other minor adverse effects encountered in less than 5% of patients were asthenia, burning or stinging sensation, unpleasant taste, blurred vision, eye dryness and tearing. == References ==
Atenolol	Atenolol is a beta blocker medication primarily used to treat high blood pressure and heart-associated chest pain. Atenolol, however, does not seem to improve mortality in those with high blood pressure. Other uses include the prevention of migraines and treatment of certain irregular heart beats. It is taken by mouth or by injection into a vein. It can also be used with other blood pressure medications.Common side effects include feeling tired, heart failure, dizziness, depression, and shortness of breath. Other serious side effects include bronchospasm. Use is not recommended during pregnancy and alternative drugs are preferred when breastfeeding. It works by blocking β1-adrenergic receptors in the heart, thus decreasing the heart rate and workload.Atenolol was patented in 1969 and approved for medical use in 1975. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2020, it was the 53rd most commonly prescribed medication in the United States, with more than 12 million prescriptions. Medical uses Atenolol is used for a number of conditions including hyperthyroidism, hypertension, angina, long QT syndrome, acute myocardial infarction, supraventricular tachycardia, ventricular tachycardia, and the symptoms of alcohol withdrawal.The role for β-blockers in general in hypertension was downgraded in June 2006 in the United Kingdom, and later in the United States, as they are less appropriate than other agents such as ACE inhibitors, calcium channel blockers, thiazide diuretics and angiotensin receptor blockers, particularly in the elderly. Side effects Hypertension treated with a β-blocker such as atenolol, alone or in conjunction with a thiazide diuretic, is associated with a higher incidence of new onset type 2 diabetes mellitus compared to those treated with an ACE inhibitor or angiotensin receptor blocker. β-blockers, of which atenolol is mainly studied, provides weaker protection against stroke and mortality in patients over 60 years old compared to other antihypertensive medications. Diuretics may be associated with better cardiovascular and cerebrovascular outcomes than β-blockers in the elderly. Overdose Symptoms of overdose are due to excessive pharmacodynamic actions on β1 and also β2-receptors. These include bradycardia (slow heartbeat), severe hypotension with shock, acute heart failure, hypoglycemia and bronchospastic reactions. Treatment is largely symptomatic. Hospitalization and intensive monitoring is indicated. Activated charcoal is useful to absorb the drug. Atropine will counteract bradycardia, glucagon helps with hypoglycemia, dobutamine can be given against hypotension and the inhalation of a β2-mimetic as hexoprenalin or salbutamol will terminate bronchospasms. Blood or plasma atenolol concentrations may be measured to confirm a diagnosis of poisoning in hospitalized patients or to assist in a medicolegal death investigation. Plasma levels are usually less than 3 mg/L during therapeutic administration, but can range from 3–30 mg/L in overdose victims. Society and culture Atenolol has been given as an example of how slow healthcare providers are to change their prescribing practices in the face of medical evidence that indicates that a drug is not as effective as others in treating some conditions. In 2012, 33.8 million prescriptions were written to American patients for this drug. In 2014, it was in the top (most common) 1% of drugs prescribed to Medicare patients. Although the number of prescriptions has been declining steadily since limited evidence articles contesting its efficacy was published, it has been estimated that it would take 20 years for doctors to stop prescribing it for hypertension. Despite its diminished efficacy when compared to newer antihypertensive drugs, atenolol and other beta blockers are still a relevant clinical choice for treating some conditions, since beta blockers are a diverse group of medicines with different properties that still requires further research. As consequence, reasons for the popularity of beta blockers cannot be fully attributed to a slow healthcare system – patient compliance factor, such as treatment cost and duration, also affect adherence and popularity of therapy. References External links "Atenolol". Drug Information Portal. U.S. National Library of Medicine.
Pioglitazone/metformin	Pioglitazone/metformin, sold under the brand name Actoplus Met among others, is a fixed-dose combination anti-diabetic medication used to improve glycemic control in adults with type 2 diabetes. It contains pioglitazone, a thiazolidinedione, and metformin, a biguanide. Mechanisms Pioglitazone is a member of the thiazolidinedione class, it decreases insulin resistance in the periphery and in the liver resulting in increased insulin dependent glucose disposal and decreased hepatic glucose output. Metformin is a member of the biguanide class, improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Indication Pioglitazone/metformin is indicated as an adjunct to diet and exercise: To improve glycemic control in patients with type 2 diabetes, or For patients who are already treated with a separate combination of pioglitazone and metformin, For patients whose diabetes is not adequately controlled with metformin alone, or For patients who have initially responded to pioglitazone alone and require additional glycemic control. Dosage and administration Use in pregnancy and lactation Pioglitazone/metformin should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant women with combination of pioglitazone and metformin or its individual components. It is not known whether pioglitazone and/or metformin are secreted in human milk. Because many drugs are excreted in human milk, pioglitazone/metformin should not be administered to a breastfeeding woman. Precautions Pioglitazone/metformin should not be used in people with type 1 diabetes or for the treatment of diabetic ketoacidosis and should be used with caution in people with edema. Serum ALT levels should be evaluated prior to the initiation of therapy with combination of pioglitazone and metformin and periodically thereafter per the clinical judgment of the health care professional. Side-effects The most common side-effects are upper respiratory tract infection, diarrhea, combined edema/peripheral edema and headache, respectively. Most clinical adverse events were similar between groups treated with pioglitazone in combination with metformin and those treated with pioglitazone monotherapy. Contraindications Pioglitazone/metformin is contraindicated in people with known hypersensitivity to any components of this combination. These combination also contraindicated in renal disease which may also result from conditions, e.g., acute myocardial infarction, sepsis, acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Drug interaction Pioglitazone/metformin may interact with furosemide, nifedipine, cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) and certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control (e.g., thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid). References External links "Metformin hydrochloride mixture with pioglitazone hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Clotrimazole/betamethasone dipropionate	Clotrimazole/betamethasone dipropionate, sold under the brand name Lotrisone among others, is a topical medication used for the treatment of fungal infections of the feet, groin, and body in people 17 years of age and older. It is a combination of clotrimazole and betamethasone dipropionate. It is applied to the skin.Common side effects include paresthesia, rash, edema, and secondary infections.In 2019, it was the 366th most commonly prescribed medication in the United States, with more than 600 thousand prescriptions. Medical uses Clotrimazole/betamethasone dipropionate is indicated for the topical treatment of symptomatic inflammatory tinea pedis, tinea cruris, and tinea corporis due to Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton rubrum in people 17 years of age and older. Society and culture Legal status Clotrimazole/betamethasone dipropionate cream was approved for medical use in the United States in July 1984, and the lotion was approved for use in the United States in December 2000. References External links "Betamethasone dipropionate mixture with Clotrimazole". Drug Information Portal. U.S. National Library of Medicine. "Betamethasone Topical: MedlinePlus Drug Information". MedlinePlus. "Clotrimazole Topical: MedlinePlus Drug Information". MedlinePlus.
Calfactant	Calfactant, also known as Infasurf, is an intratracheal suspension derived from the natural surfactant in calf lungs. It is used in premature infants with lung surfactant deficiency that causes infant respiratory distress syndrome (IRDS). Mechanism of action Lung surfactant is essential for effective ventilation as it modifies alveolar surface tension. IRDS is caused by a lung surfactant deficiency. Calfactant serves as a substitute for the natural surfactant. == References ==
Tolbutamide	Tolbutamide is a first-generation potassium channel blocker, sulfonylurea oral hypoglycemic medication. This drug may be used in the management of type 2 diabetes if diet alone is not effective. Tolbutamide stimulates the secretion of insulin by the pancreas. It is not routinely used due to a higher incidence of adverse effects compared to newer, second-generation sulfonylureas, such as Glibenclamide. It generally has a short duration of action due to its rapid metabolism, so is safe for use in older people. It was discovered in 1956. Side effects Hypoglycemia Weight gain Hypersensitivity: cross-allergicity with sulfonamides Drug interactions (especially first-generation drugs): Increased hypoglycemia with cimetidine, insulin, salicylates, and sulfonamidesSalicylates displace tolbutamide from its binding site on plasma binding proteins which lead to increase in free tolbutamide concentration, thus hypoglycemic shock. History Orinase was developed by Upjohn Co. at a time when the primary medical treatment for diabetes was insulin injections. Eli Lilly had a lock on the market for insulin production at the time. Orinase, like other treatments for drugs detected by so-called paraclinical signs rather than clinically observable signs or patient-reported symptoms, benefitted from an increased sensitivity and availability of blood glucose testing. Milton Moskowitz (editor in 1961 of Drug and Cosmetic Industry) claimed the introduction of Orinase, "expanded the total market by bringing under medical care diabetics who were formerly not treated." It did this by changing the mindset about diabetes even more than insulin had. Treatment of this chronic disease was no longer seen as a mere slowing of "inexorable degeneration", but instead viewed through "a model of surveillance and early detection.": 84 Orinase and other sulfonylureas emerged from European pharmaceutical research into antibiotics, specifically from attempts to develop sulfa compounds. One of the contenders for a new sulfa antibiotic had serious side effects during clinical trials at the University of Montpellier including blackouts, convulsions, and coma, side effects not observed with any other drugs in the sulfa cohort. An insulin researcher at the same university heard of these side effects and recognized them as common results of hypoglycemia. The resulting class of drugs for lowering blood sugar came to be known as the sulfonylureas, starting with Orinase and still in use today in other forms. Unfortunately for diabetics dependent on insulin as a treatment for their condition, this research at Montpellier occurred in the early 1940s and was significantly disrupted by the German occupation of France during World War II. Development of these compounds was taken over by German pharmaceutical companies, which were obviously disinclined to share their bounty with nations upon which they were waging war. The German research was, in turn, disrupted by Germanys defeat in 1945 and the partition of Germany into East and West Germany. The sulfonylureas were trapped in East Germany. In 1952, someone smuggled a sample to a West German pharmaceutical company and research resumed. Clinical trials in diabetics began in 1954 in Berlin. In 1956, two different sulfonylureas were brought to market in Germany under the trade names Nadisan and Rastinon. American pharmaceutical companies in the postwar period had been seeking to establish business relations with the remnants of German pharmaceutical giants weakened by the war and partition of Germany. Upjohn (based in Kalamazoo until its purchase by Pharmacia in the 1990s) made deals with Hoechst, maker of Rastinon. The result was a cross-licensing agreement which produced Orinase. Upjohn stood to open up a whole new arena of treatment for diabetes, one with a built-in and sustainable market, i.e. patient population. Just as two German companies brought sulfonylureas to market within the same year, Upjohn discovered Eli Lilly had begun clinical trials for carbutamide, another oral hypoglycemic. Upjohn pushed for large-scale clinical trials from 1955–1957, enrolling over 5,000 patients at multiple sites. Upjohns formulation was preferred when the Lilly formulation demonstrated evidence of toxicity in parallel trials at the Joslin Clinic. Lilly pulled carbutamide and halted development, leaving the field open for Upjohn to market its new treatment. In 1956, Upjohn filed for approval from the Food and Drug Administration. Jeremy A. Greene found the applications size – 10,580 pages in 23 volumes with 5,786 cases reports – was necessary to "render visible the relatively small improvements provided in less severe forms of diabetes." Indeed, Orinase was marketed by Upjohn not as a cure-all for all diabetics, but specifically as a treatment that was "not an oral insulin" and "did not work in all diabetics". Those were the instructions for marketing given to Upjohns salespeople. As indicated by the FDA application, Orinase had been demonstrated "not to be effective in severe diabetes, but only in milder cases of the disease.": 93 Orinase was one of a new class of drugs (including treatments for hypertension and hypercholesterolemia) aimed at providing marginal benefits over existing treatments for patients who had not previously been a target market for pharmaceuticals. As blood sugar testing for diagnosis of diabetes became more widespread, a curious side effect occurred: because blood sugar testing is not absolutely definitive in diagnoses of diabetes, more people were receiving borderline tests regarding their glycemic status. These borderline persons could be considered as being at risk for diabetes – prediabetic. Prediabetic patients have elevated blood sugar, but normal levels of sugar in their urine (glycosuria). Upjohn saw an opportunity to benefit and definitely market to a yet-greater expansion of the diabetic population, beyond even the "hidden diabetics" revealed by earlier public health campaigns. Upjohn also found a new use for Orinase: as a diagnostic. Orinase Diagnostic was added to the Orinase product line and, by 1962, was being sold as means of detecting prediabetes in that an abnormal response to Orinase following administration of cortisone in a "stress test" could be taken to indicate prediabetes. Orinase thus not only served to detect a previously hidden patient population, but also detected a patient population most likely to be interested in Orinase as a treatment for their newly diagnosed prediabetes. By the late 1960s, Orinase Diagnostic was withdrawn and the drug reverted to its therapeutic purpose. By that point, prediabetes had become a diagnosable and treatable condition which had dramatically increased the market for Orinase. Orinase began to fall out of favor in May 1970 when asymptomatic prediabetics on long-term regimens of Orinase began to see news reports (beginning with the Washington Post) that Orinase may have serious side effects including death from cardiovascular problems, according to a long-term study. In many cases, patients learned of this before their physicians, and also before FDA could advise relabeling the medication or suggesting alterations in appropriate usage. The question of whether Orinase did or did not increase cardiovascular problems has not been conclusively settled. The result was that Orinase and other medical treatments for prediabetes were "rolled back" by the FDA and practitioners in an attempt to focus on symptomatic patients for whom the risks of treatment might be balanced by the symptoms of the disease. Pharmacia and Upjohn (now merged) stopped making Orinase in 2000, though a generic is still available and occasionally used. Historical consequences The history of tolbutamide has had a lasting effect on medicine and the pharmaceutical industry. Patients today are still diagnosed with prediabetes, many of them managing to delay the onset of diabetes through dietary and lifestyle changes, but many also have the option to take metformin, which demonstrated a 31% reduction in three-year incidence of development of diabetes relative to placebo. While impressive, the lifestyle-modification arm of that same trial demonstrated a 58% reduction. See also Chlorpropamide == References ==
Basiliximab	Basiliximab (trade name Simulect) is a chimeric mouse-human monoclonal antibody to the α chain (CD25) of the IL-2 receptor of T cells. It is used to prevent rejection in organ transplantation, especially in kidney transplants. Uses Basiliximab is an immunosuppressant agent used to prevent immediate transplant rejection in people who are receiving kidney transplants, in combination with other agents. It has been reported that some cases of lichen planus have been successfully treated with basiliximab as an alternative therapy to cyclosporin. No short-term side effects have been reported. Mechanism of action Basiliximab competes with IL-2 to bind to the alpha chain subunit of the IL2 receptor on the surface of the activated T lymphocytes and thus prevents the receptor from signaling. This prevents T cells from replicating and also from activating B cells, which are responsible for the production of antibodies, which would bind to the transplanted organ and stimulate an immune response against the transplant. Chemistry It is a chimeric CD25 monoclonal antibody of the IgG1 isotype. History It is a Novartis product and was approved by the Food and Drug Administration (FDA) in 1998. See also Daclizumab == References and notes ==
Digoxin	Digoxin (better known as Digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is one of the oldest medications used in the field of cardiology. It works by increasing myocardial contractility, increasing stroke volume and blood pressure, reducing heart rate, and somewhat extending the time frame of the contraction. Digoxin is taken by mouth or by injection into a vein. Digoxin has a half life of approximately 36 hours given at average doses in patients with normal renal function. It is excreted mostly unchanged in the urine. Common side effects include breast enlargement with other side effects generally due to an excessive dose. These side effects may include loss of appetite, nausea, trouble seeing, confusion, and an irregular heartbeat. Greater care is required in older people and those with poor kidney function. It is unclear whether use during pregnancy is safe.Digoxin is in the cardiac glycoside family of medications. It was first isolated in 1930 from the foxglove plant, Digitalis lanata. It is on the World Health Organizations List of Essential Medicines. In 2019, it was the 206th most commonly prescribed medication in the United States, with more than 2 million prescriptions. Medical uses Irregular heartbeat The most common indications for digoxin are atrial fibrillation and atrial flutter with rapid ventricular response, though beta blockers and/or calcium channel blockers may be preferred in some patients, such as those without heart failure or hemodynamic instability.Some reviews suggest that digoxin increases the risk of death, while others suggest no change in mortality. It has been suggested that the effect on mortality seen in some studies was due to inappropriately high doses of digoxin and that the low doses often used in practice (levels <0.9 ng/mL) may not increase mortality. Cardiac arrhythmias may also occur when patients are prescribed digoxin alongside thiazides and loop diuretics. Heart failure Digoxin is no longer the first choice for heart failure; it has fallen out of favor in people with heart failure because it may increase the risk of death. Currently, the recommendation for heart failure is a triple therapy of ACE inhibitor, beta blocker and mineralocorticoid antagonists. Digoxin is a third-line therapy. Abortion Digoxin is also used intrafetally or amniotically during abortions in the late second trimester and third trimester of pregnancy. It typically causes fetal demise (measured by cessation of cardiac activity) within hours of administration. Side effects The occurrence of adverse drug reactions is common, owing to its narrow therapeutic index (the margin between effectiveness and toxicity). Gynaecomastia (enlargement of breast tissue) is mentioned in many textbooks as a side effect, thought to be due to the estrogen-like steroid moiety of the digoxin molecule, but when systematically sought, the evidence for this is equivocal as of 2005. The combination of increased (atrial) arrhythmogenesis and inhibited atrioventricular (AV) conduction (for example paroxysmal atrial tachycardia with AV block – so-called "PAT with block") is said to be pathognomonic (that is, diagnostic) of digoxin toxicity.Digoxin can lead to cardiac arrhythmias when given with thiazides and loop diuretics. This is because co-administration of Digoxin with drugs such as thiazides and loop diuretics which can cause hypokalemia, low serum levels of potassium in the blood. This exacerbates the potential for cardiac arrythmias because the low levels of potassium reduces the amount of K+ at the ATPase pump and increase calcium levels too much which leads to these arrythmias. It can also cause visual disturbances as well as dizziness or fainting. Several other drugs associated with ADRs in concommitant use include verapamil, amiodarone, quinidine, tetracycline, and erythromycin. Overdose In overdose, the usual supportive measures are needed. If arrhythmias prove troublesome, or malignant hyperkalemia occurs (inexorably rising potassium level due to paralysis of the cell membrane-bound, ATPase-dependent Na/K pumps), the specific antidote is antidigoxin (antibody fragments against digoxin, trade names Digibind and Digifab). The mechanism of action for drugs such as Digibind and Digifab, used when adverse events occur with the use of digoxin, is that the FAB regions on the antibodies created against digoxin expedite the excretion of the drug into urine. Therefore, the amount of digoxin in the body decreases quickly as it gets excreted rapidly. Pharmacology Pharmacodynamics Digoxins primary mechanism of action involves inhibition of the sodium potassium adenosine triphosphatase (Na+/K+ ATPase), mainly in the myocardium. This inhibition causes an increase in intracellular sodium levels, resulting in decreased activity of the sodium-calcium exchanger, which normally imports three extracellular sodium ions into the cell and transports one intracellular calcium ion out of the cell. The reversal of this exchanger, triggered by the increase in intracellular sodium, results in an increase in the intracellular calcium concentration that is available to the contractile proteins. The increased calcium concentrations lead to the binding of more calcium to troponin C, which results in increased inotropy. Increased intracellular calcium lengthens phase 4 and phase 0 of the cardiac action potential, which leads to a decrease in heart rate. Increased amounts of Ca2+ also leads to increased storage of calcium in the sarcoplasmic reticulum, causing a corresponding increase in the release of calcium during each action potential. This leads to increased contractility (the force of contraction) of the heart without increasing heart energy expenditure.The inhibition of the sodium pump may also improve baroreceptor sensitivity in heart failure and may explain some of the neurohormonal effects of digoxin.Digoxin also has important parasympathetic effects, particularly on the atrioventricular node. While it does increase the magnitude of myocardial contractility, the duration of the contraction is only slightly increased. Its use as an antiarrhythmic drug, then, comes from its direct and indirect parasympathetic stimulating properties. Vagus nerve stimulation slows down conduction at the AV node by increasing the refractory period of cardiac myocytes. The slowed AV node gives the ventricles more time to fill before contracting. This negative chronotropic effect is synergistic with the direct effect on cardiac pacemaker cells. The arrhythmia itself is not affected, but the pumping function of the heart improves, owing to improved filling. Overall, the heart rate is decreased while stroke volume is increased, resulting in a net increase in blood pressure, leading to increased tissue perfusion. This causes the myocardium to work more efficiently, with optimized hemodynamics and an improved ventricular function curve. Other electrical effects include a brief initial increase in action potential, followed by a decrease as the K+ conductance increases due to increased intracellular amounts of Ca2+ ions. The refractory period of the atria and ventricles is decreased, while it increases in the sinoatrial and AV nodes. A less negative resting membrane potential is made, leading to increased irritability. The conduction velocity increases in the atria, but decreases in the AV node. The effect upon Purkinje fibers and ventricles is negligible. Automaticity is also increased in the atria, AV node, Purkinje fibers, and ventricles.ECG changes seen in people taking digoxin include increased PR interval (due to decreased AV conduction) and a shortened QT interval. Also, the T wave may be inverted and accompanied by ST depression. It may cause AV junctional rhythm and ectopic beats (bigeminy) resulting in ventricular tachycardia and fibrillation. Pharmacokinetics Digoxin is usually given orally, but can also be given by IV injection in urgent situations (the IV injection should be slow, and heart rhythm should be monitored). While IV therapy may be better tolerated (less nausea), digoxin has a very long distribution half-life into the cardiac tissue, which will delay its onset of action by a number of hours. The half-life is about 36 hours for patients with normal renal function, digoxin is given once daily, usually in 125 μg or 250 μg doses.Digoxin elimination is mainly by renal excretion and involves P-glycoprotein, which leads to significant clinical interactions with P-glycoprotein inhibitor drugs. Examples commonly used in patients with heart problems include spironolactone, verapamil and amiodarone. In patients with decreased kidney function the half-life is considerably longer, along with decrease in Vd (volume of distribution), calling for a reduction in dose or a switch to a different glycoside, such as digitoxin (not available in the United States), which has a much longer elimination half-life of around seven days and is eliminated by the liver.Effective plasma levels vary depending on the medical indication. For congestive heart failure, levels between 0.5 and 1.0 ng/mL are recommended. This recommendation is based on post hoc analysis of prospective trials, suggesting higher levels may be associated with increased mortality rates. For heart rate control (atrial fibrillation), plasma levels are less defined and are generally titrated to a goal heart rate. Typically, digoxin levels are considered therapeutic for heart rate control between 0.5 and 2.0 ng/mL (or 0.6 and 2.6 nmol/L). In suspected toxicity or ineffectiveness, digoxin levels should be monitored. Plasma potassium levels also need to be closely controlled (see side effects, below). Quinidine, verapamil, and amiodarone increase plasma levels of digoxin (by displacing tissue binding sites and depressing renal digoxin clearance), so plasma digoxin must be monitored carefully when coadministered.A study which looked to see if digoxin affected men and women differently found that digoxin did not reduce deaths overall, but did result in less hospitalization. Women who took digoxin died "more frequently" (33%) than women who took placebo (29%). Digoxin increased the risk of death in women by 23%. There was no difference in the death rate for men in the study.Digoxin is also used as a standard control substance to test for P-glycoprotein inhibition.Digoxin appears to be a peripherally selective drug due to limited brain uptake caused by binding to P-glycoprotein. Pharmacomicrobiomics The bacteria Eggerthella lenta has been linked to a decrease in the toxicity of Digoxin. These effects have been studied through comparisons of North Americans and Southern Indians, in which a reduced digoxin metabolite profile correlates with E. lentum abundance. Further studies have also revealed an increase in digoxin toxicity when used alongside erythromycin or tetracycline, the researches attributed this to the decrease in the E. lentum population.Overall, bacterial inactivation of Digoxin, as in Digoxin being inactivated by bacteria in the gut microbiome occurs often. This is why Digoxin is given as a capsule or as a solution in capsule. History Derivatives of plants of the genus Digitalis have a long history of medical use. The English physician William Withering is credited with the first published description of the use of Digitalis derivatives in his 1785 book An Account of the Foxglove and some of its Medical Uses With Practical Remarks on Dropsy and Other Diseases. Its effects were first explained by Arthur Robertson Cushny. The name is derived from that of digitoxin, which explains its pronunciation. In 1930, Digoxin was first isolated by Dr. Sydney Smith from the foxglove plant, Digitalis lanata. Initially, the digoxin was purified by dissolving the dried plant material in acetone and boiling the solution in chloroform. The solution was then reacted with acetic acid and small amount of ferric chloride and sulfuric acid (Keller reaction). Digoxin was distinguishable from other glucosides by the olive-green colored solution produced from this reaction, completely free of red. Society and culture Charles Cullen admitted in 2003 to killing as many as 40 hospital patients with overdoses of heart medication—usually digoxin—at hospitals in New Jersey and Pennsylvania over his 19-year career as a nurse. On March 10, 2006, he was sentenced to 18 consecutive life sentences and is not eligible for parole.On April 25, 2008, the U.S. Federal Drug Administration (FDA) issued a press release alerting the public to a Class I recall of Digitek, a brand of digoxin produced by Mylan. Some tablets had been released at double thickness and therefore double strength, causing some patients to experience digoxin toxicity. A class-action lawsuit against the Icelandic generic drug maker Actavis was announced two weeks later.On March 31, 2009, the FDA announced another generic digoxin pill recall by posting this company press release on the agencys web site: "Caraco Pharmaceutical Laboratories, Ltd. Announces a Nationwide Voluntary Recall of All Lots of Digoxin Tablets Due to Size Variability". A March 31 press release from Caraco, a generic pharmaceutical company, stated: [All] tablets of Caraco brand Digoxin, USP, 0.125 mg, and Digoxin, USP, 0.25 mg, distributed prior to March 31, 2009, which are not expired and are within the expiration date of September, 2011, are being voluntarily recalled to the consumer level. The tablets are being recalled because they may differ in size and therefore could have more or less of the active ingredient, digoxin. A 2008 study suggested digoxin has beneficial effects not only for the heart, but also in reducing the risk of certain kinds of cancer. However, comments on this study suggested that digoxin is not effective at reducing cancer risk at therapeutic concentrations of the drug, so the results need further investigation. Brand names Digoxin preparations are marketed under the brand names Cardigox; Cardiogoxin; Cardioxin; Cardoxin; Coragoxine; Digacin; Digicor; Digomal; Digon; Digosin; Digoxine Navtivelle; Digoxina-Sandoz; Digoxin-Sandoz; Digoxin-Zori; Dilanacin; Eudigox; Fargoxin; Grexin; Lanacordin; Lanacrist; Lanicor; Lanikor; Lanorale; Lanoxicaps; Lanoxin; Lanoxin PG; Lenoxicaps; Lenoxin; Lifusin; Mapluxin; Natigoxin; Novodigal; Purgoxin; Sigmaxin; Sigmaxin-PG; Toloxin. Digoxin and cancer Cardiac glycosides, particularly digoxin, have been conventionally used for treatment of common cardiac problems, mainly heart failure and cardiac arrhythmias. The interaction of digoxin and cancer has also been studied. Despite existence of numerous preclinical studies that investigated the anticancer effects of digoxin, there are no solid and conclusive results so far. Several studies have suggested that digoxin may have anticancer properties, others not.Digoxin, as a cardiac glycoside, has a chemical structure basically similar to that of estradiol. Digoxin has the ability to bind oestrogen receptors, and therefore it has been proposed that it might increase the risk of oestrogen-sensitive breast and uterine cancers. A large Danish study found a complicated picture, with slightly increased risk of breast cancer amongst women taking digoxin, but better prognostic features. The Nurses Health Study found a similar slight increase of risk.Digoxin inhibits the proliferation of many cancerous cell lines in vitro, but its relevance to cancer in vivo remains unclear. References Further reading External links "Digoxin". Drug Information Portal. U.S. National Library of Medicine. Commonly used website to calculate empiric digoxin doses for medical purposes for heart problems
Tafluprost	Tafluprost (trade names Taflotan by Santen Pharmaceutical, Zioptan by Merck in the US and Saflutan by Mundipharma in Australia) is a prostaglandin analogue. It is used topically (as eye drops) to control the progression of open-angle glaucoma and in the management of ocular hypertension, alone or in combination with other medication. It reduces intraocular pressure by increasing the outflow of aqueous fluid from the eyes. Adverse effects The most common side effect is conjunctival hyperemia, which occurs in 4 to 20% of patients. Less common side effects include stinging of the eyes, headache, and respiratory infections. Rare side effects are dyspnoea (breathing difficulties), worsening of asthma, and macular oedema. Interactions Nonsteroidal anti-inflammatory drugs (NSAIDs) can either reduce or increase the effect of tafluprost. Timolol eye drops, a common kind of glaucoma medication, does not negatively interact with this drug.No interactions with systemic (for example, oral) drugs are expected because tafluprost does not reach relevant concentrations in the bloodstream. Pharmacology Mechanism of action Tafluprost is a prodrug of the active substance, tafluprost acid, a structural and functional analogue of prostaglandin F2α (PGF2α). Tafluprost acid is a selective agonist at the prostaglandin F receptor, increasing outflow of aqueous fluid from the eyes and thus lowering intraocular pressure.Other PGF2α analogues with the same mechanism include latanoprost and travoprost. Pharmacokinetics Tafluprost, as a lipophilic ester, easily penetrates the cornea and is then activated to the carboxylic acid, tafluprost acid. Onset of action is 2 to 4 hours after application, the maximal effect is reached after 12 hours, and ocular pressure remains lowered for at least 24 hours.Tafluprost acid is inactivated by beta oxidation to 1,2-dinortafluprost acid, 1,2,3,4-tetranortafluprost acid, and its lactone, which are subsequently glucuronidated or hydroxylated. The cytochrome P450 liver enzymes play no role in the metabolism.An analogous pathway (at least up to the tetranor-metabolites) has been found for latanoprost and travoprost. == References ==
Amifostine	Amifostine (ethiofos) is a cytoprotective adjuvant used in cancer chemotherapy and radiotherapy involving DNA-binding chemotherapeutic agents. It is marketed by Clinigen Group under the trade name Ethyol. Indications Amifostine is used therapeutically to reduce the incidence of neutropenia-related fever and infection induced by DNA-binding chemotherapeutic agents including alkylating agents (e.g. cyclophosphamide) and platinum-containing agents (e.g. cisplatin). It is also used to decrease the cumulative nephrotoxicity associated with platinum-containing agents. Amifostine is also indicated to reduce the incidence of xerostomia in patients undergoing radiotherapy for head and neck cancer. Amifostine was originally indicated to reduce the cumulative renal toxicity from cisplatin in non-small cell lung cancer. However, while nephroprotection was observed, the probability that amifostine could protect tumors could not be excluded. Additional data have shown that amifostine-mediated tumor protection, in any clinical scenario, is unlikely. Pharmacokinetics Amifostine is an organic thiophosphate prodrug which is hydrolysed in vivo by alkaline phosphatase to the active cytoprotective thiol metabolite, WR-1065. The selective protection of non-malignant tissues is believed to be due to higher alkaline phosphatase activity, higher pH, and vascular permeation of normal tissues. Amifostine can be administered intravenously or subcutaneously after reconstitution with normal saline. Infusions lasting less than 15 minutes decrease the risk of adverse effects. The patient should be well-hydrated prior to administration. Mechanism of action Inside cells, amifostine detoxifies reactive metabolites of platinum and alkylating agents, as well as scavenges free radicals. Other possible effects include accelerated DNA repair, induction of cellular hypoxia, inhibition of apoptosis, alteration of gene expression and modification of enzyme activity. Amifostine is believed to radioprotect normal tissue via Warburg-type effects. Adverse effects Common side effects of amifostine include hypocalcemia, diarrhea, nausea, vomiting, sneezing, somnolence, and hiccups. Serious side effects include: hypotension (found in 62% of patients), erythema multiforme, Stevens–Johnson syndrome and toxic epidermal necrolysis, immune hypersensitivity syndrome, erythroderma, anaphylaxis, and loss of consciousness (rare). Contraindications Contraindications to receiving amifostine include hypersensitivity to amifostine and aminothiol compounds like WR-1065. Ethyol contains mannitol. == References ==
Donnatal	Donnatal is a combination medication that provides natural belladonna alkaloids in a specific fixed ratio combined with phenobarbital to provide peripheral anticholinergic/antispasmodic action and mild sedation. Donnatal is manufactured for Concordia Pharmaceuticals by IriSys, LLC. It is available as tablets and 5 mL elixir. Active ingredients are listed as: phenobarbital (16.2 mg), hyoscyamine sulfate (0.1037 mg), atropine sulfate (0.0194 mg), and scopolamine hydrobromide (0.0065 mg). The latter two ingredients are found in plants of the family Solanaceae, such as belladonna. Indication Based on a review of this drug by the National Academy of Sciences–National Research Council and/or other information, FDA has classified the indications as follows: "possibly" effective: For use as adjunctive therapy in the treatment of irritable bowel syndrome (irritable colon, spastic colon, mucous colitis) and acute enterocolitis. May also be useful as adjunctive therapy in the treatment of duodenal ulcer. History Clinical Research with Combinations of Belladonna Alkaloids and Phenobarbital Clinical studies have been performed on different combinations of belladonna alkaloids and phenobarbital over the last 70 years. For example, Steigmann et al. evaluated a combination of 0.25 mg belladonna alkaloids and 50 mg phenobarbital on gastrointestinal symptoms in 93 patients. The population included 33 IBS patients. Eighteen out of 33 patients reported complete relief of symptoms and 13 reported fair response with partial relief within 24 hours. Only 2 IBS patients reported no response. A small assessment of sustained release of 0.4 mg belladonna alkaloids and ~60 mg phenobarbital (1 grain) was performed in patients with functional GI disorders (i.e., gastric hyperacidity, dyspepsia, pyrosis, gas pains and epigastric distress. Overall, 23 of 25 patients reported complete or significant relief of symptoms. Hock also examined the effect of 0.25 mg belladonna alkaloids and 50 mg phenobarbital sustained release formulation in 82 clinical practice patients with various gastrointestinal disturbances including “functional distress” over 27 months. Of the 82 total patients, 33 patients reported a 50-75% and 20 reported a 75-100% improvement. There were specific reports of improvements in pain and bowel habits in over half of the patients. One of the earliest randomized double-blind clinical trials of belladonna alkaloids + phenobarbital was in 1959 by Lichstein et al. The study involved 75 patients with unstable bowel (whose symptoms are typical or similar to a current diagnosis of IBS) to investigate the combination therapy of an anticholinergic with the addition of phenobarbital against placebo over 15 months. Of these patients, 20 were treated with placebo, 43 were treated with 50 mg phenobarbital in combination with 0.25 mg Belladonna alkaloids, and 12 received both therapies (patients who lacked a response were switched therapy). Of those receiving the belladonna alkaloids / phenobarbital only, 75.6% reported a mean improvement (2+ or better) in all categories. Among the placebo patients only, only 29.8% reported mean improvement in symptoms. When improvement was clinically assessed, 69% of belladonna alkaloids/phenobarbital patients were reported to improve compared to 24% of placebo patients. For the 12 patients who were switched therapies, it was found that they originally were given placebo and switched to treatment therapy. While on placebo, 11.1% of patients reported a mean improvement, whereas 55.5% reported mean improvement on treatment therapy. The authors noted that the response for patients on placebo was rather quick with immediate effects. Further, they noted that among patients with diarrhea, 100% reported an improvement while 53.2% of those with constipation reported an improvement. In several patients with constipation, fiber and laxatives also were provided. In patients where constipation was the chief complaint, the authors noted that they failed to respond. Several office-belladonna alkaloids ed case series also presented positive outcomes for almost 1,000 patients on the effect of belladonna alkaloids and phenobarbital formulations in irritable colon, other functional disorders, and gastric/duodenal. Donnatal clinical research A. H. Robins developed and began marketing Donnatal® in the 1940s. Two studies have been performed over the years specifically with the Donnatal® formulation. Steigmann and Kaminski examined the antisecretory effect of 0.1296 mg belladonna alkaloids + 16.2 mg phenobarbital (Donnatal®) in peptic ulcer patients, motility in a subgroup of patients and clinical effects in all patients (N =176). Of the IBS patients (n =66), a reported good response with complete relief was found in 53% of male patients and 58% of female patients. Fair response with partial improvement was noted in 37% of male patients and 34% of female patients. No response was reported in 10% of male and 8% of female IBS patients. There were few side effects noted with 8% reporting dry mouth. Dosages were reduced in patients who reported drowsiness (10%) as well as 1 patient who reported visual disturbance. Otherwise, the formulation was well tolerated. Donnatal also is a common component of a GI cocktail used in emergency rooms. In 1976, Donnatal was one of the 25 most widely prescribed drugs in the U.S. It has since been displaced by H2 antagonists and proton pump inhibitors, which are more effective and lack many of the adverse effects of phenobarbital.A four-week multicenter, randomized placebo-controlled trial by Turner et al. compared Donnatal® tablets (hyoscyamine sulfate - 0.1037 mg; atropine sulfate - 0.0194 mg; scopolamine hydrobromide - 0.0065 mg and phenobarbital - 16.2 mg) to belladonna alkaloids alone (hyoscyamine sulfate - 0.1037 mg; atropine sulfate - 0.0194 mg; scopolamine hydrobromide - 0.0065 mg), phenobarbital alone (16.2 mg) and placebo. The intent-to-treat population of 204 IBS patients was evaluated for pain (cramping), nighttime and daytime pain severity, bowel movement frequency, and with a clinician global evaluation of improvement in response to treatment. The response for improvement of pain was mixed for all groups after 1 day. After 1 day, patients exhibited significant improvement in day and night pain as well as clinician global evaluation when taking Donnatal® tablets and belladonna alkaloids, but the phenobarbital group also was statistically better for day and night pain, and the placebo group for day pain. Females taking Donnatal® tablets were 4 times more likely to experience weeks free of daytime pain compared to phenobarbital alone and twice as likely to experience weeks free of nighttime pain compared to belladonna alkaloids. Only the phenobarbital group demonstrated a significant change in pain type compared to belladonna alkaloids at the end of the study with an approximate 48% response rate. Patients on Donnatal® tablets, belladonna alkaloids, and placebo all had non-significant (p > 0.149) shifts to dull pain, 39.5%, 52.3%, and 40.4%, respectively compared to belladonna alkaloids eline. Males also showed a greater response for pain free-weeks on phenobarbital in comparison to Donnatal® tablets. All groups demonstrated an improvement in bowel movement frequency. FDA status Donnatal® is considered part of the DESI drug category and currently is listed as one of 14 drugs still under evaluation by the FDA. In response to FDA questions about Donnatal® efficacy, A. H. Robins Co. filed abbreviated new drug applications for Donnatal® tablets (ANDA 86-676), capsules (ANDA 86-677), and Elixir (ANDA 86-661). These ANDAs, with the exception of the capsule formulation, are still in force today and the FDA has not changed the review status of Donnatal® as being conditionally approved for its indication. On September 29, 2011, the FDA issued new guidance with regard to the DESI category. This effectively disallowed any new DESI formulations to enter the market. The FDA also has stated that DESI drugs do not have any therapeutic equivalent drugs listed in the “Orange Book”. In their description of therapeutic equivalence, the FDA specifically cites Donnatal®. Therefore, any so-called generic drugs on the market with similar formulation to DESI drugs, are considered illegal drugs as the FDA has not reviewed their composition or therapeutic equivalence. Donnatal, although containing phenobarbital, is exempt from the Controlled Substances Act due to the belladonna alkaloids present in the formulation. References External links "Donnatal Extended Release Tablet Information". Archived from the original on 2008-12-27.
Aliskiren/hydrochlorothiazide	Aliskiren/hydrochlorothiazide, sold under the brand name Tekturna HCT among others, is a fixed-dose combination medication for the treatment of hypertension (high blood pressure). It contains aliskiren, a renin inhibitor, and hydrochlorothiazide, a diuretic. It is taken by mouth.The most common side effect is diarrhea.Aliskiren/hydrochlorothiazide was approved for medical use in the United States in January 2008, and for use in the European Union in January 2009. Medical uses Aliskiren/hydrochlorothiazide is indicated for the treatment of essential hypertension in adults. References External links "Aliskiren hemifumarate mixture with hydrochlorothiazide". Drug Information Portal. U.S. National Library of Medicine.
