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Doxazosin	Doxazosin, sold under the brand names Cardura among others, is a medication used to treat symptoms of benign prostatic hyperplasia (enlarged prostate) and hypertension (high blood pressure). For high blood pressure, it is a less preferred option. It is taken by mouth.Common side effects include dizziness, sleepiness, swelling, nausea, shortness of breath, and abdominal pain. Severe side effects may include low blood pressure with standing, an irregular heart beat, and priapism. It is a α1-selective adrenergic blocker in the quinazoline class of compounds.Doxazosin was patented in 1977 and came into medical use in 1988. It is available as a generic medication. In 2019, it was the 210th most commonly prescribed medication in the United States, with more than 2 million prescriptions. Medical uses High blood pressure Doxazosin is usually added to other antihypertensive therapy such as calcium channel antagonists, diuretics, beta-adrenoreceptor antagonists, angiotensin-converting enzyme inhibitors and angiotensin-2 receptor blockers.Doxazosin is generally considered to be safe, well tolerated and effective as an add-on antihypertensive drug.Like other alpha-1 receptor antagonists, it has a role in the peri-operative management of pheochromocytoma. Benign prostatic hyperplasia Doxazosin is considered to be effective in reducing urinary symptom scores and improving peak urinary flow in men with benign prostatic hypertrophy. History The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study stopped its arm of the trial looking at alpha blockers, because doxazosin was less effective than a simple diuretic, and because patients on doxazosin had a 25% higher rate of cardiovascular disease and twice the rate of congestive heart failure as patients on diuretics. Pfizer, aware of the results before publication, launched a marketing campaign in early 2000, and sales were largely unaffected, despite the dangers highlighted by the study. References External links "Doxazosin". Drug Information Portal. U.S. National Library of Medicine.
Alirocumab	Alirocumab, sold under the brand name Praluent, is a medication used as a second-line treatment for high cholesterol for adults whose cholesterol is not controlled by diet and statin treatment. It is a human monoclonal antibody that belongs to a novel class of anti-cholesterol drugs, known as PCSK9 inhibitors, and it was the first such agent to receive FDA approval. The FDA approval was contingent on the completion of further clinical trials to better determine efficacy and safety.Common side effects include nasopharyngitis (cold), injection site reactions, and influenza.It was approved for medical use in the United States and in the European Union in 2015. Medical uses Alirocumab is used as a second-line treatment to lower LDL cholesterol for adults who have a severe form of hereditary high cholesterol and people with atherosclerosis who require additional lowering of LDL cholesterol when diet and statin treatment have not worked. It is administered by subcutaneous injection. As of July 2015, it is not known whether alirocumab prevents early death from cardiovascular disease or prevents heart attacks; a clinical trial to determine outcomes was ongoing at that time, the results of which were expected in 2017. In November 2018, The New England Journal of Medicine published positive results from a clinical trial with alirocumab. According to the study, alirocumab significantly reduced major adverse cardiovascular events by 15% and it was associated with a 15% lower risk of death from any cause (hazard ratio [HR] 0.85; 95% confidence interval [CI], 0.73 to 0.98).In 2021, the U.S. Food and Drug Administration (FDA) added an indication for alirocumab to treat adults with homozygous familial hypercholesterolemia (HoFH), a genetic condition that causes severely high cholesterol. It is not intended to be used alone but instead added to other treatments for HoFH. Side effects Side effects that occurred in more than 2% of people treated with alirocumab in clinical trials and that occurred more frequently than with placebo, included nose and throat irritation, injection site reactions and bruising, flu-like symptoms, urinary tract infection, diarrhea, bronchitis and cough, and muscle pain, soreness, and spasms.There are no available data on use of alirocumab in pregnant women to assess risks to the fetus, nor is there data on use in children. Pharmacology Alirocumab works by inhibiting the PCSK9 protein. PCSK9 binds to the low-density lipoprotein receptor (LDLR) (which takes cholesterol out of circulation), and that binding leads to the receptor being degraded, and less LDL cholesterol being removed from circulation. Inhibiting PCSK9 prevents the receptor from being degraded, and promotes removal of LDL cholesterol from circulation.After subcutaneous administration of alirocumab, maximal suppression of free PCSK9 occurs within 4 to 8 hours and has an apparent half-life of 17 to 20 days. Inhibition is dose-dependent. The antibody is distributed through the circulation, and it is eliminated at low concentrations by binding to its target, and at higher concentrations through a proteolytic pathway. Chemistry Alirocumab is a human monoclonal antibody of the IgG1 isotype. It is made of two disulfide-linked human heavy chains, each disulfide-linked to a human light chain. It has an approximate molecular weight of 146 kDa.It is produced using Chinese hamster ovary cells transfected with recombinant DNA, that are grown in tanks. History The importance of PCSK9 as a biological target for drug discovery emerged in 2003, when a series of discoveries led to identification of the protein and its gene, its role in causing some cases of familial hypercholesterolaemia when some mutations are present, and its role in causing very low levels of LDL cholesterol when other mutations are present.The discovery and validation of the target set off a race among pharmaceutical and biotech companies.Alirocumab was discovered by Regeneron Pharmaceuticals using its "VelocImmune" mouse, in which many of the genes coding for antibodies have been replaced with human genes.: 255–258 In an investor presentation, Regeneron claimed that with their system, it took only about 19 months from when they first immunized mice with PCSK9 until they filed their IND.: Slide 26 Alirocumab was co-developed with Sanofi under a deal made in 2007. Before it received its international nonproprietary name it was known as REGN727 and SAR236553.Phase 1 trial results were reported in 2012 in The New England Journal of Medicine. A phase 3 trial of statin intolerant patients called ODYSSEY ran for 65 weeks. Results were presented at the 2014 European Society of Cardiology meeting. A 78-week study of alirocumab in 2341 people taking statins who were at high risk for cardiovascular events and had high LDL cholesterol levels was published in April 2015. This study showed a significant reduction of LDL cholesterol levels in patients taking both Alirocumab and oral statins compared to placebo patients solely taking oral statins. Studies are ongoing to assess the effects of alirocumab in normocholesterolemic individuals.In July 2014, Regeneron and Sanofi announced that they had purchased a priority review voucher that BioMarin had won for a recent rare disease drug approval for $67.5 million; the voucher cut four months off the regulatory review time for alirocumab and was part of their strategy to beat Amgen to market with the first approval of a PCSK9 inhibitor.In July 2015, the FDA approved alirocumab as a second-line treatment to lower LDL cholesterol for adults who have hereditary high cholesterol and people with atherosclerosis who require additional lowering of LDL cholesterol when diet and statin treatment have not worked. This was the first approval of a PCSK9 inhibitor. The FDA approval was contingent on the completion of further clinical trials to better determine efficacy