Chloroquine	Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medication. Chloroquine is also occasionally used for amebiasis that is occurring outside the intestines, rheumatoid arthritis, and lupus erythematosus. While it has not been formally studied in pregnancy, it appears safe. It was studied to treat COVID-19 early in the pandemic, but these studies were largely halted in the summer of 2020, and is not recommended for this purpose. It is taken by mouth.Common side effects include muscle problems, loss of appetite, diarrhea, and skin rash. Serious side effects include problems with vision, muscle damage, seizures, and low blood cell levels. Chloroquine is a member of the drug class 4-aminoquinoline. As an antimalarial, it works against the asexual form of the malaria parasite in the stage of its life cycle within the red blood cell. How it works in rheumatoid arthritis and lupus erythematosus is unclear.Chloroquine was discovered in 1934 by Hans Andersag. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. Medical uses Malaria Chloroquine has been used in the treatment and prevention of malaria from Plasmodium vivax, P. ovale, and P. malariae. It is generally not used for Plasmodium falciparum as there is widespread resistance to it.Chloroquine has been extensively used in mass drug administrations, which may have contributed to the emergence and spread of resistance. It is recommended to check if chloroquine is still effective in the region prior to using it. In areas where resistance is present, other antimalarials, such as mefloquine or atovaquone, may be used instead. The Centers for Disease Control and Prevention recommend against treatment of malaria with chloroquine alone due to more effective combinations. Amebiasis In treatment of amoebic liver abscess, chloroquine may be used instead of or in addition to other medications in the event of failure of improvement with metronidazole or another nitroimidazole within 5 days or intolerance to metronidazole or a nitroimidazole. Rheumatic disease As it mildly suppresses the immune system, chloroquine is used in some autoimmune disorders, such as rheumatoid arthritis and has an off label indication for lupus erythematosus. Side effects Side effects include blurred vision, nausea, vomiting, abdominal cramps, headache, diarrhea, swelling legs/ankles, shortness of breath, pale lips/nails/skin, muscle weakness, easy bruising/bleeding, hearing and mental problems. Unwanted/uncontrolled movements (including tongue and face twitching) Deafness or tinnitus. Nausea, vomiting, diarrhea, abdominal cramps Headache. Mental/mood changes (such as confusion, personality changes, unusual thoughts/behavior, depression, feeling being watched, hallucinating) Signs of serious infection (such as high fever, severe chills, persistent sore throat) Skin itchiness, skin color changes, hair loss, and skin rashes.Chloroquine-induced itching is very common among black Africans (70%), but much less common in other races. It increases with age, and is so severe as to stop compliance with drug therapy. It is increased during malaria fever; its severity is correlated to the malaria parasite load in blood. Some evidence indicates it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally. Unpleasant metallic taste This could be avoided by "taste-masked and controlled release" formulations such as multiple emulsions. Chloroquine retinopathy Electrocardiographic changesThis manifests itself as either conduction disturbances (bundle-branch block, atrioventricular block) or Cardiomyopathy – often with hypertrophy, restrictive physiology, and congestive heart failure. The changes may be irreversible. Only two cases have been reported requiring heart transplantation, suggesting this particular risk is very low. Electron microscopy of cardiac biopsies show pathognomonic cytoplasmic inclusion bodies. Pancytopenia, aplastic anemia, reversible agranulocytosis, low blood platelets, neutropenia. Pregnancy Chloroquine has not been shown to have any harmful effects on the fetus when used in the recommended doses for malarial prophylaxis. Small amounts of chloroquine are excreted in the breast milk of lactating women. However, this drug can be safely prescribed to infants, the effects are not harmful. Studies with mice show that radioactively tagged chloroquine passed through the placenta rapidly and accumulated in the fetal eyes which remained present five months after the drug was cleared from the rest of the body. Women who are pregnant or planning on getting pregnant are still advised against traveling to malaria-risk regions. Elderly There is not enough evidence to determine whether chloroquine is safe to be given to people aged 65 and older. Since it is cleared by the kidneys, toxicity should be monitored carefully in people with poor kidney functions. Drug interactions Chloroquine has a number of drug–drug interactions that might be of clinical concern: Ampicillin- levels may be reduced by chloroquine; Antacids- may reduce absorption of chloroquine; Cimetidine- may inhibit metabolism of chloroquine; increasing levels of chloroquine in the body; Cyclosporine- levels may be increased by chloroquine; and Mefloquine- may increase risk of convulsions. Overdose Chloroquine, in overdose, has a risk of death of about 20%. It is rapidly absorbed from the gut with an onset of symptoms generally within an hour. Symptoms of overdose may include sleepiness, vision changes, seizures, stopping of breathing, and heart problems such as ventricular fibrillation and low blood pressure. Low blood potassium may also occur.While the usual dose of chloroquine used in treatment is 10 mg/kg, toxicity begins to occur at 20 mg/kg, and death may occur at 30 mg/kg. In children as little as a single tablet can cause problems.Treatment recommendations include early mechanical ventilation, cardiac monitoring, and activated charcoal. Intravenous fluids and vasopressors may be required with epinephrine being the vasopressor of choice. Seizures may be treated with benzodiazepines. Intravenous potassium chloride may be required, however this may result in high blood potassium later in the course of the disease. Dialysis has not been found to be useful. Pharmacology Absorption of chloroquine is rapid and primarily happens in the gastrointestinal tract. It is widely distributed in body tissues. Protein binding in plasma ranges from 46% to 79%. Its metabolism is partially hepatic, giving rise to its main metabolite, desethylchloroquine. Its excretion is ≥50% as unchanged drug in urine, where acidification of urine increases its elimination. It has a very high volume of distribution, as it diffuses into the bodys adipose tissue.Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. It and related quinines have been associated with cases of retinal toxicity, particularly when provided at higher doses for longer times. With long-term doses, routine visits to an ophthalmologist are recommended.Chloroquine is also a lysosomotropic agent, meaning it accumulates preferentially in the lysosomes of cells in the body. The pKa for the quinoline nitrogen of chloroquine is 8.5, meaning it is about 10% deprotonated at physiological pH (per the Henderson-Hasselbalch equation). This decreases to about 0.2% at a lysosomal pH of 4.6. Because the deprotonated form is more membrane-permeable than the protonated form, a quantitative "trapping" of the compound in lysosomes results. Mechanism of action Malaria The lysosomotropic character of chloroquine is believed to account for much of its antimalarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its lysosomotropic properties further allow for its use for in vitro experiments pertaining to intracellular lipid related diseases, autophagy, and apoptosis.Inside red blood cells, the malarial parasite, which is then in its asexual lifecycle stage, must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasitic cell.Hemoglobin is composed of a protein unit (digested by the parasite) and a heme unit (not used by the parasite). During this process, the parasite releases the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a nontoxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.Chloroquine enters the red blood cell by simple diffusion, inhibiting the parasite cell and digestive vacuole. Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form the FP-chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. Parasites that do not form hemozoin are therefore resistant to chloroquine. Resistance in malaria Since the first documentation of P. falciparum chloroquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast Asia, and South America. The effectiveness of chloroquine against P. falciparum has declined as resistant strains of the parasite evolved. Resistant parasites are able to rapidly remove chloroquine from the digestive vacuole using a transmembrane pump. Chloroquine-resistant parasites pump chloroquine out at 40 times the rate of chloroquine-sensitive parasites; the pump is coded by the P. falciparum chloroquine resistance transporter (PfCRT) gene. The natural function of the chloroquine pump is to transport peptides: mutations to the pump that allow it to pump chloroquine out impairs its function as a peptide pump and comes at a cost to the parasite, making it less fit.Resistant parasites also frequently have mutation in the ABC transporter P. falciparum multidrug resistance (PfMDR1) gene, although these mutations are thought to be of secondary importance compared to PfCRT. An altered chloroquine-transporter protein, CG2 has been associated with chloroquine resistance, but other mechanisms of resistance also appear to be involved.Verapamil, a Ca2+ channel blocker, has been found to restore both the chloroquine concentration ability and sensitivity to this drug. Other agents which have been shown to reverse chloroquine resistance in malaria are chlorpheniramine, gefitinib, imatinib, tariquidar and zosuquidar.As of 2014 chloroquine is still effective against poultry malaria in Thailand. Sohsuebngarm et al. 2014 test P. gallinaceum at Chulalongkorn University and find the parasite is not resistant.: 1237 Sertraline, fluoxetine and paroxetine reverse chloroquine resistance, making resistant biotypes susceptible if used in a cotreatment. Antiviral Chloroquine has antiviral effects against some viruses. It increases late endosomal and lysosomal pH, resulting in impaired release of the virus from the endosome or lysosome – release of the virus requires a low pH. The virus is therefore unable to release its genetic material into the cell and replicate.Chloroquine also seems to act as a zinc ionophore that allows extracellular zinc to enter the cell and inhibit viral RNA-dependent RNA polymerase. Other Chloroquine inhibits thiamine uptake. It acts specifically on the transporter SLC19A3. Against rheumatoid arthritis, it operates by inhibiting lymphocyte proliferation, phospholipase A2, antigen presentation in dendritic cells, release of enzymes from lysosomes, release of reactive oxygen species from macrophages, and production of IL-1. History In Peru, the indigenous people extracted the bark of the Cinchona tree (Cinchona officinalis) and used the extract to fight chills and fever in the seventeenth century. In 1633 this herbal medicine was introduced in Europe, where it was given the same use and also began to be used against malaria. The quinoline antimalarial drug quinine was isolated from the extract in 1820.: 130–131 After World War I, the German government sought alternatives to quinine. Chloroquine, a synthetic analogue with the same mechanism of action was discovered in 1934, by Hans Andersag and coworkers at the Bayer laboratories, who named it Resochin. It was ignored for a decade, because it was considered too toxic for human use. Instead, in World War II, the German Africa Corps used the chloroquine analogue 3-methyl-chloroquine, known as Sontochin. After Allied forces arrived in Tunis, Sontochin fell into the hands of Americans, who sent the material back to the United States for analysis, leading to renewed interest in chloroquine. United States government-sponsored clinical trials for antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug.: 61–66 It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria. Chemical synthesis The first synthesis of chloroquine was disclosed in a patent filed by IG Farben in 1937. In the final step, 4,7-dichloroquinoline was reacted with 1-diethylamino-4-aminopentane. By 1949, chloroquine manufacturing processes had been established to allow its widespread use. Society and culture Formulations Chloroquine comes in tablet form as the phosphate, sulfate, and hydrochloride salts. Chloroquine is usually dispensed as the phosphate. Names Brand names include Chloroquine FNA, Resochin, Dawaquin, and Lariago. Other animals Chloroquine, in various chemical forms, is used to treat and control surface growth of anemones and algae, and many protozoan infections in aquariums, e.g. the fish parasite Amyloodinium ocellatum. It is also used in poultry malaria.: 1237 Research Chloroquine was proposed as a treatment for SARS, with in vitro tests inhibiting the SARS-CoV virus. In October 2004, a published report stated that chloroquine acts as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro. In August 2005, a peer-reviewed study confirmed and expanded upon the results.Chloroquine was being considered in 2003, in pre-clinical models as a potential agent against chikungunya fever. COVID-19 Other The radiosensitizing and chemosensitizing properties of chloroquine are being evaluated for anticancer strategies in humans. In biomedicinal science, chloroquine is used for in vitro experiments to inhibit lysosomal degradation of protein products. Chloroquine and its modified forms have also been evaluated as treatment options for inflammatory conditions like rheumatoid arthritis and inflammatory bowel disease. References External links "Chloroquine". Drug Information Portal. U.S. National Library of Medicine. "Medicines for the Prevention of Malaria While Traveling – Chloroquine (Aralen)" (PDF) (Fact sheet). U.S. Centers for Disease Control and Prevention (CDC). The dictionary definition of chloroquine at Wiktionary
Phenylephrine/ketorolac	Phenylephrine/ketorolac, sold under the brand name Omidria, is a combination drug used during cataract surgery or intraocular lens replacement to prevent intraoperative miosis and to reduce postoperative pain. It contains phenylephrine and ketorolac.Phenylephrine/ketorolac was approved for medical use in the United States in May 2014, and in the European Union in July 2015. References External links "Ketorolac mixture with phenylephrine". Drug Information Portal. U.S. National Library of Medicine.
Vusion	Vusion is a topical antifungal drug product that contains the active ingredients miconazole nitrate, zinc oxide, and white petrolatum. It is indicated for the adjunctive treatment of diaper dermatitis only when complicated by documented candidiasis, in immunocompetent pediatric patients 4 weeks and older. Vusion is manufactured Barrier Therapeutics. The formulation is 0.25% Miconazole nitrate, 15% Zinc oxide, and 81.35% White petrolatum. It is available by prescription only.
Hormone replacement therapy	Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal atrophy, accelerated skin aging, vaginal dryness, decreased muscle mass, sexual dysfunction, and bone loss. They are in large part related to the diminished levels of sex hormones that occur during menopause.Estrogens and progestogens are the main hormone drugs used in HRT. Progesterone is the main female sex hormone that occurs naturally and is also manufactured into a drug that is used in menopausal hormone therapy. Although both classes of hormones can have symptomatic benefit, progestogen is specifically added to estrogen regimens when the uterus is present to avoid the increased risk of endometrial cancer. Unopposed estrogen therapy promotes endometrial hyperplasia and increases the risk of cancer, while progestogen reduces this risk. Androgens like testosterone are sometimes used as well. HRT is available through a variety of different routes.The long-term effects of HRT on most organ systems vary by age and time since the last physiological exposure to hormones, and there can be large differences in individual regimens, factors which have made analyzing effects difficult. The Womens Health Initiative (WHI) is an ongoing study of over 27,000 women that began in 1991, with the most recent analyses suggesting that, when initiated within 10 years of menopause, HRT reduces all-cause mortality and risks of coronary disease, osteoporosis, and dementia; after 10 years the beneficial effects on mortality and coronary heart disease are no longer apparent, though there are decreased risks of hip and vertebral fractures and an increased risk of venous thromboembolism when taken orally."Bioidentical" hormone replacement is a development in the 21st century and uses manufactured compounds with "exactly the same chemical and molecular structure as hormones that are produced in the human body." These are mainly steroids derived from plants and can be a component of either registered pharmaceutical or custom-made compounded preparations, with the latter generally not recommended by regulatory bodies due to their lack of standardization and formal oversight. Bioidentical hormone replacement has inadequate clinical research to determine its safety and efficacy as of 2017.The current indications for use from the United States Food and Drug Administration (FDA) include short-term treatment of menopausal symptoms, such as vasomotor hot flashes or vaginal atrophy, and prevention of osteoporosis. Medical uses Approved uses of HRT in the United States include short-term treatment of menopausal symptoms such as hot flashes and vaginal atrophy, and prevention of osteoporosis. The American College of Obstetrics and Gynecology (ACOG) approves of HRT for symptomatic relief of menopausal symptoms, and advocates its use beyond the age of 65 in appropriate scenarios. The North American Menopause Society (NAMS) 2016 annual meeting mentioned that HRT may have more benefits than risks in women before the age of 60.A consensus expert opinion published by The Endocrine Society stated that when taken during perimenopause or the initial years of menopause, HRT carries fewer risks than previously published, and reduces all cause mortality in most scenarios. The American Association of Clinical Endocrinologists (AACE) has also released position statements approving of HRT when appropriate.Women receiving this treatment are usually post-, peri-, or surgically menopausal. Menopause is the permanent cessation of menstruation resulting from loss of ovarian follicular activity, defined as beginning twelve months after the final natural menstrual cycle. This twelve month time point divides menopause into early and late transition periods known as perimenopause and postmenopause. Premature menopause can occur if the ovaries are surgically removed, as can be done to treat ovarian or uterine cancer. Demographically, the vast majority of data available is in postmenopausal American women with concurrent pre-existing conditions and an average age of over 60 years. Menopausal symptoms HRT is often given as a short-term relief from menopausal symptoms during perimenopause. Potential menopausal symptoms include: Hot flashes – vasomotor symptoms Vulvovaginal atrophy – atrophic vaginitis and dryness Dyspareunia – painful sexual intercourse due to vaginal atrophy and lack of lubrication Bone loss – decreased bone mineral density, which can eventually lead to osteopenia, osteoporosis, and associated fractures Decreased sexual desire Defeminization – diminished feminine fat distribution and accelerated skin aging Sleep disturbances and joint painThe most common of these are loss of sexual drive and vaginal dryness. Heart disease The effect of HRT in menopause appears to be divergent, with lower risk of heart disease when started within five years, but no impact after ten. There may be an increase in heart disease if HRT is given twenty years post-menopause. This variability has led some reviews to suggest an absence of significant effect on morbidity. Importantly, there is no difference in long-term mortality from HRT, regardless of age.A Cochrane review suggested that women starting HRT less than 10 years after menopause had lower mortality and coronary heart disease, without any strong effect on the risk of stroke and pulmonary embolism. Those starting therapy more than 10 years after menopause showed little effect on mortality and coronary heart disease, but an increased risk of stroke. Both therapies had an association with venous clots and pulmonary embolism.HRT with estrogen and progesterone also improves cholesterol levels. With menopause, HDL decreases, while LDL, triglycerides and lipoprotein a increase, patterns that reverse with estrogen. Beyond this, HRT improves heart contraction, coronary blood flow, sugar metabolism, and decreases platelet aggregation and plaque formation. HRT may promote reverse cholesterol transport through induction of cholesterol ABC transporters. HRT also results in a large reduction in the pro-thrombotic lipoprotein a. Studies on cardiovascular disease with testosterone therapy have been mixed, with some suggesting no effect or a mild negative effect, though others have shown an improvement in surrogate markers such as cholesterol, triglycerides and weight. Testosterone has a positive effect on vascular endothelial function and tone with observational studies suggesting that women with lower testosterone may be at greater risk for heart disease. Available studies are limited by small sample size and study design. Low sex hormone binding globulin, which occurs with menopause, is associate with increased body mass index and risk for type 2 diabetes. Blood clots Effects of hormone replacement therapy on venous blood clot formation and potential for pulmonary embolism may vary with different estrogen and progestogen therapies, and with different doses or method of use. Comparisons between routes of administration suggest that when estrogens are applied to the skin or vagina, there is a lower risk of blood clots, whereas when used orally, the risk of blood clots and pulmonary embolism is increased. Skin and vaginal routes of hormone therapy are not subject to first pass metabolism, and so lack the anabolic effects that oral therapy has on liver synthesis of vitamin K-dependent clotting factors, possibly explaining why oral therapy may increase blood clot formation.While a 2018 review found that taking progesterone and estrogen together can decrease this risk, other reviews reported an increased risk of blood clots and pulmonary embolism when estrogen and progestogen were combined, particularly when treatment was started 10 years or more after menopause and when the women were older than 60 years.The risk of venous thromboembolism may be reduced with bioidentical preparations, though research on this is only preliminary. Stroke Multiple studies suggest that the possibility of HRT related stroke is absent if therapy is started within five years of menopause, and that the association is absent or even preventive when given by non-oral routes. Ischemic stroke risk was increased during the time of intervention in the WHI, with no significant effect after the cessation of therapy and no difference in mortality at long term follow up. When oral synthetic estrogen or combined estrogen-progestogen treatment is delayed until five years from menopause, cohort studies in Swedish women have suggested an association with hemorrhagic and ischemic stroke. Another large cohort of Danish women suggested that the specific route of administration was important, finding that although oral estrogen increased risk of stroke, absorption through the skin had no impact, and vaginal estrogen actually had a decreased risk. Endometrial cancer In postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence. The duration of progestogen therapy should be at least 14 days per cycle to prevent endometrial disease.Endometrial cancer has been grouped into two forms in the context of hormone replacement. Type 1 is the most common, can be associated with estrogen therapy, and is usually low grade. Type 2 is not related to estrogen stimulation and usually higher grade and poorer in prognosis. The endometrial hyperplasia that leads to endometrial cancer with estrogen therapy can be prevented by concomitant administration of progestogen. The extensive use of high-dose estrogens for birth control in the 1970s is thought to have resulted in a significant increase in the incidence of type 1 endometrial cancer.Paradoxically, progestogens do promote the growth of uterine fibroids, and a pelvic ultrasound can be performed before beginning HRT to make sure there are no underlying uterine or endometrial lesions.Androgens do not stimulate endometrial proliferation in post menopausal women, and appear to inhibit the proliferation induced by estrogen to a certain extent.There is insufficient high‐quality evidence to inform women considering hormone replacement therapy after treatment for endometrial cancer. Breast cancer Studies regarding the association of breast cancer with hormone replacement are inconsistent and vary with type of replacement and time since menopause. While some evaluations suggest an increased risk, in others it is decreased. This inconsistency of effect has been suggested to imply a lack of meaningful impact of HRT on breast cancer risk.There is a non-statistically significant increased rate of breast cancer for hormone replacement therapy with synthetic progesterone. The risk may be reduced with bioidentical progesterone, though the only prospective study that suggested this was underpowered due to the rarity of breast cancer in the control population. There have been no randomized controlled trials as of 2018. The relative risk of breast cancer also varies depending on the interval between menopause and HRT and route of synthetic progestin administration.The most recent follow up of the Womens Health Initiative participants demonstrated a lower incidence of breast cancer in post-hysterectomy participants taking equine estrogen alone, though the relative risk was increased if estrogen was taken with medroxy-progesterone. Estrogen is usually only given alone in the setting of a hysterectomy due to the increased risk of vaginal bleeding and uterine cancer with unopposed estrogen.HRT has been more strongly associated with risk of breast cancer in women with lower body mass indices (BMIs). No breast cancer association has been found with BMIs of over 25. It has been suggested by some that the absence of significant effect in some of these studies could be due to selective prescription to overweight women who have higher baseline estrone, or to the very low progesterone serum levels after oral administration leading to a high tumor inactivation rate.Evaluating the response of breast tissue density to HRT using mammography appears to help assessing the degree of breast cancer risk associated with therapy; women with dense or mixed-dense breast tissue have a higher risk of developing breast cancer than those with low density tissue.Micronized progesterone does not appear to be associated with breast cancer risk when used for less than five years with limited data suggesting an increased risk when used for longer duration.A retrospective Cox proportional hazards analysis from Richard Neapolitan endorsed the reduced risk breast cancer with conjugated equine estrogen usage alone, but also suggested that conjugated equine estrogen with medroxyprogesterone acetate was associated with a risk reduction in breast cancer and that bioidentical hormone therapy was not associated with a statistically significant effect. There have been no prospective randomized clinical trials comparing the two routes of administration with regards to breast cancer.For women who previously have had breast cancer, it is recommended to first consider other options for menopausal effects, such as bisphosphonates or selective estrogen receptor modulators (SERMs) for osteoporosis, cholesterol-lowering agents and aspirin for cardiovascular disease, and vaginal estrogen for local symptoms. Observational studies of systemic HRT after breast cancer are generally reassuring. If HRT is necessary after breast cancer, estrogen-only therapy or estrogen therapy with a progestogen may be safer options than combined systemic therapy. In women who are BRCA1 or BRCA2 mutation carriers, HRT does not appear to impact breast cancer risk. The relative number of women using HRT who also obtain regular screening mammograms is higher than that in women who do not use HRT, a factor which has been suggested as contributing to different breast cancer detection rates in the two groups.With androgen therapy, pre-clinical studies have suggested an inhibitory effect on breast tissue though the majority of epidemiological studies suggest a positive association. Ovarian cancer HRT is associated with an increased risk of ovarian cancer, with women using HRT having about one additional case of ovarian cancer per 1,000 users. This risk is decreased when progestogen therapy is given concomitantly, as opposed to estrogen alone, and also decreases with increasing time since stopping HRT. Regarding the specific subtype, there may be a higher risk of serous cancer, but no association with clear cell, endometrioid, or mucinous ovarian cancer. Hormonal therapy in ovarian cancer survivors after surgical removal of the ovaries is generally thought to improval survival rates. Other malignancies Colorectal cancer In the WHI, women who took combined estrogen-progesterone therapy had a lower risk of getting colorectal cancer. However, the cancers they did have were more likely to have spread to lymph nodes or distant sites than colorectal cancer in women not taking hormones. In colorectal cancer survivors, usage of HRT is thought to lead to lower recurrence risk and overall mortality. Cervical cancer There appears to be a significantly decreased risk of cervical squamous cell cancer in post menopausal women treated with HRT and a weak increase in adenocarcinoma. No studies have reported an increased risk of recurrence when HRT is used with cervical cancer survivors. Sexual function HRT can help with the lack of sexual desire and sexual dysfunction that can occur with menopause. Epidemiological surveys of women between 40 and 69 years suggest that 75% of women remain sexually active after menopause. With increasing life spans, women today are living one third or more of their lives in a postmenopausal state, a period during which healthy sexuality can be integral to their quality of life.Decreased libido and sexual dysfunction are common issues in postmenopausal women, an entity referred to hypoactive sexual desire disorder (HSDD); its signs and symptoms can both be improved by HRT. Several hormonal changes take place during this period, including a decrease in estrogen and an increase in follicle-stimulating hormone. For most women, the majority of change occurs during the late perimenopausal and postmenopausal stages. Decreases in sex hormone-binding globulin (SHBG) and inhibin (A and B) also occur. Testosterone is present in women at a lower level than men, peaking at age 30 and declining gradually with age; there is less variation during the menopausal transition relative to estrogen and progesterone.A global consensus position statement has advised that postmenopausal testosterone replacement to premenopausal levels can be effective for HSDD. Safety information for testosterone treatment is not available beyond two years of continuous therapy however and dosing above physiologic levels is not advised. Testosterone patches have been found to restore sexual desire in post menopausal women. There is insufficient data to evaluate the impact of testosterone replacement on heart disease, breast cancer, with most trials having included women taking concomitant estrogen and progesterone and with testosterone therapy itself being relatively short in duration. In the setting of this limited data, testosterone therapy has not been associated with adverse events.Not all women are responsive, especially those with preexisting sexual difficulties. Estrogen replacement can restore vaginal cells, pH levels, and blood flow to the vagina, all of which tend to deteriorate at the onset of menopause. Pain or discomfort with sex appears to be the most responsive component to estrogen. It also has been shown to have positive effects on the urinary tract. Estrogen can also reduce vaginal atrophy and increase sexual arousal, frequency and orgasm.The effectiveness of hormone replacement can decline in some women after long-term use. A number of studies have also found that the combined effects of estrogen/androgen replacement therapy can increase libido and arousal over estrogen alone. Tibolone, a synthetic steroid with estrogenic, androgenic, and progestogenic properties that is available in Europe, has the ability to improve mood, libido, and physical symptomatology. In various placebo-controlled studies, improvements in vasomotor symptoms, emotional response, sleep disturbances, physical symptoms, and sexual desire have been seen, though it also carries a similar risk profile to conventional HRT. Neurodegenerative disorders For prevention, the WHI suggested that HRT may increase risk of dementia if initiated after 65 years of age, but have a neutral outcome or be neuroprotective for those between 50 and 55 years. Other studies in perimenopause have shown HRT to be consistently associated with a lower risk of Alzheimers. With Parkinsons the majority of clinical and epidemiological studies show have demonstrated either no association or inconclusive results. A Danish study suggested an increased risk of Parkinsons with HRT in cyclical dosing schedules.With regards to treatment, randomized trials have shown that HRT improves executive and attention processes outside of the context of dementia in postmenopausal women, both in those that are asymptomatic and those with mild cognitive impairment. Estrogen replacement appears to improve motor symptoms and activities of daily living in post menopausal women with Parkinsons, with significant improvement of UPDRS scores. Clinical trials have also shown testosterone replacement to be associated with small statistically significant improvements in verbal learning and memory in postmenopausal women. DHEA has not been found to improve cognitive performance after menopause. Pre-clinical studies indicate that endogenous estrogen and testosterone are neuroprotective and can prevent brain amyloid deposition. Muscle and bone There is a significant decrease in hip fracture risk during treatment that to a lesser degree persists after HRT is stopped. It also helps collagen formation, which in turn improves intervertebral disc and bone strength.Hormone replacement therapy in the form of estrogen and androgen can be effective at reversing the effects of aging on muscle. Lower testosterone is associated with lower bone density and higher free testosterone is associated with lower hip fracture rates in older women. Testosterone therapy, which can be used for decreased sexual function, can also increase bone mineral density and muscle mass. Side effects Side effects in HRT occur with varying frequency and include: Contraindications The following are absolute and relative contraindications to HRT: Absolute contraindications Undiagnosed vaginal bleeding Severe liver disease Pregnancy Severe coronary artery disease Aggressive breast, uterine or ovarian cancer Relative contraindications Migraine headaches History of breast cancer History of ovarian cancer Venous thrombosis History of uterine fibroids Atypical ductal hyperplasia of the breast Active gallbladder disease (cholangitis, cholecystitis) Well-differentiated and early endometrial cancer – once treatment for the malignancy is complete, is no longer an absolute contraindication. History and research The extraction of CEEs from the urine of pregnant mares led to the marketing in 1942 of Premarin, one of the earlier forms of estrogen to be introduced. From that time until the mid-1970s, estrogen was administered without a supplemental progestogen. Beginning in 1975, studies began to show that without a progestogen, unopposed estrogen therapy with Premarin resulted in an eight-fold increased risk of endometrial cancer, eventually causing sales of Premarin to plummet. It was recognized in the early 1980s that the addition of a progestogen to estrogen reduced this risk to the endometrium. This led to the development of combined estrogen–progestogen therapy, most commonly with a combination of conjugated equine estrogen (Premarin) and medroxyprogesterone (Provera). Trials The Womens Health Initiative trials were conducted between 1991 and 2006 and were the first large, double-blind, placebo-controlled clinical trials of HRT in healthy women. Their results were both positive and negative, suggesting that during the time of hormone therapy itself, there are increases in invasive breast cancer, stroke and lung clots. Other risks include increased endometrial cancer, gallbladder disease, and urinary incontinence, while benefits include decreased hip fractures, decreased incidence of diabetes, and improvement of vasomotor symptoms. There is also an increased risk of dementia with HRT in women over 65, though at younger ages it appears to be neuroprotective. After the cessation of HRT, the WHI continued to observe its participants, and found that most of these risks and benefits dissipated, though some elevation in breast cancer risk did persist. Other studies have also suggested an increased risk of ovarian cancer.The arm of the WHI receiving combined estrogen and progestin therapy was closed prematurely in 2002 by its Data Monitoring Committee (DMC) due to perceived health risks, though this occurred a full year after the data suggesting increased risk became manifest. In 2004, the arm of the WHI in which post-hysterectomy patients were being treated with estrogen alone was also closed by the DMC. Clinical medical practice changed based upon two parallel Womens Health Initiative (WHI) studies of HRT. Prior studies were smaller, and many were of women who electively took hormonal therapy. One portion of the parallel studies followed over 16,000 women for an average of 5.2 years, half of whom took placebo, while the other half took a combination of CEEs and MPA (Prempro). This WHI estrogen-plus-progestin trial was stopped prematurely in 2002 because preliminary results suggested risks of combined CEEs and progestins exceeded their benefits. The first report on the halted WHI estrogen-plus-progestin study came out in July 2002.Initial data from the WHI in 2002 suggested mortality to be lower when HRT was begun earlier, between age 50 to 59, but higher when begun after age 60. In older patients, there was an apparent increased incidence of breast cancer, heart attacks, venous thrombosis, and stroke, although a reduced incidence of colorectal cancer and bone fracture. At the time, The WHI recommended that women with non-surgical menopause take the lowest feasible dose of HRT for the shortest possible time to minimize associated risks. Some of the WHI findings were again found in a larger national study done in the United Kingdom, known as the Million Women Study (MWS). As a result of these findings, the number of women taking HRT dropped precipitously. In 2012, the United States Preventive Task Force (USPSTF) concluded that the harmful effects of combined estrogen and progestin therapy likely exceeded their chronic disease prevention benefits.In 2002 when the first WHI follow up study was published, with HRT in post menopausal women, both older and younger age groups had a slightly higher incidence of breast cancer, and both heart attack and stroke were increased in older patients, although not in younger participants. Breast cancer was increased in women treated with estrogen and a progestin, but not with estrogen and progesterone or estrogen alone. Treatment with unopposed estrogen (i.e., an estrogen alone without a progestogen) is contraindicated if the uterus is still present, due to its proliferative effect on the endometrium. The WHI also found a reduced incidence of colorectal cancer when estrogen and a progestogen were used together, and most importantly, a reduced incidence of bone fractures. Ultimately, the study found disparate results for all cause mortality with HRT, finding it to be lower when HRT was begun during ages 50–59, but higher when begun after age 60. The authors of the study recommended that women with non-surgical menopause take the lowest feasible dose of hormones for the shortest time to minimize risk.The data published by the WHI suggested supplemental estrogen increased risk of venous thromboembolism and breast cancer but was protective against osteoporosis and colorectal cancer, while the impact on cardiovascular disease was mixed. These results were later supported in trials from the United Kingdom, but not in more recent studies from France and China. Genetic polymorphism appears to be associated with inter-individual variability in metabolic response to HRT in postmenopausal women. The WHI reported statistically significant increases in rates of breast cancer, coronary heart disease, strokes and pulmonary emboli. The study also found statistically significant decreases in rates of hip fracture and colorectal cancer. "A year after the study was stopped in 2002, an article was published indicating that estrogen plus progestin also increases the risks of dementia." The conclusion of the study was that the HRT combination presented risks that outweighed its measured benefits. The results were almost universally reported as risks and problems associated with HRT in general, rather than with Prempro, the specific proprietary combination of CEEs and MPA studied. After the increased clotting found in the first WHI results was reported in 2002, the number of Prempro prescriptions filled reduced by almost half. Following the WHI results, a large percentage of HRT users opted out of them, which was quickly followed by a sharp drop in breast cancer rates. The decrease in breast cancer rates has continued in subsequent years. An unknown number of women started taking alternatives to Prempro, such as compounded bioidentical hormones, though researchers have asserted that compounded hormones are not significantly different from conventional hormone therapy.The other portion of the parallel studies featured women who were post hysterectomy and so received either placebo progestogen or CEEs alone. This group did not show the risks demonstrated in the combination hormone study, and the estrogen-only study was not halted in 2002. However, in February 2004 it, too, was halted. While there was a 23% decreased incidence of breast cancer in the estrogen-only study participants, risks of stroke and pulmonary embolism were increased slightly, predominantly in patients who began HRT over the age of 60.Several other large studies and meta-analyses have reported reduced mortality for HRT in women younger than age 60 or within 10 years of menopause, and a debatable or absent effect on mortality in women over 60.Though research thus far has been substantial, further investigation is needed to fully understand differences in effect for different types of HRT and lengths of time since menopause. Available forms There are five major human steroid hormones: estrogens, progestogens, androgens, mineralocorticoids, and glucocorticoids. Estrogens and progestogens are the two most often used in menopause. They are available in a wide variety of FDA approved and non–FDA-approved formulations.In women with intact uteruses, estrogens are almost always given in combination with progestogens, as long-term unopposed estrogen therapy is associated with a markedly increased risk of endometrial hyperplasia and endometrial cancer. Conversely, in women who have undergone a hysterectomy or do not have a uterus, a progestogen is not required, and estrogen can be used alone. There are many combined formulations which include both estrogen and progestogen. Specific types of hormone replacement include: Estrogens – bioidentical estrogens like estradiol and estriol, animal-derived estrogens like conjugated estrogens (CEEs), and synthetic estrogens like ethinylestradiol Progestogens – bioidentical progesterone, and progestins (synthetic progestogens) like medroxyprogesterone acetate (MPA), norethisterone, and dydrogesterone Androgens – bioidentical testosterone and dehydroepiandrosterone (DHEA), and synthetic anabolic steroids like methyltestosterone and nandrolone decanoateTibolone – a synthetic medication available in Europe but not the
Hormone replacement therapy	United States– is more effective than placebo but less effective than combination hormone therapy in postmenopausal women. It may have a decreased risk of breast and colorectal cancer, though conversely it can be associated with vaginal bleeding, endometrial cancer, and increase the risk of stroke in women over age 60 years.Vaginal estrogen can improve local atrophy and dryness, with fewer systemic effects than estrogens delivered by other routes. Sometimes an androgen, generally testosterone, can be added to treat diminished libido. Continuous versus cyclic Dosage is often varied cyclically to more closely mimic the ovarian hormone cycle, with estrogens taken daily and progestogens taken for about two weeks every month or every other month, a schedule referred to as cyclic or sequentially combined. Alternatively, continuous combined HRT can be given with a constant daily hormonal dosage. Continuous combined HRT is associated with less complex endometrial hyerplasia than cyclic. Impact on breast density appears to be similar in both regimen timings. Route of administration The medications used in menopausal HRT are available in numerous different formulations for use by a variety of different routes of administration: Oral administration – tablets, capsules Transdermal administration – patches, gels, creams Vaginal administration – tablets, creams, suppositories, rings Intramuscular or subcutaneous injection – solutions in vials or ampoules Subcutaneous implant – surgically-inserted pellets placed into fat tissue Less commonly sublingual, buccal, intranasal, and rectal administration, as well as intrauterine devicesMore recently developed forms of drug delivery are alleged to have increased local effect lower dosing, fewer side effects, and constant rather than cyclical serum hormone levels. Transdermal and vaginal estrogen, in particular, avoid first pass metabolism through the liver. This in turn prevents an increase in clotting factors and accumulation of anti-estrogenic metabolites, resulting in fewer adverse side effects, particularly with regard to cardiovascular disease and stroke.Injectable forms of estradiol are no longer recommended in menopausal hormone therapy due to the availability of other formulations. Bioidentical hormone therapy Bioidentical hormone therapy (BHT) is the usage of hormones that are chemically identical to those produced in the body. Although proponents of BHT claim advantages over non-bioidentical or conventional hormone therapy, the FDA does not recognize the term bioidentical hormone, stating there is no scientific evidence that these hormones are identical to their naturally occurring counterparts. There are, however, FDA approved products containing hormones classified as bioidentical.Bioidentical hormones can be used in either pharmaceutical or compounded preparations, with the latter generally not recommended by regulatory bodies due to their lack of standardization and regulatory oversight. Most classifications of bioidentical hormones do not take into account manufacturing, source, or delivery method of the products, and so describe both non-FDA approved compounded products and FDA approved pharmaceuticals as bioidentical. The British Menopause Society has issued a consensus statement endorsing the distinction between "compounded" forms (cBHRT), described as unregulated, custom made by specialty pharmacies and subject to heavy marketing and "regulated" pharmaceutical grade forms (rBHRT), which undergo formal oversight by entities such as the FDA and form the basis of most clinical trials. Some practitioners recommending compounded bioidentical HRT also use salivary or serum hormonal testing to monitor response to therapy, a practice not endorsed by current clinical guidelines in the United States and Europe.Bioidentical hormones in pharmaceuticals may have very limited clinical data, with no randomized controlled prospective trials to date comparing them to their animal derived counterparts. Some pre-clinical data has suggested a decreased risk of venous thromboembolism, cardiovascular disease, and breast cancer. As of 2012, guidelines from the North American Menopause Society, the Endocrine Society, the International Menopause Society, and the European Menopause and Andropause Society endorsed the reduced risk of bioidentical pharmaceuticals for those with increased clotting risk. Compounding Compounding for HRT is generally discouraged by the FDA and medical industry in the United States due to a lack of regulation and standardized dosing. The U.S. Congress did grant the FDA explicit but limited oversight of compounded drugs in a 1997 amendment to the Federal Food, Drug, and Cosmetic Act (FDCA), but they have encountered obstacles in this role since that time. After 64 patient deaths and 750 harmed patients from a 2012 meningitis outbreak due to contaminated steroid injections, Congress passed the 2013 Drug Quality and Security Act, authorizing creation by the FDA of a voluntary registration for facilities that manufactured compounded drugs, and reinforcing FDCA regulations for traditional compounding. The DQSA and its reinforcement of provision §503A of the FDCA solidifies FDA authority to enforce FDCA regulation of against compounders of bioidentical hormone therapy.In the United Kingdom, on the other hand, compounding is a regulated activity. The Medicines and Healthcare products Regulatory Agency regulates compounding performed under a Manufacturing Specials license and the General Pharmaceutical Council regulates compounding performed within a pharmacy. All testosterone prescribed in the United Kingdom is bioidentical, with its use supported by the National Health Service. There is also marketing authorisation for male testosterone products. National Institute for Health and Care Excellence guideline 1.4.8 states: "consider testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective". The footnote adds: "at the time of publication (November 2015), testosterone did not have a United Kingdom marketing authorisation for this indication in women. Bioidentical progesterone is used in IVF treatment and for pregnant women who are at risk of premature labour." Society and public perception Wyeth controversy Wyeth, now a subsidiary of Pfizer, was a pharmaceutical company that marketed the HRT products Premarin (CEEs) and Prempro (CEEs + MPA). In 2009, litigation involving Wyeth resulted in the release of 1,500 documents that revealed practices concerning its promotion of these medications. The documents showed that Wyeth commissioned dozens of ghostwritten reviews and commentaries that were published in medical journals to promote unproven benefits of its HRT products, downplay their harms and risks, and cast competing therapies in a negative light. Starting in the mid-1990s and continuing for over a decade, Wyeth pursued an aggressive "publication plan" strategy to promote its HRT products through the use of ghostwritten publications. It worked mainly with DesignWrite, a medical writing firm. Between 1998 and 2005, Wyeth had 26 papers promoting its HRT products published in scientific journals.These favorable publications emphasized the benefits and downplayed the risks of its HRT products, especially the "misconception" of the association of its products with breast cancer. The publications defended unsupported cardiovascular "benefits" of its products, downplayed risks such as breast cancer, and promoted off-label and unproven uses like prevention of dementia, Parkinsons disease, vision problems, and wrinkles. In addition, Wyeth emphasized negative messages against the SERM raloxifene for osteoporosis, instructed writers to stress the fact that "alternative therapies have increased in usage since the WHI even though there is little evidence that they are effective or safe...", called into question the quality and therapeutic equivalence of approved generic CEE products, and made efforts to spread the notion that the unique risks of CEEs and MPA were a class effect of all forms of menopausal HRT: "Overall, these data indicate that the benefit/risk analysis that was reported in the Womens Health Initiative can be generalized to all postmenopausal hormone replacement therapy products."Following the publication of the WHI data in 2002, the stock prices for the pharmaceutical industry plummeted, and huge numbers of women stopped using HRT. The stocks of Wyeth, which supplied the Premarin and Prempro that were used in the WHI trials, decreased by more than 50%, and never fully recovered. Some of their articles in response promoted themes such as the following: "the WHI was flawed; the WHI was a controversial trial; the population studied in the WHI was inappropriate or was not representative of the general population of menopausal women; results of clinical trials should not guide treatment for individuals; observational studies are as good as or better than randomized clinical trials; animal studies can guide clinical decision-making; the risks associated with hormone therapy have been exaggerated; the benefits of hormone therapy have been or will be proven, and the recent studies are an aberration." Similar findings were observed in a 2010 analysis of 114 editorials, reviews, guidelines, and letters by five industry-paid authors. These publications promoted positive themes and challenged and criticized unfavorable trials such as the WHI and MWS. In 2009, Wyeth was acquired by Pfizer in a deal valued at US$68 billion. Pfizer, a company that produces Provera and Depo-Provera (MPA) and has also engaged in medical ghostwriting, continues to market Premarin and Prempro, which remain best-selling medications.According to Fugh-Berman (2010), "Today, despite definitive scientific data to the contrary, many gynecologists still believe that the benefits of [HRT] outweigh the risks in asymptomatic women. This non-evidence–based perception may be the result of decades of carefully orchestrated corporate influence on medical literature." As many as 50% of physicians have expressed skepticism about large trials like the WHI and HERS. The positive perceptions of many physicians of HRT in spite of large trials showing risks that potentially outweigh any benefits may be due to the efforts of pharmaceutical companies like Wyeth. Popularity The 1990s showed a dramatic decline in prescription rates, though more recently they have begun to rise again. Transdermal therapy, in part due to its lack of increase in venous thromboembolism, is now often the first choice for HRT in the United Kingdom. Conjugate equine estrogen, in distinction, has a potentially higher thrombosis risk and is now not commonly used in the UK, replaced by estradiol based compounds with lower thrombosis risk. Oral progestogen combinations such as medroxyprogesterone acetate have changed to dyhydrogesterone, due to a lack of association of the latter with venous clot. See also Hormone therapy Androgen replacement therapy Transgender hormone therapy References External links Menopause treatment, Hormone Health Network, The Endocrine Society Sexual Health and Menopause Online, The North American Menopause Society Menopause, US Food and Drug Administration
Hyaluronic acid	Hyaluronic acid (; abbreviated HA; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans as it is non-sulfated, forms in the plasma membrane instead of the Golgi apparatus, and can be very large: human synovial HA averages about 7 million Da per molecule, or about 20,000 disaccharide monomers, while other sources mention 3–4 million Da.The average 70 kg (150 lb) person has roughly 15 grams of hyaluronan in the body, one-third of which is turned over (i.e., degraded and synthesized) per day.As one of the chief components of the extracellular matrix, it contributes significantly to cell proliferation and migration, and is involved in the progression of many malignant tumors. Hyaluronic acid is also a component of the group A streptococcal extracellular capsule, and is believed to play a role in virulence. Physiological function Until the late 1970s, hyaluronic acid was described as a "goo" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix. For example, hyaluronic acid is a major component of the synovial fluid and was found to increase the viscosity of the fluid. Along with lubricin, it is one of the fluids main lubricating components. Hyaluronic acid is an important component of articular cartilage, where it is present as a coat around each cell (chondrocyte). When aggrecan monomers bind to hyaluronan in the presence of HAPLN1 (hyaluronic acid and proteoglycan link protein 1), large, highly negatively charged aggregates form. These aggregates imbibe water and are responsible for the resilience of cartilage (its resistance to compression). The molecular weight (size) of hyaluronan in cartilage decreases with age, but the amount increases.A lubricating role of hyaluronan in muscular connective tissues to enhance the sliding between adjacent tissue layers has been suggested. A particular type of fibroblasts, embedded in dense fascial tissues, has been proposed as being cells specialized for the biosynthesis of the hyaluronan-rich matrix. Their related activity could be involved in regulating the sliding ability between adjacent muscular connective tissues.Hyaluronic acid is also a major component of skin, where it is involved in repairing tissue. When skin is exposed to excessive UVB rays, it becomes inflamed (sunburn), and the cells in the dermis stop producing as much hyaluronan and increase the rate of its degradation. Hyaluronan degradation products then accumulate in the skin after UV exposure.While it is abundant in extracellular matrices, hyaluronan also contributes to tissue hydrodynamics, movement, and proliferation of cells and participates in a number of cell surface receptor interactions, notably those including its primary receptors, CD44 and RHAMM. Upregulation of CD44 itself is widely accepted as a marker of cell activation in lymphocytes. Hyaluronans contribution to tumor growth may be due to its interaction with CD44. Receptor CD44 participates in cell adhesion interactions required by tumor cells. Although hyaluronan binds to receptor CD44, there is evidence hyaluronan degradation products transduce their inflammatory signal through toll-like receptor 2 (TLR2), TLR4, or both TLR2 and TLR4 in macrophages and dendritic cells. TLR and hyaluronan play a role in innate immunity. There are limitations including the in vivo loss of this compound limiting the duration of effect. Wound repair As a major component of the extracellular matrix, hyaluronic acid has a key role in tissue regeneration, inflammation response, and angiogenesis, which are phases of wound repair. As of 2016, however, reviews of its effect on wound healing in burns, diabetic foot ulcers or surgical skin repairs show only limited positive clinical research evidence. Hyaluronic acid combines with water and swells to form a gel, making it useful in skin treatments as a dermal filler for facial wrinkles; its effect lasts for about 6 to 12 months, and treatment has regulatory approval from the US Food and Drug Administration. Granulation Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. It typically grows from the base of a wound and is able to fill wounds of almost any size it heals. HA is abundant in granulation tissue matrix. A variety of cell functions that are essential for tissue repair may attribute to this HA-rich network. These functions include facilitation of cell migration into the provisional wound matrix, cell proliferation, and organization of the granulation tissue matrix. Initiation of inflammation is crucial for the formation of granulation tissue; therefore, the pro-inflammatory role of HA as discussed above also contributes to this stage of wound healing. Cell migration Cell migration is essential for the formation of granulation tissue. The early stage of granulation tissue is dominated by a HA-rich extracellular matrix, which is regarded as a conducive environment for the migration of cells into this temporary wound matrix. HA provides an open hydrated matrix that facilitates cell migration, whereas, in the latter scenario, directed migration and control of related cell mechanisms are mediated via the specific cell interaction between HA and cell surface HA receptors. It forms links with several protein kinases associated with cell locomotion, for example, extracellular signal-regulated kinase, focal adhesion kinase, and other non-receptor tyrosine kinases. During fetal development, the migration path through which neural crest cells migrate is rich in HA. HA is closely associated with the cell migration process in granulation tissue matrix, and studies show that cell movement can be inhibited, at least partially, by HA degradation or blocking HA receptor occupancy.By providing the dynamic force to the cell, HA synthesis has also been shown to associate with cell migration. Basically, HA is synthesized at the plasma membrane and released directly into the extracellular environment. This may contribute to the hydrated microenvironment at sites of synthesis, and is essential for cell migration by facilitating cell detachment. Skin healing HA plays an important role in the normal epidermis. HA also has crucial functions in the reepithelization process due to several of its properties. These include being an integral part of the extracellular matrix of basal keratinocytes, which are major constituents of the epidermis; its free-radical scavenging function, and its role in keratinocyte proliferation and migration. In normal skin, HA is found in relatively high concentrations in the basal layer of the epidermis where proliferating keratinocytes are found. CD44 is collocated with HA in the basal layer of epidermis where additionally it has been shown to be preferentially expressed on plasma membrane facing the HA-rich matrix pouches. Maintaining the extracellular space and providing an open, as well as hydrated, structure for the passage of nutrients are the main functions of HA in epidermis. A report found HA content increases in the presence of retinoic acid (vitamin A). The proposed effects of retinoic acid against skin photo-damage and photoaging may be correlated, at least in part, with an increase of skin HA content, giving rise to increased tissue hydration. It has been suggested that the free-radical scavenging property of HA contributes to protection against solar radiation, supporting the role of CD44 acting as a HA receptor in the epidermis. Epidermal HA also functions as a manipulator in the process of keratinocyte proliferation, which is essential in normal epidermal function, as well as during reepithelization in tissue repair. In the wound healing process, HA is expressed in the wound margin, in the connective tissue matrix, and collocating with CD44 expression in migrating keratinocytes. Medical uses Hyaluronic acid has been FDA-approved to treat osteoarthritis of the knee via intra-articular injection. A 2012 review showed that the quality of studies supporting this use was mostly poor, with a general absence of significant benefits, and that intra-articular injection of HA could possibly cause adverse effects. A 2020 meta-analysis found that intra-articular injection of high molecular weight HA improved both pain and function in people with knee osteoarthritis.Hyaluronic acid has been used in various formulations to create artificial tears to treat dry eye.Hyaluronic acid is a common ingredient in skin care products. Hyaluronic acid is used as a dermal filler in cosmetic surgery. It is typically injected using either a classic sharp hypodermic needle or a micro-cannula. Some studies have suggested that the use of micro-cannulas can significantly reduce vessel embolisms during injections. Currently, hyaluronic acid is used frequently as a soft tissue filler due to its bio-compatibility and reversibility. Complications include the severing of nerves and microvessels, pain, and bruising. Some side effects can also appear by way of erythema, itching, and vascular occlusion; vascular occlusion is the most worrisome side effect due to the possibility of skin necrosis, or even blindness in a patient. In some cases, hyaluronic acid fillers can result in a granulomatous foreign body reaction. Structure Hyaluronic acid is a polymer of disaccharides, which are composed of D-glucuronic acid and N-acetyl-D-glucosamine, linked via alternating β-(1→4) and β-(1→3) glycosidic bonds. Hyaluronic acid can be 25,000 disaccharide repeats in length. Polymers of hyaluronic acid can range in size from 5,000 to 20,000,000 Da in vivo. The average molecular weight in human synovial fluid is 3–4 million Da, and hyaluronic acid purified from human umbilical cord is 3,140,000 Da; other sources mention average molecular weight of 7 million Da for synovial fluid. Hyaluronic acid also contains silicon, ranging 350–1,900 μg/g depending on location in the organism.Hyaluronic acid is energetically stable, in part because of the stereochemistry of its component disaccharides. Bulky groups on each sugar molecule are in sterically favored positions, whereas the smaller hydrogens assume the less-favorable axial positions. Biological synthesis Hyaluronic acid is synthesized by a class of integral membrane proteins called hyaluronan synthases, of which vertebrates have three types: HAS1, HAS2, and HAS3. These enzymes lengthen hyaluronan by repeatedly adding D-glucuronic acid and N-acetyl-D-glucosamine to the nascent polysaccharide as it is extruded via ABC-transporter through the cell membrane into the extracellular space. The term fasciacyte was coined to describe fibroblast-like cells that synthesize HA.Hyaluronic acid synthesis has been shown to be inhibited by 4-methylumbelliferone (hymecromone), a 7-hydroxy-4-methylcoumarin derivative. This selective inhibition (without inhibiting other glycosaminoglycans) may prove useful in preventing metastasis of malignant tumor cells. There is feedback inhibition of hyaluronan synthesis by low-molecular-weight hyaluronan (<500 kDa) at high concentrations, but stimulation by high-molecular-weight hyaluronan (>500 kDa), when tested in cultured human synovial fibroblasts.Bacillus subtilis recently has been genetically modified to culture a proprietary formula to yield hyaluronans, in a patented process producing human-grade product. Fasciacyte A fasciacyte is a type of biological cell that produces hyaluronan-rich extracellular matrix and modulates the gliding of muscle fasciae.Fasciacytes are fibroblast-like cells found in fasciae. They are round-shaped with rounder nuclei and have less elongated cellular processes when compared with fibroblasts. Fasciacytes are clustered along the upper and lower surfaces of a fascial layer. Fasciacytes produce hyaluronan, which regulates fascial gliding. Biosynthetic mechanism Hyaluronic acid (HA) is a linear glycosaminoglycan (GAG), an anionic, gel-like, polymer, found in the extracellular matrix of epithelial and connective tissues of vertebrates. It is part of a family of structurally complex, linear, anionic polysaccharides. The carboxylate groups present in the molecule make it negatively charged, therefore allowing for successful binding to water, and making it valuable to cosmetic and pharmaceutical products.HA consists of repeating β4-glucuronic acid (GlcUA)-β3-N-acetylglucosamine (GlcNAc) disaccharides, and is synthesized by hyaluronan synthases (HAS), a class of integral membrane proteins that produce the well-defined, uniform chain lengths characteristic to HA. There are three existing types of HASs in vertebrates: HAS1, HAS2, HAS3; each of these contribute to elongation of the HA polymer. For an HA capsule to be created, this enzyme must be present because it polymerizes UDP-sugar precursors into HA. HA precursors are synthesized by first phosphorylating glucose by hexokinase, yielding glucose-6-phosphate, which is the main HA precursor. Then, two routes are taken to synthesize UDP-n-acetylglucosamine and UDP-glucuronic acid which both react to form HA. Glucose-6-phosphate gets converted to either fructose-6-phosphate with hasE (phosphoglucoisomerase), or glucose-1-phosphate using pgm (α -phosphoglucomutase), where those both undergo different sets of reactions.UDP-glucuronic acid and UDP-n-acetylglucosamine get bound together to form HA via hasA (HA synthase). Synthesis of UDP-glucuronic acid UDP-glucuronic acid is formed from hasC (UDP-glucose pyrophosphorylase) converting glucose-1-P into UDP-glucose, which then reacts with hasB (UDP-glucose dehydrogenase) to form UDP-glucuronic acid. Synthesis of N-acetyl glucosamine The path forward from fructose-6-P utilizes glmS (amidotransferase) to form glucosamine-6-P. Then, glmM (Mutase) reacts with this product to form glucosamine-1-P. hasD (acetyltransferase) converts this into n-acetylglucosamine-1-P, and finally, hasD (pyrophosphorylase) converts this product into UDP-n-acetylglucosamine. Final step: Two disaccharides form hyaluronic acid UDP-glucuronic acid and UDP-n-acetylglucosamine get bound together to form HA via hasA (HA synthase). Completion of HA Synthesis. Degradation Hyaluronic acid can be degraded by a family of enzymes called hyaluronidases. In humans, there are at least seven types of hyaluronidase-like enzymes, several of which are tumor suppressors. The degradation products of hyaluronan, the oligosaccharides and very low-molecular-weight hyaluronan, exhibit pro-angiogenic properties. In addition, recent studies showed hyaluronan fragments, not the native high-molecular weight molecule, can induce inflammatory responses in macrophages and dendritic cells in tissue injury and in skin transplant.Hyaluronan can also be degraded via non-enzymatic reactions. These include acidic and alkaline hydrolysis, ultrasonic disintegration, thermal decomposition, and degradation by oxidants. Etymology Hyaluronic acid is derived from hyalos (Greek for vitreous, meaning ‘glass-like’) and uronic acid because it was first isolated from the vitreous humour and possesses a high uronic acid content. The term hyaluronate refers to the conjugate base of hyaluronic acid. Since the molecule typically exists in vivo in its polyanionic form, it is most commonly referred to as hyaluronan. History Hyaluronic acid was first obtained by Karl Meyer and John Palmer in 1934 from the vitreous body in a cows eye. The first hyaluronan biomedical product, Healon, was developed in the 1970s and 1980s by Pharmacia, and approved for use in eye surgery (i.e., corneal transplantation, cataract surgery, glaucoma surgery, and surgery to repair retinal detachment). Other biomedical companies also produce brands of hyaluronan for ophthalmic surgery.Native hyaluronic acid has a relatively short half-life (shown in rabbits) so various manufacturing techniques have been deployed to extend the length of the chain and stabilise the molecule for its use in medical applications. The introduction of protein-based cross-links, the introduction of free-radical scavenging molecules such as sorbitol, and minimal stabilisation of the HA chains through chemical agents such as NASHA (non-animal stabilised hyaluronic acid) are all techniques that have been used to preserve its shelf life.In the late 1970s, intraocular lens implantation was often followed by severe corneal edema, due to endothelial cell damage during the surgery. It was evident that a viscous, clear, physiologic lubricant to prevent such scraping of the endothelial cells was needed.The name "hyaluronan" is also used for a salt. Other animals Hyaluronan is used in treatment of articular disorders in horses, in particular those in competition or heavy work. It is indicated for carpal and fetlock joint dysfunctions, but not when joint sepsis or fracture are suspected. It is especially used for synovitis associated with equine osteoarthritis. It can be injected directly into an affected joint, or intravenously for less localized disorders. It may cause mild heating of the joint if directly injected, but this does not affect the clinical outcome. Intra-articularly administered medicine is fully metabolized in less than a week.Note that, according to Canadian regulation, hyaluronan in HY-50 preparation should not be administered to animals to be slaughtered for horse meat. In Europe, however, the same preparation is not considered to have any such effect, and edibility of the horse meat is not affected.Naked mole rats have very high molecular weight hyaluronan (6–12 MDa) that has been shown to give them resistance to cancer. This large HA is due to both differently sequenced HAS2 and lower HA degradation mechanisms. Research Due to its high biocompatibility and its common presence in the extracellular matrix of tissues, hyaluronan is gaining popularity as a biomaterial scaffold in tissue engineering research. In particular, a number of research groups have found hyaluronans properties for tissue engineering and regenerative medicine are significantly improved with cross-linking, producing a hydrogel. The pioneering work on crosslinked hyaluronan derivatives was initiated by a small research group headed by Prof. Aurelio Romeo in the late 1980s. Crosslinking allows a researcher to form a desired shape, as well as to deliver therapeutic molecules, into a host. Hyaluronan can be crosslinked by attaching thiols (trade names: Extracel, HyStem), methacrylates, hexadecylamides (trade name: Hymovis), and tyramines (trade name: Corgel). Hyaluronan can also be crosslinked directly with formaldehyde (trade name: Hylan-A) or with divinylsulfone (trade name: Hylan-B).Due to its ability to regulate angiogenesis by stimulating endothelial cells to proliferate, hyaluronan can be used to create hydrogels to study vascular morphogenesis. These hydrogels have properties similar to human soft tissue, but are also easily controlled and modified, making HA very suitable for tissue-engineering studies. For example, HA hydrogels are appealing for engineering vasculature from endothelial progenitor cells by using appropriate growth factors such as VEGF and Ang-1 to promote proliferation and vascular network formation. Vacuole and lumen formation have been observed in these gels, followed by branching and sprouting through degradation of the hydrogel and finally complex network formation. The ability to generate vascular networks using HA hydrogels leads to opportunities for in vivo and clinical applications. One in vivo study, where HA hydrogels with endothelial colony forming cells were implanted into mice three days after hydrogel formation, saw evidence that the host and engineered vessels joined within 2 weeks of implantation, indicating viability and functionality of the engineered vasculature.Hyaluronic acid-mediated drug delivery system was deemed useful for targeting inflammatory skin diseases condition. See also Alguronic acid Sodium hyaluronate References External links ATC codes: D03AX05 (WHO), M09AX01 (WHO), R01AX09 (WHO), S01KA01 (WHO) Hyaluronan at the US National Library of Medicine Medical Subject Headings (MeSH)
Calamine	Calamine, also known as calamine lotion, is a medication used to treat mild itchiness. This includes from sunburn, insect bites, poison ivy, poison oak, and other mild skin conditions. It may also help dry out skin irritation. It is applied on the skin as a cream or lotion.Side effects may include skin irritation. It is considered to be safe in pregnancy. Calamine is a combination of zinc oxide and 0.5% ferric oxide (Fe2O3). The lotion is produced with additional ingredients such as phenol and calcium hydroxide.The use of calamine lotion dates back as far as 1500 BC. It is on the World Health Organizations List of Essential Medicines. Calamine is available over-the-counter as a generic medication. Medical uses Calamine is used to treat itchiness. This includes sunburn, insect bite, or other mild skin conditions. Effectiveness The FDA recommends applying some topical over-the-counter skin products, such as calamine, to absorb the weeping of the skin caused by poisonous plants such as poison ivy, poison oak, and poison sumac. For relieving the pain or itching caused by these plants, the FDA document recommends a cold water compress and topical corticosteroids. References External links "Calamine". Drug Information Portal. U.S. National Library of Medicine.
Brodalumab	Brodalumab, sold under the brand name Siliq in the US and Kyntheum in the EU, is a human monoclonal antibody designed for the treatment of inflammatory diseases.In February 2017, it received US FDA approval to treat moderate to severe plaque psoriasis in people who have not improved with other treatments. Mechanism of action Brodalumab binds to the interleukin-17 receptor and so prevents interleukin 17 (IL-17) from activating the receptor. This mechanism is similar to that of another anti-psoriasis antibody, ixekizumab, which however binds to IL-17 itself. History Brodalumab was developed by Amgen, Inc. as AMG 827. In 2013, it was in two phase III clinical trials for the treatment of moderate to severe psoriasis.In November 2014, Amgen and AstraZeneca reported encouraging results for the compound. The companies stated that the compound met the primary endpoint showing superior skin clearance in a Phase III trial when compared to ustekinumab and a placebo.However, in May 2015, Amgen announced that it was ending its participation in co-development of the compound because of reports of patients having "events of suicidal ideation and behavior". AstraZeneca will be solely responsible for any future development and marketing of brodalumab in all territories except for certain Asian territories such as Japan, where Kyowa Hakko Kirin has rights to brodalumab and continued as KHK4827. In September 2015, AstraZeneca announced a partnership with Valeant Pharmaceuticals in which Valeant took over exclusive rights to develop and commercialize brodalumab. In July 2016, the rights to commercialize brodalumab in Europe were sold to LEO Pharma.In January 2016, a biologics license application (BLA) was submitted to the US FDA. Approval followed in February 2017. References External links "Brodalumab". Drug Information Portal. U.S. National Library of Medicine.
Cyclophosphamide	Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer, small cell lung cancer, neuroblastoma, and sarcoma. As an immune suppressor it is used in nephrotic syndrome, granulomatosis with polyangiitis, and following organ transplant, among other conditions. It is taken by mouth or injection into a vein.Most people develop side effects. Common side effects include low white blood cell counts, loss of appetite, vomiting, hair loss, and bleeding from the bladder. Other severe side effects include an increased future risk of cancer, infertility, allergic reactions, and pulmonary fibrosis. Cyclophosphamide is in the alkylating agent and nitrogen mustard family of medications. It is believed to work by interfering with the duplication of DNA and the creation of RNA.Cyclophosphamide was approved for medical use in the United States in 1959. It is on the World Health Organizations List of Essential Medicines. Medical uses Cyclophosphamide is used to treat cancers and autoimmune diseases. It is used to quickly control the disease. Due to its toxicity, it is replaced as soon as possible by less toxic drugs. Regular and frequent laboratory evaluations are required to monitor kidney function, avoid drug-induced bladder complications and screen for bone marrow toxicity. Cancer The main use of cyclophosphamide is with other chemotherapy agents in the treatment of lymphomas, some forms of brain cancer, neuroblastoma, leukemia and some solid tumors.Oncovet C (Chemovet S.A.), is the first-based drug approved in Latin America for veterinary use for canine and feline cancer (carcinomas of anal sacs, bladder carcinomas, urethral carcinomas, hemangiosarcomas, lymphomas, mast cell tumor, osteosarcomas, soft tissue sarcoma), feline cancers (mammary carcinomas, hemangiosarcomas, lymphomas, plasmacytomas, chronic lymphocytic leukemia, acute myelogenous leukemia, mast cell tumor). It can be administered in different treatment schemes, such as induction therapy, adjuvant, neoadjuvant, maintenance and metronomic chemotherapy. Autoimmune diseases Cyclophosphamide decreases the immune systems response, and although concerns about toxicity restrict its use to patients with severe disease, it remains an important treatment for life-threatening autoimmune diseases where disease-modifying antirheumatic drugs (DMARDs) have been ineffective. For example, systemic lupus erythematosus with severe lupus nephritis may respond to pulsed cyclophosphamide. Cyclophosphamide is also used to treat minimal change disease, severe rheumatoid arthritis, granulomatosis with polyangiitis, Goodpasture syndrome and multiple sclerosis.Because of its potential side effects such as amenorrhea or ovarian failure, cyclophosphamide is used for early phases of treatment and later substituted by other medications, such as mycophenolic acid or ACA. AL amyloidosis Cyclophosphamide, used in combination with thalidomide or lenalidomide and dexamethasone has documented efficacy as an off-label treatment of AL amyloidosis. It appears to be an alternative to the more traditional treatment with melphalan in people who are ill-suited for autologous stem cell transplant. Graft-versus-host disease Graft-versus-host disease (GVHD) is a major barrier for allogeneic stem cell transplant because of the immune reactions of donor T cell against the person receiving them. GVHD can often be avoided by T-cell depletion of the graft. The use of a high dose cyclophosphamide post-transplant in a half matched or haploidentical donor hematopoietic stem cell transplantation reduces GVHD, even after using a reduced conditioning regimen. Contraindications Like other alkylating agents, cyclophosphamide is teratogenic and contraindicated in pregnant women (pregnancy category D) except for life-threatening circumstances in the mother. Additional relative contraindications to the use of cyclophosphamide include lactation, active infection, neutropenia or bladder toxicity.Cyclophosphamide is a pregnancy category D drug and causes birth defects. First trimester exposure to cyclophosphamide for the treatment of cancer or lupus displays a pattern of anomalies labeled "cyclophosphamide embryopathy", including growth restriction, ear and facial abnormalities, absence of digits and hypoplastic limbs. Side effects Adverse drug reactions from cyclophosphamide are related to the cumulative medication dose and include chemotherapy-induced nausea and vomiting, bone marrow suppression, stomach ache, hemorrhagic cystitis, diarrhea, darkening of the skin/nails, alopecia (hair loss) or thinning of hair, changes in color and texture of the hair, lethargy, and profound gonadotoxicity. Other side effects may include easy bruising/bleeding, joint pain, mouth sores, slow-healing existing wounds, unusual decrease in the amount of urine or unusual tiredness or weakness. Potential side effects also include leukopenia, infection, bladder toxicity, and cancer.Pulmonary injury appears rare, but can present with two clinical patterns: an early, acute pneumonitis and a chronic, progressive fibrosis. Cardiotoxicity is a major problem with people treated with higher dose regimens.High-dose intravenous cyclophosphamide can cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a potentially fatal hyponatremia when compounded by intravenous fluids administered to prevent drug-induced cystitis. While SIADH has been described primarily with higher doses of cyclophosphamide, it can also occur with the lower doses used in the management of inflammatory disorders. Bladder bleeding Acrolein is toxic to the bladder epithelium and can lead to hemorrhagic cystitis, which is associated with microscopic or gross hematuria and occasionally dysuria. Risks of hemorrhagic cystitis can be minimized with adequate fluid intake, avoidance of nighttime dosage and mesna (sodium 2-mercaptoethane sulfonate), a sulfhydryl donor which binds and detoxifies acrolein. Intermittent dosing of cyclophosphamide decreases cumulative drug dose, reduces bladder exposure to acrolein and has equal efficacy to daily treatment in the management of lupus nephritis. Infection Neutropenia or lymphopenia arising secondary to cyclophosphamide usage can predispose people to a variety of bacterial, fungal and opportunistic infections. No published guidelines cover PCP prophylaxis for people with rheumatological diseases receiving immunosuppressive drugs, but some advocate its use when receiving high-dose medication. Infertility Cyclophosphamide has been found to significantly increase the risk of premature menopause in females and of infertility in males and females, the likelihood of which increases with cumulative drug dose and increasing patient age. Such infertility is usually temporary, but can be permanent. The use of leuprorelin in women of reproductive age before administration of intermittently dosed cyclophosphamide may diminish the risks of premature menopause and infertility. Cancer Cyclophosphamide is carcinogenic and may increase the risk of developing lymphomas, leukemia, skin cancer, transitional cell carcinoma of the bladder or other malignancies. Myeloproliferative neoplasms, including acute leukemia, non-Hodgkin lymphoma and multiple myeloma, occurred in 5 of 119 rheumatoid arthritis patients within the first decade after receiving cyclophosphamide, compared with one case of chronic lymphocytic leukemia in 119 rheumatoid arthritis patients with no history. Secondary acute myeloid leukemia (therapy-related AML, or "t-AML") is thought to occur either by cyclophosphamide-inducing mutations or selecting for a high-risk myeloid clone.This risk may be dependent on dose and other factors, including the condition, other agents or treatment modalities (including radiotherapy), treatment length and intensity. For some regimens, it is rare. For instance, CMF-therapy for breast cancer (where the cumulative dose is typically less than 20 grams of cyclophosphamide) carries an AML risk of less than 1/2000, with some studies finding no increased risk compared to background. Other treatment regimens involving higher doses may carry risks of 1–2% or higher. Cyclophosphamide-induced AML, when it happens, typically presents some years after treatment, with incidence peaking around 3–9 years. After nine years, the risk falls to background. When AML occurs, it is often preceded by a myelodysplastic syndrome phase, before developing into overt acute leukemia. Cyclophosphamide-induced leukemia will often involve complex cytogenetics, which carries a worse prognosis than de novo AML. Pharmacology Oral cyclophosphamide is rapidly absorbed and then converted by mixed-function oxidase enzymes (cytochrome P450 system) in the liver to active metabolites. The main active metabolite is 4-hydroxycyclophosphamide, which exists in equilibrium with its tautomer, aldophosphamide. Most of the aldophosphamide is then oxidised by the enzyme aldehyde dehydrogenase (ALDH) to make carboxycyclophosphamide. A small proportion of aldophosphamide freely diffuses into cells, where it is decomposed into two compounds, phosphoramide mustard and acrolein. The active metabolites of cyclophosphamide are highly protein bound and distributed to all tissues, are assumed to cross the placenta and are known to be present in breast milk.It is specifically in the oxazaphosphorine group of medications.Cyclophosphamide metabolites are primarily excreted in the urine unchanged, and drug dosing should be appropriately adjusted in the setting of renal dysfunction. Drugs altering hepatic microsomal enzyme activity (e.g., alcohol, barbiturates, rifampicin, or phenytoin) may result in accelerated metabolism of cyclophosphamide into its active metabolites, increasing both pharmacologic and toxic effects of the drug; alternatively, drugs that inhibit hepatic microsomal enzymes (e.g. corticosteroids, tricyclic antidepressants, or allopurinol) result in slower conversion of cyclophosphamide into its metabolites and consequently reduced therapeutic and toxic effects.Cyclophosphamide reduces plasma pseudocholinesterase activity and may result in prolonged neuromuscular blockade when administered concurrently with succinylcholine. Tricyclic antidepressants and other anticholinergic agents can result in delayed bladder emptying and prolonged bladder exposure to acrolein. Mechanism of action The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells that have low levels of ALDH. Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cell apoptosis.Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in bone marrow stem cells, liver and intestinal epithelium. ALDHs protect these actively proliferating tissues against toxic effects of phosphoramide mustard and acrolein by converting aldophosphamide to carboxycyclophosphamide that does not give rise to the toxic metabolites phosphoramide mustard and acrolein. This is because carboxycyclophosphamide cannot undergo β-elimination (the carboxylate acts as an electron-donating group, nullifying the potential for transformation), preventing nitrogen mustard activation and subsequent alkylation.Cyclophosphamide induces beneficial immunomodulatory effects in adaptive immunotherapy. Suggested mechanisms include: Elimination of T regulatory cells (CD4+CD25+ T cells) in naive and tumor-bearing hosts Induction of T cell growth factors, such as type I IFNs, and/or Enhanced grafting of adoptively transferred, tumor-reactive effector T cells by the creation of an immunologic space niche.Thus, cyclophosphamide preconditioning of recipient hosts (for donor T cells) has been used to enhance immunity in naïve hosts, and to enhance adoptive T cell immunotherapy regimens, as well as active vaccination strategies, inducing objective antitumor immunity. History As reported by O. M. Colvin in his study of the development of cyclophosphamide and its clinical applications, Phosphoramide mustard, one of the principal toxic metabolites of cyclophosphamide, was synthesized and reported by Friedman and Seligman in 1954 …It was postulated that the presence of the phosphate bond to the nitrogen atom could inactivate the nitrogen mustard moiety, but the phosphate bond would be cleaved in gastric cancers and other tumors which had a high phosphamidase content. However, in studies carried out after the clinical efficacy of cyclophosphamide was demonstrated, phosphoramide mustard proved to be cytotoxic in vitro (footnote omitted), but to have a low therapeutic index in vivo. Cyclophosphamide and the related nitrogen mustard–derived alkylating agent ifosfamide were developed by Norbert Brock and ASTA (now Baxter Oncology). Brock and his team synthesised and screened more than 1,000 candidate oxazaphosphorine compounds. They converted the base nitrogen mustard into a nontoxic "transport form". This transport form was a prodrug, subsequently actively transported into cancer cells. Once in the cells, the prodrug was enzymatically converted into the active, toxic form. The first clinical trials were published at the end of the 1950s. In 1959 it became the eighth cytotoxic anticancer agent to be approved by the FDA. Society and culture The abbreviation CP is common, although abbreviating drug names is not best practice in medicine. Research Because of its impact on the immune system, it is used in animal studies. Rodents are injected intraperitoneally with either a single dose of 150 mg/kg or two doses (150 and 100 mg/kg) spread over two days. This can be used for applications such as: The EPA may be concerned about potential human pathogenicity of an engineered microbe when conducting an MCAN review. Particularly for bacteria with potential consumer exposure they require testing of the microbe on immuno-compromised rats. Cyclophosphamide provides a positive control when studying immune-response of a new drug. References External links "Cyclophosphamide". Drug Information Portal. U.S. National Library of Medicine. U.S. Patent 3,018,302 Novel cyclic phosphoric acid ester amides, and the production thereof. (patent for cyclophosphamide).
Mecasermin rinfabate	Mecasermin rinfabate (INN, USAN) (brand name Iplex), also known as rhIGF-1/rhIGFBP-3, is a drug consisting of recombinant human insulin-like growth factor 1 (IGF-1) and recombinant human insulin-like growth factor binding protein-3 (IGFBP-3) which is used for the treatment of amyotrophic lateral sclerosis (Lou Gehrigs disease).It is similar in action to mecasermin, but with fewer side effects (such as hypoglycemia). Potential uses Mecasermin rinfabate was developed by INSMED corporation for the treatment of growth failure in children with severe primary IGF-I deficiency (primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH. Due to a patent settlement, Iplex is being taken off the market for short stature related indications. However, Iplex is being studied as a treatment for other several serious medical conditions. On March 11, 2009 the FDA announced that mecasermin rinfabate would be made available to Americans with amyotrophic lateral sclerosis (ALS), more commonly known as Lou Gehrigs disease, as a part of a clinical trial. The drug is currently available in Italy for this condition. Myotonic muscular dystrophy Iplex was investigated in a Phase II clinical study at the University of Rochester School of Medicine, with funding provided by the Muscular Dystrophy Association and the National Institutes of Health. This Phase II program studied the safety and tolerability of once-daily, subcutaneous injection of Iplex in patients with MMD. While patients with MMD showed significant increases in total muscle weight, testosterone levels, and LDL levels, and significant decreases in triglyceride and HDL levels, functional assays such as grip strength and walk tests did not show improvement. HIV-associated adipose redistribution syndrome Iplex is also being explored as a possible therapy for HIV- Associated Adipose Redistribution Syndrome (HARS). Data is being collected from a Phase II open-label clinical study directed by Morris Schambelan, M.D., a professor of medicine at University of California San Francisco. Dr Schambelan serves as Chief of Endocrinology and Director of the General Clinical Research Center at San Francisco General Hospital. This study is designed to evaluate the safety and efficacy of Iplex treatment with the primary goal of determining the effects of Iplex on visceral fat distribution and glucose and lipid metabolism. Initial data from this trial is to be available in 2007, with Phase III trials initiating in 2009. Retinopathy of prematurity Clinical work is at an earlier stage in the development of Iplex to treat Retinopathy of Prematurity (ROP). This disease, affecting an estimated 14,000 to 16,000 premature infants each year, causes the lack of development of the small blood vessels in the back of the eye leading to blindness in the majority of cases. A Phase I clinical study investigating Iplex as a treatment for ROP has been initiated at the University of Gothenburg in Sweden, in collaboration with scientists at the Harvard Medical School in the U.S. results of this study are expected by the end of 2007. Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrigs Disease is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Motor neurons reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body. The progressive degeneration of the motor neurons in ALS eventually leads to their death. When the motor neurons die, the ability of the brain to initiate and control muscle movement is lost. With voluntary muscle action progressively affected, patients in the later stages of the disease may become totally paralyzed. In January 2007, INSMED announced that the Italian Ministry of Health requested INSMED corporation to make Iplex available to treat Italian patients sufferings from ALS. IGF-1, the main component of Iplex, was the subject of a recent clinical trial in ALS. It involved 330 people with ALS from 20 ALS treatment centres across the United States. The drug was injected under the skin (subcutaneous delivery) in a randomized double-blinded placebo-controlled trial – this is the gold standard way of conducting a clinical trial. At the end of the two-year treatment period, there were no differences between people with ALS who received IGF-1 and those who received placebo in muscle strength, the need for a tracheostomy for breathing, or survival, indicating that IGF-1 provided patients no benefit. The current results are published in the November 25 issue of Neurology. The researchers were led by Eric J. Sorenson, MD, from the Mayo Clinic in Rochester, Minnesota "While this is very disappointing, at least it was definitive and gives, I think, a pretty definitive answer, at least for this strategy for this drug," Dr. Sorenson said. However, he added, "there is still a great deal of evidence that the IGF-1 pathway can be beneficial to people who have ALS, but just not the way we administered it."Novel methods of delivering IGF-1 in a more selected fashion are now under way, including the use of viral mediators or stem cells. Two previous phase 3 trials of IGF-1 in ALS showed inconsistent results: 1 trial, carried out in North America, did find a benefit, whereas the other, a European trial, did not confirm the earlier findings. "The results of our study most resemble those of the previous European study, with no benefit in either survival or functional scales,", De Sorenson concludes. "It is disappointing that we were unable to confirm the benefit that was noted in the previous North American study." Conclusive evidence points, what Iplex (and any form of IGF-1) cant slow progression in human ALS. Lot of sites that have published articles about the link between Lyme disease and ALS are sponsored by clinics specializing in the treatment of chronic Lyme disease, or by the sellers of products for treating this, or both. Myotonia congenita Myotonia congenita is a genetic muscle disorder. The two main types of myotonia congenita are Thomsen disease, which begins in infancy, and Becker disease (sometimes called generalized myotonia), which usually begins between the ages four and 12. References External links INSMED
Toremifene	Toremifene, sold under the brand name Fareston among others, is a medication which is used in the treatment of advanced breast cancer in postmenopausal women. It is taken by mouth.Side effects of toremifene include hot flashes, sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding. It can also cause blood clots, irregular heartbeat, cataracts, visual disturbances, elevated liver enzymes, endometrial hyperplasia, and endometrial cancer. High blood calcium levels can occur in women with bone metastases.The medication is a selective estrogen receptor modulator (SERM) and hence is a mixed agonist–antagonist of the estrogen receptor (ER), the biological target of estrogens like estradiol. It has estrogenic effects in bone, the liver, and the uterus and antiestrogenic effects in the breasts. It is a triphenylethylene derivative and is closely related to tamoxifen.Toremifene was introduced for medical use in 1997. It was the first antiestrogen to be introduced since tamoxifen in 1978. It is available as a generic medication in the United States. Medical uses Toremifene is approved for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or unknown-status tumors. This is its only approved use in the United States. It shows equivalent effectiveness to tamoxifen for this indication. Toremifene has been found to be effective in the treatment of breast pain and may be a more effective medication than tamoxifen for this indication. It also has superior effects on bone mineral density and lipid profile, including levels of cholesterol and triglycerides, compared to tamoxifen. Toremifene has been reported to significantly improve symptoms of gynecomastia in men. Available forms Toremifene is provided in the form of 60 mg oral tablets. Side effects The side effects of toremifene are similar to those of tamoxifen. The most common side effect is hot flashes. Other side effects include sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding. In women with bone metastases, hypercalcemia may occur. Toremifene has a small risk of thromboembolic events. Cataracts, vision changes, and elevation of liver enzymes have been reported. The drug prolongs the QT interval and hence has a risk of potentially fatal dysrhythmias. The risk of dysrhythmias can be reduced by avoiding use in patients with hypokalemia, hypomagnesemia, pre-existing QT prolongation, and in those taking other QT-prolonging drugs. Because toremifene has estrogenic actions in the uterus, it can increase the risk of endometrial hyperplasia and endometrial cancer.Toremifene appears to be safer than tamoxifen. It has a lower risk of venous thromboembolism (VTE) (e.g., pulmonary embolism), stroke, and cataracts. The lower risk of VTE may be related to the fact tamoxifen decreases levels of the antithrombin III to a significantly greater extent than either 60 or 200 mg/day toremifene. Interactions Toremifene is a substrate of CYP3A4, a cytochrome P450 enzyme, and hence drugs that induce or inhibit this enzyme can respectively decrease or increase levels of toremifene in the body. Pharmacology Pharmacodynamics Toremifene is a selective estrogen receptor modulator (SERM). That is, it is a selective mixed agonist–antagonist of the estrogen receptors (ERs), with estrogenic actions in some tissues and antiestrogenic actions in other tissues. The medication has estrogenic effects in bone, partial estrogenic effects in the uterus and liver, and antiestrogenic effects in the breasts. The affinity of toremifene for the ER is similar to that of tamoxifen. In studies using rat ER, toremifene had about 1.4% and tamoxifen had about 1.6% of the affinity of estradiol for the ER. The affinities (Ki) of toremifene at the human ERs have been reported as 20.3 ± 0.1 nM for the ERα and 15.4 ± 3.1 nM for the ERβ. In other rat ER studies, toremifene had 3–9% of the affinity of estradiol for the ER while its metabolites N-desmethyltoremifene and 4-hydroxytoremifene had 3–5% and 64–158% of the affinity of estradiol for the ER, respectively. The affinity of another metabolite, 4-hydroxy-N-desmethyltoremifene, was not assessed. 4-Hydroxytoremifene showed about 100-fold higher antiestrogenic potency than toremifene in vitro in one study, but not in another. 4-Hydroxy-N-desmethyltoremifene has also been found to be strongly antiestrogenic in vitro. The metabolites of toremifene, particularly 4-hydroxytoremifene, may contribute importantly to the clinical activity of the medication. On the other hand, some authorities consider toremifene not to be a prodrug.Toremifene is very similar to tamoxifen and shares most of its properties. There are some indications that toremifene may be safer than tamoxifen as it is not a hepatocarcinogen in animals and may have less potential for genotoxicity. However, clinical studies have found no significant differences between toremifene and tamoxifen, including in terms of effectiveness, tolerability, and safety, and hence the clinical use of toremifene has been somewhat limited. Toremifene is thought to have about one-third of the potency of tamoxifen; i.e., 60 mg toremifene is roughly equivalent to 20 mg tamoxifen in the treatment of breast cancer.Toremifene has been found to have antigonadotropic effects in postmenopausal women, progonadotropic effects in men, to increase sex hormone-binding globulin levels, and to decrease insulin-like growth factor 1 levels by about 20% in postmenopausal women and men.In addition to its activity as a SERM, 4-hydroxytoremifene is an antagonist of the estrogen-related receptor γ (ERRγ). Pharmacokinetics Absorption The bioavailability of toremifene has not been precisely determined but is known to be good and has been estimated to be approximately 100%. Levels of toremifene at steady state with a dosage of 60 mg/day are 800 to 879 ng/mL. Levels of N-desmethyltoremifene at steady state with toremifene were 3,058 ng/mL at 60 mg/day, 5,942 ng/mL at 200 mg/day, and 11,913 ng/mL at 400 mg/day. Levels of 4-hydroxytoremifene at steady state with toremifene were 438 ng/mL at 200 mg/day and 889 ng/mL at 400 mg/day. Concentrations of toremifene increase linearly across a dose range of 10 to 680 mg. Distribution Toremifene is 99.7% bound to plasma proteins, with 92% bound specifically to albumin, about 6% to β1 globulin fraction, and about 2% to a fraction between albumin and α1 globulins. The apparent volume of distribution of toremifene ranged from 457 to 958 L. Metabolism Toremifene is metabolized in the liver primarily by CYP3A4 and then undergoes secondary hydroxylation. The metabolites of toremifene include N-desmethyltoremifene, 4-hydroxytoremifene, and 4-hydroxy-N-desmethyltoremifene, among others. Ospemifene (deaminohydroxytoremifene) is also a major metabolite of toremifene. Elimination The elimination half-life of toremifene is 3 to 7 days in healthy individuals. In people with impaired liver function, the half-life is 11 days. The elimination half-lives of the metabolites of toremifene are 5 to 21 days for N-desmethyltoremifene, 5 days for 4-hydroxytoremifene, and 4 days for ospemifene. The long elimination half-lives of toremifene and its metabolites are thought to be due to enterohepatic recirculation and high plasma protein binding. Toremifene is eliminated 70% in the feces, as metabolites. Chemistry Toremifene, also known as 4-chlorotamoxifen, is a derivative of triphenylethylene and a close analogue of tamoxifen. It is also closely related to afimoxifene (4-hydroxytamoxifen) and ospemifene (deaminohydroxytoremifene). History Toremifene was introduced in the United States in 1997. It was the first antiestrogen to be introduced in this country since tamoxifen in 1978. Society and culture Generic names Toremifene is the generic name of the drug and its INN and BAN, while toremifene citrate is its USAN and JAN and torémifène is its DCF. Brand names Toremifene is marketed almost exclusively under the brand name Fareston. Availability Toremifene is marketed widely throughout the world and is available in the United States, the United Kingdom, Ireland, many other European countries, South Africa, Australia, New Zealand, and elsewhere throughout the world. Research Toremifene was also evaluated for prevention of prostate cancer and had the tentative brand name Acapodene.In 2007 the pharmaceutical company GTx, Inc was conducting two different phase 3 clinical trials; First, a pivotal Phase clinical trial for the treatment of serious side effects of androgen deprivation therapy (ADT) (especially vertebral/spine fractures and hot flashes, lipid profile, and gynecomastia) for advanced prostate cancer, and second, a pivotal Phase III clinical trial for the prevention of prostate cancer in high risk men with high grade prostatic intraepithelial neoplasia, or PIN. Results of these trials are expected by first quarter of 2008An NDA for the first application (relief of prostate cancer ADT side effects) was submitted in Feb 2009, and in Oct 2009 the FDA said they would need more clinical data, e.g. another phase III trial.Ultimately, development was discontinued and toremifene was never marketed for complications associated with ADT or the treatment or prevention of prostate cancer.Toremifene may be useful in the prevention of bicalutamide-induced gynecomastia. Phase III Trial Results A double-blind, placebo-controlled, randomized, 3 year clinical trial of toremifene was conducted using a sample of 1,260 men. Subjects had a median age of 64 years and were diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN), which is considered premalignant, though Thompson and Leach feel a low grade PIN could also be deemed premalignant.The sponsor, GTx, who designed and managed the study, found 34.7% of the placebo and 32.3% of the toremifene groups had cancer events. No distinction was found in Gleason scores of either group.Previous murine studies using transgenic adenocarcinoma of mouse prostate (TRAMP) mice showed toremifene prevented palpable tumors in 60% of the animals. This study used toremifene as an early prophylactic, which differentiates it from the phase III human studies. References Further reading Taras TL, Wurz GT, Linares GR, DeGregorio MW (2000). "Clinical pharmacokinetics of toremifene". Clin Pharmacokinet. 39 (5): 327–34. doi:10.2165/00003088-200039050-00002. PMID 11108432. S2CID 26647296. Harvey HA, Kimura M, Hajba A (2006). "Toremifene: an evaluation of its safety profile". Breast. 15 (2): 142–57. doi:10.1016/j.breast.2005.09.007. PMID 16289904. Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA (2006). "Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy". Expert Opin Investig Drugs. 15 (3): 293–305. doi:10.1517/13543784.15.3.293. PMID 16503765. S2CID 29510508. Zhou WB, Ding Q, Chen L, Liu XA, Wang S (2011). "Toremifene is an effective and safe alternative to tamoxifen in adjuvant endocrine therapy for breast cancer: results of four randomized trials". Breast Cancer Res. Treat. 128 (3): 625–31. doi:10.1007/s10549-011-1556-5. PMID 21553116. S2CID 36985808. Gennari L, Merlotti D, Stolakis K, Nuti R (2012). "Pharmacokinetic evaluation of toremifene and its clinical implications for the treatment of osteoporosis". Expert Opin Drug Metab Toxicol. 8 (4): 505–13. doi:10.1517/17425255.2012.665873. PMID 22356442. S2CID 19547631. Mao C, Yang ZY, He BF, Liu S, Zhou JH, Luo RC, Chen Q, Tang JL (2012). "Toremifene versus tamoxifen for advanced breast cancer". Cochrane Database Syst Rev. 2021 (7): CD008926. doi:10.1002/14651858.CD008926.pub2. PMC 8407374. PMID 22786516. Vogel CL, Johnston MA, Capers C, Braccia D (2014). "Toremifene for breast cancer: a review of 20 years of data". Clin. Breast Cancer. 14 (1): 1–9. doi:10.1016/j.clbc.2013.10.014. PMID 24439786. Mustonen MV, Pyrhönen S, Kellokumpu-Lehtinen PL (2014). "Toremifene in the treatment of breast cancer". World J Clin Oncol. 5 (3): 393–405. doi:10.5306/wjco.v5.i3.393. PMC 4127610. PMID 25114854. External links Toremifene - AdisInsight