and safety.Regeneron and Amgen had each filed for patent protection on their monoclonal antibodies and the companies ended up in patent litigation in the U.S. In March 2016, a district court found that alirocumab infringed Amgens patents; Amgen then requested an injunction barring Regeneron and Sanofi from marketing alirocumab, which was granted in January 2017. The judge gave Regeneron and Sanofi 30 days to appeal before the injunction went into effect. In October, 2017 the US Court of Appeals reversed the ban and ordered a new trial after finding the jury was given improper instructions and evidence was withheld. Regeneron and Sanofi were allowed to continue marketing alirocumab during the appeals process.The U.S. Food and Drug Administration (FDA) granted approval of Praluent to Regeneron Pharmaceuticals, Inc. Society and culture In 2014 as PCSK9 inhibitors approached regulatory approval, market analysts estimated that the overall market for these drugs could be $10B per year, with each of alirocumab and Amgens competing drugs having sales of $3B per year, and other competitors dividing the remaining $4B, based on estimates of an annual price for alirocumab of $10,000 per year. At the same time, pharmacy benefit managers such as Express Scripts and CVS Caremark, while recognizing that the new drugs could help patients who were otherwise left with uncontrolled cholesterol levels, and recognizing that injectable biopharmaceuticals will always be more expensive than pills, and especially more expensive than generic pills, expressed concerns about the burden of the new costs on the health care system.When the drug was approved in July 2015, the announced price was higher than analysts had predicted: $14,600 a year. Pharmacy benefit managers continued expressing their concerns, as did insurance companies and some doctors, who were especially concerned over the price, in light of the fact that the FDA approval was based on lowering cholesterol alone, and not on better health outcomes, such as fewer heart attacks or longer life.The treatment for people with very high cholesterol that cannot be controlled with diet or statins is apheresis, which is similar to dialysis in that a person visits a clinic each month and his or her blood is mechanically filtered, in this case to remove LDL cholesterol. That treatment costs $8000 per month, or $96,000 per year. The price of alirocumab was determined based in part on making apheresis no longer necessary. Names Alirocumab is the International nonproprietary name. References External links "Alirocumab". Drug Information Portal. U.S. National Library of Medicine.
Anthrax vaccine adsorbed	Anthrax vaccine adsorbed (AVA) is the only FDA-licensed human anthrax vaccine in the United States. It is produced under the trade name BioThrax by the Emergent BioDefense Corporation (formerly known as BioPort Corporation) in Lansing, Michigan. The parent company of Emergent BioDefense is Emergent BioSolutions of Rockville, Maryland. It is sometimes called MDPH-PA or MDPH-AVA after the former Michigan Department of Public Health (MDPH; succeeded by the Michigan Department of Health and Human Services), which formerly was involved in its production. AVA originated in studies done in the 1950s and was first licensed for use in humans in 1970. In the US, the principal purchasers of the vaccine are the Department of Defense and Department of Health and Human Services. Ten million courses (60 million doses) of the vaccine have been purchased for the US Strategic National Stockpile in anticipation of the need for mass vaccinations owing to a future bio-terrorist anthrax attack. The product has attracted some controversy owing to alleged adverse events and questions as to whether it is effective against the inhalational form of anthrax. Description Antigen AVA is classified as a subunit vaccine that is cell-free and containing no whole or live anthrax bacteria. The antigen (immunologically active) portions are produced from culture filtrates of a toxigenic, but avirulent, nonencapsulated mutant — known as V770-NP1-R — of the B. anthracis Vollum strain. (The Vollum strain was the same one weaponized by the old U.S. biological warfare program.) As with the Sterne (veterinary) anthrax vaccine strain and the similar British anthrax vaccine (known as AVP), AVA lacks the capsule plasmid pXO2 (required for full virulence) and is composed chiefly of the anthrax protective antigen (PA) with small amounts of edema factor (EF) and lethal factor (LF) that may vary from lot to lot. Other uncharacterized bacterial byproducts are also present. Whether or not the EF and LF contribute to the vaccines efficacy is not known. AVA has smaller amounts of EF and LF than AVP. Adjuvant AVA contains aluminium hydroxide (alhydrogel) to adsorb PA as well as to serve as an adjuvant (immune enhancer). As such it is believed to stimulate humoral, but not cell-mediated, immunity. Each dose of the vaccine contains no more than 0.83 mg aluminum per 0.5 mL dose. (This is near the allowed upper limit of 0.85 mg/dose.) It also contains 0.0025% benzethonium chloride as a preservative and 0.0037% formaldehyde as a stabilizer. The mechanism of action of the adjuvant is not entirely understood. Potency/immunogenicity Vaccination of humans with AVA induces an immune response to PA. More than 1/3 of subjects develop detectable anti-PA IgG after a single inoculation; 95% do so after a 2nd injection; and 100% after 3 doses. The peak IgG response occurs after the 4th (6 month) dose. The potency of AVA vaccine lots is routinely determined both by the survival rates of parenterally challenged guinea pigs and their anti-PA antibody titres as measured by an enzyme linked immunosorbant assay (ELISA). The shelf-life of AVA is reported to be three years when stored between 2 °C and 8 °C (36 °F and 46 °F) and never frozen. History Initial research and development (1954-1970) The vaccine efficacy of AVA in humans was initially established by Philip S. Brachman of the United States Public Health Service (USPHS) in a controlled study undertaken between 1954 and 1959. The study field sites were four wool-sorting mills in the northeastern United States where employees were sometimes exposed to anthrax spores in the course of their work. Over the five years, 379 vaccinees were compared against 414 unvaccinated control subjects. There were 23 cases among controls (5 of them inhalation anthrax) compared with 3 cases among vaccinated (0 inhalation cases). The vaccine was judged to have a 92.5% vaccine efficacy against all types of anthrax experienced. Subsequently, there were no controlled clinical trials in humans of the efficacy of AVA due to the rarity of the condition (especially in the inhalational form) in humans and the ethical inadmissibility of conducting dangerous challenge studies in human subjects. Supportive animal challenge studies were done, however, showing that unvaccinated animals uniformly die whereas vaccinated animals are protected. About 95% of rhesus monkeys (62 of 65) survived challenge, as did 97% of rabbits (114 of 117). Guinea pigs (which are a poorer model for human anthrax than are monkeys or rabbits) showed a 22% protection (19 of 88). Licensure and limited occupational use (1970-1991) In 1970, AVA was first licensed by the USPHS for protection against cutaneous anthrax to a state-owned facility operated by the Michigan Department of Public Health. In 1973, the US Food and Drug Administration (FDA) first published standards for making, using and storing AVA. In the mid-1980s, the FDA approved it specifically for two limited preventive indications: 1) individuals who may come in contact with animal products or high-risk persons such as veterinarians and others handling potentially infected animals; and 2) individuals engaged in diagnostic or investigational activities involving anthrax spores. In 1985, the FDA published a Proposed Rule for a specific product review of the AVA, stating that the vaccines "efficacy against inhalation anthrax is not well documented" (a statement quoted controversially many years later). For many years, AVA was a little known product considered to be safe for pre-exposure use in the US in at-risk veterinarians, laboratory workers, livestock handlers, and textile plant workers who process animal hair. In 1990, the State of Michigan changed the name of its original production plant facility to the Michigan Biologic Products Institute (MBPI) as it gave up state ownership and converted it to a private entity. The same year (as later revealed) MBPI changed both the fermenters and the filters used in manufacturing AVA without notifying the FDA, thus reportedly causing a 100 fold increase in the PA levels present in vaccine lots.Only several thousand people had ever received the vaccine up to 1991 when — coincident with Saddam Husseins invasion of Kuwait and the subsequent Gulf War — MBPI and the U.S. Army entered into an agreement for the manufacture of the vaccine. Later that year, the Army awarded MBPI the Commanders Award for Public Service for their efforts in supplying the US military with increased amounts of AVA for use during the conflict in which the use of anthrax bio-weapons by Iraq had been anticipated. Initial use in US military (1991-1997) Use of AVA expanded dramatically in 1991, when the US military, concerned that Iraq possessed anthrax bioweapons, administered it to some 150,000 service members deployed for the Gulf War. Hussein never deployed his bio-weapons, but subsequent confirmation of an Iraqi bioweapons program — including 8,500 liters of concentrated anthrax spores (6,500 liters of it filled into munitions) — came in 1995 and later when the Iraqi government began to fully disclose the scope and scale of the effort, which it had pursued since the 1980s. Meanwhile, MBPI fell afoul of FDA inspectors and reviewers when it failed inspections (1993, 1997) and received warning letters (1995) and Notices of Intention to Revoke (1997) from the agency. At issue were a failure to validate the AVA manufacturing process to the FDAs satisfaction and various quality control failures, including reuse of expired vaccine, inadequate testing procedures, and use of lots that had failed testing. All of these developments vexed the Army, not only in its efforts to obtain sufficient vaccine for the troops, but in its desire to have AVA validated and fully licensed for prevention of inhalational anthrax, which is the expected weaponized form of the disease (as opposed to the cutaneous form for which the vaccine had been licensed in 1970). In 1995, the Army contracted with the Science Applications International Corporation (SAIC) to develop a plan to obtain FDA approval for a license amendment for AVA in order to add inhalational anthrax exposure to the product license thus enabling the manufacturer to list on the product license that the vaccine was effective against that form of the disease. The following year, MBPI submitted an "IND application" to modify the products license to add an indication for inhalation anthrax, thus formally establishing AVA as an "experimental" vaccine when used to prevent anthrax in the inhalational form. In 1996, the US Department of Defense (DoD) sought and received permission from the FDA to begin vaccinations of all military personnel without obtaining a new licensed indication for AVA. It announced a plan the following year for the mandatory vaccination of all US service members. Under the plan all military personnel, including new recruits, would begin receiving what was then a six-shot series of inoculations in the following fashion: Phase 1: Forces assigned now, or soon rotating, to high threat areas in Southwest Asia and Korea; Phase 2: Early deploying forces into high threat areas; Phase 3: Remainder of the force and new recruits; and Phase 4: Continuation of the program with annual booster shots. The AVIP and initial mandatory military use (1997-2000) There were no published studies of AVAs safety in humans until the advent of the Anthrax Vaccine Immunization Program (AVIP). This program, initiated by the Clinton administration and announced by Secretary of Defense William Cohen in 1997, made the vaccine mandatory for active duty US service personnel. Vaccinations began in March 1998 with personnel sent to high-risk areas, such as South Korea and Southwest Asia. Also in 1998, MBPI was purchased by BioPort Corporation of Lansing, Michigan (jointly with former MBPI laboratory directors) for approximately $24 million. The same year, a particularly damning FDA report was issued resulting in the temporary suspension of AVA shipments from the production plant. Much controversy ensued due to the FDA infractions, the mandatory nature of the program, and to a public perception that AVA was unsafe — possibly causing sometimes serious side effects — and might be contributing to the highly politically charged malady known as "Gulf War syndrome". Hundreds of service members were compelled to leave the military (some of them court-martialed) for resisting the inoculations during the first six years of the program. Adverse events following AVA administration were assessed in several studies conducted by the DoD in the context of the routine anthrax vaccination program. Between 1998 and 2000, at U.S. Forces, Korea, data were collected at the time of anthrax vaccination from 4,348 service personnel regarding adverse events experienced from a previous dose of anthrax vaccine. Most reported events were localized, minor, and self-limited. After the first or second dose, 1.9% reported limitations in work performance or had been placed on limited duty. Only 0.3% reported >1 day lost from work; 0.5% consulted a clinic for evaluation; and one person (0.02%) required hospitalization for an injection-site reaction. Adverse events were reported more commonly among women than among men. A second study, also between 1998 and 2000, at Tripler Army Medical Center, Hawaii, assessed adverse events among 603 military health-care workers. Rates of events that resulted in seeking medical advice or taking time off work were 7.9% after the first dose; 5.1% after the second dose; 3.0% after the third dose; and 3.1% after the fourth dose. Events most commonly reported included muscle or joint aches, headache, and fatigue. However, these studies are subject to several methodological limitations, including sample size, the limited ability to detect adverse events, loss to follow-up, exemption of vaccine recipients with previous adverse events, observational bias, and the absence of unvaccinated control groups.By 2000, some 425,976 US service members had received 1,620,793 doses of AVA. The IOM review (2000-2004) In October 2000, a committee of the Institute of Medicine (IOM) of the National Academy of Sciences was asked by the US Congress to review AVA according to the best available evidence. It issued its study in March 2002. The IOM panel noted that human data on inhalational anthrax prevention is limited due to the natural low incidence of disease and that therefore animal model data are the best we are ever likely to have. Primates and rabbits were considered the best models for human disease. As regards vaccine effectiveness, "The committee finds that the available evidence from studies with humans and animals, coupled with reasonable assumptions of analogy, show that AVA as licensed is an effective vaccine for the protection of humans against anthrax, including inhalational anthrax, caused by all known or plausible engineered strains of B. anthracis." With regard to safety, "The committee found no evidence that people face an increased risk of experiencing life-threatening or permanently disabling adverse events immediately after receiving AVA, when compared with the general population. Nor did it find any convincing evidence that people face elevated risk of developing adverse health effects over the longer term, although data are limited in this regard (as they are for all