Flunisolide	Flunisolide (marketed as AeroBid among others) is a corticosteroid often prescribed as treatment for allergic rhinitis. Intranasal corticosteroids are the most effective medication for controlling symptoms. The principal mechanism of action of flunisolide is to activate glucocorticoid receptors, meaning it has an anti-inflammatory action. The effects of topical corticosteroids is not immediate and requires regular use and at least a few days to start experiencing noticeable symptom relief. As-needed use has been shown to be not as effective as regular recommended use. Flunisolide should not be used in the presence of nasal infection. It should not be continued if there is no relief of symptoms after regular use over two to three weeks. It was patented in 1958 and approved for medical use in 1978. It is on the World Health Organizations List of Essential Medicines. Side effects Temporary nose and throat dryness, irritation, bleeding or unpleasant taste or smell may occur. Nasal septum perforation is rarely reported. Rare, but localized infections of the nose and pharynx with Candida albicans have been reported and long-term use may raise the chance of cataracts or glaucoma.Flunisolide nasal spray is absorbed into the circulatory system (blood). Corticosteroid nasal sprays may affect the hypothalamic-pituitary-adrenal axis function in humans. After the desired clinical effect is obtained, the maintenance dose should be reduced to the smallest amount necessary to control symptoms, which can be as low as 1 spray in each nostril a day. Utilizing the minimum effective dose will reduce possibility of side effects. Recommended amounts of intranasal corticosteroids are generally not associated with systemic side effects. Corticosteroids inhibit wound healing. Therefore, use of corticosteroid nasal sprays in patients who have experienced recent nasal septal ulcers, recurrent epistaxis, nasal surgery or trauma, a nasal corticosteroid should be used with caution until healing has occurred. In pregnancy, recommended doses of intranasal corticosteroids are safe and effective. == References ==
Carbidopa	Carbidopa (Lodosyn) is a drug given to people with Parkinsons disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–brain barrier for central nervous system effect, instead of being peripherally metabolised into substances unable to cross said barrier. Pharmacology Carbidopa inhibits aromatic-L-amino-acid decarboxylase (DOPA decarboxylase or DDC), an enzyme important in the biosynthesis of L-tryptophan to serotonin and in the biosynthesis of L-DOPA to dopamine (DA). DDC exists both outside of (body periphery) and within the confines of the blood–brain barrier. Carbidopa is used in the treatment of, among other diseases, Parkinsons disease (PD), a condition characterized by death of dopaminergic neurons in the substantia nigra. Increased dopamine availability may increase the effectiveness of the remaining neurons and alleviate symptoms for a time. The pharmacologic objective is to get an exogenous dopamine-precursor known as levodopa/L-DOPA into the dopamine-deficient brains of PD patients. Levodopa/L-DOPA can cross the blood–brain barrier, but dopamine cannot. The use of carbidopa seems counter-intuitive in Parkinsons disease (PD) in that it prevents DDC conversion of levodopa/L-DOPA to dopamine. However, exogenously provided, levadopa/L-DOPA gets metabolized peripherally to its active metabolite dopamine before reaching the blood–brain barrier. Therefore, the PD brain, which is deficient in dopamine, will not receive as much of its prodrug precursor levodopa/L-DOPA due to peripheral DDC breakdown. However, carbidopa can decrease peripheral DDC conversion of levodopa/L-DOPA before it crosses the blood–brain barrier. Carbidopa acts as a peripheral DDC inhibitor, as carbidopa, itself, cannot cross the blood–brain barrier. In other words, carbidopa has no effect on brain DDC conversion of levodopa/L-DOPA to dopamine. Ultimately, a greater proportion of the exogenously provided levodopa/L-DOPA reaches the brain. Commercially, carbidopa/levodopa combinations are available in the treatment of central dopamine deficiencies. Along with carbidopa, other DDC inhibitors are benserazide (Ro-4-4602), difluromethyldopa, and α-methyldopa. pharmacology 2 Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as N-amino-α-methyl-3-hydroxy-L-tyrosine monohydrate. Its empirical formula is C10H14N2O4•H2O. Used in tandem with L-DOPA (also known as levodopa, a dopamine precursor converted in the body to dopamine), it increases the plasma half-life of levodopa from 50 minutes to 1½ hours. CarbiDOPA cannot cross the blood–brain barrier, so it inhibits only peripheral DDC. It thus prevents the conversion of L-DOPA to dopamine peripherally. This reduces the side effects caused by dopamine on the periphery, as well as increasing the concentration of L-DOPA and dopamine in the brain. The combination of carbidopa/levodopa carries the brand names of Kinson, Sinemet, Pharmacopa and Atamet; while Stalevo is a combination with entacapone, which enhances the bioavailability of carbidopa and levodopa. Carbidopa is most commonly used as a method to inhibit the activity of dopamine decarboxylase. This is an enzyme that breaks down L-Dopa in the periphery and converts it to dopamine. This results in the newly formed dopamine being unable to cross the blood–brain barrier and the effectiveness of L-Dopa treatments is greatly decreased. Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid. Elimination half-life of levodopa in the presence of carbidopa is about 1.5 hours. Following SINEMET CR, the apparent half-life of levodopa may be prolonged because of continuous absorption. This is extremely useful in the treatment of Parkinsons disease symptoms because the amount of levodopa administered to the patient can be greatly reduced. This reduction in dosage is extremely useful due to the side effects that may occur from an overdose of L-Dopa within the body. Carbidopa is also used in combination with 5-HTP, a naturally occurring amino acid which is a precursor to the neurotransmitter serotonin and an intermediate in tryptophan metabolism. carbidopa, which is used in PD to prevent conversion of the levodopa to dopamine, prevents 5-Hydroxytryptophan’s (5-HTP) metabolism in the liver and causes decreased levels of serotonin in the blood. Research shows that co-administration of 5-HTP and carbidopa greatly increases plasma 5-HTP levels. Several cases of scleroderma-like illness have been reported in patients using carbidopa and 5-HTP. In Europe, 5-HTP is prescribed with carbidopa to prevent the conversion of 5-HTP into serotonin until it reaches the brain. Synthesis The synthesis begins with a modified Strecker reaction using hydrazine and potassium cyanide on arylacetone (1) to give 2. This is then hydrolyzed with cold HCl to give carboxamide 3. More vigorous hydrolysis with 48% HBr cleaves the amide bond and the aryl ether group to produce carbidopa (4). References External links Lodosyn prescribing information Sinemet datasheet for New Zealand
Rifampicin	Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), Mycobacterium avium complex, leprosy, and Legionnaires’ disease. It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended" for latent TB infection; and when used as post-exposure prophylaxis to prevent Haemophilus influenzae type b and meningococcal disease in people who have been exposed to those bacteria. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.Common side effects include nausea, vomiting, diarrhea, and loss of appetite. It often turns urine, sweat, and tears a red or orange color. Liver problems or allergic reactions may occur. It is part of the recommended treatment of active tuberculosis during pregnancy, though its safety in pregnancy is not known. Rifampicin is of the rifamycin group of antibiotics. It works by decreasing the production of RNA by bacteria.Rifampicin was discovered in 1965, marketed in Italy in 1968, and approved in the United States in 1971. It is on the World Health Organizations List of Essential Medicines. The World Health Organization classifies rifampicin as critically important for human medicine. It is available as a generic medication. Rifampicin is made by the soil bacterium Amycolatopsis rifamycinica. Medical uses Mycobacteria Rifampicin is used for the treatment of tuberculosis in combination with other antibiotics, such as pyrazinamide, isoniazid, and ethambutol. For the treatment of tuberculosis, it is administered daily for at least six months. Combination therapy is used to prevent the development of resistance and to shorten the length of treatment. Resistance of Mycobacterium tuberculosis to rifampicin develops quickly when it is used without another antibiotic, with laboratory estimates of resistance rates from 10−7 to 10−10 per tuberculosis bacterium per generation.Rifampicin can be used alone in patients with latent tuberculosis infections to prevent or delay the development of active disease because only small numbers of bacteria are present. A Cochrane review found no difference in efficacy between a 3- to 4-month regimen of rifampicin and a 6-month regimen of isoniazid for preventing active tuberculosis in patients not infected with HIV, and patients who received rifampicin had a lower rate of hepatotoxicity. However, the quality of the evidence was judged to be low. A shorter 2-month course of rifampicin and pyrazinamide had previously been recommended but is no longer recommended due to high rates of hepatotoxicity.Rifampicin should be taken on an empty stomach with a glass of water. It is generally taken either at least one hour before meals or two hours after meals.Rifampicin is also used to treat nontuberculous mycobacterial infections including leprosy (Hansens disease) and Mycobacterium kansasii.With multidrug therapy used as the standard treatment of Hansens disease, rifampicin is always used in combination with dapsone and clofazimine to avoid causing drug resistance.It is also used in the treatment of Mycobacterium ulcerans infections as associated with Buruli ulcer, usually in combination with clarithromycin or other antibiotics. Other bacteria and protozoans In 2008, tentative evidence showed rifampicin may be useful in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in combination with other antibiotics, including in difficult-to-treat infections such as osteomyelitis and prosthetic joint infections. As of 2012, if rifampicin combination therapy was useful for pyogenic vertebral osteomyelitis was unclear. A meta-analysis concluded that adding adjunctive rifampicin to a β-lactam or vancomycin may improve outcomes in staphylococcus aureus bacteremia. However, a more recent trial found no benefit from adjunctive rifampicin.It is also used as preventive treatment against Neisseria meningitidis (meningococcal) infections. Rifampicin is also recommended as an alternative treatment for infections by the tick-borne pathogens Borrelia burgdorferi and Anaplasma phagocytophilum when treatment with doxycycline is contraindicated, such as in pregnant women or in patients with a history of allergy to tetracycline antibiotics.It is also sometimes used to treat infections by Listeria species, Neisseria gonorrhoeae, Haemophilus influenzae, and Legionella pneumophila. For these nonstandard indications, antimicrobial susceptibility testing should be done (if possible) before starting rifampicin therapy. The Enterobacteriaceae, Acinetobacter species, and Pseudomonas species are intrinsically resistant to rifampicin.It has been used with amphotericin B in largely unsuccessful attempts to treat primary amoebic meningoencephalitis caused by Naegleria fowleri.Rifampicin can be used as monotherapy for a few days as prophylaxis against meningitis, but resistance develops quickly during long-term treatment of active infections, so the drug is always used against active infections in combination with other antibiotics.Rifampicin is relatively ineffective against spirochetes, which has led to its use as a selective agent capable of isolating them in materials being cultured in laboratories. Viruses Rifampicin has some effectiveness against vaccinia virus. Pathogen susceptibility The minimum inhibitory concentrations of rifampicin for several medically significant pathogens are: Mycobacterium tuberculosis — 0.002 – 64 µg/ml Mycobacterium bovis — 0.125 µg/ml Staphylococcus aureus (methicillin resistant) — ≤ 0.006–256 µg/ml Chlamydia pneumoniae — 0.005 µg/ml Primary biliary cholangitis Rifampicin is used to treat itchiness caused by primary biliary cholangitis. The treatment-related adverse effects include hepatotoxicity, nephrotoxicity, hemolysis, and interactions with other drugs. For those reasons as well as some ethical concerns regarding off-label use of antibiotics, rifampin as a very effective preventive antibiotic for meningitis, is not considered appropriate for itchiness. Hidradenitis suppurativa Rifampicin with clindamycin has been used to treat the skin disease hidradenitis suppurativa. Adverse effects The most serious adverse effect is hepatotoxicity, and people receiving it often undergo baseline and frequent liver function tests to detect early liver damage.The more common side effects include fever, gastrointestinal disturbances, rashes, and immunological reactions. Taking rifampicin usually causes certain bodily fluids, such as urine, sweat, and tears, to become orange-red in color, a benign side effect that nonetheless can be frightening if it is not expected. This may also be used to monitor effective absorption of the drug (if drug color is not seen in the urine, the patient may wish to move the drug dose farther in time from food or milk intake). The discolorization of sweat and tears is not directly noticeable, but sweat may stain light clothing orange, and tears may permanently stain soft contact lenses. Since rifampicin may be excreted in breast milk, breastfeeding should be avoided while it is being taken.Other adverse effects include: Liver toxicity—hepatitis, liver failure in severe cases Respiratory—breathlessness Cutaneous—flushing, pruritus, rash, hyperpigmentation, redness and watering of eyes Abdominal — nausea, vomiting, abdominal cramps, diarrhea Flu-like symptoms—chills, fever, headache, arthralgia, and malaise. Rifampicin has good penetration into the brain, and this may directly explain some malaise and dysphoria in a minority of users. Allergic reaction—rashes, itching, swelling of the tongue or throat, severe dizziness, and trouble breathing Chemical structure Rifampicin is a polyketide belonging to the chemical class of compounds termed ansamycins, so named because of their heterocyclic structure containing a naphthoquinone core spanned by an aliphatic ansa chain. The naphthoquinonic chromophore gives rifampicin its characteristic red-orange crystalline color.The critical functional groups of rifampicin in its inhibitory binding of bacterial RNA polymerase are the four critical hydroxyl groups of the ansa bridge and the naphthol ring, which form hydrogen bonds with amino acid residues on the protein.Rifampicin is the 3-(4-methyl-1-piperazinyl)-iminomethyl derivative of rifamycin SV. Interactions Rifampicin is the most powerful known inducer of the hepatic cytochrome P450 enzyme system, including isoenzymes CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, and CYP3A7. It increases metabolism of many drugs and as a consequence, can make them less effective, or even ineffective, by decreasing their levels. For instance, patients undergoing long-term anticoagulation therapy with warfarin have to increase their dosage of warfarin and have their clotting time checked frequently because failure to do so could lead to inadequate anticoagulation, resulting in serious consequences of thromboembolism.Rifampicin can reduce the efficacy of birth control pills or other hormonal contraception by its induction of the cytochrome P450 system, to the extent that unintended pregnancies have occurred in women who use oral contraceptives and took rifampicin even for very short courses (for example, as prophylaxis against exposure to bacterial meningitis).Other interactions include decreased levels and less effectiveness of antiretroviral agents, everolimus, atorvastatin, rosiglitazone, pioglitazone, celecoxib, clarithromycin, caspofungin, voriconazole, and lorazepam.Rifampicin is antagonistic to the microbiologic effects of the antibiotics gentamicin and amikacin. The activity of rifampicin against some species of mycobacteria can be potentiated by isoniazid (through inhibiting mycolate synthesis) and ambroxol (through host directed effects in autophagy and pharmacokinetics). Pharmacology Mechanism of action Rifampicin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase.Crystal structure data and biochemical data suggest that rifampicin binds to the pocket of the RNA polymerase β subunit within the DNA/RNA channel, but away from the active site. The inhibitor prevents RNA synthesis by physically blocking elongation, and thus preventing synthesis of host bacterial proteins. By this "steric-occlusion" mechanism, rifampicin blocks synthesis of the second or third phosphodiester bond between the nucleotides in the RNA backbone, preventing elongation of the 5 end of the RNA transcript past more than 2 or 3 nucleotides.In a recent study Rifampicin was shown to bind to cytochrome P450 reductase and alter its conformation as well as activity towards supporting metabolism of progesterone via CYP21A2. Mechanism of resistance Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin. Resistance mutations map to the rpoB gene, encoding the beta subunit of RNA polymerase. The majority of resistance mutations in E. coli are in 3 clusters on rpoB. Cluster I is amino acids 509 to 533, cluster II is amino acids 563 to 572, and cluster III is amino acid 687. When describing mutations in rpoB in other species, the corresponding amino acid number in E. coli is usually used. In Mycobacterium tuberculosis, the majority of mutations leading to rifampicin resistance are in cluster I, in a 81bp hotspot core region called RRDR for "rifampcin resistance determining region". A change in amino acid 531 from serine to leucine arising from a change in the DNA sequence of TCG to TTG is the most common mutation. Tuberculosis resistance has also occurred due to mutations in the N-terminal region of rpoB and cluster III.An alternative mechanism of resistance is through Arr-catalyzed ADP-ribosylation of rifampicin. With the assistance of the enzyme Arr produced by the pathogen Mycobacterium smegmatis, ADP-ribose is added to rifampicin at one of its ansa chain hydroxy groups, thereby inactivating the drug. Resistance in tuberculosis Mycobacterial resistance to rifampicin may occur alone or along with resistance to other first-line antitubercular drugs. Early detection of such multidrug or extensively drug-resistant tuberculosis is critical in improving patient outcomes by instituting appropriate second-line treatments, and in decreasing transmission of drug-resistant TB. Traditional methods of detecting resistance involve mycobacterial culture and drug susceptibility testing, results of which could take up to 6 weeks. Xpert MTB/RIF assay is an automated test that can detect rifampicin resistance, and also diagnose tuberculosis. A Cochrane review updated in 2014 concluded that for rifampicin resistance detection, Xpert MTB/RIF was accurate, that is (95%) sensitive and (98%) specific. Pharmacokinetics Orally administered rifampicin results in peak plasma concentrations in about 2–4 hours. 4-Aminosalicylic acid (another antituberculosis drug) significantly reduces absorption of rifampicin, and peak concentrations may be lower. If these two drugs must be used concurrently, they must be given separately, with an interval of 8 to 12 hours between administrations. Rifampicin is easily absorbed from the gastrointestinal (GI) tract; its ester functional group is quickly hydrolyzed in bile, and it is catalyzed by a high pH and substrate-specific esterases. After about 6 hours, almost all of the drug is deacetylated. Even in this deacetylated form, rifampicin is still a potent antibiotic; however, it can no longer be reabsorbed by the intestines and is eliminated from the body. Only about 7% of the administered drug is excreted unchanged in urine, though urinary elimination accounts for only about 30% of the drug excretion. About 60% to 65% is excreted through feces.The half-life of rifampicin ranges from 1.5 to 5.0 hours, though hepatic impairment significantly increases it. Food consumption inhibits its absorption from the GI tract, and the drug is more quickly eliminated. When rifampicin is taken with a meal, its peak blood concentration falls by 36%. Antacids do not affect its absorption. The decrease in rifampicin absorption with food is sometimes enough to noticeably affect urine color, which can be used as a marker for whether or not a dose of the drug has been effectively absorbed.Distribution of the drug is high throughout the body, and reaches effective concentrations in many organs and body fluids, including the cerebrospinal fluid. Since the substance itself is red, this high distribution is the reason for the orange-red color of the saliva, tears, sweat, urine, and feces. About 60% to 90% of the drug is bound to plasma proteins. Use in biotechnology Rifampicin inhibits bacterial RNA polymerase, thus it is commonly used to inhibit the synthesis of host bacterial proteins during recombinant protein expression in bacteria. RNA encoding for the recombinant gene is usually transcribed from DNA by a viral T7 RNA polymerase, which is not affected by rifampicin. History In 1957, a soil sample from a pine forest on the French Riviera was brought for analysis to the Lepetit Pharmaceuticals research lab in Milan, Italy. There, a research group headed by Piero Sensi and Maria Teresa Timbal discovered a new bacterium. This new species produced a new class of molecules with antibiotic activity. Because Sensi, Timbal and the researchers were particularly fond of the French crime story Rififi (about a jewel heist and rival gangs), they decided to call these compounds rifamycins. After two years of attempts to obtain more stable semisynthetic products, a new molecule with high efficacy and good tolerability was produced in 1965 and was named rifampicin.Rifampicin was first sold in Italy in 1968 and was approved by the FDA in 1971. Society and culture Cancer-causing impurities In August 2020, the U.S. Food and Drug Administration (FDA) became aware of nitrosamine impurities in certain samples of rifampin. The FDA and manufacturers are investigating the origin of these impurities in rifampin, and the agency is developing testing methods for regulators and industry to detect the 1-methyl-4-nitrosopiperazine (MNP). MNP belongs to the nitrosamine class of compounds, some of which are classified as probable or possible human carcinogens (substances that could cause cancer), based on laboratory tests such as rodent carcinogenicity studies. Although there are no data available to directly evaluate the carcinogenic potential of MNP, information available on closely related nitrosamine compounds was used to calculate lifetime exposure limits for MNP.As of January 2021, the FDA continues to investigate the presence of 1-methyl-4-nitrosopiperazine (MNP) in rifampin or 1-cyclopentyl-4-nitrosopiperazine (CPNP) in rifapentine approved for sale in the US. Names Rifampicin is the INN and BAN, while rifampin is the USAN. Rifampicin may be abbreviated R, RMP, RA, RF, or RIF (US). Rifampicin is also known as rifaldazine, rofact, and rifampin in the United States, also as rifamycin SV.Its chemical name is 5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[N-(4-methyl-1-piperazinyl)formimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)-naphtho[2,1-b]furan-1,11(2H)-dione 21-acetate. Rifampicin is available under many brand names worldwide. References External links "Rifampicin". Drug Information Portal. U.S. National Library of Medicine.
Tetracycline	Tetracycline, sold under various brand names, is an oral antibiotic in the tetracyclines family of medications, used to treat a number of infections, including acne, cholera, brucellosis, plague, malaria, and syphilis.Common side effects include vomiting, diarrhea, rash, and loss of appetite. Other side effects include poor tooth development if used by children less than eight years of age, kidney problems, and sunburning easily. Use during pregnancy may harm the baby. It works by inhibiting protein synthesis in bacteria.Tetracycline was patented in 1953 and came into commercial use in 1978. It is on the World Health Organizations List of Essential Medicines. Tetracycline is available as a generic medication. Tetracycline was originally made from bacteria of the Streptomyces type. Medical uses Spectrum of activity Tetracyclines have a broad spectrum of antibiotic action. Originally, they possessed some level of bacteriostatic activity against almost all medically relevant aerobic and anaerobic bacterial genera, both Gram-positive and Gram-negative, with a few exceptions, such as Pseudomonas aeruginosa and Proteus spp., which display intrinsic resistance. However, acquired (as opposed to inherent) resistance has proliferated in many pathogenic organisms and greatly eroded the formerly vast versatility of this group of antibiotics. Resistance amongst Staphylococcus spp., Streptococcus spp., Neisseria gonorrhoeae, anaerobes, members of the Enterobacteriaceae, and several other previously sensitive organisms is now quite common. Tetracyclines remain especially useful in the management of infections by certain obligately intracellular bacterial pathogens such as Chlamydia, Mycoplasma, and Rickettsia. They are also of value in spirochaetal infections, such as syphilis, and Lyme disease. Certain rare or exotic infections, including anthrax, plague, and brucellosis, are also susceptible to tetracyclines. Tetracycline tablets were used in the plague outbreak in India in 1994. Tetracycline is first-line therapy for Rocky Mountain spotted fever (Rickettsia), Lyme disease (B. burgdorferi), Q fever (Coxiella), psittacosis, Mycoplasma pneumoniae, and nasal carriage of meningococci. It is also one of a group of antibiotics which together may be used to treat peptic ulcers caused by bacterial infections. The mechanism of action for the antibacterial effect of tetracyclines relies on disrupting protein translation in bacteria, thereby damaging the ability of microbes to grow and repair; however, protein translation is also disrupted in eukaryotic mitochondria leading to effects that may confound experimental results.The following list presents MIC susceptibility data for some medically significant microorganisms: Escherichia coli: 1 μg/mL to >128 μg/mL Shigella spp.: 1 μg/mL to 128 μg/mL Anti-eukaryote use The tetracyclines also have activity against certain eukaryotic parasites, including those responsible for diseases such as dysentery caused by an amoeba, malaria (a plasmodium), and balantidiasis (a ciliate). Use as a biomarker Since tetracycline is absorbed into bone, it is used as a marker of bone growth for biopsies in humans. Tetracycline labeling is used to determine the amount of bone growth within a certain period of time, usually a period around 21 days. Tetracycline is incorporated into mineralizing bone and can be detected by its fluorescence. In "double tetracycline labeling", a second dose is given 11–14 days after the first dose, and the amount of bone formed during that interval can be calculated by measuring the distance between the two fluorescent labels.Tetracycline is also used as a biomarker in wildlife to detect consumption of medicine- or vaccine-containing baits. Side effects Use of tetracycline antibiotics can: Discolor permanent teeth (yellow-gray-brown), from prenatal period through childhood and adulthood. Children receiving long- or short-term therapy with a tetracycline or glycylcycline may develop permanent brown discoloration of the teeth. Be inactivated by calcium ions, so are not to be taken with milk, yogurt, and other dairy products Be inactivated by aluminium, iron, and zinc ions, not to be taken at the same time as indigestion remedies (some common antacids and over-the-counter heartburn medicines) Cause skin photosensitivity, so exposure to the sun or intense light is not recommended Cause drug-induced lupus, and hepatitis Cause microvesicular fatty liver Cause tinnitus Interfere with methotrexate by displacing it from the various protein-binding sites Cause breathing complications, as well as anaphylactic shock, in some individuals Affect bone growth of the fetus, so should be avoided during pregnancy Fanconi syndrome may result from ingesting expired tetracyclines.Caution should be exercised in long-term use when breastfeeding. Short-term use is safe; bioavailability in milk is low to nil. According to the U.S. Food and Drug Administration (FDA), cases of Stevens–Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme associated with doxycycline use have been reported, but a causative role has not been established. Pharmacology Mechanism of action Tetracycline inhibits protein synthesis by blocking the attachment of charged tRNA at the P site peptide chain. Tetracycline blocks the A-site so that a hydrogen bond is not formed between the amino acids. Tetracycline binds to the 30S and 50S subunit of microbial ribosomes. Thus, it prevents the formation of a peptide chain. The action is usually not inhibitory and irreversible even with the withdrawal of the drug. Mammalian cells are less vulnerable to the effect of tetracyclines, despite the fact that tetracycline binds to the small ribosomal subunit of both prokaryotes and eukaryotes (30S and 40S, respectively). This is because bacteria actively pump tetracycline in, even against a concentration gradient, whereas mammalian cells are simply not affected by the mechanisms of tetracycline within the cytoplasm. This accounts for the relatively small off-site effect of tetracycline on human cells. Mechanisms of resistance Bacteria usually acquire resistance to tetracycline from horizontal transfer of a gene that either encodes an efflux pump or a ribosomal protection protein. Efflux pumps actively eject tetracycline from the cell, preventing the buildup of an inhibitory concentration of tetracycline in the cytoplasm. Ribosomal protection proteins interact with the ribosome and dislodge tetracycline from the ribosome, allowing for translation to continue. History Discovery The tetracyclines, a large family of antibiotics, were discovered by Benjamin Minge Duggar in 1948 as natural products, and first prescribed in 1948. Benjamin Duggar, working under Yellapragada Subbarow at Lederle Laboratories, discovered the first tetracycline antibiotic, chlortetracycline (Aureomycin), in 1945. The structure of Aureomycin was elucidated in 1952 and published in 1954 by the Pfizer-Woodward group. After the discovery of the structure, researchers at Pfizer began chemically modifying aureomycin by treating it with hydrogen in the presence of a palladized carbon catalyst. This chemical reaction replaced a chlorine moiety with a hydrogen, creating a compound named tetracycline via hydrogenolysis. Tetracycline displayed higher potency, better solubility, and more favorable pharmacology than the other antibiotics in its class, leading to its FDA approval in 1954. The new compound was one of the first commercially successful semi-synthetic antibiotics that was used, and laid the foundation for the development of Sancycline, Minocycline, and later the Glycylcyclines. Evidence in antiquity Our modern understanding of tetracyclines dates their discovery to 1948, but there is evidence that early inhabitants of Northeastern Africa consumed tetracycline antibiotics. Nubian mummies from between 350 and 550 C.E. were found to exhibit patterns of fluorescence identical with that of modern tetracycline labelled bone.Tetracycline has a high affinity for calcium and is incorporated into bones during the active mineralization of hydroxyapatite. When incorporated into bones, tetracycline can be identified using ultraviolet light.It is conjectured that the beer brewed at the time was the source of the tetracycline found in these bones. Society and culture Price According to data from EvaluatePharma and published in the Boston Globe, in the USA the price of tetracycline rose from $0.06 per 250-mg pill in 2013 to $4.06 a pill in 2015. The Globe described the "big price hikes of some generic drugs" as a "relatively new phenomenon" which has left most pharmacists "grappling" with large upswings" in the "costs of generics, with overnight price changes sometimes exceeding 1,000%." Names It is marketed under the brand names Sumycin, Tetracyn, and Panmycin, among others. Actisite is a thread-like fiber formulation used in dental applications. It is also used to produce several semisynthetic derivatives, which together are known as the tetracycline antibiotics. The term "tetracycline" is also used to denote the four-ring system of this compound; "tetracyclines" are related substances that contain the same four-ring system. Media Due to the drugs association with fighting infections, it serves as the main "commodity" in the science fiction series Aftermath, with the search for tetracycline becoming a major preoccupation in later episodes. Research Genetic engineering In genetic engineering, tetracycline is used in transcriptional activation. It has been used as an engineered "control switch" in chronic myelogenous leukemia models in mice. Engineers were able to develop a retrovirus that induced a particular type of leukemia in mice, and could then "switch" the cancer on and off through tetracycline administration. This could be used to grow the cancer in mice and then halt it at a particular stage to allow for further experimentation or study.A technique being developed for the control of the mosquito species Aedes aegypti (the infection vector for yellow fever, dengue fever, Zika fever, and several other diseases) uses a strain that is genetically modified to require tetracycline to develop beyond the larval stage. Modified males raised in a laboratory develop normally as they are supplied with this chemical and can be released into the wild. Their subsequent offspring inherit this trait, but find no tetracycline in their environments, so never develop into adults. References Author Title External links "Tetracycline". Drug Information Portal. U.S. National Library of Medicine.
Isatuximab	Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody (mAb) medication for the treatment of multiple myeloma.The most common side effects include neutropenia (low levels of neutrophils, a type of white blood cell), infusion reactions, pneumonia (infection of the lungs), upper respiratory tract infection (such as nose and throat infections), diarrhoea and bronchitis (inflammation of the airways in the lungs).Isatuximab is an anti-CD38 mAb intended to treat relapsed or refractory multiple myeloma. It entered in Phase II trials for multiple myeloma and T-cell leukemia in 2015. Medical uses In the United States it is indicated, in combination with pomalidomide and dexamethasone, for the treatment of adults with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. It is also indicated in combination with carfilzomib and dexamethasone, for the treatment of adults with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.In the European Union it is indicated, in combination with pomalidomide and dexamethasone, for the treatment of adults with relapsed and refractory multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor (PI) and have demonstrated disease progression on the last therapy. History It was granted orphan drug designation for multiple myeloma by the European Medicines Agency (EMA) in April 2014, and by the U.S. Food and Drug Administration (FDA) in December 2016.Researchers started a Phase I study with isatuximab in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM). The results during the Phase I trial showed that 26 out of the 45 patients discontinued the treatment due to progression of the disease. The patients had already been heavily pretreated. The latter lead to a manageable safety profile where the dose of isatuximab in combination with pomalidomide and dexamethasone would be capped to the maximum of 10 mg/kg weekly every two weeks for future studies.Based on the remarkable findings during the Phase I trial, a Phase II trial was launched where researchers investigated isatuximab as a single agent in patients with MM. The heavily pretreated patients reacted well to the single administration of isatuximab during Phase II of the trial.A Phase III combination trial for plasma cell myeloma is comparing pomalidomide and dexamethasone with and without isatuximab is in progress with an estimated completion date of 2021.Additionally, two Phase III trials were added in 2017. The first trial highlights whether there is an added value in the combination of isatuximab with bortezomib, lenalidomide and dexamethasone. The latter will be tested in patients with newly diagnosed MM who are not qualified for a transplant (IMROZ trial). The second trial evaluates the combinations of isatuximab with carfilzomib and dexamethasone compared to carfilzomib with dexamethasone. The second trial was designed for patients who were previously treated with one to three prior lines (IKEMA). There is currently no treatment for MM, however promising improvements have been made and the study is still ongoing.In March 2020, it was approved for medical use in the United States.The U.S. Food and Drug Administration (FDA) approved isatuximab-irfc in March 2020, based on evidence from a clinical trial (NCT02990338) of 307 subjects with previously treated multiple myeloma. The trial was conducted at 102 sites in Europe, North America, Asia, Australia and New Zealand.The trial evaluated the efficacy and side effects of isatuximab-irfc in subjects with previously treated multiple myeloma. Subjects were randomly assigned to receive either isatuximab-irfc (in combination with pomalidomide and low-dose dexamethasone) or active comparator (pomalidomide and low-dose dexamethasone). Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity. Both subjects and health care providers knew which treatment was given. The trial measured the time patients lived without the cancer growing (progression-free survival or PFS).It was approved for medical use in the European Union in May 2020. Structure and reactivity The structure of isatuximab consists of two identical immunoglobulin kappa light chains and also two equal immunoglobulin gamma heavy chains. Chemically, isatuximab is similar to the structure and reactivity of daratumumab, hence both drugs show the same CD38 targeting. However, isatuximab shows a more potent inhibition of its ectozyme function. The latter gives potential for some non-cross reactivity. Isatuximab shows action of an allosteric antagonist with the inhibition of the CD38 enzymatic activity. Additionally, isatuximab shows potential where it can induce apoptosis without cross linking. Lastly, Isatuximab reveals direct killing activity when a larger increase in apoptosis is detected in CD38 expressing cancer cells. Furthermore, isatuximab demonstrated a dose dependent inhibition of CD38 enzymatic activity. However, daratumumab with the same experimental conditions shows a more limited inhibition without a dose response. Reactions Isatuximab binds uniquely to an epitope on the CD38 receptor and is the only CD38 antibody which can start apoptosis directly. Isatuximab binds to a different CD38 epitope amino-acid sequence than does the anti-CD38 monoclonal antibody daratumumab. The binding with the CD38 receptor is mainly via the gamma heavy chains and are more potent than other CD38 antibodies such as daratumumab which can inhibit the enzymatic activity of CD38. Moreover, isatuximab inhibits the hydrolase activity of CD38.The antibodies show signs of improving antitumor immunity by eliminating regulatory T cells, B cells and myeloid-derived suppressor cells. The difference in binding between isatuximab and daratumumab is in the recognition of the different amino acid groups. Isatuximab identifies 23 amino acids of CD38 to the contrary with daratumumab who has 27. The residue of Glu233 has a flexible sidechain and faces the N-terminal of Asp1 residue in the isatuximab light chain. The latter light chain of isatuximab is also flexible which makes the interaction between CD38/Glu233 and the Asp1 weaker than the other interactions between CD38 and isatuximab. The caspase-dependent apoptotic pathway and the lysosomal mediated cell death pathway in MM cells is induced by isatuximab. The MM cell death follows the downstream reactions of the lysosomal activation. The latter also activates the production of reactive oxygen species. Available forms Isatuximab or isatuximab-irfc is available as a drug in an intravenous infusion form. Injection doses are 100 mg/5 mL (20 mg/mL) solution in single-dose vial or 500 mg/25 mL (20 mg/mL) solution in single-dose vial. Mechanism of action Cancer of the blood that is distinguished by an overproduction of malignant plasma cells in the bone marrow is called multiple myeloma. The myeloma cells are marked with uniformed overexpression of CD38 surface glycoproteins. Although these proteins are also expressed on other myeloid and lymphoid cells, the extent is relatively minor compared to myeloma cells. The fact that CD38 glycoproteins carry out various important cellular functions, and that they are plentiful on the surface of myeloma cells, has made them an appealing target for multiple myeloma treatment. CD38 was first described as an activation marker, but later the molecule displayed functions in adhesion to endothelial CD31 proteins, e.g. as an aiding component of the synapse complex, as well as an ectoenzyme implicated in the metabolism of extracellular NAD+ and cytoplasmic NADP. The tumour cells can evade the immune system, possibly due to adenosine, an immunosuppressive molecule that arises as a product of the ectoenzymatic activity of CD38.Isatuximab-irfc is an IgG1-derived monoclonal antibody that selectively binds to the CD38 that exists on the exterior of hematopoietic and multiple myeloma cells (as well as other tumor cells). This drug induces apoptosis of tumor cells and activates immune effector mechanisms such as complement dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). Isatuximab-irfc is able to stimulate natural killer (NK) cells in the absence of CD38-positive target tumor cells and blocks CD38-positive T-regulatory cells. Furthermore, the NADase activity of CD38 is adjusted by isatuximab, similarly to other CD38 antibodies. Contrarily to daratumumab however, isatuximab can incite apoptosis directly without cross-linking, and in its binding epitope. According to the FDA, isatuximab-irfc alone has reduced ADCC and direct tumor cell killing activity in vitro in comparison to when it is combined with pomalidomide. As well as increased anti-tumor activity as opposed to isatuximab-irfc or pomalidomide only in a human multiple myeloma xenograft model. Metabolism and toxicity Metabolism Isatuximab-irfc is likely to be metabolized through catabolic pathways into smaller peptides. When isatuximab is at a constant state it is expected that the ≥99% elimination will occur approximately two months after the last dose was administered. The clearance percentage diminished when the dosages were increased over time, as well as when multiple doses were administered. However, the elimination of isatuximab-irfc did not differ when applied as a single agent or as a combination therapy. Toxicity A dose-limiting toxicity (DLT) has been characterized as the development of any of the following: grade ≥ 3 non-hematologic toxicity; grade 4 neutropenia or grade 4 thrombocytopenia lasting more than 5 days; grade ≥ 2 allergic reactions or hypersensitivity (i.e., infusion reactions); or any other toxicity considered to be dose-limiting by the investigators or sponsor. Grade ≤ 2 infusion reactions were excluded from the DLT definition, because, with suitable care, patients that had a grade 2 infusion reaction prior to completion of the infusion were able to finalize isatuximab administration.There is no recommended reduced dose of isatuximab-irfc. In the eventuality of hematological toxicity it may be necessary to delay administration so that the blood count may be recovered. Although there is no counteracting agent for isatuximab, clinical experience with overdoses is seemingly nonexistent as well. Overdose symptoms will probably be in line with the side effects attached to isatuximab. Therefore, infusion reactions, gastrointestinal disturbances and an elevated risk of infections may occur. It is necessary to carefully monitor the patient in case of an overdose and to employ clinically indicated symptomatic and supportive procedures.No studies have been conducted with isatuximab concerning carcinogenicity, genotoxicity or fertility. Pregnancy When given to pregnant women isatuximab-irfc can cause fetal injury, due to the mechanism of action. It can precipitate depletion of immune cells as well as decreased bone density in the fetus. Pregnant women are therefore notified of the potential risks to a fetus, and women that are able to reproduce are advised to use effective contraceptives during treatment and at least five months subsequent to the last dose of isatuximab-irfc. Furthermore, it is not recommended to combine isatuximab-irfc with pomalidomide in women that are carrying a child, because pomalidomide may cause birth defects and death of the unborn child. Indications Isatuximab is indicated as a CD38-directed cytolytic antibody. By inhibiting the enzymatic activity of CD38. The binding of isatuximab to CD38 on multiple myeloma (MM) cells leads to a trigger to several mechanisms leading to direct apoptosis of target cancer cells. The triggered pathways are the caspase-dependent apoptotic and the lysosome-mediated cell death pathway in MM cells.It is used in a combination with dexamethasone and pomalidomide. The drug is thus to treat patients with multiple myeloma. Restrictions for the use of isatuximab is that the patients have to be adults who have at least received two previous treatments with lenalidomide and a proteasome inhibitor.Isatuximab is currently also being tested in a Phase II trial as a monotherapy against refractory/recurrent systemic light-chain amyloidosis. Efficacy and side effects Efficacy A Phase III study of patients with refractory and relapsed MM, who were resistant to lenalidomide and a proteasome inhibitor, and could not have received daratumumab, another anti-CD38 monoclonal antibody was published in 2019 (ICARIA-MM). The addition of isatuximab to pomalidomide and dexamethasone improved progression free survival to 11.5 months compared to 6.5 months, with an overall response rate of 63%. Side effects Adverse reactions to isatuximab-irfc may include neutropenia, infusion-related reactions and/or secondary primary malignancies. Of these three the most commonly occurring ones are the infusion-related reactions. Examples of the most frequent symptoms of infusion-related reactions are dyspnea, cough, chills, and nausea, while the severest signs and symptoms included hypertension and dyspnea. Effects on animals The activity of isatuximab has been researched in mouse tumor models. It has been proven that isatuximab leads to antitumor activity in MM cells. Furthermore, the combination of isatuximab and pomalidomide will lead to an extra enhanced antitumor activity in MM cells. Thus, pomalidomide in vivo and in vitro leads to an increase of the activity of isatuximab.Animal studies in reproduction toxicity have not yet been carried out. So, the risks of birth defects and miscarriage risks are unknown. Names Isatuximab is the United States Adopted Name (USAN).It was developed by ImmunoGen and Sanofi-Aventis with the development name SAR-650984. See also Daratumumab, another anti-CD38 antibody References External links "Isatuximab". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT02990338 for "Multinational Clinical Study Comparing Isatuximab, Pomalidomide, and Dexamethasone to Pomalidomide and Dexamethasone in Refractory or Relapsed and Refractory Multiple Myeloma Patients (ICARIA-MM)" at ClinicalTrials.gov
Peginterferon beta-1a	Peginterferon beta-1a, sold under the brand name Plegridy, is medication used to treat multiple sclerosis. The most common side effects include headache, muscle pain, joint pain, influenza (flu)-like symptoms, pyrexia (fever), chills, asthenia (weakness), and erythema (reddening of the skin), pain or pruritus (itching) at the injection site.Peginterferon beta-1a was approved for medical use in the United States and in the European Union in 2014. Medical uses In the United States peginterferon beta-1a is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.In the European Union peginterferon beta-1a is indicated for the treatment of relapsing remitting multiple sclerosis in adults. References External links "Peginterferon beta-1a". Drug Information Portal. U.S. National Library of Medicine. Plegridy at the US National Library of Medicine Medical Subject Headings (MeSH)
Ifosfamide	Ifosfamide (IFO), sold under the brand name Ifex among others, is a chemotherapy medication used to treat a number of types of cancer. This includes testicular cancer, soft tissue sarcoma, osteosarcoma, bladder cancer, small cell lung cancer, cervical cancer, and ovarian cancer. It is administered by injection into a vein.Common side effects include hair loss, vomiting, blood in the urine, infections, and kidney problems. Other severe side effects include bone marrow suppression and decreased level of consciousness. Use during pregnancy will likely result in harm to the baby. Ifosfamide is in the alkylating agent and nitrogen mustard family of medications. It works by disrupting the duplication of DNA and the creation of RNA.Ifosfamide was approved for medical use in the United States in 1987. It is on the World Health Organizations List of Essential Medicines. Medical uses It is given as a treatment for a variety of cancers, including: Testicular cancer Breast cancer Lymphoma (Hodgkin and non-Hodgkin) Soft tissue sarcoma Osteosarcoma or bone tumor Lung cancer Cervical cancer Ovarian cancer Administration It is a white powder which, when prepared for use in chemotherapy, becomes a clear, colorless fluid. The delivery is intravenous. Ifosfamide is often used in conjunction with mesna to avoid internal bleeding in the patient, in particular hemorrhagic cystitis. Ifosfamide is given quickly, and in some cases can be given as quickly as an hour. Side effects Hemorrhagic cystitis is rare when ifosfamide is given with mesna. A common and dose-limiting side effect is encephalopathy (brain dysfunction). It occurs in some form in up to 50% of people receiving the agent. The reaction is probably mediated by chloroacetaldehyde, one of the breakdown products of the ifosfamide molecule, which has chemical properties similar to acetaldehyde and chloral hydrate. The symptoms of ifosfamide encephalopathy can range from mild (difficulty concentrating, fatigue), to moderate (delirium, psychosis), to severe (nonconvulsive status epilepticus or coma). In children, this can interfere with neurological development. Apart from the brain, ifosfamide can also affect peripheral nerves. The severity of the reaction can be classified according to either the National Cancer Institute or the Meanwell criteria (grade I–IV). Previous brain problems and low levels of albumin in the blood increase the likelihood of ifosfamide encephalopathy. In most cases, the reaction resolves spontaneously within 72 hours. If it develops during an infusion of the drug, discontinuing the infusion is advised. The most effective treatment for severe (grade III–IV) encephalopathy is an intravenous solution of methylene blue, which appears to shorten the duration of encephalopathy; the exact mechanism of action of methylene blue is unclear. In some cases, methylene blue may be used as a prophylaxis before further doses of ifosfamide are administered. Other treatments include albumin and thiamine, and dialysis as a rescue modality.Ifosfamide may also cause a normal anion gap acidosis, specifically renal tubular acidosis type 2. References External links ACS Drug Guide: Ifosfamide Harvard Medical School Health Information on Ifosfamide BC Cancer Agency Ifosamide Information (Professional) RxList Online Drug Index Ifosamide Listing "Ifosfamide". Drug Information Portal. U.S. National Library of Medicine.