vaccines)." Side effects of AVA were found to be "comparable to those observed with other vaccines regularly administered to adults". The committee concluded that AVA is "safe and efficacious" for pre-exposure prevention of inhalational anthrax. It also asserted that a new and improved anthrax vaccine might have greater assurance of consistency than AVA and recommended licensure of a new vaccine requiring fewer doses and producing fewer local reactions.In the months after the October 2001 anthrax letters attacks, Washington and New York area mail sorters were advised to receive prophylactic vaccination with AVA. Owing to the controversy surrounding the administration of the vaccine to military personnel, however, some 6,000 US Postal Service employees balked at this, preferring to take their chances with the risks of residual anthrax spores in the workplace.BioPort changed its name to Emergent BioSolutions in 2004. Injunctions and FDA re-reviews (2004-2006) Despite the positive IOM assessment, mandatory vaccinations of military personnel were halted due to an injunction which was put into place on October 27, 2004. The injunction cast questions about numerous substantive challenges regarding the anthrax vaccine in footnote #10, yet the procedural findings centered on FDA procedural issues, stating that additional public comment should have been sought before the FDA issued its Final Rule declaring the vaccine safe and effective on 30 December 2003. The FDAs incomplete rulemaking from 1985 effectively rendered the anthrax vaccine program illegal. The basis was the never finalized FDA Proposed Rule. In that rulemaking the FDA published, but never finalized, a licensing rule for the anthrax vaccine in the Federal Register, which included an expert review panels findings. Those findings included the fact that the "Anthrax vaccine efficacy against inhalation anthrax is not well documented," and that "No meaningful assessment of its value against inhalation anthrax is possible due to its low incidence," and that "The vaccine manufactured by the Michigan Department of Public Health has not been employed in a controlled field trial."On December 15, 2005, the FDA re-issued a Final Rule & Order on the license status of the anthrax vaccine. After reviewing the extensive scientific evidence and carefully considering comments from the public, the FDA again determined that the vaccine is appropriately licensed for the prevention of anthrax, regardless of the route of exposure. Also in 2005, the George W. Bush administration established a policy to ensure that the Strategic National Stockpile retains a current unexpired inventory of 60 million doses of AVA. (The US GAO reports that 4 million doses of the inventory will expire every year, requiring vaccine destruction services.) These would be used for pre- or post-exposure vaccination — of emergency first responders (police, firefighters), federal responders, medical practitioners, and private citizens — in the event of a bioterrorist anthrax attack. Reinstatement of the AVIP (2006-2016) On October 16, 2006, the DoD announced the reinstatement of mandatory anthrax vaccinations for more than 200,000 troops and defense contractors. (Another lawsuit was filed by the same attorneys as before, challenging the basis of the vaccines license on scientific grounds.) The reinstated policy required vaccinations for most military units and civilian contractors assigned to homeland bioterrorism defense or deployed in Iraq, Afghanistan or South Korea. A modification of previous policy allowed military personnel no longer deployed to higher threat areas to receive follow up doses and booster shots on a voluntary basis. As of June 2008, over 8 million doses of AVA had been administered to over 2 million US military personnel as part of the AVIP. In December 2008, the FDA approved the new BioThrax IM formulation for intramuscular injections thus reducing the immunization schedule from a total of 6 shots to 5 shots (see below). On February 12, 2009, Emergent BioSolutions announced that the Drugs Controller General of India (DGCI) had approved licensing of BioThrax for distribution by Biological E. of Hyderabad.In 2011, BioThrax was approved for sale in Singapore by the Singapore Health Sciences Authority. Building 55 approval (2016) The FDA approved the companys license (officially called a supplemental Biologics License Application, or sBLA) to manufacture BioThrax in a large building in Lansing, Michigan known as "Building 55." According to Homeland Preparedness News, "The use of Building 55 to manufacture BioThrax could expand manufacturing capacity to an estimated 20 to 25 million doses annually."The US federal government has a goal to stockpile 75 million doses of anthrax vaccines. The new facility and its capacity will help Emergent meet the governments security needs.Emergent worked with the Biomedical Advanced Research and Development Authority (BARDA) within the Office of the Assistant Secretary for Preparedness and Response in the United States Department of Health and Human Services on the project. The facilitys value is estimated at $104 million, according to Yahoo Finance. Administration Vaccination schedule Vaccination with Emergent BioSolutions BioThrax AVA and BioThrax IM intramuscular injections in the deltoid is given at 0 and 4 weeks, with three vaccinations at 6, 12, and 18 months, followed by annual boosters. As of 11 December 2008, the new BioThrax IM for intramuscular injections in the deltoid was approved by the US FDA which changes the immunity initialization sequence from 6 to 5 shots given at 0 and 4 weeks and then at 6, 12, and 18 months, followed by annual boosters. This prolonged initialization sequence is required with annual booster shots, because the anthrax vaccines primary ingredient, the Anthrax Protective Antigen, can impair the life-cycle of the human immune systems memory B-Cells and memory T-cells, through inducing the production of immunoglobulin G (IgG) which sequesters furin.The loss of memory B-Cells leads to declining concentrations of IgG which can sequester APA, and therefore declining tolerance to the presence of anthrax bacteria. There is the potential that other memory B-Cell populations will be adversely affected as well.Furin is the protein activator for pro-parathyroid hormone, transforming growth factor beta 1, von Willebrand factor, pro-albumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, gonadotropin, and nerve growth factor. Furin is also essential to maintain peripheral immune tolerance by creating memory T-cells and suppressor T-cells.Based on a retrospective cohort study of female military members inoculated during pregnancy, there may be a small risk of birth defect for inoculation during first trimester. However, the difference between the vaccinated and unvaccinated control groups was not large enough to be conclusive.The approved US FDA package insert for AVA contains the following notice: Pregnant women should not be vaccinated against anthrax unless the potential benefits of vaccination have been determined to outweigh the potential risk to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this product, the patient should be apprised of the potential hazard to the fetus. Contraindications The approved US FDA package insert for AVA contains the following notice: Severe allergic reaction (e.g., anaphylaxis) after a previous dose of BioThrax. Administer with caution to patients with a possible history of latex sensitivity because the vial stopper contains dry natural rubber and may cause allergic reactions. Adverse reactions There have been no long-term sequelae of the known adverse events (local or systemic reactions) and no pattern of frequently reported serious adverse events for AVA.The approved FDA package insert for AVA contains the following notice: "The most common (>10%) local (injection-site) adverse reactions observed in clinical studies were tenderness, pain, erythema and arm motion limitation. The most common (>5%) systemic adverse reactions were muscle aches, fatigue and headache." Also, "Serious allergic reactions, including anaphylactic shock, have been observed during post-marketing surveillance in individuals receiving BioThrax". Drug interactions The approved US FDA package insert for AVA contains the following notice: Immunosuppressive therapies may diminish the immune response to BioThrax. Post-exposure vaccination Some studies show that use of antibiotics effective against anthrax plus administration of AVA is the most beneficial approach for purposes of post-exposure prophylaxis. This practice has been endorsed by the Advisory Committee on Immunization Practices (ACIP), the Johns Hopkins Working Group on Civilian Biodefense, and the 2002 Institute of Medicine report on the vaccine. However, AVA is not licensed for post-exposure prophylaxis for inhalational anthrax or for use in a 3-dose regimen. Any such use, therefore, would be on an off-label or IND (officially experimental) basis. "... the safety and efficacy of BioThrax for post-exposure setting have not been established.". Controversy In the United States Although many individuals have expressed health concerns after receiving anthrax vaccine, a congressionally directed study by the Institute of Medicine (part of the National Academy of Sciences) concluded that this anthrax vaccine is as safe as other vaccines. The academy considered more than a dozen studies using various scientific designs, and heard personally from many concerned US military service members. Development of a replacement vaccine While effective in protecting against anthrax, the licensed vaccine schedule is not very efficient, involving a cumbersome five (previously six) dose injection series. Typically, five injections are given over a period of 18 months in order to induce a protective immune system response. In addition, in 2004 the US Department of Health and Human Services contracted with Vaxgen Inc. to supply up to 75 million doses of a recombinant anthrax vaccine, for $877 million. To be acceptable to HHS, this vaccine was to be protective against anthrax in three doses or less. On December 19, 2006, HHS voided the contract, because of stability problems with the vaccine, and a failure to start a Phase 2 clinical trial on time. In May 2008, Emergent Biosolutions, the Maryland-based successor to BioPort, both controlled by former Lebanese banker Faud el Hibri, acquired rights to Vaxgens patents and processes.On 30 October 2012, the US National Institute of Allergy and Infectious Diseases agreed to provide $6.5 million to the United Kingdoms Health Protection Agency for initial work on a potential future anthrax vaccine that could be delivered through the nasal passage instead of via a needle. The HPA has long produced the UKs AVP anthrax vaccine. Research is being continuously done to develop and test new improved candidate anthrax vaccines. The primary immunogen of acellular existing vaccines, i.e., Protective Antigen (PA), is highly thermolabile due to inherent structural and chemical instability. Various endeavors are underway to thermostabilize PA molecule by solvent engineering and genetic engineering approaches to generate a thermostable anthrax vaccine formulation without compromising on the immunogenicity and its protective potential. The generation of a thermostable anthrax vaccine would minimize the current cold chain requirement for its storage and transport. Anthrax vaccines which would be amenable to other modes of administration such as oral, nasal, skin patch etc., are also being experimented. Human Genome Sciences announced in 2007, the development of a new anthrax neutralizing monoclonal antibody with the trademark name of ABthrax. The vaccine sensitizes the human immune system to the presence of the Anthrax Toxin Factor. In 2008, HGS reported on testing on 400 human volunteers given ABthrax. In 2009, HGS announced that they had made first delivery of 20,000 doses of ABthrax to the United States Department of Defense. Currently three anthrax antitoxin antibodies, namely, Anthrax immune globulin intravenous or AIGIV (polyclonal), Obiltoxaximab or ANTHIM (monoclonal), and Raxibacumab or ABthrax (monoclonal) are approved for the treatment of inhalation anthrax. References Further reading External links "Anthrax Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 8 January 2020. "Biothrax". U.S. Food and Drug Administration (FDA). 22 July 2017. STN: BL 103821. Anthrax Vaccines at the US National Library of Medicine Medical Subject Headings (MeSH)
Benzylpenicillin	Benzylpenicillin, also known as penicillin G (PenG) or BENPEN, and in military slang "Peanut Butter Shot" is an antibiotic used to treat a number of bacterial infections. This includes pneumonia, strep throat, syphilis, necrotizing enterocolitis, diphtheria, gas gangrene, leptospirosis, cellulitis, and tetanus. It is not a first-line agent for pneumococcal meningitis. Benzylpenicillin is given by injection into a vein or muscle. Two long-acting forms benzathine benzylpenicillin and procaine benzylpenicillin are available for use by injection into a muscle.Side effects include diarrhea, seizures, and allergic reactions including anaphylaxis. When used to treat syphilis or Lyme disease a reaction known as Jarisch–Herxheimer may occur. It is not recommended in those with a history of penicillin allergy. Use during pregnancy is generally safe in the penicillin and β-lactam class of medications.Benzylpenicillin is on the World Health Organizations List of Essential Medicines. Medical uses Antimicrobial potency As an antibiotic, benzylpenicillin is noted to possess effectiveness mainly against gram-positive organisms. Some gram-negative organisms such as Neisseria gonorrhoeae and Leptospira weilii are also reported to be susceptible to benzylpenicillin. Adverse effects Adverse effects can include hypersensitivity reactions including urticaria, fever, joint pains, rashes, angioedema, anaphylaxis, serum sickness-like reaction. Rarely CNS toxicity including convulsions (especially with high doses or in severe renal impairment), interstitial nephritis, haemolytic anaemia, leucopenia, thrombocytopenia, and coagulation disorders. Also reported diarrhoea (including antibiotic-associated colitis). Benzylpenicillin serum concentrations can be monitored either by traditional microbiological assay or by more modern chromatographic techniques. Such measurements can be useful to avoid central nervous system toxicity in any person receiving large doses of the drug on a chronic basis, but they are especially relevant to patients with kidney failure, who may accumulate the drug due to reduced urinary excretion rates. Manufacture The production of benzylpenicillin involves fermentation, recovery and purification of the penicillin.The fermentation process of the production of benzylpenicillin creates the product. The presence of the product in solution inhibits the reaction and reduces the product rate and yield. Thus, in order to obtain the most product and increase the rate of reaction, it is continuously extracted. This is done by mixing the mold with either glucose, sucrose, lactose, starch, or dextrin, nitrate, ammonium salt, corn steep liquor, peptone, meat or yeast extract, and small amounts of inorganic salts.The recovery of the benzylpenicillin is the most important part of the production process because it affects the later purification steps if done incorrectly. There are several types of techniques used to recover benzyl penicillin: aqueous two-phase extraction, liquid membrane extraction, microfiltration, and solvent extraction. Extraction is more commonly used in the recovery process.In the purification step, the benzylpencillin is separated from the extraction solution. This is normally done by using a separation column. Synonyms Penicillin II (old UK nomenclature for naming penicillins) References External links "Benzylpenicillin". Drug Information Portal. U.S. National Library of Medicine.