Butabarbital	Butabarbital (brand name Butisol) is a prescription barbiturate sleep aid and anxiety medication. Butabarbital has a particularly fast onset of effects and short duration of action compared to other barbiturates, which makes it useful for certain applications such as treating severe insomnia, relieving general anxiety and relieving anxiety before surgical procedures; however it is also relatively dangerous particularly when combined with alcohol, and so is now rarely used, although it is still prescribed in some Eastern European and South American countries. Its intermediate duration of action gives butabarbital an abuse potential slightly lower than secobarbital. Butabarbital can be hydrolyzed to Valnoctamide. Butabarbital is also sold in combination with belladonna alkaloids under the brand name Butibel. The belladonna is added for antispasmodic effect. This product contains a low dose of butabarbital combined with a standardised mix of belladonna alkaloids and is used as an antispasmodic taken to relieve cramping and spasms of the stomach and intestines. They are used also to decrease the amount of acid formed in the stomach. Another similar product is Donnatal, which contains belladonna alkaloids combined with phenobarbital. History Barbiturates were first discovered to have medical use in 1903, when a research at Bayer showed barbital to be an effective sedative for dogs. It was not until the mid 20th century that the habit forming nature of barbiturates and behavioral side effects were first notedBenzodiazepines are more commonly administered today for their similar sedative and hypnotic properties, and reduced risk of physical dependence. Barbiturate drugs such as butabarbital sodium are used now for short-term and acute treatment under strict doctor supervision only Clinical uses Barbiturates are non-selective depressants of the central nervous system, inducing drowsiness and mild sedative effects. Barbiturate hypnotics are used in the treatment of sleep and anxiety disorders for their calming and sedative properties, however are usually restricted to short term use due to risk of dependency.Butabarbital, most commonly known as Butisol commercially, is an approved Schedule III drug in the US and Canada used in the short-term treatment of anxiety disorders and as a pre-surgical sedative aid. Approved commercial forms are available in tablet or elixir forms. Recently, butabarbital was approved for medical use in 2007 under the brand name Butisol Sodium. Butisol sodium is manufactured by Meda Pharmaceuticals as a Schedule III controlled substance due to its high risk for abuse and dependence. Administration It is most often administered orally as either sodium solution or tablet, however can also be given by intravenous injection. Tablets contain either 30 mg or 50 mg of butabarbital sodium, or 30 mg/5mL with 7% alcohol/vol in solution. For preoperative sedation, adults are administered 50–100 mg 60-90min prior to surgery, with varying doses for pediatric and geriatric patients. Clinical effects & elimination Effects from oral doses often are felt within an hour of administration, lasting somewhere from six to eight hours in effect. A non-selective depressant of the CNS, Butabarbital sodium is used as a sedative hypnotic, depending on dose, to induce drowsiness or sleep, or reduce anxiety and tension. Butabarbital sodium can be used as a pre-surgical anesthetic aid or in the short-term treatment of sleep and anxiety disorders. For short term sleep maintenance and induction butabarbital sodium treatment is recommended to be limited to two weeks, after which it begins to lose efficacy. The half life is approximately 100hrs, eliminated primarily by hepatic microsomal enzymes and excreted in the urine. Overdose & abuse Butabarbital sodium is a Schedule III controlled substance in the US and Canada due to risk of abuse and dependence. A psychoactive substance, butabarbital drugs are often abused with risk of acute intoxication and addiction. Barbiturates such as butabarbital are thought to be habit-forming and addictive, and have severe risks from withdrawal including death. Due to the high risk of dependence and overdose, use of butabarbital is highly regulated and has become less common in clinical application. Side effects Those taking Butabarbital are asked to watch out for signs of severe allergic reaction, such as swelling or difficulty breathing. Less serious side effects include dizziness or drowsiness, excitation, headache, nausea, vomiting, or constipation. Psychiatric disturbances (hallucinations, agitation, confusion, depression, or memory problems), ataxia, difficulty breathing, or slow heartbeat could be signs of serious adverse effects and should be brought to the attention of a doctor immediately. Adverse effects 1-10% Somnolence<1% Contradictions Those with a hypersensitivity to barbiturates or a history of porphyria should discuss with a doctor before using butisol sodium treatment. Butabarbital has also been shown to interact with some medicines; Talk to your doctor if taking Monoamine oxidase inhibitors (MAOIs), beta-blockers, oral-contraceptives, or other medications, as their efficacy may be affected.At low doses Butabarbital has been shown clinically to induce drowsiness, depressing the sensory cortex and motor activity. In some rare cases Butabarbital has been shown to produce small bursts of excitement or euphoria prior to the sedative effects. Butabarbital is a highly potent drug however, with addictive properties, and small variations in dose can result in significant escalation of effects. Pharmacology Butabarbital is a sedative hypnotic member of the barbiturate family. It is relatively fast acting, with a short duration, producing a range of effects from mild sedation to hypnosis as a function of dosage. An overdose of butabarbital can result in deep coma or even death. Absorption, distribution and excretion Butabarbituates are rapidly distributed and absorbed in the brain, liver and kidneys. One of the more lipophilic barbiturates, butabarbital crosses the blood brain barrier with relative ease, and is slightly more potent then other less lipophilic barbiturates such as phenobarbital. Butabarbital, a weak acid, is most commonly administered orally in its sodium salt form. 3–4 hours after oral administration butabarbital sodium reaches peak plama concentrations of 203 ug/mL for sedation, or 25 ug/mL to induce sleep, absorbed via the GI tract.Once absorbed, butabarbitals effects have a duration of 6–8 hours if orally administered, or 3–6 hours following intravaneous administration. General consensus has it with a half-life of approximately 100hr, however it has also been reported in one study to have a half life of 34-42 hr.The primary way the body terminates activity is by oxidation of radicals at C5, with other biotransformations contributing to a lesser extent. Butabarbital is metabolized almost entirely by the liver, products including polar alcohols, ketones, phenols, or carboxylic acids, before it is renally excreted in the urine.Half-Life: ~100 hr Duration: 6-8 hr Onset: 45-60 min Enzymes induced: CYP1A2, CYP2C9/10, CYP3A4 Excretion: Urine Mechanism of action The mechanism of action by which barbiturates exert their effect is not yet completely understood, however they are believed to be involved in the enhancement of GABA inhibitory neurotransmitter activity in the CNS via GABAA receptors. Butabarbital, as a member of this drug class, acutely potentiates inhibitory GABAergic tone by binding with a specific site associated with a Cl− ionopore at the GABAA receptor. Butabarbitals binding causes the channel to remain open longer and thus prolongs post-synaptic inhibition by GABA. Less well characterized effects of barbiturates include direct inhibition of AMPA-type glutamate receptors, suppressing excitatory glutamatergic neurotransmission. References External links "Butabarbital". Drug Information Portal. U.S. National Library of Medicine.
Lifitegrast	Lifitegrast, sold under the brand name Xiidra (), is a medication for the treatment of signs and symptoms of dry eye, a syndrome called keratoconjunctivitis sicca. Lifitegrast reduces inflammation by inhibiting inflammatory cell binding. It is often used in conjunction with ciclosporin (Ikervis, Restasis, or Cequa) for dry eye treatment including meibomian gland dysfunction and inflammatory dry eye. Adverse effects Common side effects in clinical trials were eye irritation, discomfort, blurred vision, and dysgeusia (a distortion of the sense of taste). Pharmacology Lifitegrast is supplied as an eye drop. Mechanism of action Lifitegrast inhibits an integrin, lymphocyte function-associated antigen 1 (LFA-1), from binding to intercellular adhesion molecule 1 (ICAM-1). This mechanism down-regulates inflammation mediated by T lymphocytes. History Lifitegrast was initially designed and developed by SARcode Bioscience which was acquired by Shire in 2013, which submitted a new drug application to the US Food and Drug Administration (FDA) in March 2015. The FDA granted Shire a priority review a month later, and requested additional clinical data, which were supplied in January 2016; approval was granted on 11 July 2016. Lifitegrast was approved by Health Canada in January 2018, and available in Canadian pharmacies as of March 2018. Shire was acquired by Takeda Pharmaceutical Company in late 2018. In May 2019 Novartis reached an agreement to purchase the assets associated with Lifitegrast. Novartis will pay Takeda an upfront payment of $3.4 billion, while the latter drugmaker is eligible for milestone payments of as much as $1.9 billion. Novartis noted that the drug amassed approximately $400 million in revenue in 2018. See also Restasis (ciclosporin eye drops for keratoconjunctivitis sicca) == References ==
Icatibant	Icatibant, sold under the brand name Firazyr, is a medication for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults with C1-esterase-inhibitor deficiency. It is not effective in angioedema caused by medication from the ACE inhibitor class.It is a peptidomimetic consisting of ten amino acids, which is a selective and specific antagonist of bradykinin B2 receptors. Mechanism of action Bradykinin is a peptide-based hormone that is formed locally in tissues, very often in response to a trauma. It increases vessel permeability, dilates blood vessels and causes smooth muscle cells to contract. Bradykinin plays an important role as the mediator of pain. Surplus bradykinin is responsible for the typical symptoms of inflammation, such as swelling, redness, overheating and pain. These symptoms are mediated by activation of bradykinin B2 receptors. Icatibant acts as a bradykinin inhibitor by blocking the binding of native bradykinin to the bradykinin B2 receptor. Little is known about the effects of icatibant on the bradykinin B1 receptor. Society and culture Legal status Icatibant received orphan drug status in Australia, the EU, Switzerland, and the US for the treatment of hereditary angioedema (HAE).In the EU, the approval by the European Commission (July 2008) allows Jerini to market Firazyr in the European Unions 27 member states, as well as Switzerland, Liechtenstein and Iceland, making it the first product to be approved in all EU countries for the treatment of HAE. In the US, the drug was granted FDA approval on August 25, 2011. References External links "Icatibant". Drug Information Portal. U.S. National Library of Medicine. "Icatibant acetate". Drug Information Portal. U.S. National Library of Medicine.
Sodium picosulfate	Sodium picosulfate (INN, also known as sodium picosulphate) is a contact stimulant laxative used as a treatment for constipation or to prepare the large bowel before colonoscopy or surgery. It is sold under the trade names Sodipic Picofast, Laxoberal, Laxoberon, Purg-Odan, Picolax, Guttalax, Namilax, Pico-Salax, PicoPrep, and Prepopik, among others. Effects Orally administered sodium picosulfate is generally used for thorough evacuation of the bowel, usually for patients who are preparing to undergo a colonoscopy. It takes 12–24 hours to work, since it works in the colon.Abdominal cramps and diarrhea are normal effects of picosulfate and should be expected. The use of sodium picosulfate has also been associated with certain electrolyte disturbances, such as hyponatremia and hypokalemia. Patients are often required to drink large amounts of clear fluids, to compensate for dehydration and to reestablish normal electrolyte balance. Mechanism of action Sodium picosulfate is a prodrug. It has no significant direct physiological effect on the intestine; however, it is metabolised by gut bacteria into the active compound 4,4-dihydroxydiphenyl-(2-pyridyl)methane (DPM, BHPM). This compound is a stimulant laxative and increases peristalsis in the gut.Sodium picosulfate is typically prescribed in a combined formulation with magnesium citrate, an osmotic laxative. This combination is a highly effective laxative, often prescribed to patients for bowel cleansing prior to colonoscopies. == References ==
Cefiderocol	Cefiderocol, sold under the brand name Fetroja among others, is an antibiotic used to treat complicated urinary tract infections when no other options are available. It is indicated for the treatment of multi-drug-resistant Gram-negative bacteria including Pseudomonas aeruginosa. It is given by injection into a vein.In September 2020, cefiderocol (Fetroja) received FDA approval as supplemental New Drug Application (sNDA) for treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) when caused by Gram-negative bacteria resistant to other antibiotics. Common side effects include diarrhea, infusion site reactions, constipation and rash.It is in the cephalosporin family of medications. Cefiderocol was approved for medical use in the United States in November 2019, and in the European Union in April 2020. It is on the World Health Organizations List of Essential Medicines. Medical uses Cefiderocol is used to treat adults with complicated urinary tract infections, including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options.In the United States, cefiderocol is indicated in adults 18 years of age or older who have limited or no alternative treatment options for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.For the treatment of severe pneumonia (HABP and VABP), it is indicated in patients 18 years of age and older whose pneumonia is not responding to other, more commonly used antibiotics and is confirmed to be caused by one of the following Gram-negative organisms: Acinetobacter baumannii complex Escherichia coli Enterobacter cloacae complex Klebsiella pneumoniae Pseudomonas aeruginosa Serratia marcescensThis indication is supported by the 2018 APEKS-NP study, where cefiderocol was compared in nosocomial pneumonia caused by Gram-Negative bacteria to meropenem, where it was shown not to be inferior to meropenem. The primary endpoint of the study was all-cause mortality at day 14, where both antibiotics were shown to be almost equally effective. As of 2020, cefiderocol is indicated in the European Union for the treatment of infections due to aerobic Gram-negative bacteria in adults with limited treatment options. Adverse effects Cefiderocol may cause serious and life-threatening allergic reactions, severe diarrhea caused by C. difficile and seizures.An increased risk of all-cause mortality was observed in people treated with cefiderocol as compared to other antibiotics in a separate clinical trial in critically ill people with multidrug-resistant Gram-negative bacterial infections. The higher all-cause mortality rate was observed in people treated for hospital-acquired/ventilator-associated pneumonia (i.e.nosocomial pneumonia), bloodstream infections, or sepsis. The cause of death has not been established, but some of the deaths were a result of worsening or complications of infection, or underlying co-morbidities. The safety and efficacy of cefiderocol has not been established for the treatment of these types of infections. Hence, cefiderocol label includes a warning regarding the higher all-cause mortality rate.Already in 2021, the first cases of antibiotic resistance were reported, and as of 2022 alarming proportions of up to 50% of resistance in some cohorts have been reported. In September 2022, the German RKI reported victims of the Ukraine War with cefidercol resistant surgical infections (Klebsiella specie. and Acinetobacter baumannii) who had been treated in Germany. Pharmacology Its structure is similar to cefepime and ceftazidime, but a chlorocatechol group at the end of the C-3 side chain further enhances its β-lactamase stability and renders it a siderophore.This means it enters into bacterial cells by binding to iron, which is actively transported into the bacterial cells. It was the first siderophore antibiotic to be approved by the U.S. Food and Drug Administration (FDA). It bypasses the bacterial porin channels by using the bacterias own iron-transport system for being transported in. History Cefiderocol received a Qualified Infectious Disease Product designation from the U.S. Food and Drug Administration (FDA) and was granted priority review. In November 2019, the FDA granted approval of cefiderocol to Shionogi & Co. as an antibacterial drug for treatment of adults 18 years of age or older with complicated urinary tract infections (cUTI), including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options.The safety and effectiveness of cefiderocol was demonstrated in a study (NCT02321800) of 448 participants with cUTIs. Of the participants who were administered cefiderocol, 72.6% had resolution of symptoms and eradication of the bacteria approximately seven days after completing treatment, compared with 54.6% in participants who received an alternative antibiotic. The clinical response rates were similar between the two treatment groups. The trial included participants from Europe, United States and Mexico.In the clinical trial, participants with cUTI were chosen at random to receive cefiderocol, or another antibacterial drug called imipenem/cilastatin. Both treatments were given intravenously for 7–14 days and neither the participants nor the health care professionals knew which drugs were given until after the trial was complete. Participants could not be switched to an oral antibacterial drug to complete the treatment for cUTI.The benefit of cefiderocol was measured by the proportion of participants who achieved cure or improvement in their symptoms related to cUTI and a negative urine culture test in comparison to imipenem/cilastatin.In April 2020, Cefiderocol was approved for medical use in the European Union . References Further reading Committee for Medicinal Products for Human Use (27 February 2020). "Fetcroja : EPAR - Public assessment report" (PDF). European Medicines Agency (EMA). EMA/136096/2020. External links "Cefiderocol". Drug Information Portal. U.S. National Library of Medicine. "Cefiderocol sulfate tosylate". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT02321800 for "A Study of Efficacy and Safety of Intravenous Cefiderocol (S-649266) Versus Imipenem/Cilastatin in Complicated Urinary Tract Infections (APEKS-cUTI)" at ClinicalTrials.gov
Sevoflurane	Sevoflurane is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflurane, it is the volatile anesthetic with the fastest onset. While its offset may be faster than agents other than desflurane in a few circumstances, its offset is more often similar to that of the much older agent isoflurane. While sevoflurane is only half as soluble as isoflurane in blood, the tissue blood partition coefficients of isoflurane and sevoflurane are quite similar. For example, in the muscle group: isoflurane 2.62 vs. sevoflurane 2.57. In the fat group: isoflurane 52 vs. sevoflurane 50. As a result, the longer the case, the more similar will be the emergence times for sevoflurane and isoflurane. Medical uses It is one of the most commonly used volatile anesthetic agents, particularly for outpatient anesthesia, across all ages, as well as in veterinary medicine. Together with desflurane, sevoflurane is replacing isoflurane and halothane in modern anesthesia practice. It is often administered in a mixture of nitrous oxide and oxygen. Sevoflurane has an excellent safety record, but is under review for potential hepatotoxicity, and may accelerate Alzheimers. There were rare reports involving adults with symptoms similar to halothane hepatotoxicity. Sevoflurane is the preferred agent for mask induction due to its lesser irritation to mucous membranes. Sevoflurane was discovered by Ross Terrell and independently by Bernard M Regan. A detailed report of its development and properties appeared in 1975 in a paper authored by Richard Wallin, Bernard Regan, Martha Napoli and Ivan Stern. It was introduced into clinical practice initially in Japan in 1990 by Maruishi Pharmaceutical Co., Ltd. Osaka, Japan. The rights for sevoflurane worldwide were held by AbbVie. It is now available as a generic drug. Sevoflurane is an inhaled anaesthetic that is often used to put children asleep for surgery. During the process of waking up from the medication, it has been known to cause agitation and delirium. It is not clear if this can be prevented. Adverse effects Studies examining a current significant health concern, anesthetic-induced neurotoxicity (including with sevoflurane, and especially with children and infants) are "fraught with confounders, and many are underpowered statistically", and so are argued to need "further data... to either support or refute the potential connection".Concern regarding the safety of anaesthesia is especially acute with regard to children and infants, where preclinical evidence from relevant animal models suggest that common clinically important agents, including sevoflurane, may be neurotoxic to the developing brain, and so cause neurobehavioural abnormalities in the long term; two large-scale clinical studies (PANDA and GAS) were ongoing as of 2010, in hope of supplying "significant [further] information" on neurodevelopmental effects of general anaesthesia in infants and young children, including where sevoflurane is used.In 2021, researchers at Massachusetts General Hospital published in Communications Biology research that sevoflurane may accelerate existing Alzheimers or existing tau protein to spread: "These data demonstrate anesthesia-associated tau spreading and its consequences. [...] This tau spreading could be prevented by inhibitors of tau phosphorylation or extracellular vesicle generation." According to Neuroscience News, "Their previous work showed that sevoflurane can cause a change (specifically, phosphorylation, or the addition of phosphate) to tau that leads to cognitive impairment in mice. Other researchers have also found that sevoflurane and certain other anesthetics may affect cognitive function." Pharmacology The exact mechanism of the action of general anaesthetics has not been delineated. Sevoflurane acts as a positive allosteric modulator of the GABAA receptor in electrophysiology studies of neurons and recombinant receptors. However, it also acts as an NMDA receptor antagonist, potentiates glycine receptor currents, and inhibits nAChR and 5-HT3 receptor currents. Global-warming potential Sevoflurane is a greenhouse gas. The twenty-year global-warming potential, GWP(20), for sevoflurane is 349. References Further reading External links "Propofol and Sevoflurane Anesthesia".
Prestige Consumer Healthcare	Prestige Consumer Healthcare Inc. is an American company that markets and distributes over-the-counter healthcare and household cleaning products. It was formed by the merger of Medtech Products, Inc., Prestige Brands International, and the Spic and Span Company in 1996. The company is headquartered in Tarrytown, New York.Among the brands owned by Prestige Brands are Chloraseptic sore throat products, Clear Eyes, Compound W wart treatment, Dramamine motion sickness treatment, Efferdent denture care, Ludens throat drops, BC Powder and Goodys Headache Powder, Pediacare & Little Remedies childrens OTC products, Beano (dietary supplement), Comet and Spic and Span household cleaning products. The companys CEO and president is Ron Lombardi, who replaced Matthew Mannelly on June 1, 2015. History Prestige Brands Holdings, Inc. was established in 1999 to acquire, revitalize, and line extend leading, often neglected but healthy brands that were considered non-core at major consumer products companies. In 2004, MidOcean Partners sold Prestige Brands to GTCH Golder Rauner. Acquisitions The company acquired Blacksmith Brands portfolio of five brands in 2010. In December 2011, the company agreed to purchase 17 brands from GlaxoSmithKline including BC Powder, Beano, Ecotrin, Fiber Choice, Goodys Powder, Sominex and Tagamet for $660 million.In 2013, Prestige Brands Holdings, Inc. acquired Care Pharmaceuticals of Bondi Junction, New South Wales, Australia, a privately held marketer and distributor of over-the-counter (OTC) healthcare brands for children and adults.In 2014, the company purchased Hydralyte in Australia and New Zealand from the Hydration Pharmaceuticals Trust of Victoria, Australia. Hydralyte is the leading oral rehydration product in Australia and New Zealand.In April 2014, Prestige Brands Holdings, Inc. announced that it has entered into a definitive agreement to acquire Insight Pharmaceuticals Corporation, a marketer and distributor of feminine care and other over-the-counter healthcare products, for $750 million in cash.In November 2015, Prestige Brands Holdings, Inc. announced that it has entered into a definitive agreement to acquire DenTek Oral Care Inc. (DenTek), a privately-held marketer and distributor of oral care products for $225 million in cash.In December 2016, Prestige Brands Holdings, Inc. agreed to buy C.B. Fleet Co. from private-equity firm Gryphon Investors for about $825 million. Divestitures In 2009, Prestige sold its Denorex and Prell brands of shampoo. It has since divested Fiber Choice, PediaCare, New-Skin, and Dermoplast (2016). Products Prestige Brands owns many over-the counter medicines and products, including: References External links Official website Marketwatch - Prestige Brands Hldgs Inc.
Luliconazole	Luliconazole, trade names Luzu among others, is an imidazole antifungal medication. As a 1% topical cream, It is indicated for the treatment of athletes foot, jock itch, and ringworm caused by dermatophytes such as Trichophyton rubrum, Microsporum gypseum and Epidermophyton floccosum. References External links Media related to Luliconazole at Wikimedia Commons Luliconazole
Abametapir	Abametapir, sold under the brand name Xeglyze, is a medication used for the treatment of head lice infestation in people six months of age and older.The most common side effects include skin redness, rash, skin burning sensation, skin inflammation, vomiting, eye irritation, skin itching, and hair color changes.Abametapir is a metalloproteinase inhibitor. Abametapir was approved for medical use in the United States in July 2020. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Medical uses Abametapir is indicated for the topical treatment of head lice infestation in people six months of age and older. Contraindications Abametapir has no contraindications according to the labeling. Adverse effects Common adverse effects are burning skin sensations (in 3% of patients), contact dermatitis (2%), skin redness (4%), rash (3%), and vomiting (2%). Interactions Abametapir blocks the liver enzymes CYP3A4, CYP2B6 and CYP1A2 in vitro. A single application of the drug may lead to increased blood concentrations of drugs that are metabolized by these enzymes. Pharmacology Mechanism of action The drug inhibits enzymes called metalloproteinases. In lice, these enzymes play a role in egg development and survival; and consequently, blocking them will disrupt the lices life cycle. Pharmacokinetics After application to the scalp, part of the substance reaches the bloodstream, where most of it (91.3–92.3%) is bound to plasma proteins. It is metabolized primarily by the liver enzyme CYP1A2 to abametapir hydroxyl and further to abametapir carboxyl (see structure drawings). Abametapir carboxyl has a plasma protein binding of 96.0–97.5% and is the predominant of the three substances in the circulation, having a Cmax 30 times and an area under the curve (AUC) 250 times that of abametapir itself.The elimination half-life of abametapir is 21 hours. That of abametapir carboxyl is not well known; it is thought to be 71±40 hours or longer. It is not known whether the drug is eliminated via the urine or the faeces. History The U.S. Food and Drug Administration (FDA) approved abametapir based on evidence from two identical clinical trials of 699 participants with head lice. The trials were conducted at fourteen sites in the United States.The benefit and side effects of abametapir were evaluated in two clinical trials that enrolled participants with head lice who were at least six months old.About half of all enrolled participants was randomly assigned to abametapir and the other half to placebo. Abametapir lotion or placebo lotion were applied once as a ten-minute treatment to infested hair. The benefit of abametapir in comparison to placebo was assessed after 1, 7 and 14 days by comparing the counts of participants in each group who were free of live lice. References Further reading Bowles VM, VanLuvanee LJ, Alsop H, Hazan L, Shepherd K, Sidgiddi S, et al. (September 2018). "Clinical studies evaluating abametapir lotion, 0.74%, for the treatment of head louse infestation". Pediatr Dermatol. 35 (5): 616–621. doi:10.1111/pde.13612. PMC 6175393. PMID 29999197. External links "Abametapir". Drug Information Portal. U.S. National Library of Medicine.
Anthim	Anthim may refer to: Anthim the Iberian (1650–1716), Georgian theologian, scholar, calligrapher and philosopher Anthim I (1816–1888), Bulgarian education figure and clergyman Anthim, a brand name of obiltoxaximab, an antibody designed for the treatment of exposure to etiologic agent of anthrax.
Trabectedin	Trabectedin, sold under the brand name Yondelis, is an antitumor chemotherapy medication for the treatment of advanced soft-tissue sarcoma and ovarian cancer.The most common adverse reactions include nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache.It is sold by Pharma Mar S.A. and Johnson and Johnson. It is approved for use in the European Union, Russia, South Korea and the United States. The European Commission and the U.S. Food and Drug Administration (FDA) granted orphan drug status to trabectedin for soft-tissue sarcomas and ovarian cancer. Discovery and production During the 1950s and 1960s, the National Cancer Institute carried out a wide-ranging program of screening plant and marine organism material. As part of that program, extract from the sea squirt Ecteinascidia turbinata was found to have anticancer activity in 1969. Separation and characterization of the active molecules had to wait many years for the development of sufficiently sensitive techniques, and the structure of one of them, Ecteinascidin 743, was determined by KL Rinehart at the University of Illinois in 1984. Rinehart had collected his sea squirts by scuba diving in the reefs of the West Indies. Recently, 1774 the biosynthetic pathway responsible for producing the drug has been determined to come from Candidatus Endoecteinascidia frumentensis, a microbial symbiont of the tunicate. The Spanish company PharmaMar licensed the compound from the University of Illinois before 1994 and attempted to farm the sea squirt with limited success. Yields from the sea squirt are extremely low - 1 tonne of animals is needed to isolate 1 gram of trabectedin - and about 5 grams were believed to be needed for a clinical trial so Rinehart asked the Harvard chemist E. J. Corey to search for a synthetic method of preparation. His group developed such a method and published it in 1996. This was later followed by a simpler and more tractable method which was patented by Harvard and subsequently licensed to PharmaMar. The current supply is based on a semisynthetic process developed by PharmaMar starting from safracin B, an antibiotic obtained by fermentation of the bacterium Pseudomonas fluorescens. PharmaMar entered into an agreement with Johnson & Johnson to market the compound outside Europe. Approvals and indications Trabectedin was first trialed in humans in 1996. Soft tissue sarcoma In 2007, the European Commission gave authorization for the marketing of trabectedin, under the trade name Yondelis, "for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents". The European Medicine Agencys evaluating committee, the Committee for Medicinal Products for Human Use (CHMP), observed that trabectedin had not been evaluated in an adequately designed and analyzed randomized controlled trial against current best care, and that the clinical efficacy data were mainly based on patients with liposarcoma and leiomyosarcoma. However, the pivotal study did show a significant difference between two different trabectedin treatment regimens, and due to the rarity of the disease, the CHMP considered that marketing authorization could be granted under exceptional circumstances. As part of the approval PharmaMar agreed to conduct a further trial to identify whether any specific chromosomal translocations could be used to predict responsiveness to trabectedin.Trabectedin is also approved in South Korea and Russia.In 2015, (after a phase III study comparing trabectedin with dacarbazine), the US FDA approved trabectedin (Yondelis) for the treatment of liposarcoma and leiomyosarcoma that is either unresectable or has metastasized. Patients must have received prior chemotherapy with an anthracycline. Ovarian cancer and other In 2008, the submission was announced of a registration dossier to the European Medicines Agency and the FDA for Yondelis when administered in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer. In 2011, Johnson & Johnson voluntarily withdrew the submission in the United States following a request by the FDA for an additional phase III study to be done in support of the submission.Trabectedin is also in phase II trials for prostate, breast, and paediatric cancers. Structure Trabectedin is composed of three tetrahydroisoquinoline moieties, eight rings including one 10-membered heterocyclic ring containing a cysteine residue, and seven chiral centers. Biosynthesis The biosynthesis of trabectedin in Candidatus Endoecteinascidia frumentensis starts with a fatty acid loading onto the acyl-ligase domain of the EtuA3 module. A cysteine and glycine are then loaded as canonical NRPS amino acids. A tyrosine residue is modified by the enzymes EtuH, EtuM1, and EtuM2 to add a hydroxyl at the meta position of the phenol, and adding two methyl groups at the para-hydroxyl and the meta carbon position. This modified tyrosine reacts with the original substrate via a Pictet-Spengler reaction, where the amine group is converted to an imine by deprotonation, then attacks the free aldehyde to form a carbocation that is quenched by electrons from the methyl-phenol ring. This is done in the EtuA2 T-domain. This reaction is done a second time to yeid a dimer of modified tyrosine residues that have been further cyclized via Pictet-Spengler reaction, yielding a bicyclic ring moiety. The EtuO and EtuF3 enzymes continue to post-translationally modify the molecule, adding several functional groups and making a sulfide bridge between the original cysteine residue and the beta-carbon of the first tyrosine to form ET-583, ET-597, ET-596, and ET-594 which have been previously isolated. A third O-methylated tyrosine is added and cyclized via Pictet-Spangler to yield the final product. Total synthesis The total synthesis by E.J. Corey used this proposed biosynthesis to guide their synthetic strategy. The synthesis uses such reactions as the Mannich reaction, Pictet-Spengler reaction, the Curtius rearrangement, and chiral rhodium-based diphosphine-catalyzed enantioselective hydrogenation. A separate synthetic process also involved the Ugi reaction to assist in the formation of the pentacyclic core. This reaction was unprecedented for using such a one pot multicomponent reaction in the synthesis of such a complex molecule. Mechanism of action Recently, it has been shown that trabectedin blocks DNA binding of the oncogenic transcription factor FUS-CHOP and reverses the transcriptional program in myxoid liposarcoma. By reversing the genetic program created by this transcription factor, trabectedin promotes differentiation and reverses the oncogenic phenotype in these cells.Other than transcriptional interference, the mechanism of action of trabectedin is complex and not completely understood. The compound is known to bind and alkylate DNA at the N2 position of guanine. It is known from in vitro work that this binding occurs in the minor groove, spans approximately three to five base pairs and is most efficient with CGG sequences. Additional favorable binding sequences are TGG, AGC, or GGC. Once bound, this reversible covalent adduct bends DNA toward the major groove, interferes directly with activated transcription, poisons the transcription-coupled nucleotide excision repair complex, promotes degradation of RNA polymerase II, and generates DNA double-strand breaks. Society and culture Legal status In September 2020, the European Medicines Agency recommended that the use of trabectedin in treating ovarian cancer remain unchanged. == References ==
Elagolix	Elagolix, sold under the brand name Orilissa, is a gonadotropin-releasing hormone antagonist (GnRH antagonist) medication which is used in the treatment of pain associated with endometriosis in women. It is also under development for the treatment of uterine fibroids and heavy menstrual bleeding in women. The medication was under investigation for the treatment of prostate cancer and enlarged prostate in men as well, but development for these conditions was discontinued. Elagolix is taken by mouth once or twice per day. It can be taken for up to 6 to 24 months, depending on the dosage.Side effects of elagolix include menopausal-like symptoms such as hot flashes, night sweats, insomnia, amenorrhea, mood changes, anxiety, and decreased bone density, among others. Elagolix is a GnRH antagonist, or an antagonist of the gonadotropin-releasing hormone receptor (GnRHR), the biological target of the hypothalamic hormone gonadotropin-releasing hormone (GnRH). By blocking the GnRHR, it dose-dependently suppresses the gonadal production and hence circulating levels of sex hormones such as estradiol, progesterone, and testosterone. Elagolix is a short-acting GnRH antagonist, and can be used to achieve either partial or more substantial suppression of sex hormone levels. Reduced estrogen levels in the endometrium are responsible for the efficacy of elagolix in the treatment of endometriosis.Elagolix was first described in 2008 and was approved for medical use in July 2018. It has been described as a "second-generation" GnRH modulator due to its non-peptide and small-molecule nature and its oral activity. Unlike GnRH agonists and older GnRH antagonists, which are peptides and first-generation GnRH modulators, elagolix is not a GnRH analogue as it is not structurally related to GnRH. Elagolix was the first second-generation and orally active GnRH modulator to be introduced for medical use. The introduction of elagolix in the United States and Canada was followed by that of relugolix (brand name Relumina), the next second-generation GnRH antagonist, in Japan in January 2019. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Medical uses Elagolix is used in the treatment of moderate to severe pain associated with endometriosis in premenopausal women. Endometriosis is a condition in which the endometrium, the inner lining of the uterus, grows outside of the uterus into surrounding tissues and causes symptoms such as pelvic pain and infertility. Around 10% of women may be affected by endometriosis. Elagolix significantly decreases symptoms of dysmenorrhea (menstrual pelvic pain), non-menstrual pelvic pain, and dyspareunia (pain during sexual intercourse) in women with endometriosis. The medication is used at a lower dosage of 150 mg once per day or at a higher dosage of 200 mg twice per day, depending on the severity of symptoms.The effectiveness of elagolix in the treatment of symptoms of endometriosis was demonstrated in the 6-month Elaris Endometriosis I and II (EM-I and EM-II) phase III clinical trials. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P < 0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to non-menstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P < 0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P = 0.003 and P < 0.001, respectively). The reductions in symptoms of endometriosis with elagolix resulted in an improved quality of life.The duration of use of elagolix in the treatment of endometriosis should be limited due to a progressive risk of bone loss, and the lowest effective dosage should be used. Elagolix can be used for up to 24 months at the 150 mg once per day dosage and for up to 6 months at the 200 mg twice per day dosage.Because of its relatively short duration, elagolix should be taken at approximately the same time each day. In the case of twice-daily administration, elagolix should be taken at approximate 12-hour intervals, for instance once in the morning and once at night. It can be taken with or without food.Elagolix is approved only for the treatment of endometriosis. Other approved and off-label uses of GnRH antagonists in general are the same as those of GnRHR desensitization therapy with GnRH agonists such as leuprorelin, and include uterine fibroids and breast cancer in premenopausal women, prostate cancer in men, precocious puberty in children, and hormone therapy in transgender adolescents and adults, among others. Available forms Elagolix is available in the form of Orilissa 150 and 200 mg oral tablets. The 150 mg tablets are light pink, oblong, and film-coated with "EL 150" debossed on one side, while the 200 mg tablets are light orange, oblong, and film-coated with "EL 200" debossed on one side. The inactive ingredients in the tablets include mannitol, sodium carbonate monohydrate, pregelatinized starch, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and a distinct color additive (carmine high tint in the 150 mg tablets and iron oxide red in the 200 mg tablets). Contraindications Contraindications of elagolix include pregnancy, known osteoporosis, severe hepatic impairment, and concomitant use with strong organic anion-transporting polypeptide (OATP) 1B1 inhibitors such as ciclosporin and gemfibrozil. Elagolix may increase the risk of miscarriage in early pregnancy. Women should avoid pregnancy while taking elagolix, for instance by using birth control, and should discontinue the medication if they become or wish to become pregnant. Elagolix should not be used in women with osteoporosis because it may increase the risk of further bone loss. Severe hepatic impairment is associated with 7-fold increased exposure to elagolix, which may increase the risk of bone loss. In women with moderate hepatic impairment, which is associated with 3-fold increased exposure to elagolix, the medication at 200 mg twice per day should not be used, while 150 mg once per day should be used for no more than 6 months. OATP1B1 inhibitors are likely to greatly increase exposure to elagolix similarly to moderate to severe hepatic impairment.Combined birth control is not contraindicated with elagolix, but because of the estrogen component, is expected to decrease the effectiveness of elagolix in the treatment of endometriosis, and hence is not recommended. Other forms of birth control, such as non-hormonal birth control, can be used instead. Elagolix is not contraindicated in women who are breastfeeding, but it is unknown whether the medication is excreted in breast milk or if it has adverse effects on milk production or the breastfed child. The use of elagolix in women who are breastfeeding should be considered carefully, weighing both benefits and risks. Side effects The side effects of elagolix are in general similar to menopausal symptoms. The most common side effects of elagolix (incidence ≥10%) are hot flashes, night sweats, headaches, nausea, and amenorrhea (cessation of menstruation). The next most frequent side effects of elagolix (incidence ≥5%) are insomnia, anxiety, arthralgia (joint pain), depression, and mood changes. Less common side effects of elagolix (incidence ≥3% and <5%) include decreased sex drive, diarrhea, abdominal pain, weight gain, dizziness, constipation, and irritability. Other common side effects of elagolix include decreased bone mineral density (BMD) and changes in the blood lipid profile. Rare but serious adverse effects that were observed during elagolix therapy in clinical trials included appendicitis (0.3%), abdominal pain (0.2%), and back pain (0.2%), though it is unknown if these were due to elagolix. Other serious adverse effects of elagolix may include bone loss, miscarriage, suicidality, and elevated liver enzymes. Elagolix was discontinued due to side effects by 5 to 10% of women in clinical trials, with the most common reasons being hot flashes or night sweats, nausea, and decreased BMD.Elagolix dose- and duration-dependently decreases BMD in premenopausal women with long-term therapy. After 6 months of treatment with elagolix, lumbar spine BMD was decreased by 0.3 to 1.3% with 150 mg once per day and by 2.5 to 3.1% with 200 mg twice per day. The decrease in BMD during elagolix therapy may not be fully reversible with discontinuation, as only partial recovery was observed 12 months after discontinuation of therapy. The cause of the decrease in BMD with elagolix is estrogen deficiency, and is analogous to that associated with postmenopause. The consequences of the effects of elagolix on BMD are unknown, but may be an increase in the risk of bone loss and fractures. This is why the duration of use of elagolix should be limited. In women with risk factors for bone loss and osteoporosis, such as a history of low-trauma fracture, assessment of BMD may be considered. Elagolix should not be used in premenopausal women with known osteoporosis. Supplementation with calcium and/or vitamin D during treatment with elagolix has not been studied, but may be beneficial for helping to maintain bone health.Elagolix decreases the amount, intensity, and duration of menstrual bleeding. Amenorrhea, the cessation of menstruation, was observed in 4 to 17% of women with 150 mg once per day and in 7 to 57% of women with 200 mg twice per day, compared to less than 1% of women given placebo. The decreased menstrual bleeding caused by elagolix may impede the ability to recognize pregnancy in a timely manner. Based on its mechanism of action, elagolix may increase the risk of miscarriage in early pregnancy, and so should be discontinued if pregnancy occurs. If pregnancy is suspected, pregnancy testing can be performed. Elagolix decreases the rate of ovulation and thereby decreases the likelihood of pregnancy, but has not been shown to be a fully effective contraceptive and should not be relied on to prevent pregnancy.The incidence of depression and mood changes in clinical trials with elagolix was increased in premenopausal women taking elagolix relative to placebo. Mood- and depression-type side effects such as altered mood, mood swings, depressed mood, depression, depressive symptoms, and tearfulness occurred in 3 to 6% of women with 150 mg per day and in 5 to 6% of women with 200 mg twice per day, compared to 2 to 3% in women given placebo. Suicidal ideation and behavior occurred in a few women (0.2–0.4%), with one suicide observed. People taking elagolix with new or existing depressive symptoms should be promptly evaluated to determine whether the benefits of treatment outweigh the risks. In those with new or existing depressive symptoms, referral to a mental health professional, as appropriate, may be warranted. Immediate medical attention should be sought for those with suicidal ideation and behavior.Elagolix dose-dependently produced elevated liver enzymes, including elevations of serum alanine aminotransferase of at least 3-fold the upper limit, in clinical trials. This was observed in one woman (0.2%) with 150 mg once per day and in five women (1.1%) with 200 mg twice per day, compared to one woman (0.1%) given placebo. Medical attention should be sought if signs or symptoms of liver injury, such as jaundice, are noticed. The lowest effective dosage of elagolix may be used to minimize the risk of liver problems, and in those who develop elevated liver enzymes during elagolix therapy, prompt evaluation should be done to determine whether the benefits of treatment outweigh the risks. Overdose In the event of an overdose of elagolix, the person should be monitored for any signs or symptoms of adverse reactions and should be treated on a symptomatic basis as needed. Elagolix has been assessed in clinical studies at a dose as high as a single administration of 1,200 mg, which resulted in concentrations of the medication that were 17 times higher than with the typical high clinical dosage of 200 mg twice per day. No adverse effects were mentioned. Chronic overdosage of elagolix may result in greater suppression of estradiol levels and a consequent increased risk of bone loss with long-term therapy. Interactions Elagolix has a number of potential drug interactions with other medications. Elagolix is a substrate of the cytochrome P450 (CYP450) enzyme CYP3A, and inhibitors and inducers of CYP3A4 may alter the metabolism of elagolix and increase or decrease its circulating levels. The strong CYP3A4 inhibitor ketoconazole has been found to increase peak levels of and total exposure to a single 150 mg dose of elagolix by about 2-fold. Paradoxically, rifampin, a strong inducer of CYP3A4 and other CYP450 enzymes, increased peak levels of and total exposure to a single 150 mg dose of elagolix as well. A single dose of rifampin increased peak levels of elagolix by 4.4-fold and total exposure by 5.6-fold, whereas continuous rifampin therapy increased peak levels of elagolix by 2-fold and total exposure by 1.7-fold. The use of elagolix at 200 mg twice per day concomitantly with rifampin is not recommended, whereas the concomitant use of elagolix at 150 mg once per day with rifampin should be limited to 6 months. No significant changes in exposure to elagolix were observed with concomitant administration of rosuvastatin (a substrate of OATP1B1, OATP1B3, and BCRP), sertraline (a moderate inhibitor of CYP2D6 and CYP2B6), or fluconazole (a strong inhibitor of CYP2C19 and a moderate inhibitor of CYP2C9 and CYP3A4).Elagolix is a substrate of the hepatic OATP1B1 transporter. Levels of elagolix have been found to be increased by 78% in people with a genotype characterized by reduced OATP1B1 transporter function. The concomitant use of elagolix with medications that inhibit OATP1B1 may increase elagolix levels, and the use of elagolix with strong OATP1B1 inhibitors like ciclosporin and gemfibrozil, which may markedly increase elagolix exposure, is contraindicated.Elagolix is a weak to moderate inducer of CYP3A, and may decrease levels of medications that are substrates of CYP3A4. In addition, elagolix is an inhibitor of P-glycoprotein, and may increase levels of medications that are substrates of P-glycoprotein, such as digoxin. Elagolix has been found to increase exposure to digoxin and ethinylestradiol, whereas it has been found to decrease exposure to rosuvastatin, midazolam, norethisterone, norelgestromin, and norgestrel.Because combined birth control pills and other forms of combined birth control contain an estrogen, and because elagolix treats endometriosis by decreasing estrogen levels in the endometrium, these form of hormonal birth control are likely and expected to decrease the effectiveness of elagolix in the treatment of this condition. The effect of progestogen-only birth control on the effectiveness of elagolix in endometriosis is unknown. However, progestogens are antiestrogenic in the uterus, and high-dose progestin therapy is known to be effective in the treatment of endometriosis similarly to GnRH antagonists. On the basis of limited clinical research, combined birth control pills have also been found to be effective in the treatment of endometriosis, but are likely not as effective as GnRH modulator monotherapy. It is advised that women use non-hormonal methods of birth control during elagolix therapy and for one week following discontinuation of elagolix. Pharmacology Pharmacodynamics Elagolix acts as a potent and selective competitive antagonist of the gonadotropin-releasing hormone receptor (GnRHR), the biological target of the hypothalamic peptide hormone gonadotropin-releasing hormone (GnRH). As such, it is a GnRH antagonist. The affinity (KD) of elagolix for the GnRHR is 54 pM. By blocking the GnRHR in the pituitary gland, elagolix suppresses the GnRH-induced secretion of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary, and thereby decreases the production of sex hormones by the gonads. In women, elagolix dose-dependently suppresses the production of ovarian hormones including estradiol, progesterone, and testosterone, and thereby decreases the circulating levels of these hormones. In men, GnRH modulators suppress the testicular production of testosterone and estradiol, decreasing the circulating levels of these hormones similarly. Unlike previous GnRH agonists and antagonists, referred to collectively as GnRH analogues, elagolix is a non-peptide and small-molecule compound that can be taken orally.Estrogens like estradiol stimulate the growth of the endometrium, and thereby aggravate symptoms of endometriosis. By suppressing estrogen production and levels, elagolix decreases the growth of the endometrium and decreases endometriosis symptoms such as pelvic pain.Elagolix is a short-acting GnRH antagonist, with a terminal half-life of typically about 4 to 6 hours. Because of the short duration of elagolix in the body, the activation of the GnRHR by GnRH is not fully blocked throughout the day with once-daily administration of elagolix. As a result, gonadotropin and sex hormone levels are only partially suppressed when elagolix is taken once per day. In addition, the degree of suppression can be dose-dependently adjusted as needed, for instance with higher-dose twice-daily administration to achieve greater hormonal suppression. Because of its short duration in the body, the effects of elagolix are rapidly reversible upon discontinuation. In addition, due to its partial and incomplete suppression of estradiol levels, the side effects of elagolix, such as hot flashes and decreased BMD, are lower than with first-generation GnRH modulators. In clinical trials, elagolix produced dose-dependent decreases in gonadotropin, estradiol, and progesterone levels in women. Median levels of estradiol were partially suppressed to 42 pg/mL (follicular phase levels) with 150 mg once daily and were fully or near-fully suppressed to 12 pg/mL (postmenopausal levels) with 200 mg twice daily. In a 21-day study in premenopausal women, the effects of elagolix on FSH levels were found to be maximal at a dosage of 300 mg twice per day or above, whereas its effects on LH and estradiol levels were maximal at a dosage of 200 mg twice per day or above. Levels of progesterone were maintained at anovulatory levels (<2 ng/mL) across the 21-day study period at dosages of elagolix of 100 mg twice per day and above. A dosage of elagolix of 400 mg twice per day appears to produce no greater suppression in gonadotropin or estradiol levels than a dosage of 300 mg twice per day in premenopausal women. Suppression of gonadotropin and sex hormone levels with elagolix occurs rapidly, within hours, and upon discontinuation of elagolix, gonadotropin and sex hormone levels remain suppressed for at least 12 hours, but show recovery within 24 to 48 hours. As a consequence of its suppression of gonadotropin and sex hormone levels, elagolix inhibits ovulation in women. Over the course of three menstrual cycles, the ovulation rate with elagolix was 50% at 150 mg once daily and 32% at 200 mg twice daily. Because ovulation is triggered by a surge in estradiol levels at mid-cycle, estrogen exposure during elagolix therapy might be greater around this time in some women.In addition to its activity as a GnRH antagonist, elagolix is a weak to moderate inducer of CYP3A and an inhibitor of P-glycoprotein. As a result, elagolix may affect the metabolism and/or transport of other medications, and this may contribute to drug interactions with elagolix. Pharmacokinetics Elagolix is taken by the oral route of administration, in contrast to other GnRH modulators. The oral bioavailability of elagolix in humans is not described in the Food and Drug Administration (FDA) label for the medication, but in animal research elagolix showed a low oral bioavailability of 5.8% in rats and 11% in monkeys. Following administration, elagolix is rapidly absorbed, with peak concentrations occurring after 0.5 to 1.5 hours. The drug accumulation ratio of elagolix at 150 mg once per day is 0.98 and at 200 mg twice per day is 0.89, indicating that it is not accumulated in the body with continuous administration. At steady state, peak levels of elagolix at 150 mg once per day are 574 ng/mL and at 200 mg twice per day are 774 ng/mL while area-under-the-curve levels of elagolix at 150 mg once per day are 1,292 ng•hour/mL and at 200 mg twice per day are 1,725 ng•hour/mL. A toxicology study found that levels of elagolix in women after a single dose of 1,200 mg were 17 times higher than in women taking 200 mg twice daily. Taking elagolix with a high-fat meal has been found to decrease its peak levels by 36% and its area-under-the-curve levels by 24%. In terms of distribution, the plasma protein binding of elagolix is 80% and its blood-to-plasma ratio is 0.6. The volume of distribution at steady state is 1,674 L at 150 mg once per day and 881 L at 200 mg twice per day.Elagolix is metabolized in the liver, with the major pathway being by CYP3A and minor pathways including by CYP2D6, CYP2C8, and UDP-glucuronosyltransferases. The terminal half-life of elagolix is typically about 4 to 6 hours. A study found that its half-life was 2.4 to 6.3 hours with a single dose and was 2.2 to 10.8 hours with continuous administration. The oral clearance of elagolix is 123 L/hour at 150 mg once per day and 144 L/hour at 200 mg twice per day. The major pathway of elimination of elagolix is hepatic metabolism. Elagolix is taken up from the circulation into the liver by the hepatic OATP1B1 carrier. In people with two reduced function alleles of the gene that encodes OATP1B1 (SLCO1B1 521T>C; SLCO1B1 521 C/C genotype), plasma levels of elagolix have been found to be increased by 78% relative to in people with normal OATP1B1 function (SLCO1B1 521T/T genotype). The frequency of this reduced function OATP1B1 genotype is generally less than 5% in most racial and ethnic groups. Elagolix is excreted less than 3% in urine and 90% in feces.Exposure to elagolix is not affected by renal impairment or mild hepatic impairment, but is increased by approximately 3-fold in women with moderate hepatic impairment and by approximately 7-fold in women with severe hepatic impairment. There were no differences in the pharmacokinetics of elagolix between individuals of different racial and ethnic groups. Similarly, the pharmacokinetics of elagolix were unaffected by body weight and body mass index. Peak and area-under-the-curve levels of elagolix have been shown to be altered by CYP3A4 inhibitors like ketoconazole and CYP3A4 inducers like rifampin. Inhibitors of OATP1B1 may increase circulating levels of elagolix, and elagolix is considered to be contraindicated in combination with strong OATP1B1 inhibitors. Elagolix is a substrate of P-glycoprotein, but the effect of inhibitors and inducers of P-glycoprotein on the pharmacokinetics of elagolix is unknown. Elagolix itself is an inhibitor of P-glycoprotein. Chemistry Elagolix is a small-molecule and non-peptide compound. This is in contrast to GnRH analogues such as leuprorelin and cetrorelix, which are peptides and analogues of GnRH. Other small-molecule and non-peptide orally active GnRH antagonists besides elagolix include linzagolix, opigolix, relugolix, and sufugolix, although none of these compounds have been introduced for medical use at this time.Elagolix is used as elagolix sodium, the sodium salt of elagolix. It is a white to off white to light yellow powder. The compound is freely soluble in water. The chemical name of elagolix sodium is sodium 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate. It has a molecular formula of C32H29F5N3O5Na and a molecular weight of 653.58 g/mol. The free acid form of el
Elagolix	agolix has a molecular formula of C32H29F5N3O5 and a molecular weight of 631.60 g/mol. History Elagolix was first described in the literature in 2005. It was originally developed by the pharmaceutical company Neurocrine Biosciences, and was later developed together by Neurocrine Biosciences and AbbVie (previously Abbott Laboratories). In June 2010, Neurocrine Biosciences and Abbott announced a global agreement to develop and commercialize elagolix for the treatment of endometriosis. The medication completed phase III clinical trials for endometriosis in November 2016. Two phase III clinical trials, the Elaris Endometriosis I and II (EM-I and EM-II) studies, were conducted. The studies included almost 1,700 women, about 950 of whom were treated with elagolix. In September 2017, AbbVie filed a New Drug Application (NDA) for elagolix for the treatment of pain associated with endometriosis in the United States. The medication was approved by the FDA for the treatment of endometriosis-associated pain in the United States on 23 July 2018. It was the first new medication to be approved by the FDA for the treatment of endometriosis in more than a decade. Elagolix was the first member of a new class of GnRH modulators described as "second-generation" due to their non-peptide and small-molecule nature and oral activity to be marketed. A second member of this group, relugolix (brand name Relumina), was introduced in Japan in January 2019. In addition to endometriosis, elagolix is under development for the treatment of uterine fibroids and menorrhagia. It is in phase III clinical trials for these indications. Society and culture Generic names Elagolix is the generic name of the drug and its INN and USAN. It is also known by its former developmental code names NBI-56418 and ABT-620. Brand names Elagolix is marketed under the brand name Orilissa. Availability Elagolix is available in the United States and Canada. A similar medication, relugolix, is available in Japan. Economics Prior to its introduction, elagolix was estimated to cost about US$850 per month. It is not available as a generic medication. Research As of November 2018, elagolix in phase III clinical trials for the treatment of uterine fibroids (uterine leiomyoma) and menorrhagia (abnormally heavy bleeding during menstruation) in women. An efficacy and safety study of elagolix in combination with add-back estradiol, an estrogen, and norethisterone acetate, a progestin, for the treatment of menorrhagia associated with uterine fibroids in premenopausal women has been published. The medication was also under investigation for the treatment of prostate cancer and benign prostatic hyperplasia (enlarged prostate) in men, but development for these indications was discontinued. References Further reading Ezzati M, Carr BR (January 2015). "Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain". Womens Health. 11 (1): 19–28. doi:10.2217/whe.14.68. PMID 25581052. Melis GB, Neri M, Corda V, Malune ME, Piras B, Pirarba S, Guerriero S, Orrù M, DAlterio MN, Angioni S, Paoletti AM (May 2016). "Overview of elagolix for the treatment of endometriosis". Expert Opin Drug Metab Toxicol. 12 (5): 581–8. doi:10.1517/17425255.2016.1171316. PMID 27021205. S2CID 28684228. Alessandro P, Luigi N, Felice S, Maria PA, Benedetto MG, Stefano A (April 2017). "Research development of a new GnRH antagonist (Elagolix) for the treatment of endometriosis: a review of the literature". Arch. Gynecol. Obstet. 295 (4): 827–832. doi:10.1007/s00404-017-4328-6. PMID 28255765. S2CID 26422467. Perricos A, Wenzl R (September 2017). "Efficacy of elagolix in the treatment of endometriosis". Expert Opin Pharmacother. 18 (13): 1391–1397. doi:10.1080/14656566.2017.1359258. PMID 28737050. S2CID 32467159. Surrey E, Taylor HS, Giudice L, Lessey BA, Abrao MS, Archer DF, Diamond MP, Johnson NP, Watts NB, Gallagher JC, Simon JA, Carr BR, Dmowski WP, Leyland N, Singh SS, Rechberger T, Agarwal SK, Duan WR, Schwefel B, Thomas JW, Peloso PM, Ng J, Soliman AM, Chwalisz K (July 2018). "Long-Term Outcomes of Elagolix in Women With Endometriosis: Results From Two Extension Studies". Obstet Gynecol. 132 (1): 147–160. doi:10.1097/AOG.0000000000002675. PMID 29889764. Taylor HS (July 2018). "Use of Elagolix in Gynaecology". J Obstet Gynaecol Can. 40 (7): 931–934. doi:10.1016/j.jogc.2018.01.004. PMID 29921430. Lamb YN (September 2018). "Elagolix: First Global Approval". Drugs. 78 (14): 1501–1508. doi:10.1007/s40265-018-0977-4. PMC 6244606. PMID 30194661. Vercellini P, Viganò P, Barbara G, Buggio L, Somigliana E (February 2019). "Elagolix for endometriosis: all that glitters is not gold". Hum. Reprod. 34 (2): 193–199. doi:10.1093/humrep/dey368. PMID 30551159. Barra F, Scala C, Ferrero S (April 2019). "Elagolix sodium for the treatment of women with moderate to severe endometriosis-associated pain". Drugs Today. 55 (4): 237–246. doi:10.1358/dot.2019.55.4.2930713. PMID 31050692. S2CID 143434963. External links "Elagolix". Drug Information Portal. U.S. National Library of Medicine.
Travoprost	Travoprost, sold under the brand name Travatan among others, is a medication used to treat high pressure inside the eye including glaucoma. Specifically it is used for open angle glaucoma when other agents are not sufficient. It is used as an eye drop. Effects generally occur within two hours.Common side effects include red eyes, blurry vision, eye pain, dry eyes, and change in color of the eyes. Other significant side effects may include cataracts. Use during pregnancy or breastfeeding is generally not recommended. It is a prostaglandin analog and works by increasing the outflow of aqueous fluid from the eyes.Travoprost was approved for medical use in the United States and in the European Union in 2001. It is available as a generic medication in the United Kingdom. In 2017, it was the 212th most commonly prescribed medication in the United States, with more than two million prescriptions. Medical uses Travoprost is used to treat high pressure inside the eye including glaucoma. Specifically it is used for open angle glaucoma when other agents are not sufficient. Side effects Possible side effects are: blurred vision eyelid redness permanent darkening of eyelashes eye discomfort permanent darkening of the iris to brown (heterochromia) burning sensation during use thickening of the eyelashes inflammation of the prostate gland, restricting urine flow (BPH)Research suggests that wiping the eye with an absorbent pad after the administration of eye drops can result in shorter eyelashes and a lesser chance of hyperpigmentation in the eyelid, compared to not wiping off excess fluid. Pharmacology Mechanism of action It is a synthetic prostaglandin analog (or more specifically, an analog of prostaglandin F2α) that works by increasing the outflow of aqueous fluid from the eyes.Like other analogs of prostaglandin F2α such as tafluprost and latanoprost, travoprost is an ester prodrug of the free acid, which acts as an agonist at the prostaglandin F receptor, increasing outflow of aqueous fluid from the eye and thus lowering intraocular pressure. Pharmacokinetics Travoprost is absorbed through the cornea, where it is hydrolysed to the free travoprost acid. Highest concentrations of the acid in the eye are reached one to two hours after application, and its half-life in the aqueous fluid is 1.5 hours. Once it reaches the bloodstream, it is quickly metabolised, so that concentrations in the system do not exceed 25 pg/ml (compared to 20 ng/ml in the eye, which is higher by nearly a factor of 1000).Metabolites are formed by beta oxidation of the acidic chain (compare Tafluprost#Pharmacokinetics), oxidation of the OH-group in the other side chain, and reduction of the double bond next to this OH-group. Travoprost acid and its metabolites are mainly excreted via the kidney with a terminal half-life of 45 minutes. References External links "Travoprost". Drug Information Portal. U.S. National Library of Medicine.
Tioguanine	Tioguanine, also known as thioguanine or 6-thioguanine (6-TG) is a medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML). Long-term use is not recommended. It is given by mouth.Common side effects include bone marrow suppression, liver problems and inflammation of the mouth. It is recommended that liver enzymes be checked weekly when on the medication. People with a genetic deficiency in thiopurine S-methyltransferase are at higher risk of side effects. Avoiding pregnancy when on the medication is recommended for both males and females. Tioguanine is in the antimetabolite family of medications. It is a purine analogue of guanine and works by disrupting DNA and RNA.Tioguanine was developed between 1949 and 1951. It is on the World Health Organizations List of Essential Medicines. Medical uses Acute leukemias in both adults and children Chronic myelogenous leukemia Inflammatory bowel disease, especially ulcerative colitis Psoriasis Side effects Leukopenia and neutropenia Thrombocytopenia Anemia Anorexia Nausea and vomiting Hepatotoxicity: this manifests as: Hepatic veno-occlusive disease The major concern that has inhibited the use of thioguanine has been veno-occlusive disease (VOD) and its histological precursor nodular regenerative hyperplasia (NRH). The incidence of NRH with thioguanine was reported as between 33 and 76%. The risk of ensuing VOD is serious and frequently irreversible so this side effect has been a major concern. However, recent evidence using an animal model for thioguanine-induced NRH/VOD has shown that, contrary to previous assumptions, NRH/VOD is dose dependent and the mechanism for this has been demonstrated. This has been confirmed in human trials, where thioguanine has proven to be safe but efficacious for coeliac disease when used at doses below those commonly prescribed. This has led to a revival of interest in thioguanine because of its higher efficacy and faster action compared to other thiopurines and immunosuppressants such as mycophenylate. Contraindications Pregnancy Lactation: The safety warning against breastfeeding may have been a conservative assessment, but research evidence suggests that thiopurines do not enter breastmilk. Interactions Cancers that do not respond to treatment with mercaptopurine do not respond to thioguanine. On the other hand, some cases of IBD that are resistant to mercaptopurine (or its pro-drug azathioprine) may be responsive to thioguanine. Pharmacogenetics The enzyme thiopurine S-methyltransferase (TPMT) is responsible for the direct inactivation of thioguanine to its methylthioguanine base – this methylation prevents thioguanine from further conversion into active, cytotoxic thioguanine nucleotide (TGN) metabolites. Certain genetic variations within the TPMT gene can lead to decreased or absent TPMT enzyme activity, and individuals who are homozygous or heterozygous for these types of genetic variations may have increased levels of TGN metabolites and an increased risk of severe bone marrow suppression (myelosuppression) when receiving thioguanine. In many ethnicities, TPMT polymorphisms that result in decreased or absent TPMT activity occur with a frequency of approximately 5%, meaning that about 0.25% of patients are homozygous for these variants. However, an assay of TPMT activity in red blood cells or a TPMT genetic test can identify patients with reduced TPMT activity, allowing for the adjustment of thiopurine dose or avoidance of the drug entirely. The FDA-approved drug label for thioguanine notes that patients who are TPMT-deficient may be prone to developing myelosuppression and that laboratories offer testing for TPMT deficiency. Indeed, testing for TPMT activity is currently one of the few examples of pharmacogenetics being translated into routine clinical care. Metabolism and pharmacokinetics A single oral dose of thioguanine has incomplete metabolism, absorption and high interindividual variability. The bioavailability of thioguanine has an average of 30% (range 14-46%). The maximum concentration in plasma after a single oral dose is attained after 8 hours. Thioguanine, like other thiopurines, is cytotoxic to white cells; as a result it is immunosuppressive at lower doses and anti-leukemic/anti-neoplastic at higher doses. Thioguanine is incorporated into human bone marrow cells, but like other thiopurines, it is not known to cross the blood-brain barrier. Thioguanine cannot be demonstrated in cerebrospinal fluid, similar to the closely related compound 6-mercaptopurine which also cannot penetrate to the brain. The plasma half-life of thioguanine is short, due to the rapid uptake into liver and blood cells and conversion to 6-TGN. The median plasma half-life of 80-minutes with a range of 25–240 minutes. Thioguanine is excreted primarily through the kidneys in urine, but mainly as a metabolite, 2-amino-6-methylthiopurine. However, the intra-cellular thio-nucleotide metabolites of thioguanine (6-TGN) have longer half-lives and can therefore be measured after thioguanine is eliminated from the plasma. Thioguanine is catabolized (broken down) via two pathways. One route is through the deamination by the enzyme guanine deaminase to 6-thioxanthine, which has minimal anti-neoplastic activity, then by oxidation by xanthine oxidase of the thioxanthine to thiouric acid. This metabolic pathway is not dependent on the efficacy of xanthine oxidase, so that the inhibitor of xanthine oxidase, the drug allopurinol, does not block the breakdown of thioguanine, in contrast to its inhibition of the breakdown of the related thiopurine 6-mercaptopurine. The second pathway is the methylation of thioguanine to 2-amino-6-methylthiopurine, which is minimally effective as an anti-neoplastic and significantly less toxic than thioguanine. This pathway also is independent of the enzyme activity of xanthine oxidase. Mechanism of action 6-Thioguanine is a thio analogue of the naturally occurring purine base guanine. 6-thioguanine utilises the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) to be converted to 6-thioguanosine monophosphate (TGMP). High concentrations of TGMP may accumulate intracellularly and hamper the synthesis of guanine nucleotides via the enzyme Inosine monophosphate dehydrogenase (IMP dehydrogenase), leading to DNA mutations.TGMP is converted by phosphorylation to thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP). Simultaneously deoxyribosyl analogs are formed, via the enzyme ribonucleotide reductase. The TGMP, TGDP and TGTP are collectively named 6-thioguanine nucleotides (6-TGN). 6-TGN are cytotoxic to cells by: (1) incorporation into DNA during the synthesis phase (S-phase) of the cell; and (2) through inhibition of the GTP-binding protein (G protein) Rac1, which regulates the Rac/Vav pathway. Chemistry It is a pale yellow, odorless, crystalline powder. Names Tioguanine (INN, BAN, AAN), or thioguanine (USAN). Thioguanine is administered by mouth (as a tablet – Lanvis). References Further reading Dean L (2012). "Thioguanine Therapy and TPMT Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520351. Bookshelf ID: NBK100663. External links "Tioguanine". Drug Information Portal. U.S. National Library of Medicine.
Fidaxomicin	Fidaxomicin, sold under the brand name Dificid among others, is the first member of a class of narrow spectrum macrocyclic antibiotic drugs called tiacumicins. It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis. Fidaxomicin is minimally absorbed into the bloodstream when taken orally, is bactericidal, and selectively eradicates pathogenic Clostridioides difficile with relatively little disruption to the multiple species of bacteria that make up the normal, healthy intestinal microbiota. The maintenance of normal physiological conditions in the colon may reduce the probability of recurrence of Clostridioides difficile infection.It is marketed by Merck, which acquired Cubist Pharmaceuticals in 2015, and had in turn bought the originating company, Optimer Pharmaceuticals. It is used for the treatment of Clostridioides difficile infection, which is also known as Clostridioides difficile-associated diarrhea or Clostridioides difficile-associated illness (CDI), and can develop into Clostridioides difficile colitis and pseudomembranous colitis. Fidaxomicin is available in a 200 mg tablet that is administered every 12 hours for a recommended duration of 10 days. Total duration of therapy should be determined by the patients clinical status. It is currently one of the most expensive antibiotics approved for use. A standard course costs upwards of £1350. Mechanism Fidaxomicin binds to and prevents movement of the "switch regions" of bacterial RNA polymerase. Switch motion occurs during the opening and closing of the DNA:RNA clamp, a process that occurs throughout RNA transcription but is especially important in the opening of double-stranded DNA during the initiation of transcription. It has minimal systemic absorption and a narrow spectrum of activity; it is active against Gram positive bacteria, especially clostridia. The minimal inhibitory concentration (MIC) range for C. difficile (ATCC 700057) is 0.03–0.25 μg/mL. Clinical trials Good results were reported by the company in 2009, from a North American Phase III clinical trial comparing it with oral vancomycin for the treatment of Clostridioides difficile infection. The study met its primary endpoint of clinical cure, showing that fidaxomicin was non-inferior to oral vancomycin (92.1% vs. 89.8%). In addition, the study met its secondary endpoint of recurrence: 13.3% of the subjects had a recurrence with fidaxomicin vs. 24.0% with oral vancomycin. The study also met its exploratory endpoint of global cure (77.7% for fidaxomicin vs. 67.1% for vancomycin). Clinical cure was defined as patients requiring no further therapy for the treatment of Clostridioides difficile infection two days after completion of study medication. Global cure was defined as patients who were cured at the end of therapy and did not have a recurrence in the next four weeks. Fidaxomicin was shown to be as good as the standard-of-care, vancomycin, for treating Clostridioides difficile infection in a Phase III clinical trial published in February 2011. The authors also reported significantly fewer recurrences of infection, a frequent problem with C. difficile, and similar drug side effects. Based on a multicenter clinical trial, fidaxomicin was reported well tolerated in children with Clostridioides difficile–associated diarrhea and has a pharmacokinetic profile in children similar to that in adults.Regarding the high budget to spend for fidaxomicin, a systematic literature review published in 2017, showed that fidaxomicin was demonstrated to be cost-effective versus metronidazole and vancomycin in patients with Clostridioides difficile infection. Approvals and indications On April 5, 2011, the drug won an FDA advisory panels unanimous approval for the treatment of Clostridioides difficile infection, and gained full FDA approval on May 27, 2011. As of January 2020, fidaxomicin is FDA-approved for use in children aged 6 months and older for C. difficile associated diarrhea (CDAD). Adverse Effects The most common side effects reported in adults with the use of fidaxomicin include nausea, abdominal pain, vomiting, anemia, neutropenia, and gastrointestinal hemorrhage. In children the most common side effects include fever, vomiting, diarrhea, constipation, abdominal pain, rash, and increased aminotransferases. References External links "Fidaxomicin". Drug Information Portal. U.S. National Library of Medicine.
Anagrelide	Anagrelide (Agrylin/Xagrid, Shire and Thromboreductin, AOP Orphan Pharmaceuticals AG) is a drug used for the treatment of essential thrombocytosis (also known as essential thrombocythemia), or overproduction of blood platelets. It also has been used in the treatment of chronic myeloid leukemia.Anagrelide controlled release (GALE-401) is in phase III clinical trials by Galena Biopharma for the treatment of essential thrombocytosis. Medical uses Anagrelide is used to treat essential thrombocytosis, especially when the current treatment of the patient is insufficient. Essential thrombocytosis patients who are suitable for anagrelide often meet one or more of the following factors: age over 60 years platelet count over 1000×109/L a history of thrombosisAccording to a 2005 Medical Research Council randomized trial, the combination of hydroxyurea with aspirin is superior to the combination of anagrelide and aspirin for the initial management of essential thrombocytosis. The hydroxyurea arm had a lower likelihood of myelofibrosis, arterial thrombosis, and bleeding, but it had a slightly higher rate of venous thrombosis. Anagrelide can be useful in times when hydroxyurea proves ineffective. Side-effects Common side effects are headache, diarrhea, unusual weakness/fatigue, hair loss, nausea. The same MRC trial mentioned above also analyzed the effects of anagrelide on bone marrow fibrosis, a common feature in patients with myelofibrosis. The use of anagrelide was associated with a rapid increase in the degree of reticulin deposition (the mechanism by which fibrosis occurs), when compared to those in whom hydroxyurea was used. Patients with myeloproliferative conditions are known to have a very slow and somewhat variable course of marrow fibrosis increase. This trend may be accelerated by anagrelide. This increase in fibrosis appeared to be linked to a drop in hemoglobin as it progressed. Stopping anagrelide (and switching patients to hydroxyurea) appeared to reverse the degree of marrow fibrosis. Thus, patients on anagrelide may need to be monitored on a periodic basis for marrow reticulin scores, especially if anemia develops, or becomes more pronounced if present initially.Less common side effects include: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericarditis, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, pancreatitis, gastric/duodenal ulceration, renal impairment/failure and seizure. Due to these issues, anagrelide should not generally be considered for first line therapy for essential thrombocytosis. Mechanism of action Anagrelide works by inhibiting the maturation of platelets from megakaryocytes. The exact mechanism of action is unclear, although it is known to be a phosphodiesterase inhibitor. It is a potent (IC50 = 36nM) inhibitor of phosphodiesterase-II. It inhibits PDE-3 and phospholipase A2. Synthesis Phosphodiesterase inhibitor with antiplatelet activity. Condensation of benzyl chloride 1 with ethyl ester of glycine gives alkylated product 2. Reduction of the nitro group leads to the aniline and reaction of this with cyanogen bromide possibly gives cyanamide 3 as the initial intermediate. Addition of the aliphatic would then lead to formation of the quinazoline ring (4). Amide formation between the newly formed imide and the ester would then serve to form the imidazolone ring, whatever the details of the sequence, there is obtained anagrelide (5). References External links Shire Pharmaceuticals Agrylin/Xagrid website for international visitors Shire Pharmaceuticals Xagrid website for UK visitors AOP Orphan Pharmceuticals website
Rufinamide	Rufinamide is an anticonvulsant medication. It is used in combination with other medication and therapy to treat Lennox–Gastaut syndrome and various other seizure disorders. Rufinamide, a triazole derivative, was developed in 2004 by Novartis Pharma, AG, and is manufactured by Eisai. Rufinamide was approved by the US Food and Drug Administration (FDA) on November 14, 2008, as adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children four years and older and adults. Its official FDA-approved labeling does not mention use in the treatment of partial seizures inasmuch as clinical trials submitted to the FDA were marginal. However, several recent clinical trials suggest that the drug has efficacy for partial seizures It is marketed under the brand name Banzel. It is also marketed in the European Union under the brand name Inovelon.The mechanism of action of rufinamide is not fully understood. There is some evidence that rufinamide can modulate the gating of voltage-gated sodium channels, a common target for antiepileptic drugs. A recent study indicates subtle effects on the voltage-dependence of gating and the time course of inactivation in some sodium channel isoforms that could reduce neuronal excitability. However, this action cannot explain the unique spectrum of activity of rufinamide. References External links "Rufinamide". Drug Information Portal. U.S. National Library of Medicine.
Diosmin	Diosmin (diosmetin 7-O-rutinoside), a flavone glycoside of diosmetin, is manufactured from citrus fruit peels as a phlebotonic non-prescription dietary supplement used to aid treatment of hemorrhoids or chronic venous diseases, mainly of the legs. Uses Diosmin is a dietary supplement used to aid treatment of hemorrhoids and venous diseases, i.e., chronic venous insufficiency including spider and varicose veins, leg swelling (edema), stasis dermatitis and venous ulcers. The mechanism of action of Diosmin and other phlebotonics is undefined, and clinical evidence of benefit is limited. Diosmin is not recommended for treating the rectal mucosa, skin irritations, or wounds, and should not be used to treat dermatitis, eczema, or urticaria. Diosmin is not recommended for use in children or women during pregnancy. There is moderate-quality evidence that diosmin or other phlebotonics improved leg and ankle swelling and lower leg pain, and low-quality evidence for treating hemorrhoids. Phlebotonics Diosmin is included among a small class of agents called "phlebotonics" having heterogeneous composition and consisting partly of citrus peel extracts (flavonoids, such as hesperidin) and synthetic compounds, which are used to treat chronic venous insufficiency or hemorrhoids.In 2017, the American Working Group in Chronic Venous Disease recommended use of micronized purified flavonoid fraction (diosmiplex) as a medical food for chronic venous disease symptoms and venous ulcers, having "beneficial outcomes without serious adverse events", alone or combined with compression therapy, concurring with the previous guidance of the International European Society for Vascular Surgery. The German Dermatological Society indicated that Diosmin may be used with other treatments for symptoms of chronic venous diseases.The American Society of Colon and Rectal Surgeons mentions phlebotonics as a possible treatment for symptoms of hemorrhoid grades I to II, as there is only moderate-quality evidence of effectiveness with "expectations of minimal harm", while having no evidence of long-term benefit. French, Indian, Portuguese, and Italian professional societies of coloproctology issued similar recommendations regarding phlebotonics for hemorrhoids. Adverse effects In some 10% of users, diosmin causes mild gastrointestinal disorders or skin irritations (hives, itching), stomach pain, nausea, heart arrhythmias, or anemia. Preliminary research indicates no evidence of toxicity. The US Food and Drug Administration (FDA) concluded in 2001 that there was inadequate evidence on which to base an expectation of safety. As of 2013, the FDA did not revise this position. Regulatory status Diosmin is distributed in the U.S. as a dietary supplement called Daflon. Diosmin is not approved as a prescription drug in the United States or Europe. Phlebotonics are not approved in Germany, and are restricted in Spain only for the treatment of chronic venous diseases. See also Daflon Venalex == References ==
Brincidofovir	Brincidofovir, sold under the brand name Tembexa, is an antiviral drug used to treat smallpox. Brincidofovir is a prodrug of cidofovir. Conjugated to a lipid, the compound is designed to release cidofovir intracellularly, allowing for higher intracellular and lower plasma concentrations of cidofovir, effectively increasing its activity against dsDNA viruses, as well as oral bioavailability.The most common side effects include diarrhea, nausea, vomiting, and abdominal pain.Brincidofovir was approved for medical use in the United States in June 2021. Medical uses Brincidofovir is indicated for the treatment of human smallpox disease caused by variola virus. Mechanism of Action Brincidofovir is a pro-drug that is composed of cidofovir, conjugated with a lipid molecule. The lipid aspect of the molecule takes on the action of endogenous lysopghosphatidyl choline, which then is able to enter cells in the body which are infected with smallpox. Once the infected cell takes in the drug, the drug cleaves to generate cidofovir. Cidofovir is then consequently phosphorylated to yield Cidofovir Diphosphate, which is the active drug.Cidofovir diphosphate arises from two key mechanisms. Firstly, cidofovir diphosphate inhibits the variola viruss DNA-polymerase mediated DNA synthesis.The second mechanism is that the drug acts as an acyclic nucleotide and incorporates itself into the viral DNA chain, which then stops viral DNA synthesis. Pharmacokinetics The oral bioavailability of Brincidofovir is 13.4% as a tablet and 16.8% in a suspension. The metabolism of the drug is as such: once the drug enters the target infected cell, Brincidofovirs phosphodiester bond is then hydrolyzed to generate cidofovir which is then phosphorylated to the active cidofovir diphosphate. The volume of distribution of the drug is 1230 L. Brincidofovir is almost entirely absorbed in plasma. History Because smallpox is eradicated, the effectiveness of brincidofovir was studied in animals infected with viruses that are closely related to the variola virus. Effectiveness was determined by measuring animals survival at the end of the studies.Safety information to support approval of brincidofovir was derived from clinical trials of the drug for a non-smallpox indication, primarily from patients who received hematopoietic stem cell transplants.The U.S. Food and Drug Administration (FDA) granted the application for brincidofovir priority review, fast track, and orphan drug designations. The FDA approved brincidofovir under the agencys Animal Rule, which allows findings from adequate and well-controlled animal efficacy studies to serve as the basis of an approval when it is not feasible or ethical to conduct efficacy trials in humans. Ethical considerations Brincidofovir (CMX001) was the subject of widespread social media campaigning in 2014, which was then picked up by national news sources about a boy with an adenovirus infection following a bone marrow transplant. The family requested legal access to the still-unapproved drug outside of any clinical trial, and Chimerix initially denied the request. After a short and intense media campaign, Chimerix got permission from the FDA to start a limited open-label trial which allowed the boy to receive the drug. This media event sparked a debate on the ethics of using social media, the allocation of limited resources of a small company, and the emphasis on the individual over the group. The new use of any drug has the potential to interfere with the process to get the drug approved and widely marketed, through means such as consuming limited staff time that may be needed elsewhere – staff time that has the potential to save thousands of lives in the long-term, rather than one life now – overwhelming manufacturing capabilities, or by causing adverse effects or even death. These adverse events are more likely during these programs, because the people seeking access are usually much sicker than most, and problems experienced by these people can result in an unfavorable and inaccurate perception of the drugs safety profile. In this case, the boy recovered from the infection in 2014, and died in 2016 from complications of cancer.Brincidofovir is one of several experimental drugs administered to a small number of patients to treat Ebola virus disease during the 2014 outbreak. The WHO published a report on the ethics of using unregistered interventions to treat Ebola, where they concluded that "In the particular context of the current Ebola outbreak in West Africa, it is ethically acceptable to offer unproven interventions that have shown promising results in the laboratory and in animal models but have not yet been evaluated for safety and efficacy in humans as potential treatment or prevention." Research Brincidofovir is under investigation for the treatment of cytomegalovirus, adenovirus, poxvirus, and ebolavirus infections. It has been used off-label for the treatment of monkeypox. Adenovirus and cytomegalovirus As of 2014, brincidofovir is in Phase III clinical trials for use in humans against cytomegalovirus and adenovirus. Preliminary safety data from a database of 1000 patients supported progression into later phase trials, Chimerix announced in December 2015 that the Phase III trials for use of the drug in preventing cytomegalovirus infection in stem cell transplant patients had failed, and in February 2016 shut down two other late-stage trials for use of the drug in preventing infection after kidney transplants. Brincidofovir is not yet FDA approved for adenovirus or cytomegalovirus due to lack of efficacy in clinical trials. In a trial of brincidofovir for patients with CMV brincidofovir was associated with a 15.5% week 24 all-cause mortality compared with 10.1% among placebo recipients. Additionally brincidofovir was associated with increased serious adverse events (57.1% versus 37.6%) compared with placebo. Brincidofovir was initially offered via an FDA expanded access trial; however as of May 9, 2019, Chimerix discontinued clinical trials of brincidofovir for the treatment of adenovirus and discontinued the expanded access program in 2019. Ebola After initial studies by the Centers for Disease Control and Prevention (CDC, Atlanta, GA, USA) in cell culture models, on October 6, 2014, Chimerix received an FDA authorization for emergency investigational new drug applications of brincidofovir for the treatment of Ebola virus disease. Brincidofovir was administered to the first patient diagnosed in the Ebola virus disease outbreak in the US in 2014. The patient was given the drug starting six days after hospital admission when he was already critically ill; he died four days later. Brincidofovir was also given to Ebola patient Ashoka Mukpo at the Nebraska Medical Center, who had developed the disease and then was pronounced Ebola-free and released from the center on 22 October 2014.In October 2014, Chimerix reported it had been given approval by the FDA to start Phase 2 trials in patients infected with ebolaviruses for brincidofovirs safety, tolerability, and efficacy. Organised by a team of scientists at the University of Oxford, including Peter Horby, Jake Dunning, Laura Merson and Trudie Lang, a trial commenced during January 2015 in Liberia, but was subsequently discontinued. Because of a lack of suitable subjects in Liberia, Oxford University and Médecins Sans Frontières planned to extend the trial to Sierra Leone, where there were still Ebola cases; but on the 30th of January 2015, the manufacturer decided to withdraw support for the trial and end discussion of future trials. Animals In animal trials brincidofovir has shown activity against cytomegalovirus, adenoviruses, BK virus, poxviruses, and herpes simplex viruses. Brincidofovir appears to have potential for the treatment of Ebola virus disease, which is somewhat paradoxical, as ebolaviruses are RNA viruses and thus do not contain DNA as the above-mentioned viruses. References Further reading Kern ER, Hartline C, Harden E, Keith K, Rodriguez N, Beadle JR, Hostetler KY (April 2002). "Enhanced inhibition of orthopoxvirus replication in vitro by alkoxyalkyl esters of cidofovir and cyclic cidofovir". Antimicrobial Agents and Chemotherapy. 46 (4): 991–995. doi:10.1128/aac.46.4.991-995.2002. PMC 127114. PMID 11897580. External links "Brincidofovir". Drug Information Portal. U.S. National Library of Medicine.
Iron(III) pyrophosphate	Iron(III) pyrophosphate is an inorganic chemical compound with the formula Fe4(P2O7)3. Synthesis Anhydrous iron(III) pyrophosphate can be prepared by heating the mixture of iron(III) metaphosphate and iron(III) phosphate under oxygen with the stoichiometric ratio 1:3. The reactants can be prepared by reacting iron(III) nitrate nonahydrate with phosphoric acid.It can be also prepared via the following reaction: 3 Na4P2O7(aq) + 4 FeCl3(aq) → Fe4(P2O7)3(s) + 12 NaCl(aq) References External links "Ferric pyrophosphate". Drug Information Portal. U.S. National Library of Medicine. "Ferric pyrophosphate nonahydrate". Drug Information Portal. U.S. National Library of Medicine. "Ferric pyrophosphate citrate". Drug Information Portal. U.S. National Library of Medicine.
Lactulose	Lactulose is a non-absorbable sugar used in the treatment of constipation and hepatic encephalopathy. It is used by mouth for constipation and either by mouth or in the rectum for hepatic encephalopathy. It generally begins working after 8–12 hours, but may take up to 2 days to improve constipation.Common side effects include abdominal bloating and cramps. A potential exists for electrolyte problems as a result of the diarrhea it produces. No evidence of harm to the baby has been found when used during pregnancy. It is generally regarded as safe during breastfeeding. It is classified as an osmotic laxative.Lactulose was first made in 1929, and has been used medically since the 1950s. It is on the World Health Organizations List of Essential Medicines. It is available as a generic and brand-name product. Lactulose is made from the milk sugar lactose, which is composed of two simple sugars, galactose and glucose. History In 1957, Peitele discovered that lactulose is a bifidobacterium proliferation factor. In 1964, Hoffman found that only bifidobacteria, Lactobacillus and Streptococcus could metabolise lactulose into lactic acid and acetic acid. In 1966, Baicier found that lactulose can promote the growth of basophilic gram-positive bacteria lacking urease (e.g. Escherichia coli) and reduce ammonia production. It has been proven that lactulose reduces blood ammonia, and it has been successfully used in the treatment of hepatic encephalopathy. In 1979, Nianmoleyou treated viral hepatitis with lactulose and he found that lactulose has the effect of reducing plasma endotoxin. From 1980 to 1981, Leicier found that the limulus test agglutination reaction of lactulose inhibits endotoxin in vitro, alleviating the liver injury of rats induced by D-amino galactose. He believed that lactulose had anti-endotoxin activity, meaning that and it can be used in the treatment of liver and kidney syndrome. Medical uses Constipation Lactulose is used in the treatment of chronic constipation in patients of all ages as a long-term treatment. The dosage of lactulose for chronic idiopathic constipation is adjusted depending on the constipation severity and desired effect, from a mild stool softener to causing diarrhea. Lactulose is contraindicated in case of galactosemia, as most preparations contain the monosaccharide galactose due to its synthesis process.Lactulose may be used to counter the constipating effects of opioids, and in the symptomatic treatment of hemorrhoids as a stool softener.Lactulose is commonly prescribed for children who develop fear of their bowel movements and are withholders. This is because lactulose, when dosed in the proper amount, causes a bowel movement that is impossible to retain for very long. Lactulose is also used for the elderly because of its gentle and consistent results. Hyperammonemia Lactulose is useful in treating hyperammonemia (high blood ammonia), which can lead to hepatic encephalopathy. Lactulose helps trap the ammonia (NH3) in the colon and bind to it. It does this by using gut flora to acidify the colon, transforming the freely diffusible ammonia into ammonium ions (NH+4), which can no longer diffuse back into the blood. It is also useful for preventing hyperammonemia caused as a side effect of administration of valproic acid. Small intestine bacterial overgrowth Lactulose is used as a test of small intestine bacterial overgrowth (SIBO). Recently, the reliability of it for diagnosing SIBO has been seriously questioned. A large amount of it is given with subsequent testing of molecular hydrogen gas in the breath. The test is positive if an increase in exhaled hydrogen occurs before that which would be expected by normal digestion by the normal gut flora in the colon. An earlier result has been hypothesized to indicate digestion occurring within the small intestine. An alternate explanation for differences in results is the variance in small bowel transit time among tested subjects. Pregnancy No evidence of harm to the baby has been found when used during pregnancy. It is generally regarded as safe during breastfeeding. Side effects Common side effects of lactulose are abdominal cramping, borborygmus, and flatulence. In normal individuals, overdose is considered uncomfortable, but not life-threatening. Uncommon side effects are nausea and vomiting. In sensitive individuals, such as the elderly or people with reduced kidney function, excess lactulose dosage can result in dehydration and electrolyte disturbances such as low magnesium levels. Ingestion of lactulose does not cause a weight gain because it is not digestible, with no nutritional value. Although lactulose is less likely to cause dental caries than sucrose, as a sugar, a potential for this exists. This should be taken into consideration when taken by people with a high susceptibility to this condition. Mechanism of action It is a disaccharide formed from one molecule each of the simple sugars (monosaccharides) fructose and galactose. Lactulose is not normally present in raw milk, but is a product of heat processes: the greater the heat, the greater amount of this substance (from 3.5 mg/L in low-temperature pasteurized milk to 744 mg/L in in-container sterilized milk). It is produced commercially by isomerization of lactose.Lactulose is not absorbed in the small intestine nor broken down by human enzymes, thus stays in the digestive bolus through most of its course, causing retention of water through osmosis leading to softer, easier-to-pass stool. It has a secondary laxative effect in the colon, where it is fermented by the gut flora, producing metabolites which have osmotic powers and peristalsis-stimulating effects (such as acetate), but also methane associated with flatulence.Lactulose is metabolized in the colon by bacterial flora into short-chain fatty acids, including lactic acid and acetic acid. These partially dissociate, acidifying the colonic contents (increasing the H+ concentration in the gut). This favors the formation of the nonabsorbable NH+4 from NH3, trapping NH3 in the colon and effectively reducing plasma NH3 concentrations. Lactulose is therefore effective in treating hepatic encephalopathy. Specifically, it is effective as secondary prevention of hepatic encephalopathy in people with cirrhosis. Moreover, research showed improved cognitive functions and health-related quality of life in people with cirrhosis with minimal hepatic encephalopathy treated with lactulose. Society and culture Name Lactulose is its international nonproprietary name (INN). It is sold under various brand names. Availability Lactulose is available as a generic medication. It is available without prescription in most countries, but a prescription is required in the United States and Austria. Food additive In some countries where lactulose may be obtained without a prescription, lactulose is commonly used as a food additive to improve taste and promote intestinal transit. Veterinary use Lactulose is used in veterinary medicine. References External links "Lactulose". Drug Information Portal. U.S. National Library of Medicine.