Ripretinib	Ripretinib, sold under the brand name Qinlock, is a medication for the treatment of adults with advanced gastrointestinal stromal tumor (GIST), a type of tumor that originates in the gastrointestinal tract. It is taken by mouth. Ripretinib inhibits the activity of the kinases KIT and PDGFRA, which helps keep cancer cells from growing.The most common side effects include alopecia (hair loss), fatigue, nausea, abdominal pain, constipation, myalgia (muscle pain), diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (a skin reaction in the palms and soles) and vomiting.Ripretinib was approved for medical use in the United States in May 2020, in Australia in July 2020, and in the European Union in November 2021. Ripretinib is the first new drug specifically approved in the United States as a fourth-line treatment for advanced gastrointestinal stromal tumor (GIST). Medical uses Ripretinib is indicated for the treatment of adults with advanced gastrointestinal stromal tumor (GIST), a type of tumor that originates in the gastrointestinal tract, who have received prior treatment with three or more kinase inhibitor therapies, including imatinib. GIST is type of stomach, bowel, or esophagus tumor. Adverse effects The most common side effects include alopecia (hair loss), fatigue, nausea, abdominal pain, constipation, myalgia (muscle pain), diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (a skin reaction in the palms and soles) and vomiting.Ripretinib can also cause serious side effects including skin cancer, hypertension (high blood pressure) and cardiac dysfunction manifested as ejection fraction decrease (when the muscle of the left ventricle of the heart is not pumping as well as normal).Ripretinib may cause harm to a developing fetus or a newborn baby. History Ripretinib was approved for medical use in the United States in May 2020.The approval of ripretinib was based on the results of an international, multi-center, randomized, double-blind, placebo-controlled clinical trial (INVICTUS/NCT03353753) that enrolled 129 participants with advanced gastrointestinal stromal tumor (GIST) who had received prior treatment with imatinib, sunitinib, and regorafenib. The trial compared participants who were randomized to receive ripretinib to participants who were randomized to receive placebo, to determine whether progression free survival (PFS) – the time from initial treatment in the clinical trial to growth of the cancer or death – was longer in the ripretinib group compared to the placebo group. During treatment in the trial, participants received ripretinib 150 mg or placebo once a day in 28-day cycles, repeated until tumor growth was found (disease progression), or the participant experienced intolerable side effects. After disease progression, participants who were randomized to placebo were given the option of switching to ripretinib. The trial was conducted at 29 sites in the United States, Australia, Belgium, Canada, France, Germany, Italy, the Netherlands, Poland, Singapore, Spain, and the United Kingdom.The major efficacy outcome measure was progression-free survival (PFS) based on assessment by blinded independent central review (BICR) using modified RECIST 1.1 in which lymph nodes and bone lesions were not target lesions and a progressively growing new tumor nodule within a pre-existing tumor mass must meet specific criteria to be considered unequivocal evidence of progression. Additional efficacy outcome measures included overall response rate (ORR) by BICR and overall survival (OS). The trial demonstrated a statistically significant improvement in PFS for participants in the ripretinib arm compared with those in the placebo arm (HR 0.15; 95% CI: 0.09, 0.25; p<0.0001).The U.S. Food and Drug Administration (FDA) granted the application for ripretinib priority review and fast track designations, as well as breakthrough therapy designation and orphan drug designation. The FDA granted approval of Qinlock to Deciphera Pharmaceuticals, Inc. Society and culture Legal status Ripretinib was approved for medical use in the United States in May 2020, and in Australia in July 2020.On 16 September 2021, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Qinlock, intended for the treatment of advanced gastrointestinal stromal tumour (GIST) in people who have received prior treatment with three or more kinase inhibitors. The applicant for this medicinal product is Deciphera Pharmaceuticals (Netherlands) B.V. Ripretinib was approved for medical use in the European Union in November 2021. Names Ripretinib is the International nonproprietary name (INN) and the United States Adopted Name (USAN). References Further reading Schneeweiss M, Peter B, Bibi S, et al. (May 2018). "The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis". Haematologica. 103 (5): 799–809. doi:10.3324/haematol.2017.179895. PMC 5927976. PMID 29439183. External links "Ripretinib". Drug Information Portal. U.S. National Library of Medicine. "Ripretinib". NCI Drug Dictionary. National Cancer Institute. "Ripretinib". National Cancer Institute. 27 May 2020. Clinical trial number NCT03353753 for "Phase 3 Study of DCC-2618 vs Placebo in Advanced GIST Patients Who Have Been Treated With Prior Anticancer Therapies (invictus)" at ClinicalTrials.gov
Butalbital	Butalbital is a barbiturate with an intermediate duration of action. Butalbital is often combined with other medications, such as paracetamol (acetaminophen) or aspirin, for the treatment of pain and headache. The various formulations combined with codeine are FDA-approved for the treatment of tension headaches. Butalbital has the same chemical formula as talbutal but a different structure—one that presents as 5-allyl-5-isobutylbarbituric acid. Preparations Combinations include: Butalbital and acetaminophen (paracetamol) (trade names: Axocet, Bucet, Bupap, Cephadyn, Dolgic, Phrenilin, Forte, Sedapap) Butalbital, paracetamol (acetaminophen), and caffeine (trade names: Fioricet, Esgic, Esgic-Plus, Orbivan, Fiorinal, Fiormor, Fiortal, Fortabs, Laniroif) Butalbital, paracetamol (acetaminophen), caffeine, and codeine phosphate (trade name: Fioricet#3 with Codeine) Butalbital and aspirin (trade name: Axotal) Butalbital, aspirin, caffeine, and codeine phosphate (trade name: Fiorinal#3 with Codeine) Ergotamine tartrate, caffeine, butalbital, belladonna alkaloids (trade name: Cafergot-PB) Contraindications There are specific treatments which are appropriate for targeting migraines and headaches. Butalbital is not recommended as a first-line treatment because it impairs alertness, brings risk of dependence and addiction, and increases the risk that episodic headaches will become chronic. When other treatments are unavailable or ineffective, butalbital may be appropriate if the patient can be monitored to prevent the development of chronic headache. Side effects Side effects for any psychoactive drug are difficult to predict, though butalbital is usually well tolerated. Commonly reported side effects for butalbital, some of which tend to subside with continued use, include: Rare side-effects include Stevens–Johnson syndrome, an adverse reaction to barbiturates, and anaphylaxis. The risk and severity of all side effects is greatly increased when butalbital (or butalbital-containing medications) are combined with other sedatives (ex. ethanol, opiates, benzodiazepines, antihistamines). In particular, butalbital, especially when combined with other sedatives (e.g. opioids), can cause life-threatening respiratory depression and death. Inhibitors of the hepatic enzyme CYP3A4 may also increase the risk, severity, and duration of side effects, many drugs inhibit this enzyme as do some foods such as grapefruit and the blood orange. Taking butalbital-based medications with some other drugs may also increase the side effects of the other medication. Dangers and risks Butalbital can cause dependence or addiction. Mixing with alcohol, benzodiazepines, and other CNS-depressants increases the risk of intoxication, increases respiratory depression, and increases liver toxicity when in combination with paracetamol (acetaminophen). Use of butalbital and alcohol, benzodiazepines, and other CNS-depressants can contribute to coma, and in extreme cases, fatality. References External links Butalbital, Online Medical Dictionary Butalbital and Acetaminophen (Systemic) (archive), MedicinePlus Drug Information Controlled Substances in Schedule III, (archive), U.S. Drug Enforcement Administration
Calcitriol	Calcitriol is the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It is a hormone which binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the expression of many genes. Calcitriol increases blood calcium (Ca2+) mainly by increasing the uptake of calcium from the intestines.It can be given as a medication for the treatment of low blood calcium and hyperparathyroidism due to kidney disease, low blood calcium due to hypoparathyroidism, osteoporosis, osteomalacia, and familial hypophosphatemia, and can be taken by mouth or by injection into a vein. Excessive amounts or intake can result in weakness, headache, nausea, constipation, urinary tract infections, and abdominal pain. Serious side effects may include high blood calcium and anaphylaxis. Regular blood tests are recommended after the medication is started and when the dose is changed.Calcitriol was identified as the active form of vitamin D in 1971 and the drug was approved for medical use in the United States in 1978. It is available as a generic medication. In 2017, it was the 256th most commonly prescribed medication in the United States, with more than one million prescriptions.It is on the World Health Organizations List of Essential Medicines. Medical use Calcitriol is prescribed for: Treatment of hypocalcaemia – hypoparathyroidism, osteomalacia (adults), rickets (infants, children), renal osteodystrophy, chronic kidney disease Treatment of osteoporosis Prevention of corticosteroid-induced osteoporosisCalcitriol has been used in an ointment for the treatment of psoriasis, although the vitamin D analogue calcipotriol (calcipotriene) is more commonly used. Calcitriol has also been given by mouth for the treatment of psoriasis and psoriatic arthritis. Research on the noncalcemic actions of calcitriol and other VDR-ligand analogs and their possible therapeutic applications has been reviewed. Adverse effects The main adverse drug reaction associated with calcitriol therapy is hypercalcemia – early symptoms include: nausea, vomiting, constipation, anorexia, apathy, headache, thirst, pruritus, sweating, and/or polyuria. Compared to other vitamin D compounds in clinical use (cholecalciferol, ergocalciferol), calcitriol has a higher risk of inducing hypercalcemia. However, such episodes may be shorter and easier to treat due to its relatively short half-life.High calcitriol levels may also be seen in human disease states in patients not on supplementation. In someone with hypercalcaemia and high calcitriol levels, low intact parathyroid hormone levels are usually present. The major conditions with hypercalcaemia due to elevated calcitriol levels are lymphoma, tuberculosis and sarcoidosis where excess production occurs due to ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages. Other conditions producing similar findings including: Fungal infections; Pneumocystis jiroveci, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, candidiasis Other granulomatous conditions; PR3+ vasculitis, Crohns disease, acute granulomatous pneumonia, talc granuloma, silicone-induced granuloma, BCG-associated, granulomatous hepatitis, paraffin-associated granuloma Genetic conditions; Williams syndrome, pseudoxanthoma elasticum, CYP24A1 mutation (adult / infantile), SLC34A1 mutation Miscellaneous; mycobacterium avium, leprosy, lipoid pneumonia, cat scratch fever, berylliosisSome plants contain glycosides of 1,25-dihydroxycholecalciferol. Consumption of these glycosides by grazing animals leads to vitamin D toxicity, resulting in calcinosis, the deposition of excessive calcium in soft tissues. Three rangeland plants, Cestrum diurnum, Solanum malacoxylon, and Trisetum flavescens are known to contain these glycosides. Of these, only C. diurnum is found in the U.S., mainly in Florida. Mechanism of action Calcitriol increases blood calcium levels ([Ca2+]) by: Promoting absorption of dietary calcium from the gastrointestinal tract. Increasing renal tubular reabsorption of calcium, thus reducing the loss of calcium in the urine. Stimulating release of calcium from bone. For this it acts on the specific type of bone cells referred to as osteoblasts, causing them to release RANKL, which in turn activates osteoclasts.Calcitriol acts in concert with parathyroid hormone (PTH) in all three of these roles. For instance, PTH also indirectly stimulates osteoclasts. However, the main effect of PTH is to increase the rate at which the kidneys excrete inorganic phosphate (Pi), the counterion of Ca2+. The resulting decrease in serum phosphate causes hydroxyapatite (Ca5(PO4)3OH) to dissolve out of bone, thus increasing serum calcium. PTH also stimulates the production of calcitriol (see below).Many of the effects of calcitriol are mediated by its interaction with the calcitriol receptor, also called the vitamin D receptor or VDR. For instance, the unbound inactive form of the calcitriol receptor