Castor oil	Castor oil is a vegetable oil pressed from castor beans. It is a colourless or pale yellow liquid with a distinct taste and odor. Its boiling point is 313 °C (595 °F) and its density is 0.961 g/cm3. It includes a mixture of triglycerides in which about 90% of fatty acids are ricinoleates. Oleic acid and linoleic acid are the other significant components. Castor oil and its derivatives are used in the manufacturing of soaps, lubricants, hydraulic and brake fluids, paints, dyes, coatings, inks, cold-resistant plastics, waxes and polishes, nylon, and perfumes. Etymology The name probably comes from a confusion between the Ricinus plant that produces it and another plant, the Vitex agnus-castus. An alternative etymology, though, suggests that it was used as a replacement for castoreum. Composition Castor oil is well known as a source of ricinoleic acid, a monounsaturated, 18-carbon fatty acid. Among fatty acids, ricinoleic acid is unusual in that it has a hydroxyl functional group on the 12th carbon atom. This functional group causes ricinoleic acid (and castor oil) to be more polar than most fats. The chemical reactivity of the alcohol group also allows chemical derivatization that is not possible with most other seed oils. Because of its ricinoleic acid content, castor oil is a valuable chemical in feedstocks, commanding a higher price than other seed oils. As an example, in July 2007, Indian castor oil sold for about US$0.90/kg ($0.41/lb), whereas U.S. soybean, sunflower, and canola oils sold for about $0.30/kg ($0.14/lb). Uses Annually, 270,000–360,000 tonnes (600–800 million pounds) of castor oil are produced for a variety of uses. Food and preservative In the food industry, food-grade castor oil is used in food additives, flavorings, candy (e.g., polyglycerol polyricinoleate in chocolate), as a mold inhibitor, and in packaging. Polyoxyethylated castor oil (e.g., Kolliphor EL) is also used in the food industries.In India, Pakistan, and Nepal, food grains are preserved by the application of castor oil. It stops rice, wheat, and pulses from rotting. For example, the legume pigeon pea is commonly available coated in oil for extended storage. Traditional medicine Use of castor oil as a laxative is attested to in the circa 1550 BCE Ebers Papyrus, and was in use several centuries earlier.Although used in traditional medicine to induce labor in pregnant women, there is no clinical evidence that castor oil is effective for dilating the cervix or inducing labor.According to the American Cancer Society, "available scientific evidence does not support claims that castor oil on the skin cures cancer or any other disease." Skin and hair care Castor oil has been used in cosmetic products included in creams and as a moisturizer. Small amounts of castor oil are frequently used in cold-process soap to increase lathering in the finished bar. It also has been used to enhance hair conditioning in other products and for supposed anti-dandruff properties. Coatings Castor oil is used as a biobased polyol in the polyurethane industry. The average functionality (number of hydroxyl groups per triglyceride molecule) of castor oil is 2.7, so it is widely used as a rigid polyol and in coatings. One particular use is in a polyurethane concrete where a castor-oil emulsion is reacted with an isocyanate (usually polymeric methylene diphenyl diisocyanate) and a cement and construction aggregate. This is applied fairly thickly as a slurry, which is self-levelling. This base is usually further coated with other systems to build a resilient floor.Castor oil is not a drying oil, meaning that it has a low reactivity with air compared with oils such as linseed oil and tung oil. Dehydration of castor oil yields linoleic acids, which do have drying properties. In this process, the OH group on the ricinoleic acid along with a hydrogen from the next carbon atom are removed yielding a double bond which then has oxidative cross-linking properties yielding the drying oil. Precursor to industrial chemicals Castor oil can react with other materials to produce other chemical compounds that have numerous applications. Transesterification followed by steam cracking gives undecylenic acid, a precursor to specialized polymer nylon 11, and heptanal, a component in fragrances. Breakdown of castor oil in strong base gives 2-octanol, both a fragrance component and a specialized solvent, and the dicarboxylic acid sebacic acid. Hydrogenation of castor oil saturates the alkenes, giving a waxy lubricant. Castor oil may be epoxidized by reacting the OH groups with epichlorohydrin to make the triglycidyl ether of castor oil which is useful in epoxy technology. This is available commercially as Heloxy 505.The production of lithium grease consumes a significant amount of castor oil. Hydrogenation and saponification of castor oil yields 12-hydroxystearic acid, which is then reacted with lithium hydroxide or lithium carbonate to give high-performance lubricant grease.Since it has a relatively high dielectric constant (4.7), highly refined and dried castor oil is sometimes used as a dielectric fluid within high-performance, high-voltage capacitors. Lubrication Vegetable oils such as castor oil are typically unattractive alternatives to petroleum-derived lubricants because of their poor oxidative stability. Castor oil has better low-temperature viscosity properties and high-temperature lubrication than most vegetable oils, making it useful as a lubricant in jet, diesel, and racing engines. The viscosity of castor oil at 10 °C is 2,420 centipoise, but it tends to form gums in a short time, so its usefulness is limited to engines that are regularly rebuilt, such as racing engines. Lubricant company Castrol took its name from castor oil. Castor oil has been suggested as a lubricant for bicycle pumps because it does not degrade natural rubber seals. Early aviation and aeromodelling Castor oil was the preferred lubricant for rotary engines, such as the Gnome engine after that engines widespread adoption for aviation in Europe in 1909. It was used almost universally in rotary-engined Allied aircraft in World War I. Germany had to make do with inferior ersatz oil for its rotary engines, which resulted in poor reliability.The methanol-fueled, two-cycle, glow-plug engines used for aeromodelling, since their adoption by model airplane hobbyists in the 1940s, have used varying percentages of castor oil as lubricants. It is highly resistant to degradation when the engine has its fuel-air mixture leaned for maximum engine speed. Gummy residues can still be a problem for aeromodelling powerplants lubricated with castor oil, however, usually requiring eventual replacement of ball bearings when the residue accumulates within the engines bearing races. One British manufacturer of sleeve-valved four-cycle model engines has stated the "varnish" created by using castor oil in small percentages can improve the pneumatic seal of the sleeve valve, improving such an engines performance over time. Turkey red oil Turkey red oil, also called sulphonated (or sulfated) castor oil, is made by adding sulfuric acid to vegetable oils, most notably castor oil. It was the first synthetic detergent after ordinary soap. It is used in formulating lubricants, softeners, and dyeing assistants. Biodiesel Castor oil, like currently less expensive vegetable oils, can be used as feedstock in the production of biodiesel. The resulting fuel is superior for cold winters, because of its exceptionally low cloud point and pour point.Initiatives to grow more castor for energy production, in preference to other oil crops, are motivated by social considerations. Tropical subsistence farmers would gain a cash crop. Punishment Some parents punished children with a dose of castor oil. Physicians recommended against the practice because they did not want medicines associated with punishment.A heavy dose of castor oil could be used as a humiliating punishment for adults. Colonial officials used it in the British Raj (India) to deal with recalcitrant servants. Belgian military officials prescribed heavy doses of castor oil in Belgian Congo as a punishment for being too sick to work.The most famous use as punishment came in Fascist Italy under Benito Mussolini. It was a favorite tool used by the Blackshirts to intimidate and humiliate their opponents. Political dissidents were force-fed large quantities of castor oil by Fascist squads. This technique was said to have been originated by Gabriele DAnnunzio or Italo Balbo. Victims of this treatment did sometimes die, as the dehydrating effects of the oil-induced diarrhea often complicated their recovery from the nightstick beatings they also received along with the castor oil; however, even those victims who survived had to bear the humiliation of the laxative effects resulting from excessive consumption of the oil. Safety The castor seed contains ricin, a toxic lectin. Heating during the oil extraction process denatures and deactivates the lectin. Harvesting castor beans, though, may not be without risk. The International Castor Oil Association FAQ document states that castor beans contain an allergenic compound called CB1A. This chemical is described as being virtually nontoxic, but has the capacity to affect people with hypersensitivity. The allergen may be neutralized by treatment with a variety of alkaline agents. The allergen is not present in the castor oil itself. In popular culture In the 1922 film, Nanook of the North, Nanook gives one of his sons a spoonful of castor oil, and he enjoys it. In the 1934 Silly Symphony short "The Wise Little Hen", Donald Duck and Peter Pig pretend to have bellyaches to get out of helping the titular hen plant and harvest corn. When she grows wise to their ruse, she invites the two over for dinner and, rather than corn, gives them a bottle of castor oil for their "bellyaches". In the 1939 film The Great Man Votes, an early scene establishes the loving relationship between the single father played by John Barrymore and his two young children. “Socrates and his hemlock!” Pop declares as he downs the cup of coffee laced with a spoonful of castor oil prepared by his daughter (12-year-old Virginia Weidler), following doctors orders. In the 1943 Tom and Jerry cartoon short "Baby Puss", Tom Cat, dressed as a baby, is given castor oil by a child as a punishment. In the 1949 MGM Tex Avery cartoon The House of Tomorrow, the house is shown to have individual medicine cabinets for each member of the family, with “Junior’s” containing a large bottle of castor oil and a spoon. In the novel It Cant Happen Here, castor oil is used by American fascist paramilitaries in a reference to the Mussolini regime. In the 1986 film Stand by Me, protagonist Gordie tells his friends a story in which castor oil is used to violently disrupt a pie-eating contest. See also Castor wax List of unproven and disproven cancer treatments References Further reading Naughton, Frank, "Castor Oil", Kirk-Othmer Encyclopedia of Chemical Technology, New York: John Wiley, doi:10.1002/0471238961.0301192014012107.a01.pub2, ISBN 9780471238966 – overview of chemical properties and manufacturing of castor oil External links International Chemical Safety Card 1452
Cangrelor	Cangrelor, sold under the brand name Kengreal in the United States, CANREAL in India ( MSN Labs ) and Kengrexal in the European Union) is a P2Y12 inhibitor FDA approved as of June 2015 as an antiplatelet drug for intravenous application. Some P2Y12 inhibitors are used clinically as effective inhibitors of adenosine diphosphate-mediated platelet activation and aggregation. Unlike clopidogrel (Plavix), which is a prodrug, cangrelor is an active drug not requiring metabolic conversion. Poor interim results led to the abandonment of the two CHAMPION clinical trials in mid-2009. The BRIDGE study, for short term use prior to surgery, continues. The CHAMPION PHOENIX trial was a randomized study of over 11,000 patients published in 2013. It found usefulness of cangrelor in patients getting cardiac stents. Compared with clopidogrel given around the time of stenting, intravenous ADP-receptor blockade with cangrelor significantly reduced the rate of stent thrombosis and myocardial infarction. Reviewers have questioned the methodology of the trial. Medical use According to recent phase 3 randomized trials, a cangrelor–clopidogrel combination is safe and has been found to be more effective than standard clopidogrel treatment at reducing ischemic events in the heart, without increasing major bleeding in the treatment of stenotic coronary arteries. The advantages of this drug combination are most prominent in patients with myocardial infarction.Available antiplatelet drugs have delayed onset and offset of action. Since cangrelors effects are immediate and quickly reversed, it is a more desirable drug for elective treatment of stenotic coronary arteries, high risk acute coronary syndromes treated with immediate coronary stenting, and for bridging those surgery patients who require P2Y12 inhibition.Current evidence regarding cangrelor therapy is limited by the lack studies assessing cangrelor administration in conjunction with either prasugrel or ticagrelor.Recently, its been approved for adult patients undergoing percutaneous coronary intervention (PCI). Pharmacology Cangrelor is a high-affinity, reversible inhibitor of P2Y12 receptors that causes almost complete inhibition of ADP-induced platelet aggregate. It is a modified ATP derivative stable to enzymatic degradation. It does not require metabolic conversion to an active metabolite. This allows cangrelors immediate effect after infusion, and the therapeutic effects can be maintained with continuous infusion. The pharmacokinetics of cangrelor has allowed it to rapidly achieve steady-state concentrations with a clearance of 50 L/h and a half-life of 2.6 to 3.3 minutes. Cessation of its administration is associated with rapid removal, and normal platelet function is restored within 1 hour. Adverse effects Despite fewer bleeding events during cardiac surgery, cangrelor carries the risk of potential autoimmune reactions manifesting as breathlessness. Potential mechanisms for dyspnea following cangrelor treatment include: repeated binding and unbinding cycles, impaired platelet turnover, and lung sequestration or apoptosis of overloaded destructive platelets. The dyspnea risks following cangrelor treatment, suggest a common mechanism linking transfusion-related acute lung injury, dyspnea, and reversible platelet inhibition.The risk of breathlessness after intravenous cangrelor is smaller when compared with other reversible platelet P2Y12 receptor inhibitors, however, it is still significantly higher when compared to irreversible oral antiplatelet drugs or intravenous glycoprotein IIb/IIIa inhibitors; which do not increase the incidence of breathlessness at all. References External links "Cangrelor". Drug Information Portal. U.S. National Library of Medicine. "Cangrelor tetrasodium". Drug Information Portal. U.S. National Library of Medicine.
Tolvaptan	Tolvaptan, sold under the brand name Samsca among others, is an aquaretic drug that functions as a selective, competitive vasopressin receptor 2 (V2) antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca. Tolvaptan, as Jynarque, was granted approval for medical use in the United States in April 2018.The U.S. Food and Drug Administration (FDA) granted tolvaptan a fast track designation for clinical trials investigating its use for the treatment of polycystic kidney disease. The FDA granted Jynarque an orphan drug designation in April 2012, for the treatment of autosomal dominant polycystic kidney disease.Tolvaptan is available as a generic medication. Medical uses Tolvaptan (Samsca) is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.Tolvaptan (Jynarque) is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).Tolvaptan phosphate is a prodrug of tolvaptan, developed for intravenous administration. Tolvaptan phosphate is converted into the active drug tolvaptan in the human body following administration. Side effects The FDA has determined that tolvaptan should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver failure. When using to treat hyponatremia, it may cause too rapid correction of hyponatremia resulting in fatal osmotic demyelination syndrome. Pharmacology Tolvaptan is a selective vasopressin V2 receptor antagonist. Chemistry Tolvaptan is a racemate, a 1:1 mixture of the following two enantiomers: References Further reading Gheorghiade M, Niazi I, Ouyang J, et al. (2003). "Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial". Circulation. 107 (21): 2690–6. doi:10.1161/01.CIR.0000070422.41439.04. PMID 12742979. External links "Tolvaptan". Drug Information Portal. U.S. National Library of Medicine.
Faricimab	Faricimab, sold under the brand name Vabysmo, is a monoclonal antibody used for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Faricimab is the first bispecific monoclonal antibody, to target both vascular endothelial growth factor (VEGF), and angiopoietin 2 (Ang-2) inhibitor. By targeting these pathways, faricimab stabilizes blood vessels in the retina. It is given by intravitreal injection (injection into the eye) by an ophthalmologist.Faricimab was developed by Roche. Faricimab was approved for medical use in the United States in January 2022, and in the European Union in September 2022. Medical uses Faricimab is indicated for treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Adverse effects The most common adverse reaction reported in people receiving faricimab include conjunctival bleeding. Contraindications Contraindications to injection of faricimab include active infection in or around the eye, active inflammation in the eye (uveitis), and prior allergic reactions to receiving the drug (hypersensitivity). Special populations Pregnancy There are no adequate and well-controlled studies of faricimab administration in pregnant women. Breast feeding There is no information regarding faricimab accumulation in breast milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, the drug company states that many drugs are transferred in human milk with the potential for absorption and adverse reactions in the breastfed child. Fertility No studies on the effects of faricimab on human fertility have been conducted and it is not known whether faricimab can affect reproduction. Based on its mechanism of action, treatment with may pose a risk to reproductive capacity. Pharmacology Faricimab is a 150kDa-sized bispecific antibody whose molecular structure allows a high affinity bond to both vascular endothelial growth factor A (VEGF-A) and Angiopoietin (Ang-2). By blocking the action of these two growth factors, faricimab decreases migration and replication of endothelial cells allowing for stabilization of vascular structures, thereby decreasing vascular leakage. Faricimab has shown improved and sustained efficacy in comparison to agents that only target the VEGF pathway. History In 2016, pre-clinical studies looking at the mechanism of action behind faricimab showed that by blocking Ang-2, one of the drugs targets, there was decreased endothelial barrier breakdown in blood vessels. In 2017, phase I studies in neovascular age related macular degeneration (nAMD) showed that the drug was safe to use in people and well tolerated. Society and culture Legal status On 21 July 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 Vabysmo, intended for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular oedema (DME). The applicant for this medicinal product is Roche Registration GmbH. Faricimab was approved for medical use in the European Union in September 2022. Names Faricimab is the International Nonproprietary Name (INN). Faricimab was formerly named RG7716. Research Neovascular age-related macular degeneration (nAMD) Two phase II trials evaluated faricimabs efficacy and safety in comparison to ranibizumab and showed that faricimab received every 16 weeks and every twelve weeks was comparable to ranibizumab received every four weeks in visual acuity and imaging outcomes. In 2019, two phase III multi-center randomized studies were initiated on 1200 participants with neovascular age related macular degeneration (nAMD) to evaluate faricimabs safety, efficacy, and durability against aflibercept. Diabetic macular edema (DME) One phase II trial evaluated faricimabs efficacy and safety in comparison to ranibizumab and showed clinically meaningful and statistically significant improvements in visual acuity. Two phase III multi-center randomized studies were completed on 1,891 diabetic participants with diabetic macular edema (DME) References External links "Faricimab". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03622580 for "A Study to Evaluate the Efficacy and Safety of Faricimab (RO6867461) in Participants With Diabetic Macular Edema (YOSEMITE)" at ClinicalTrials.gov Clinical trial number NCT03622593 for "A Study to Evaluate the Efficacy and Safety of Faricimab (RO6867461) in Participants With Diabetic Macular Edema (RHINE)" at ClinicalTrials.gov Clinical trial number NCT03823287 for "A Study to Evaluate the Efficacy and Safety of Faricimab in Participants With Neovascular Age-Related Macular Degeneration (TENAYA)" at ClinicalTrials.gov Clinical trial number NCT03823300 for "A Study to Evaluate the Efficacy and Safety of Faricimab in Participants With Neovascular Age-Related Macular Degeneration (LUCERNE)" at ClinicalTrials.gov
Plerixafor	Plerixafor (INN and USAN, trade name Mozobil) is an immunostimulant used to mobilize hematopoietic stem cells in cancer patients into the bloodstream. The stem cells are then extracted from the blood and transplanted back to the patient. The drug was developed by AnorMED, which was subsequently bought by Genzyme. Medical uses Peripheral blood stem cell mobilization, which is important as a source of hematopoietic stem cells for transplantation, is generally performed using granulocyte colony-stimulating factor (G-CSF), but is ineffective in around 15 to 20% of patients. Combination of G-CSF with plerixafor increases the percentage of persons that respond to the therapy and produce enough stem cells for transplantation. The drug is approved for patients with lymphoma and multiple myeloma.Phase 2 clinical trials started in 2021 exploring the combination of plerixafor and MGTA-145, a CXCL2 ligand. Contraindications Pregnancy and lactation Studies in pregnant animals have shown teratogenic effects. Plerixafor is therefore contraindicated in pregnant women except in critical cases. Fertile women are required to use contraception. It is not known whether the drug is secreted into the breast milk. Breast feeding should be discontinued during therapy. Adverse effects Nausea, diarrhea and local reactions were observed in over 10% of patients. Other problems with digestion and general symptoms like dizziness, headache, and muscular pain are also relatively common; they were found in more than 1% of patients. Allergies occur in less than 1% of cases. Most adverse effects in clinical trials were mild and transient.The European Medicines Agency has listed a number of safety concerns to be evaluated on a post-marketing basis, most notably the theoretical possibilities of spleen rupture and tumor cell mobilisation. The first concern has been raised because splenomegaly was observed in animal studies, and G-CSF can cause spleen rupture in rare cases. Mobilisation of tumor cells has occurred in patients with leukaemia treated with plerixafor. Interactions No interaction studies have been conducted. The fact that plerixafor does not interact with the cytochrome system indicates a low potential for interactions with other drugs. Pharmacology Mechanism of action In the form of its zinc complex, plerixafor acts as an antagonist (or perhaps more accurately a partial agonist) of the alpha chemokine receptor CXCR4 and an allosteric agonist of CXCR7. The CXCR4 alpha-chemokine receptor and one of its ligands, SDF-1, are important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. The in vivo effect of plerixafor with regard to ubiquitin, the alternative endogenous ligand of CXCR4, is unknown. Plerixafor has been found to be a strong inducer of mobilization of hematopoietic stem cells from the bone marrow to the bloodstream as peripheral blood stem cells. Additionally, plerixafor inhibits CD20 expression on B cells by interfering with CXCR4/SDF1 axis that regulates its expression. Pharmacokinetics Following subcutaneous injection, plerixafor is absorbed quickly and peak concentrations are reached after 30 to 60 minutes. Up to 58% are bound to plasma proteins, the rest mostly resides in extravascular compartments. The drug is not metabolized in significant amounts; no interaction with the cytochrome P450 enzymes or P-glycoproteins has been found. Plasma half life is 3 to 5 hours. Plerixafor is excreted via the kidneys, with 70% of the drug being excreted within 24 hours. Chemistry Plerixafor is a macrocyclic compound and a bicyclam derivative, the cyclam rings being linked at the amine nitrogen atoms by a 1,4-xylyl spacer. It is a base; all eight nitrogen atoms accept protons readily. The two macrocyclic rings form chelate complexes with bivalent metal ions, especially zinc, copper and nickel, as well as cobalt and rhodium. The biologically active form of plerixafor is its zinc complex. Synthesis Three of the four nitrogen atoms of the macrocycle cyclam... (1,4,8,11-tetraazacyclotetradecane) are protected with tosyl groups. The product is treated with 1,4-bis(brommethyl)benzene and potassium carbonate in acetonitrile. After cleaving of the tosyl groups with hydrobromic acid, plerixafor octahydrobromide is obtained. History The molecule was first synthesised in 1987 to carry out basic studies on the redox chemistry of dimetallic coordination compounds. Then, it was serendipitously discovered by another chemist that such a molecule could have a potential use in the treatment of HIV because of its role in the blocking of CXCR4, a chemokine receptor which acts as a co-receptor for certain strains of HIV (along with the viruss main cellular receptor, CD4). Development of this indication was terminated because of lacking oral availability and cardiac disturbances. Further studies led to the new indication for cancer patients. Society and culture Plerixafor has orphan drug status in the United States and European Union for the mobilization of hematopoietic stem cells. It was approved by the U.S. Food and Drug Administration (FDA) for this indication on 15 December 2008. In the European Union, the drug was approved after a positive Committee for Medicinal Products for Human Use assessment report on 29 May 2009. The drug was approved for use in Canada by Health Canada on 8 December 2011. Research Anti-cancer properties Plerixafor was seen to reduce metastasis in mice in several studies. It has also been shown to reduce recurrence of glioblastoma in a mouse model after radiotherapy. In this model, the cancer cells that survived radiation critically depended on bone marrow derived cells for vasculogenesis, and the recruitment of the latter was mediated by SDF-1 CXCR4 interactions, which are blocked by plerixafor. Use in stem cell research Researchers at Imperial College have demonstrated that plerixafor in combination with vascular endothelial growth factor (VEGF) can mobilise mesenchymal stem cells and endothelial progenitor cells into the peripheral blood of mice.In double‐blind, randomized, placebo‐controlled trial, stem cell mobilization with plerixafor did not improve healing of ischemic diabetic wounds. Neurologic Blockade of CXCR4 signalling by plerixafor has also unexpectedly been found to be effective at counteracting opioid-induced hyperalgesia produced by chronic treatment with morphine, though only animal studies have been conducted as yet. References External links "Plerixafor". Drug Information Portal. U.S. National Library of Medicine. MeSH JM+3100
Gabapentin	Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is a first-line medication for the treatment of neuropathic pain caused by diabetic neuropathy, postherpetic neuralgia, and central pain. It is moderately effective: about 30–40% of those given gabapentin for diabetic neuropathy or postherpetic neuralgia have a meaningful benefit.Sleepiness and dizziness are the most common side effects. Serious side effects include an increased risk of suicide, respiratory depression, and allergic reactions. Lower doses are recommended in those with kidney disease. Gabapentin acts by decreasing activity of a subset of calcium channels.Gabapentin was first approved for use in 1993. It has been available as a generic medication in the United States since 2004. In 2020, it was the tenth most commonly prescribed medication in the United States, with more than 49 million prescriptions. During the 1990s, Parke-Davis, a subsidiary of Pfizer, used a number of illegal techniques to encourage physicians in the United States to prescribe gabapentin for unapproved uses. They have paid out millions of dollars to settle lawsuits regarding these activities. Medical uses Gabapentin is recommended for use in focal seizures and neuropathic pain. Gabapentin is widely prescribed off-label in the US and UK, for example, for the treatment of non-neuropathic pain, anxiety disorders and bipolar disorder. Seizures Gabapentin is approved for the treatment of focal seizures; however, it is not effective for generalized epilepsy. Neuropathic pain Gabapentin is recommended as a first-line treatment for chronic neuropathic pain by various medical authorities. This is a general recommendation applicable to all neuropathic pain syndromes except for trigeminal neuralgia.In regard to the specific diagnoses, the best evidence exists for gabapentin treatment of postherpetic neuralgia and diabetic neuropathy. Gabapentin is approved for the former indication in the US. In addition to these two neuropathies, European Federation of Neurological Societies guideline notes gabapentin effectiveness for central pain. A combination of gabapentin with an opioid or nortriptyline may work better than either drug alone.Overall, gabapentin shows moderate effectiveness for neuropathic pain. Only a minority of patients obtain meaningful relief. Out of 10 persons treated with gabapentin, three to four benefit substantially as compared to one to two persons treated with placebo.Evidence finds little or no benefit and significant risk in those with chronic low back pain or sciatica. Gabapentin is not effective in HIV-associated sensory neuropathy and neuropathic pain due to cancer. Anxiety There is a small amount research on the use of gabapentin for the treatment of anxiety disorders. In a controlled trial of breast cancer survivors with anxiety, and in a trial for social phobia, gabapentin significantly reduced anxiety levels. For panic disorder, gabapentin is ineffective. Conversely, some psychiatric textbooks see "a possible role for gabapentin in anxiety disorders, particularly social phobia and panic disorder" based on "case reports and double-blind studies" or state that controlled studies have not shown gabapentin to be very effective for psychiatric indications; "however, clinically it is effective". Sleep Gabapentin is effective in treating sleep disorders such as insomnia and restless legs syndrome. Gabapentin enhances slow-wave sleep in patients with primary insomnia. It also improves sleep quality by elevating sleep efficiency and decreasing spontaneous arousal. The results suggest that gabapentin may be beneficial in the treatment of primary insomnia. Drug dependence Gabapentin is moderately effective in reducing the symptoms of alcohol withdrawal and associated craving. The evidence in favor of gabapentin is weak in the treatment of alcoholism: it does not contribute to the achievement of abstinence, and the data on the relapse of heavy drinking and percent of days abstinent do not robustly favor gabapentin; it only decreases the percent days of heavy drinking.Gabapentin is ineffective in cocaine dependence and methamphetamine use, and it does not increase the rate of smoking cessation. Gabapentin does not significantly reduce the symptoms of opiate withdrawal. There is insufficient evidence for its use in cannabis dependence. Other Gabapentin is recommended as a first-line treatment of the acquired pendular nystagmus, torsional nystagmus, and infantile nystagmus; however, it does not work in periodic alternating nystagmus.Gabapentin decreases the frequency of hot flashes in both menopausal women and patients with breast cancer. However, antidepressants have similar efficacy, and treatment with estrogen more effectively prevents hot flashes.Gabapentin reduces spasticity in multiple sclerosis and is prescribed as one of the first-line options. It is an established treatment of restless legs syndrome. Gabapentin alleviates itching in kidney failure (uremic pruritus) and itching of other causes. It may be an option in essential or orthostatic tremor. Although the efficacy of gabapentin for insomnia has not been established, it does alleviate sleep disorder in patients with medical illness.Gabapentin does not appear to provide benefit for bipolar disorder, complex regional pain syndrome, post-surgical pain, or tinnitus, or prevent episodic migraine in adults. Contraindications Gabapentin should be used carefully and at lower doses in people with kidney problems due to possible accumulation and toxicity. It is unclear if it is safe during pregnancy or breastfeeding. Side effects Dizziness and somnolence are the most frequent side effects. Fatigue, ataxia, peripheral edema (swelling of extremities), and nystagmus are also common. Gabapentin is associated with a weight gain of 2.2 kg after 1.5 months of use. Case studies indicate that it may cause anorgasmia and erectile dysfunction, as well as myoclonus that disappear after discontinuing gabapentin or replacing it with other medication. DRESS, anaphylaxis, respiratory depression, and increased suicide behavior are the rare but serious side effects. Suicide The gabapentin label contains a warning of an increased risk of suicidal thoughts and behaviors. According to an insurance claims database study, gabapentin use is associated with about 40% increased risk of suicide, suicide attempt and violent death as compared with a reference anticonvulsant drug topiramate. The risk is increased for both bipolar disorder and epilepsy patients. Another study has shown an approximately doubled rate of suicide attempts and self-harm in patients with bipolar disorder who are taking gabapentin versus those taking lithium. A large Swedish study suggests that gabapentinoids are associated with an increased risk of suicidal behaviour, unintentional overdoses, head/body injuries, and road traffic incidents and offences. Respiratory depression Serious breathing suppression, potentially fatal, may occur when gabapentin is taken together with opioids, benzodiazepines, or other depressants, or by people with underlying lung problems such as COPD. Gabapentin and opioids are commonly prescribed or abused together, and research indicates that the breathing suppression they cause is additive. For example, gabapentin use before joint replacement or laparoscopic surgery increased the risk of respiratory depression by 30–60%. Withdrawal and dependence Withdrawal symptoms typically occur 1–2 days after abruptly stopping gabapentin. Agitation, confusion and disorientation are the most frequently reported, followed by gastrointestinal complaints and sweating, and more rare tremor, tachycardia, hypertension and insomnia. In some cases, users experience withdrawal seizures. All these symptoms subside when gabapentin is re-instated.On its own, gabapentin appears to not have a substantial addictive power. In human and animal experiments, it shows limited to no rewarding effects. The vast majority of people abusing gabapentin are current or former abusers of opioids or sedatives. In these persons, gabapentin can boost the opioid "high" as well as decrease commonly experienced opioid-withdrawal symptoms such as anxiety. Overdose Through excessive ingestion, accidental or otherwise, persons may experience overdose symptoms including drowsiness, sedation, blurred vision, slurred speech, somnolence, uncontrollable jerking motions, and anxiety. A very high amount taken is associated with breathing suppression, coma, and possibly death, particularly if combined with alcohol or opioids. Pharmacology Pharmacodynamics Gabapentin is a ligand of the α2δ calcium channel subunit. α2δ is an auxiliary protein connected to the main α1 subunit (the channel-forming protein) of high voltage activated voltage-dependent calcium channels (L-type, N-type, P/Q type, and R-type). Gabapentin is not a direct channel blocker: it exerts its actions by disrupting the regulatory function of α2δ and its interactions with other proteins. Gabapentin prevents delivery of the calcium channels to the cell membrane, reduces the activation of the channels by the α2δ subunit, decreases signaling leading to neurotransmitters release, and disrupts interactions of α2δ with NMDA receptors, neurexins, and thrombospondins. Out of the four known isoforms of α2δ protein, gabapentin binds with similar high affinity to two: α2δ-1 and α2δ-2. Most of the pharmacological properties of gabapentin are explained by its binding to just one isoform – α2δ-1.The endogenous α-amino acids L-leucine and L-isoleucine, which resemble gabapentin in chemical structure, bind α2δ with similar affinity to gabapentin and are present in human cerebrospinal fluid at micromolar concentrations. They may be the endogenous ligands of the α2δ subunit, and they competitively antagonize the effects of gabapentin. Accordingly, while gabapentin has nanomolar affinity for the α2δ subunit, its potency in vivo is in the low micromolar range, and competition for binding by endogenous L-amino acids is likely to be responsible for this discrepancy.Gabapentin is a potent activator of voltage-gated potassium channels KCNQ3 and KCNQ5, even at low nanomolar concentrations. However, this activation is unlikely to be the dominant mechanism of gabapentins therapeutic effects.Despite the fact that gabapentin is a structural GABA analogue, and in spite of its name, it does not bind to the GABA receptors, does not convert into GABA or another GABA receptor agonist in vivo, and does not modulate GABA transport or metabolism. Pharmacokinetics Gabapentin is absorbed from the intestines by an active transport process mediated via an amino acid transporter, presumably, LAT2. As a result, the pharmacokinetics of gabapentin is dose-dependent, with diminished bioavailability and delayed peak levels at higher doses.The oral bioavailability of gabapentin is approximately 80% at 100 mg administered three times daily once every 8 hours, but decreases to 60% at 300 mg, 47% at 400 mg, 34% at 800 mg, 33% at 1,200 mg, and 27% at 1,600 mg, all with the same dosing schedule. Drugs that increase the transit time of gabapentin in the small intestine can increase its oral bioavailability; when gabapentin was co-administered with oral morphine, the oral bioavailability of a 600 mg dose of gabapentin increased by 50%.Gabapentin at a low dose of 100 mg has a Tmax (time to peak levels) of approximately 1.7 hours, while the Tmax increases to 3 to 4 hours at higher doses. Food does not significantly affect the Tmax of gabapentin and increases the Cmax and area-under-curve levels of gabapentin by approximately 10%.Gabapentin can cross the blood–brain barrier and enter the central nervous system. Gabapentin concentration in cerebrospinal fluid is approximately 9–14% of its blood plasma concentration. Due to its low lipophilicity, gabapentin requires active transport across the blood–brain barrier. The LAT1 is highly expressed at the blood–brain barrier and transports gabapentin across into the brain. As with intestinal absorption mediated by an amino acid transporter, the transport of gabapentin across the blood–brain barrier by LAT1 is saturable. Gabapentin does not bind to other drug transporters such as P-glycoprotein (ABCB1) or OCTN2 (SLC22A5). It is not significantly bound to plasma proteins (<1%).Gabapentin undergoes little or no metabolism.Gabapentin is eliminated renally in the urine. It has a relatively short elimination half-life, with the reported average value of 5 to 7 hours. This value changes with increasing doses, from 5.4 hours for a 200 mg single dose, to 8.3 hours for a 1,400 mg dose. Because of its short elimination half-life, gabapentin must be administered 3 to 4 times per day to maintain therapeutic levels. Gabapentin XR (brand name Gralise) is taken once a day. Chemistry Gabapentin is a 3,3-disubstituted derivative of GABA. Therefore, it is a GABA analogue, as well as a γ-amino acid. Specifically, it is a derivative of GABA with a pentyl disubstitution at 3 position, hence, the name - gabapentin, in such a way as to form a six-membered ring. After formation of the ring, the amine and carboxylic groups are not in the same relative positions as they are in the GABA; they are more conformationally constrained. Synthesis A chemical synthesis of gabapentin has been described starting from 1,1-diacetyl hexane anhydride. History Gabapentin was designed by researchers at Parke-Davis to be an analogue of the neurotransmitter GABA that could more easily cross the blood–brain barrier and was first described in 1975 by Satzinger and Hartenstein. Under the brand name Neurontin, it was first approved in May 1993, for the treatment of epilepsy in the United Kingdom. Approval by the U.S. Food and Drug Administration followed in December 1993, for use as an adjuvant (effective when added to other antiseizure drugs) medication to control partial seizures in adults; that indication was extended to children in 2000. Subsequently, gabapentin was approved in the United States for the treatment of postherpetic neuralgia in 2002. A generic version of gabapentin first became available in the United States in 2004. An extended-release formulation of gabapentin for once-daily administration, under the brand name Gralise, was approved in the United States for the treatment postherpetic neuralgia in January 2011. Society and culture Legal status United Kingdom Effective April 2019, the United Kingdom reclassified the drug as a class C controlled substance. United States Effective 1 July 2017, Kentucky classified gabapentin as a schedule V controlled substance statewide. Effective 9 January 2019, Michigan also classified gabapentin as a schedule V controlled substance. Gabapentin is scheduled V drug in other states such as West Virginia, Tennessee, Alabama. Off-label promotion Although some small, non-controlled studies in the 1990s—mostly sponsored by gabapentins manufacturer—suggested that treatment for bipolar disorder with gabapentin may be promising, the preponderance of evidence suggests that it is not effective. Subsequent to the corporate acquisition of the original patent holder, the pharmaceutical company Pfizer admitted that there had been violations of FDA guidelines regarding the promotion of unproven off-label uses for gabapentin in the Franklin v. Parke-Davis case (see below). Reuters reported on 25 March 2010, that "Pfizer Inc violated federal racketeering law by improperly promoting the epilepsy drug Neurontin ... Under federal RICO law the penalty is automatically tripled, so the finding will cost Pfizer $141 million." The case stems from a claim from Kaiser Foundation Health Plan Inc. that "it was misled into believing Neurontin was effective for off-label treatment of migraines, bipolar disorder and other conditions. Pfizer argued that Kaiser physicians still recommend the drug for those uses", and that "the insurers website also still lists Neurontin as a drug for neuropathic pain."The Wall Street Journal noted that Pfizer spokesman Christopher Loder said, "We are disappointed with the verdict and will pursue post-trial motions and an appeal." He later added that "the verdict and the judges rulings are not consistent with the facts and the law." Franklin v. Parke-Davis case While off-label prescriptions are common for a number of drugs, marketing of off-label uses of a drug is not. In 2004, Warner-Lambert (which subsequently was acquired by Pfizer) agreed to plead guilty for activities of its Parke-Davis subsidiary, and to pay $430 million in fines to settle civil and criminal charges regarding the marketing of Neurontin for off-label purposes. The 2004 settlement was one of the largest in U.S. history, and the first off-label promotion case brought successfully under the False Claims Act. Brand names Gabapentin was originally marketed under the brand name Neurontin. Since it became generic, it has been marketed worldwide using over 300 different brand names. An extended-release formulation of gabapentin for once-daily administration was introduced in 2011, for postherpetic neuralgia under the brand name Gralise. Related drugs Parke-Davis developed a drug called pregabalin, which is related in structure to gabapentin, as a successor to gabapentin. Another similar drug atagabalin has been unsuccessfully tried by Pfizer as a treatment for insomnia. A prodrug form (gabapentin enacarbil) was approved by the U.S. Food and Drug Administration (FDA). Recreational use Gabapentin when taken in excess can induce euphoria, a sense of calm, a marijuana-like high, improved sociability, and reduced alcohol or cocaine cravings. Also known on the streets as "Gabbies", gabapentin is increasingly being abused and misused for these euphoric effects. About 1 percent of the responders to an internet poll and 22 percent of those attending addiction facilities had a history of abuse of gabapentin. Gabapentin misuse, toxicity, and use in suicide attempts among adults in the US increased from 2013 to 2017.After Kentuckys implementation of stricter legislation regarding opioid prescriptions in 2012, there was an increase in gabapentin-only and multi-drug use in 2012–2015. The majority of these cases were from overdose in suspected suicide attempts. These rates were also accompanied by increases in abuse and recreational use.Withdrawal symptoms, often resembling those of benzodiazepine withdrawal, play a role in the physical dependence some users experience. Its misuse predominantly coincides with the usage of other illicit CNS depressant drugs, namely opioids, benzodiazepines, and alcohol. Veterinary use In cats, gabapentin can be used as an analgesic in multi-modal pain management, anxiety medication to reduce stress in cats for travel or vet visits, and anticonvulsant. Veterinarians may prescribe gabapentin as an anticonvulsant and pain reliever in dogs. It is also used to treat chronic pain-associated nerve inflammation in horses and dogs. Side effects include tiredness and loss of coordination. References External links "Gabapentin". Drug Information Portal. U.S. National Library of Medicine.
Elvitegravir	Elvitegravir (EVG) is an integrase inhibitor used to treat HIV infection. It was developed by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008. The drug gained approval by the U.S. Food and Drug Administration on August 27, 2012 for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild. On September 24, 2014 the FDA approved Elvitegravir as a single pill formulation under the trade name Vitekta. On November 5, 2015 the FDA approved the drug for use in patients affected with HIV-1 as a part of a second fixed dose combination pill known as Genvoya.According to the results of the phase II clinical trial, patients taking once-daily elvitegravir boosted by ritonavir had greater reductions in viral load after 24 weeks compared to individuals randomized to receive a ritonavir-boosted protease inhibitor. Medical uses In the United States, elvitegravir can be obtained either as part of the combination pills Stribild or Genvoya, or as the single pill formulation Vitekta.Vitekta is FDA approved to be used for the treatment of HIV-1 infection in adults who have previous treatment experience with antiretroviral therapy. It must be used in combination with a protease inhibitor that is coadministered with ritonavir as well as additional antiretroviral drug(s). Adverse effects The most common side effects of taking elvitegravir are diarrhea (in 7% of patients) and nausea (4%). Other side effects that occurred in more than 1% of people are headache, tiredness, rashes, and vomiting. Interactions and contraindications Elvitegravir is metabolised via the liver enzyme CYP3A. Substances that induce this enzyme can reduce elvitegravir concentrations in the body, potentially triggering the development of resistant virus strains. Consequently, co-administration of strong CYP3A inducers is contraindicated; examples are rifampicin, the anticonvulsants carbamazepine, phenobarbital and phenytoin, as well as St Johns wort.Glucuronidation of elvitegravir is facilitated by the enzymes UGT1A1 and 3, resulting in increased blood plasma levels when taken together with strong UGT1A inhibitors such as ritonavir and other HIV protease inhibitors. (But ritonavir also increases elvitegravir levels by inhibiting CYP3A.) Furthermore, elvitegravir is a weak to medium inducer of CYP1A2, CYP2C19, CYP2C9, CYP3A, and a number of UGTs; the clinical relevance of these findings is however unclear. Pharmacology Mechanism of action Elvitegravir inhibits the enzyme integrase of HIV-1, and of HIV-2 to a lesser extent. The virus needs this enzyme to integrate its genetic code into the hosts DNA. Pharmacokinetics The drug is taken by mouth. When taken together with ritonavir and a meal, it reaches highest blood plasma concentrations after four hours. Bioavailability is better with fatty meals. In the bloodstream, 98–99% of the substance are bound to plasma proteins. It is metabolized mainly by CYP3A oxidation, and secondly by UGT1A1 and 3 glucuronidation. Nearly 95% are excreted via the feces, and the rest via urine. Plasma half-life when combined with ritonavir is 8.7 to 13.7 hours. References External links "Elvitegravir". Drug Information Portal. U.S. National Library of Medicine.
Psyllium	Psyllium , or ispaghula , is the common name used for several members of the plant genus Plantago whose seeds are used commercially for the production of mucilage. Psyllium is mainly used as a dietary fiber to relieve symptoms of both constipation and mild diarrhea, and occasionally as a food thickener. Allergy to psyllium is common in workers frequently exposed to the substance. Use of psyllium in the diet for three weeks or longer often lowers blood cholesterol levels in people with elevated cholesterol, and can lower blood glucose levels in people with type 2 diabetes. Use of psyllium for a month or longer may produce a small reduction in systolic blood pressure.The plants from which the seeds are extracted tolerate dry and cool climates and are mainly cultivated in northern India. Uses Dietary supplements containing psyllium are sold mainly to aid weight loss, although there is little scientific evidence for such effects. Food Psyllium has been used as a thickener in ice cream and other frozen desserts. A 1.5% weight/volume ratio of psyllium mucilage exhibits binding properties that are superior to a 10% weight/volume ratio of starch mucilage. The viscosity of psyllium mucilage dispersions are relatively unaffected between temperatures of 20 and 50 °C (68 and 122 °F), by pH from 2 to 10, and by salt (sodium chloride) concentrations up to 0.15 M. Human health Constipation Psyllium is mainly used as a viscous, soluble dietary fiber that is not absorbed by the small intestine. The purely mechanical action of psyllium mucilage is to absorb excess water while stimulating normal bowel elimination. Although its main use has been as a laxative, it is more accurately regarded as a dietary fiber and as such can help reduce the symptoms of both constipation and mild diarrhea. The laxative properties of psyllium are attributed to the fiber: it absorbs water and subsequently softens the stool. It increases flatulence (gas) to some degree. High blood cholesterol In 1998, the U.S. Food and Drug Administration approved a health claim on food labels for dietary psyllium as a soluble fiber – if consumed regularly – that would reduce the risk of heart disease by lowering blood cholesterol. Clinical research demonstrated that seven grams or more per day of soluble fiber from psyllium seed husk would sufficiently lower total cholesterol and low density lipoprotein cholesterol in people with hypercholesterolemia, two accepted biomarkers for risk of coronary heart disease. The findings were later confirmed in a meta-analysis that incorporated more evidence. To be eligible for the FDA-allowed health claim, one serving of a manufactured food or dietary supplement must contain at least 1.7 g of psyllium as soluble fiber. Whole oats, barley and foods containing beta-glucan soluble fiber were included as eligible sources for the label claim. Type 2 diabetes In 2014, the U.S. Food and Drug Administration approved a qualified health claim for psyllium as a possible benefit for people with diabetes, requiring FDA-approved wording on a product label: "Psyllium husk may reduce the risk of type 2 diabetes, although the FDA has concluded that there is very little scientific evidence for this claim." A meta-analysis published after the FDA decision reported that psyllium provided before meals improved fasting blood glucose and glycated hemoglobin, but that the larger effect was seen in people diagnosed with and being treated for type 2 diabetes, and only a modest improvement for people classified as pre-diabetic. Veterinary medicine Psyllium fiber dietary supplements are used in veterinary medicine to treat sand impaction in horses to aid in elimination of sand from the horses colon. Adverse effects Fiber generally has few side effects. Psyllium can cause bowel obstructions or bezoars, if taken without adequate amounts of water. Gas or stomach bloating may also occur. Choking is a hazard if psyllium is taken without adequate water as it thickens in the throat. Allergy Psyllium can cause allergic reactions, including anaphylaxis. Psyllium may act as a potent inhalant allergen capable of eliciting asthma symptoms. Health care professionals at geriatric care hospitals, who are frequently exposed to psyllium in the laxatives administered to patients, are commonly IgE sensitized to psyllium (13.8%), and 8.6% have clinical allergy to psyllium. Pharmaceutical manufacturing employees who have been exposed to psyllium during the processing have developed occupational asthma and IgE sensitization. In order to protect sensitized workers, psyllium has an extremely low occupational exposure limit of 150 ng/m3. Mechanism of action The soluble fiber in psyllium is the polysaccharide heteroxylan, a hemicellulose.Psyllium is produced mainly for its mucilage content. The term mucilage describes a group of clear, colorless, gelling agents derived from plants. The mucilage obtained from psyllium comes from the seed coat. Mucilage is obtained by mechanical milling (i.e. grinding) of the outer layer of the seed. Mucilage yield amounts to about 25% (by weight) of the total seed yield. Plantago-seed mucilage is often referred to as husk, or psyllium husk. The milled seed mucilage is a white fibrous material that is hydrophilic, meaning that its molecular structure causes it to attract and bind to water. Upon absorbing water, the clear, colorless, mucilaginous gel that forms increases in volume by tenfold or more. Cultivation The genus Plantago contains over 200 species. P. ovata and P. psyllium are produced commercially in several European countries, Russia and surrounding countries, and India. Plantago seed, known commercially as black, French, or Spanish psyllium, is obtained from P. psyllium, also known as P. arenaria. Seed produced from P. ovata is known in trading circles as white or blonde psyllium, Indian plantago, or isabgol. Isabgol is the common name in India for P. ovata. it is known as Aspaghol in Pakistan, coming from the Persian asp and gul, meaning "horse flower", which is descriptive of the shape of the seed. India dominates the world market in the production and export of psyllium. Plantago ovata is an annual herb that grows to a height of 30–46 cm (12–18 in). Leaves are opposite, linear or linear lanceolate 1 cm × 19 cm (0.39 in × 7.48 in). The root system has a well-developed tap root with few fibrous secondary roots. A large number of flowering shoots arise from the base of the plant. Flowers are numerous, small, and white. Plants flower about 60 days after planting. The seeds are enclosed in capsules that open at maturity. The fields are generally irrigated prior to seeding to achieve ideal soil moisture, to enhance seed soil contact, and to avoid burying the seed too deeply as a result of later irrigations or rainfall. Maximum germination occurs at a seeding depth of 6 mm (1/4 in). Emerging seedlings are frost sensitive; therefore, planting should be delayed until conditions are expected to remain frost free. Seed is broadcast at 5.5 to 8.25 kg/hectare (5 to 7.5 lb/acre) in India. In Arizonan trials, seeding rates of 22 to 27.5 kg/ha (20 to 25 lb/acre) resulted in stands of 1 plant/25mm (1 inch) in 15 cm (6 inch) rows produced excellent yields. Weed control is normally achieved by one or two hand weedings early in the growing season. Control of weeds by pre-plant irrigation that germinates weed seeds followed by shallow tillage may be effective on fields with minimal weed pressure. Psyllium is a poor competitor with most weed species. Plantago wilt (Fusarium oxysporum) and downy mildew (Peronospora alta) are the major diseases of Isabgol. White grubs and aphids are the major insect pests. The flower spikes turn reddish brown at ripening, the lower leaves dry and the upper leaves yellow. The crop is harvested in the morning after the dew is gone to minimize shattering and field losses. In India, mature plants are cut 15 cm above the ground and then bound, left for a few days to dry, thrashed, and winnowed. Harvested seed must be dried to below 12% moisture to allow for cleaning, milling, and storage. Seed stored for future crops has shown a significant loss in viability after 2 years in storage. Commercial history Metamucil Introduced in 1934 by G. D. Searle & Company, Metamucil was acquired by Procter & Gamble in 1985. The name is a combination of the Greek word for change (meta) and the class of fiber that it utilizes (mucilage). In its early years, Metamucil achieved sporadic drug-store distribution as a "behind the counter" product - sold in pharmacies but not on the shelf, so that the pharmacist may counsel the purchaser on correct usage. Since 1974, the brand was also marketed to consumers by print and TV advertising and became available in food outlets. Flavored versions were added in 1979. The brand is sold as powdered drink mixes, capsules and wafers in a variety of flavors. Metamucil contains psyllium seed husks as the active ingredient. It is manufactured in Phoenix, Arizona, by Procter & Gamble. When first marketed to consumers in 1974, Metamucil was marketed as a laxative. The advertising slogan at that time was "If not nature, then Metamucil". Procter & Gamble sought to make Metamucil a household name by advertising in magazines and on television, using the claim "All fiber is not created equal". References External links USDA Plants Profile: Plantago ovata Forsk. USDA Germplasm Resources Information Network: Plantago ovata Forsk. ITIS Standard Report: Plantago ovata Forsk. USDA Plants Profile: Plantago psyllium L. USDA Germplasm Resources Information Network: Plantago psyllium L. (Plantago arenaria)
Chlorpropamide	Chlorpropamide is a drug in the sulfonylurea class used to treat diabetes mellitus type 2. It is a long-acting first-generation sulfonylurea. Mechanism of action Like other sulfonylureas, chlorpropamide acts to increase the secretion of insulin, so it is only effective in patients who have some pancreatic beta cell function. It can cause relatively long episodes of hypoglycemia; this is one reason why shorter-acting sulfonylureas such as gliclazide or tolbutamide are used instead. The risk of hypoglycemia makes this drug a poor choice for the elderly and patients with mild to moderate hepatic and renal impairment. Chlorpropamide is also used in partial central diabetes insipidus. Pharmacokinetics Maximal plasma concentrations are reached 3 to 5 hours after quick and nearly complete (>90%) resorption from the gut. Plasma half life is 36 hours; the drug is effective for about 24 hours, longer than other sulfonylureas. A stable plasma level is only reached after three days of continuous application. 90% of the drug are bound to plasma proteins; at least two albumin binding sites exist. More than 99% of chlorpropamide are excreted unchanged via the kidneys. It is first filtrated in the glomeruli, then reabsorbed, and finally secreted into the tubular lumen. Cautions and contraindications Chlorpropamide and other sulfonylureas encourage weight gain, so they are generally not favored for use in very obese patients. Metformin (Glucophage) is considered a better drug for these patients. Sulfonylureas should be used with caution or generally avoided in patients with hepatic and renal impairment, patients with porphyria, patients who are breastfeeding, patients with ketoacidosis, and elderly patients. Chlorpropamide, while effective in the treatment of diabetics in patients of Chinese descent, should never be used in people of Mongolian descent. Other side effects The most common side effects are skin related, such as rashes, photoallergy and (in rare cases) Stevens–Johnson syndrome. Less common side effects of chlorpropamide include gastrointestinal symptoms such as nausea, vomiting, and diarrhea. It may cause facial flushing after the ingestion of alcohol. In very high doses it can increase secretion of antidiuretic hormone (ADH), which can lead to hyponatremia. It also markedly raises the serum level of alkaline phosphatase. Chemical properties Chlorpropamide is a white crystalline powder with no characteristic taste or smell. It exhibits polymorphism. Its acid dissociation constant pKa is 5.0 at 20 °C. Solubility See also Tolbutamide Tolazamide Glyburide Glipizide == References ==
Megestrol acetate	Megestrol acetate (MGA), sold under the brand name Megace among others, is a progestin medication which is used mainly as an appetite stimulant to treat wasting syndromes such as cachexia. It is also used to treat breast cancer and endometrial cancer, and has been used in birth control. MGA is generally formulated alone, although it has been combined with estrogens in birth control formulations. It is usually taken by mouth.Side effects of MGA include increased appetite, weight gain, vaginal bleeding, nausea, edema, low sex hormone levels, sexual dysfunction, osteoporosis, cardiovascular complications, glucocorticoid effects, and others. MGA is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has weak partial androgenic activity, weak glucocorticoid activity, and no other important hormonal activity. Due to its progestogenic activity, MGA has antigonadotropic effects. The mechanism of action of the appetite stimulant effects of MGA is unknown.MGA was discovered in 1959 and was introduced for medical use, specifically in birth control pills, in 1963. It may be considered a "first-generation" progestin. The medication was withdrawn in some countries in 1970 due to concerns about mammary toxicity observed in dogs, but this turned out not to apply to humans. MGA was approved for the treatment of endometrial cancer in 1971 and wasting syndromes in 1993. It is marketed widely throughout the world. It is available as a generic medication.In Bangladesh and India, megestrol is marketed under the trade name Megestol by Ziska Pharmaceuticals, Mezest by Beacon Pharmaceuticals, and under the trade name Varigestrol by Laboratorio Varifarma, Argentina. Medical uses MGA is used mainly as an appetite stimulant to promote weight gain in a variety of situations. When given at very high dosages, it can substantially increase appetite in most individuals, even those with advanced cancer, and is often used to boost appetite and induce weight gain in patients with cancer or HIV/AIDS-associated cachexia. In addition to its effects on appetite, MGA appears to have antiemetic effects. MGA is also used as an antineoplastic agent in the treatment of breast cancer and endometrial cancer. It is significantly inferior to aromatase inhibitors in both clinical effectiveness and tolerability as a second-line therapy for breast cancer after tamoxifen failure. MGA was formerly used in combined oral contraceptives in combination with ethinylestradiol or mestranol, and has been used in a combined injectable contraceptive in combination with estradiol as well.Although it has not been approved for these uses, MGA has been studied and/or used off-label for a variety of indications including menopausal hormone therapy and the treatment of hot flashes, gynecological/menstrual disorders, endometriosis, endometrial hyperplasia, ovarian cancer, prostate cancer, benign prostatic hyperplasia, male breast cancer, and precocious puberty. MGA can also be used to treat pattern hair loss in men, but its side effects generally make it unacceptable for this purpose.Appetite stimulation is achieved with MGA with oral dosages of 400 to 800 mg/day. The optimal dosage with maximum effect for appetite stimulation has been determined to be 800 mg/day. The recommended oral dosage of MGA for breast cancer is 40 mg four times per day (160 mg/day total), while the medication is used at an oral dosage of 40 to 320 mg/day in divided doses for endometrial cancer. It has been used at far lower dosages (e.g., 1–5 mg/day oral, 25 mg/month i.m.) in combination with an estrogen for contraceptive purposes. Available forms MGA is available as 5 mg, 20 mg, and 40 mg oral tablets and in oral suspensions of 40 mg/mL, 125 mg/mL, 625 mg/5 mL, and 820 mg/20 mL. It was used at doses of 1 mg, 2 mg, 4 mg, and 5 mg in combined oral contraceptives. MGA is formulated at a dose of 25 mg in combination with a dose of 3.75 mg estradiol in a microcrystalline aqueous suspension for use as a once-monthly combined injectable contraceptive in women. Contraindications Contraindications of MGA include hypersensitivity to MGA or any component of its formulation, known or suspected pregnancy, and breastfeeding. MGA is a teratogen in animals and may have the potential to cause fetal harm, such as decreased fetal weight and feminization of male fetuses. Side effects The most common side effect of MGA is weight gain, with an incidence of 15 to 70% at the high dosages used to treat breast cancer. Other side effects include vaginal bleeding (7–8%), nausea (7%), and edema (5%), as well as others such as dizziness and shortness of breath. MGA can cause hypogonadism and associated symptoms like diminished secondary sexual characteristics, sexual dysfunction, osteoporosis, and reversible infertility in men and premenopausal women. Combining MGA with an androgen/anabolic steroid like oxandrolone, nandrolone decanoate, or testosterone in men can alleviate MGA-associated symptoms of hypoandrogenism as well as further increase appetite and weight gain. Less common but more serious side effects of MGA include cardiovascular/thromboembolic complications such as thrombophlebitis. It may also cause glucocorticoid side effects such as Cushing syndrome-like symptoms, steroid diabetes, and adrenal insufficiency at high dosages. Case reports of deep vein thrombosis, pulmonary embolism, jaundice, intrahepatic cholestasis, and meningiomas in association with high-dosage MGA have been published. In older patients who take MGA, one in 23 will have an adverse event leading to death. Overdose MGA has been studied at very high dosages of as much as 1,600 mg/day with no serious adverse effects observed. No clear increase in rate or severity of side effects have been observed up to 1,600 mg/day MGA except for weight gain, mild increases in blood pressure, and some fluid retention. In post-marketing experience, limited reports of overdose have been received. Signs and symptoms described in these reports have included diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain. There is no specific antidote for overdose of MGA. Treatment should be supportive and based on symptoms. MGA has not been assessed for dialyzability. However, due to its low solubility, it is thought that dialysis would not be useful for treating MGA overdose. Interactions Interactions of MGA include significantly decreased exposure to indinavir, which may necessitate an increased dosage of the medication. When MGA is co-administered with zidovudine and rifabutin, there is no significant change in exposure to these medications and no dosage adjustment is necessary. Pharmacology Pharmacodynamics MGA has progestogenic activity, antigonadotropic effects, weak partial androgenic activity, and weak glucocorticoid activity. Progestogenic activity MGA is a progestogen, or an agonist of the progesterone receptor (PR). It has about 65% of the affinity of promegestone and 130% of the affinity of progesterone for the PR. Like other progestogens, MGA has functional antiestrogenic effects in certain tissues such as the endometrium and has antigonadotropic effects. The total endometrial transformation dose of MGA is 50 mg per cycle. Antigonadotropic and anticorticotropic effects MGA has antigonadotropic effects in humans at sufficient doses, capable of profoundly suppressing circulating androgen and estrogen concentrations. The antigonadotropic effects of MGA are the result of activation of the PR, which suppresses the secretion of the gonadotropins—peptide hormones responsible for signaling the body to produce not only progesterone but also the androgens and the estrogens—from the pituitary gland as a form of negative feedback inhibition, and hence downregulates the hypothalamic–pituitary–gonadal axis (HPG axis), resulting in decreased levels of the sex hormones and interference with fertility. As such, MGA has functional antiandrogenic and antiestrogenic effects as well as contraceptive effects via its antigonadotropic effects.The precise ovulation-inhibiting dosage of MGA is unknown. However, doses of 1 to 5 mg MGA were previously used in combined birth control pills in combination with the estrogen ethinylestradiol or mestranol. MGA is an effective contraceptive by itself at dosages of 0.35 to 0.5 mg/day, but is not effective at a dosage of 0.25 mg/day. MGA alone does not inhibit ovulation at a dosage of 0.5 mg/day, nor does it fully inhibit ovulation at a dosage of 0.7 mg/day or even at a dosage of 5 mg/day. The combination of 2 to 5 mg/day MGA and 100 μg/day mestranol has been found to consistently inhibit ovulation, whereas either medication alone did not completely inhibit ovulation in all women.Suppression of testosterone levels by MGA is responsible for its effectiveness in the treatment of conditions like prostate cancer and benign prostatic hyperplasia. In one study, 120 to 160 mg/day MGA suppressed testosterone levels in men by 72%. However, a recovery or "escape" of testosterone levels, gradually returning to near-normal values, has been observed in most men after 2 to 6 months of MGA therapy, and this has limited the usefulness of the medication. The combination of a lower dosage of MGA (40–80 mg/day) and a low oral dosage of an estrogen such as estradiol (0.5–1.5 mg/day), diethylstilbestrol (0.1–0.2 mg/day) or ethinylestradiol (50 µg/day) is able to suppress testosterone levels into the castrate range in men, maintain this suppression long-term, and achieve equivalent effectiveness to high-dosage estrogen monotherapy in the treatment of prostate cancer with comparatively greatly reduced toxicity and side effects. In spite of these results, however, this combination has been very rarely used to treat prostate cancer in the United States.The antigonadotropic as well as anticorticotropic effects of MGA may be involved in its effectiveness in the treatment of postmenopausal breast cancer via substantially decreasing gonadal and adrenal production of sex steroids and by extension circulating levels of estrogens, by about 80%. Androgenic and antiandrogenic activity MGA is a weak partial agonist of the androgen receptor (AR). It has been reported to bind to this receptor with 5% of the affinity of the anabolic steroid metribolone. Despite its weak intrinsic activity at the AR, at clinical doses in humans, MGA appears to behave, for all intents and purposes, purely as an antiandrogen. This is based on the fact that no virilizing side effects have been observed with the use of MGA in patients of either sex at dosages up to as high as 1,600 mg per day, the highest that has been assessed. Furthermore, MGA produces detectable androgenic effects in animals only at a dose that is the equivalent of approximately 200 times that typically used for the treatment of prostate cancer in men. However, the medication does have moderate androgenic effects on serum lipids in humans, causing a significant reduction of HDL and LDL cholesterol levels and no change in triglyceride levels at a dosage of only 5 mg/day. Conversely, MGA does not decrease SHBG levels. The weak but significant androgenic activity of MGA may serve to limit its clinical effectiveness in the treatment of prostate cancer. Glucocorticoid activity MGA is an agonist of the glucocorticoid receptor (GR), the biological target of glucocorticoids like cortisol. It has been found to possess 30% of the affinity of the corticosteroid dexamethasone for this receptor. MGA shows the lowest ratio of PR affinity to GR affinity of a broad selection of marketed progestins, suggesting that it may have among the highest relative glucocorticoid effect of the progestins used in medicine. MGA produces observable glucocorticoid effects, with one study finding that, in the dose range tested, it possessed about 50% of the eosinopenic and hyperglycemic activity (markers of glucocorticoid activity) of an equal amount of medroxyprogesterone acetate and about 25% that of hydrocortisone. Accordingly, manifestations of its glucocorticoid activity, including symptoms of Cushings syndrome, steroid diabetes, and adrenal insufficiency, have been reported with the use of MGA in the literature, albeit sporadically. Appetite stimulation MGA is frequently used as an appetite stimulant to promote weight gain. The direct mechanism of appetite enhancement is unclear, but it is known that MGA induces a variety of downstream changes to cause the effect, including stimulation of the release of neuropeptide Y in the hypothalamus, neurosteroid-like modulation of calcium channels in the ventromedial hypothalamus, and inhibition of the secretion of proinflammatory cytokines including interleukin 1α, interleukin 1β, interleukin 6, and tumor necrosis factor α, all of which have been implicated in facilitation of appetite. Increased levels of insulin-like growth factor 1 (IGF-1) may also be involved, specifically in its anabolic effects. Studies of MGA in elderly patients who experience weight loss are limited and of poor quality with most showing minimal or no weight gain, with no nutritional or clinically significant beneficial outcomes observed. In patients who take MGA, one in 12 will have an increase in weight. Miscellaneous Unlike the case of the AR, MGA has no significant affinity for the ER. As such, it does not possess the capacity to directly activate the ER. Furthermore, unlike antiandrogens such as spironolactone and bicalutamide but similarly to cyproterone acetate, there is relatively little risk of indirectly mediated estrogenic side effects (e.g., gynecomastia) with MGA. This is because MGA strongly suppresses both androgen and estrogen levels at the same time. Similarly to the case of the ER, MGA has negligible affinity for the mineralocorticoid receptor (MR), and hence does not possess mineralocorticoid or antimineralocorticoid activity.MGA has been found to dose-dependently increase total and free IGF-1 levels up to a dosage of 120 mg/day. Total IGF-1 levels were described as "profoundly" increased, gradually increasing, significantly by 3 days of treatment, up to a maximum of 2.66-fold by 5 to 6 months of treatment. Free (readily dissociable) concentrations of IGF-1 were increased to a smaller extent, by 1.23–2.15-fold, and were described as increasing "moderately". It was suggested that the increase in IGF-1 levels with high-dosage MGA therapy may explain the anabolic effects of MGA in patients with cachexia. Pharmacokinetics The oral bioavailability of MGA is approximately 100%. After a single low oral dose of 4 mg MGA, peak serum concentrations of MGA were about 7 ng/dL (18 nmol/L) and occurred after 3 hours. Following a single high oral dose of 160 mg micronized MGA in men, peak circulating levels of MGA were 125 ng/mL (325 nmol/L) and occurred after 6.3 hours. This study found that micronized MGA at this dose showed considerably improved absorption relative to its conventional tablet form. In terms of plasma protein binding, MGA is bound mostly to albumin (82.4%) and is not bound to sex hormone-binding globulin or to corticosteroid-binding globulin. MGA metabolized in the liver mainly by hydroxylation of the C21, C2α, and C6 positions, as well as by reduction and conjugation. Its elimination half-life is 34 hours on average, with a range of 13 to 105 hours. MGA is excreted 57 to 78% in urine and 8 to 30% in feces.At high doses, MGA appears to have far greater bioavailability and potency than medroxyprogesterone acetate, regardless of whether the route of administration of the latter is oral or parenteral. Following oral administration of 80 to 160 mg MGA or 500 to 1,000 mg medroxyprogesterone acetate, circulating levels of MGA were 2- to 10-fold higher than those of medroxyprogesterone acetate. Similar findings have been found for oral MGA relative to medroxyprogesterone acetate administered via intramuscular injection. MGA also reaches steady-state levels more quickly than medroxyprogesterone acetate. The improved potency of MGA compared to medroxyprogesterone acetate may be due to increased resistance to metabolism of MGA afforded by its C6(7) double bond (medroxyprogesterone acetate being identical to MGA in structure except lacking this feature).The pharmacokinetics of MGA have been reviewed. Chemistry MGA, also known as 17α-acetoxy-6-dehydro-6-methylprogesterone or as 17α-acetoxy-6-methylpregna-4,6-diene-3,20-dione, is a synthetic pregnane steroid and a derivative of progesterone. It is specifically a derivative of 17α-hydroxyprogesterone with a methyl group at the C6 position, a double bond between the C6 and C7 positions, and an acetate ester at the C17α position. MGA is the C17α acetate ester of megestrol, which, in contrast to MGA, was never marketed. Analogues of MGA include other 17α-hydroxyprogesterone derivatives such as acetomepregenol, anagestone acetate, chlormadinone acetate, cyproterone acetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, and nomegestrol acetate. MGA differs from medroxyprogesterone acetate only by its C6(7) double bond. Close analogues of MGA that were never marketed include cymegesolate (megestrol acetate 3β-cypionate) and megestrol caproate. Synthesis Chemical syntheses of MGA have been published. History MGA was synthesized at Syntex in 1959. It was derived from medroxyprogesterone acetate, which had been synthesized at Syntex in 1957. MGA was the third synthetic derivative of progesterone to be developed for use as a medication, following hydroxyprogesterone caproate in 1954 and medroxyprogesterone acetate in 1957. The medication was introduced for medical use in combination with ethinylestradiol (EE) as an oral contraceptive in 1963 by British Drug Houses in the United Kingdom under the brand name Volidan (4 mg MGA and 50 μg EE tablets), and this was followed by Serial 28 (1 mg MGA and 100 μg EE tablets) and Volidan 21 (4 mg MGA and 50 μg EE tablets) in 1964 and Nuvacon (2 mg MGA and 100 μg EE tablets) in 1967, all by British Drug Houses also in the United Kingdom. It was also marketed under the brand name Delpregnin (5 mg MGA and 100 μg mestranol tablets) by 1965, among others. MGA-containing birth control pills were withdrawn after reports in the early 1970s of a high incidence of venous thromboembolism with the preparations.In the early 1970s, MGA was found to be associated with mammary tumors in beagle dogs, and along with several other progestogens, was withdrawn as an oral contraceptive from several markets including the United Kingdom, Canada, and Germany. It was also under investigation for use as a contraceptive in the United States, but development was discontinued in 1972 following the mammary toxicity findings in dogs, and MGA was never marketed as an oral contraceptive in the United States. Subsequent research, such as monkey studies, revealed that there is no similar risk in humans. Following its withdrawal from the market, MGA was eventually reintroduced for the treatment of hormone-sensitive cancers. In addition, MGA was marketed for veterinary use in dogs in 1969 in the United Kingdom and in 1974 in the United States.Progesterone was first found to be effective in the treatment of endometrial hyperplasia in 1951, and progestins were first found to be effective in the treatment of endometrial cancer in 1959. MGA was reported to be effective in the treatment of endometrial hyperplasia in the mid-1960s. It first started to be studied as a treatment for endometrial cancer in 1967, with findings published in 1973. MGA was reportedly introduced for the treatment of endometrial cancer in the United States in 1971. Progesterone was studied in the treatment of breast cancer in 1951 and 1952, but with relatively modest results. MGA was first studied in the treatment of breast cancer in 1967, and was one of the first progestins to be evaluated for the treatment of this disease. A second study was conducted in 1974. A "breakthrough" and surge of interest in progestins for breast cancer occurred in 1978 when a study using a massive dosage of medroxyprogesterone acetate to treat breast cancer was published. A third study of MGA for breast cancer was published in 1980, and this was followed by additional studies in the 1980s and beyond. MGA was approved for the treatment of breast cancer in the United States by at least 1983.Progestogens, including progesterone and ethisterone, were studied in the treatment prostate cancer in 1949. MGA was first studied in the treatment of prostate cancer in 1970. Additional studies were conducted in 1975 and 1978, followed by others thereafter. However, results of MGA therapy for prostate cancer have been "disappointing", and the medication has not been approved for the treatment of prostate cancer in the United States or elsewhere.Clinical studies of very high dosages of MGA for breast cancer conducted in the 1980s observed markedly increased appetite and weight gain in treated patients despite them having advanced cancer. This led to potential interest in MGA as an appetite stimulant, and in 1986, a paper was published proposing the study and potential use of MGA in cachexia. MGA was subsequently studied for this indication and, following completion of phase III clinical trials, was approved as an oral suspension for the treatment of anorexia–cachexia syndrome due to cancer and other chronic conditions such as HIV/AIDS in the United States in 1993. Thereafter, the branded product, Megace ES, has been heavily promoted by its maker, Par Pharmaceutical, for treatment of unintentional weight loss in elderly patients, especially those living in long-term care facilities. In March 2013, Par settled a $45 million federal and multi-state criminal and civil lawsuit in which the company was accused of promoting the branded version of MGA, over the generic version, for use in treating non-AIDS-related geriatric wasting. This use was not approved as safe and effective by the Food and Drug Administration (FDA), and not covered by federal health care programs. The lawsuit claimed that Par marketed the product as effective for this use, despite having conducted no well-controlled studies to support a claim of greater efficacy for Megace ES, and prior knowledge of the severe adverse side effects for geriatric patients, including deep vein thrombosis, toxic reactions with impaired renal function, and mortality. Society and culture Generic names Megestrol acetate is the generic name of the drug and its INNM, USAN, USP, and BANM, while megestrol is the INN and BAN and mégestrol the DCF of megestrol, the free alcohol form of MGA. The medication is also known by its developmental code names BDH-1298, NSC-71423, and SC-10363. Brand names MGA is marketed under a variety of brand names throughout the world but is most commonly sold under the brand name Megace. It is also available under the brand name Megace ES in the United States and under the brand name Megace OS in Canada. For use in veterinary medicine, MGA is sold as Ovaban in the United States and as Ovarid in the United Kingdom. Availability MGA is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere throughout Europe, Australia, New Zealand, Latin America, Asia, and a few African countries. It does not appear to be marketed in Germany, Russia, South Africa, Japan, India, or Mexico, among other countries. Generation Progestins in birth control pills are sometimes grouped by generation. While the 19-nortestosterone progestins are consistently grouped into generations, the pregnane progestins that are or have been used in birth control pills are typically omitted from such classifications or are grouped simply as "miscellaneous" or "pregnanes". In any case, based on its date of introduction in such formulations of 1963, MGA could be considered a "first-generation" progestin. Research MGA has been studied in men in combination with testosterone as a male hormonal contraceptive to suppress spermatogenesis. Veterinary use MGA has been used in veterinary medicine under the brand name Ovaban in the treatment of medical conditions in cats and dogs. Due to its ability to suppress testosterone levels, MGA can control sexually dimorphic traits in males. As a result, MGA has been used to reduce dominance, inter-male aggression, mounting, urine spraying, and roaming in male dogs and cats. See also Estradiol/megestrol acetate Ethinylestradiol/megestrol acetate References == Further reading ==
Hydrocodone	Hydrocodone (dihydrocodeinone) is an opioid used to treat pain and as a cough suppressant. It is taken by mouth. Typically it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone for pain severe enough to require an opioid and in combination with homatropine methylbromide to relieve cough. It is also available by itself in a long-acting form under the brand name Zohydro ER, among others, to treat severe pain of a prolonged duration. Hydrocodone is a controlled drug, in the United States a Schedule II Controlled Substance. Common side effects include dizziness, sleepiness, nausea, and constipation. Serious side effects may include low blood pressure, seizures, QT prolongation, respiratory depression, and serotonin syndrome. Rapidly decreasing the dose may result in opioid withdrawal. Use during pregnancy or breastfeeding is generally not recommended. Hydrocodone is believed to work by activating opioid receptors, mainly in the brain and spinal cord. Hydrocodone 10 mg is equivalent to about 10 mg of morphine by mouth.Hydrocodone was patented in 1923, while the long-acting formulation was approved for medical use in the United States in 2013. It is most commonly prescribed in the United States, which consumed 99% of the worldwide supply as of 2010. In 2017, it was the 118th most commonly prescribed medication in the United States, with more than six million prescriptions. Hydrocodone is a semisynthetic opioid, converted from codeine or less often from thebaine. Production using genetically engineered yeasts have been developed but are not used commercially. Medical uses Hydrocodone is used to treat moderate to severe pain. In liquid formulations, it is used to treat cough. In one study comparing the potency of hydrocodone to that of oxycodone, it was found that it took 50% more hydrocodone to achieve the same degree of miosis (pupillary contraction). The investigators interpreted this to mean that oxycodone is about 50% more potent than hydrocodone. However, in a study of emergency department patients with fractures, it was found that an equal amount of either drug provided about the same degree of pain relief, indicating that there is little practical difference between them when used for that purpose. Some references state that the analgesic action of hydrocodone begins in 20–30 minutes and lasts about 4–8 hours. The manufacturers information says onset of action is about 10–30 minutes and duration is about 4–6 hours. Recommended dosing interval is 4–6 hours. Available forms Hydrocodone is available in a variety of formulations for oral administration: The original oral form of hydrocodone alone, Dicodid, as immediate-release 5- and 10-mg tablets is available for prescription in Continental Europe per national drug control and prescription laws and Title 76 of the Schengen Treaty, but dihydrocodeine has been more widely used for the same indications since the beginning in the early 1920s, with hydrocodone being regulated the same way as morphine in the German Betäubungsmittelgesetz, the similarly named law in Switzerland and the Austrian Suchtmittelgesetz, whereas dihydrocodeine is regulated like codeine. For a number of decades, the liquid hydrocodone products available have been cough medicines. Hydrocodone plus homatropine (Hycodan) in the form of small tablets for coughing and especially neuropathic moderate pain (the homatropine, an anticholinergic, is useful in both of those cases and is a deterrent to intentional overdose) was more widely used than Dicodid and was labelled as a cough medicine in the United States whilst Vicodin and similar drugs were the choices for analgesia. Extended-release hydrocodone in a time-release syrup also containing chlorphenamine/chlorpheniramine is a cough medicine called Tussionex in North America. In Europe, similar time-release syrups containing codeine (numerous), dihydrocodeine (Paracodin Retard Hustensaft), nicocodeine (Tusscodin), thebacon, acetyldihydrocodeine, dionine, and nicodicodeine are used instead. Immediate-release hydrocodone with paracetamol (acetaminophen) (Vicodin, Lortab, Lorcet, Maxidone, Norco, Zydone) Immediate-release hydrocodone with ibuprofen (Vicoprofen, Ibudone, Reprexain) Immediate-release hydrocodone with aspirin (Alor 5/500, Azdone, Damason-P, Lortab ASA, Panasal 5/500) Controlled-release hydrocodone (Hysingla ER by Purdue Pharma, Zohydro ER)Hydrocodone is not available in parenteral or any other non-oral forms. Side effects Common side effects of hydrocodone are nausea, vomiting, constipation, drowsiness, dizziness, lightheadedness, anxiety, abnormally happy or sad mood, dry throat, difficulty urinating, rash, itching, and contraction of the pupils. Serious side effects include slowed or irregular breathing and chest tightness.Several cases of progressive bilateral hearing loss unresponsive to steroid therapy have been described as an infrequent adverse reaction to hydrocodone/paracetamol misuse. This adverse effect has been considered by some to be due to the ototoxicity of hydrocodone. Other researchers have suggested that paracetamol is the primary agent responsible for the ototoxicity.Hydrocodone is in U.S. Food and Drug Administration (FDA) pregnancy category C. No adequate and well-controlled studies in humans have been conducted. A newborn of a mother taking opioid medications regularly prior to the birth will be physically dependent. The baby may also exhibit respiratory depression if the opioid dose was high. An epidemiological study indicated that opioid treatment during early pregnancy results in increased risk of various birth defects.Symptoms of hydrocodone overdose include narrowed or widened pupils; slow, shallow, or stopped breathing; slowed or stopped heartbeat; cold, clammy, or blue skin; excessive sleepiness; loss of consciousness; seizures; or death.Hydrocodone can be habit forming, causing physical and psychological dependence. Its abuse liability is similar to morphine and less than oxycodone. Interactions Patients consuming alcohol, other opioids, anticholinergic antihistamines, anti-psychotics, anti-anxiety agents, or other central nervous system (CNS) depressants together with hydrocodone may exhibit an additive CNS depression. Hydrocodone may interact with serotonergic medications. Pharmacology Pharmacodynamics Hydrocodone is a highly selective full agonist of the μ-opioid receptor (MOR). This is the main biological target of the endogenous opioid neuropeptide β-endorphin. Hydrocodone has low affinity for the δ-opioid receptor (DOR) and the κ-opioid receptor (KOR), where it is an agonist similarly.Studies have shown hydrocodone is stronger than codeine but only one-tenth as potent as morphine at binding to receptors and reported to be only 59% as potent as morphine in analgesic properties. However, in tests conducted on rhesus monkeys, the analgesic potency of hydrocodone was actually higher than morphine. Oral hydrocodone has a mean equivalent daily dosage (MEDD) factor of 0.4, meaning that 1 mg of hydrocodone is equivalent to 0.4 mg of intravenous morphine. However, because of morphines low oral bioavailability, there is a 1:1 correspondence between orally administered morphine and orally administered hydrocodone. Pharmacokinetics Absorption Hydrocodone is only pharmaceutically available as an oral medication. It is well-absorbed, but the oral bioavailability of hydrocodone is only approximately 25%. The onset of action of hydrocodone via this route is 10 to 20 minutes, with a peak effect (Tmax) occurring at 30 to 60 minutes, and it has a duration of 4 to 8 hours. Distribution The volume of distribution of hydrocodone is 3.3 to 4.7 L/kg. The plasma protein binding of hydrocodone is 20 to 50%. Metabolism In the liver, hydrocodone is transformed into several metabolites, including norhydrocodone, hydromorphone, 6α-hydrocodol (dihydrocodeine), and 6β-hydrocodol. 6α- and 6β-hydromorphol are also formed, and the metabolites of hydrocodone are conjugated (via glucuronidation). Hydrocodone has a terminal half-life that averages 3.8 hours (range 3.3–4.4 hours). The hepatic cytochrome P450 enzyme CYP2D6 converts hydrocodone into hydromorphone, a more potent opioid (5-fold higher binding affinity to the MOR). However, extensive and poor cytochrome 450 CYP2D6 metabolizers had similar physiological and subjective responses to hydrocodone, and CYP2D6 inhibitor quinidine did not change the responses of extensive metabolizers, suggesting that inhibition of CYP2D6 metabolism of hydrocodone has no practical importance. Ultra-rapid CYP2D6 metabolizers (1–2% of the population) may have an increased response to hydrocodone; however, hydrocodone metabolism in this population has not been studied.Norhydrocodone, the major metabolite of hydrocodone, is predominantly formed by CYP3A4-catalyzed oxidation. In contrast to hydromorphone, it is described as inactive. However, norhydrocodone is actually a MOR agonist with similar potency to hydrocodone, but has been found to produce only minimal analgesia when administered peripherally to animals (likely due to poor blood–brain barrier and thus central nervous system penetration). Inhibition of CYP3A4 in a child who was, in addition, a poor CYP2D6 metabolizer, resulted in a fatal overdose of hydrocodone. Approximately 40% of hydrocodone metabolism is attributed to non-cytochrome P450-catalyzed reactions. Elimination Hydrocodone is excreted in urine, mainly in the form of conjugates. Chemistry Detection in body fluids Hydrocodone concentrations are measured in blood, plasma, and urine to seek evidence of misuse, to confirm diagnoses of poisoning, and to assist in investigations into deaths. Many commercial opiate screening tests react indiscriminately with hydrocodone, other opiates, and their metabolites, but chromatographic techniques can easily distinguish hydrocodone uniquely. Blood and plasma hydrocodone concentrations typically fall into the 5–30 µg/L range among people taking the drug therapeutically, 100–200 µg/L among recreational users, and 100–1,600 µg/L in cases of acute, fatal overdosage. Co-administration of the drug with food or alcohol can very significantly increase the resulting plasma hydrocodone concentrations that are subsequently achieved. Synthesis Hydrocodone is most commonly synthesized from Thebaine, a constituent of opium latex from the dried poppy plant. Once Thebaine is obtained, the reaction undergoes hydrogenation using a palladium catalyst. Structure There are three important structures in hydrocodone: the amine group, which binds to the tertiary nitrogen binding site in the central nervous systems opioid receptor, the hydroxy group that binds to the anionic binding side, and the phenyl group which binds to the phenolic binding site. This triggers a G protein activation and subsequent release of dopamine. History Hydrocodone was first synthesized in Germany in 1920 by Carl Mannich and Helene Löwenheim. It was approved by the Food and Drug Administration on 23 March 1943 for sale in the United States and approved by Health Canada for sale in Canada under the brand name Hycodan.Hydrocodone was first marketed by Knoll as Dicodid, starting in February 1924 in Germany. This name is analogous to other products the company introduced or otherwise marketed: Dilaudid (hydromorphone, 1926), Dinarkon (oxycodone, 1917), Dihydrin (dihydrocodeine, 1911), and Dimorphan (dihydromorphine). Paramorfan is the trade name of dihydromorphine from another manufacturer, as is Paracodin, for dihydrocodeine.The name Dicodid was registered in the United States and appears without a monograph as late as 1978 in the Physicians Desk Reference; Dicodid may have been marketed to one extent or another in North America in the 1920s and early 1930s. The drug was pure hydrocodone in small 5 and 10 mg tablets, physically similar to the Dilaudid tablets. It is no longer manufactured by Knoll in Germany, nor is a generic available. Hydrocodone was never as common in Europe as it is in North America—dihydrocodeine is used for its spectrum of indications. Germany was the number two consumer of hydrocodone until the manufacture of the drug was discontinued there. Now, the world outside the United States accounts for less than 1% of annual consumption. It was listed as a Suchtgift under the German Betäubungsmittelgesetz and regulated like morphine. It became available in the Schengen Area of the European Union as of 1 January 2002 under Title 76 of the Schengen Treaty. Society and culture Formulations Several common imprints for hydrocodone are M365, M366, M367. Combination products Most hydrocodone formulations include a second analgesic, such as paracetamol (acetaminophen) or ibuprofen. Examples of hydrocodone combinations include Norco, Vicodin, Vicoprofen and Riboxen. Legal status United States The US government imposed tougher prescribing rules for hydrocodone in 2014, changing the drug from Schedule III to Schedule II. In 2011, hydrocodone products were involved in around 100,000 abuse-related emergency department visits in the United States, more than double the number in 2004. References External links "Hydrocodone". Drug Information Portal. U.S. National Library of Medicine. "DEA Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II". Federal Register. 6 October 2014.
Remimazolam	Remimazolam, sold under the brand name Byfavo, is a medication for the induction and maintenance of procedural sedation in adults for invasive diagnostic or surgical procedures lasting 30 minutes or less. is a benzodiazepine drug, developed by PAION AG in collaboration with several regional licensees as an alternative to the short-acting imidazobenzodiazepine midazolam, for use in the induction of anesthesia and conscious sedation for minor invasive procedures. Remimazolam was found to have both a more rapid onset and a shorter duration than midazolam, and human clinical trials showed a faster recovery time and predictable, consistent pharmacokinetics, suggesting some advantages over existing drugs for these applications.The most common side effects for procedural sedation include low blood pressure, high blood pressure, diastolic hypertension, systolic hypertension, low blood oxygen level, and diastolic hypotension.Remimazolam was approved for medical use in the United States in July 2020, and in the European Union in March 2021. Medical uses Remimazolam is indicated for the induction and maintenance of procedural sedation in adults lasting 30 minutes or less. History Remimazolam was approved for medical use in the United States in July 2020.The U.S. Food and Drug Administration (FDA) approved remimazolam based on evidence from three clinical trials (Trial 1/NCT02290873, Trial 2/NCT02296892 and Trial 3/NCT02532647) in adults undergoing short procedures. Trials were conducted at 32 sites in the United States.Trials 1 and 3 were conducted in participants undergoing colonoscopy and Trial 2 was conducted in participants undergoing bronchoscopy procedures.In the trials, participants were randomly divided in three groups: one group received remimazolam, one group received placebo and one group received midazolam (similar, but approved drug). In the first two groups, neither participants nor investigators knew which medications were given and participants could also receive midazolam as a rescue drug when needed for sedation. In the third group, all participants received midazolam only Additionally, in all three trials participants received a medication for pain controlTrials 1 and 2 compared participants who received remimazolam to participants in the other two groups, measuring the success of sedation with the set of pre-determined criteria. Data from Trial 3 were used primarily to assess the side effects of remimazolam when multiple dosing is used. Society and culture Legal status On 28 January 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Byfavo, intended for procedural sedation. The applicant for this medicinal product is PAION Netherlands B.V. Remimazolam (Byfavo) was approved for medical use in the European Union in March 2021. Research Phase I and Ib dose-finding studies for procedural sedation with patients recovering faster from remimazolam than midazolam. Phase II trials comparing remimazolam to the standard anesthesia protocols for cardiac surgery and colonoscopy were presented at major conferences in October 2014.A Phase IIa trial comparing remimazolam to midazolam for upper endoscopy was published in December 2014, finding a similar safety profile. Remimazolam was originally synthesized in the late 1990s at Glaxo Wellcome in their labs in Research Triangle Park, North Carolina. References External links "Remimazolam". Drug Information Portal. United States National Library of Medicine. Clinical trial number NCT02290873 for "A Phase III Study of the Efficacy and Safety of Remimazolam Compared to Placebo and Midazolam in Colonoscopy Patients" at ClinicalTrials.gov Clinical trial number NCT02296892 for "A Phase III Study of Remimazolam in Patients Undergoing Bronchoscopy" at ClinicalTrials.gov Clinical trial number NCT02532647 for "Safety and Efficacy of Remimazolam in ASA III and IV Patients Undergoing Colonoscopy" at ClinicalTrials.gov
Cambia	Cambia can mean: Cambia, Haute-Corse, a commune in the Haute-Corse department of France Cambia (non-profit organization), an open science and biology non-profit institute based in Australia Cambia Health Solutions, an American health insurance company Cambia or cambiums, the four humours in medicine Cambia, a trade name for the anti-inflammatory drug diclofenac the plural of cambium (botany), a type of tissue found in plants See also Cambio (disambiguation) Cambria (disambiguation) Kambia (disambiguation) Cumbia, a style of music and dance Cumbria, a county of England

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