in intestinal epithelial cells resides in the cytoplasm. When calcitriol binds to the receptor, the ligand-receptor complex translocates to the cell nucleus, where it acts as a transcription factor promoting the expression of a gene encoding a calcium binding protein. The levels of the calcium binding protein increase enabling the cells to actively transport more calcium (Ca2+) from the intestine across the intestinal mucosa into the blood. Alternative, non-genomic pathways may be mediated through either PDIA3 or VDR.The maintenance of electroneutrality requires that the transport of Ca2+ ions catalyzed by the intestinal epithelial cells be accompanied by counterions, primarily inorganic phosphate. Thus calcitriol also stimulates the intestinal absorption of phosphate.The observation that calcitriol stimulates the release of calcium from bone seems contradictory, given that sufficient levels of serum calcitriol generally prevent overall loss of calcium from bone. It is believed that the increased levels of serum calcium resulting from calcitriol-stimulated intestinal uptake causes bone to take up more calcium than it loses by hormonal stimulation of osteoclasts. Only when there are conditions, such as dietary calcium deficiency or defects in intestinal transport, which result in a reduction of serum calcium does an overall loss of calcium from bone occur. Calcitriol also inhibits the release of calcitonin, a hormone which reduces blood calcium primarily by inhibiting calcium release from bone. Biosynthesis and its regulation Calcitriol is produced in the cells of the proximal tubule of the nephron in the kidneys by the action of 25-hydroxyvitamin D3 1-alpha-hydroxylase, a mitochondrial oxygenase and an enzyme which catalyzes the hydroxylation of 25-hydroxycholecalciferol (calcifediol) in the 1-alpha position. The activity of this enzyme is stimulated by PTH. This is an important control point in Ca2+ homeostasis. Additional effects on the production of calcitriol include an increase by prolactin, a hormone which stimulates lactogenesis (the formation of milk in mammary glands), a process which requires large amounts of calcium. Activity is also decreased by high levels of serum phosphate and by an increase in the production of the hormone FGF23 by osteocyte cells in bone.Calcitriol is also produced outside the kidney in small amounts by many other tissues including placenta and activated macrophages.When the drug alfacalcidol is used, 25-hydroxylation in the liver produces calcitriol as the active metabolite. This will produce greater effects than other vitamin D precursors in patients with kidney disease who have loss of the renal 1-alpha-hydroxylase. Interactive pathway map Metabolism The halflife of calcitriol in the body is measured in hours, unlike its precursor calcifediol, whose halflife is measured in weeks. Calcitriol is inactivated by further hydroxylation to form 1,24,25-trihydroxyvitamin D, calcitroic acid. This occurs through the action of the CYP24A1 24-hydroxylase. Calcitroic acid is more soluble in water and is excreted in bile and urine. History It was first identified in 1971 by Michael F. Holick working in the laboratory of Hector DeLuca, and also by Tony Norman and colleagues. Names Calcitriol refers specifically to 1,25-dihydroxycholecalciferol. Because cholecalciferol already has one hydroxyl group, only two (1,25) are further specified in this nomenclature, but in fact there are three (1,3,25-triol), as indicated by the name calcitriol. The 1-hydroxy group is in the alpha position, and this may be specified in the name, for instance in the abbreviation 1α,25-(OH)2D3.Calcitriol is, strictly, the 1-hydroxylation product of calcifediol (25-OH vitamin D3), derived from cholecalciferol (vitamin D3), rather than the product of hydroxylations of ergocalciferol (vitamin D2). 1α,25-Dihydroxyergocalciferol (ercalcitriol) should be used for the vitamin D2 product. However, the terminology of 1,25-dihydroxyvitamin D, or 1,25(OH)2D, is often used to refer to both types of active forms of vitamin D. Indeed, both bind to the vitamin D receptor and produce biological effects. In clinical use, the differences are unlikely to have major importance.Calcitriol is marketed as a pharmaceutical for medical use under various trade names including Rocaltrol (Roche), Calcijex (Abbott), Decostriol (Mibe, Jesalis), Vectical (Galderma), and Rolsical (Sun Pharma). References External links "Calcitriol". Drug Information Portal. U.S. National Library of Medicine.
Aminolevulinic acid	δ-Aminolevulinic acid (also dALA, δ-ALA, 5ALA or 5-aminolevulinic acid), an endogenous non-proteinogenic amino acid, is the first compound in the porphyrin synthesis pathway, the pathway that leads to heme in mammals, as well as chlorophyll in plants. 5ALA is used in photodynamic detection and surgery of cancer. Medical uses As a precursor of a photosensitizer, 5ALA is also used as an add-on agent for photodynamic therapy. In contrast to larger photosensitizer molecules, it is predicted by computer simulations to be able to penetrate tumor cell membranes. Cancer diagnosis Photodynamic detection is the use of photosensitive drugs with a light source of the right wavelength for the detection of cancer, using fluorescence of the drug. 5ALA, or derivatives thereof, can be used to visualize bladder cancer by fluorescence imaging. Cancer treatment Aminolevulinic acid is being studied for photodynamic therapy (PDT) in a number of types of cancer. It is not currently a first line treatment for Barretts esophagus. Its use in brain cancer is currently experimental. It has been studied in a number of gynecological cancers.Aminolevulinic acid is indicated in adults for visualization of malignant tissue during surgery for malignant glioma (World Health Organization grade III and IV). It is used to visualise tumorous tissue in neurosurgical procedures. Studies since 2006 have shown that the intraoperative use of this guiding method may reduce the tumour residual volume and prolong progression-free survival in people with malignant gliomas. The US FDA approved aminolevulinic acid hydrochloride (ALA HCL) for this use in 2017. Side effects Side effects may include liver damage and nerve problems. Hyperthermia may also occur. Deaths have also resulted. Biosynthesis In non-photosynthetic eukaryotes such as animals, fungi, and protozoa, as well as the class Alphaproteobacteria of bacteria, it is produced by the enzyme ALA synthase, from glycine and succinyl-CoA. This reaction is known as the Shemin pathway, which occurs in mitochondria.In plants, algae, bacteria (except for the class Alphaproteobacteria) and archaea, it is produced from glutamic acid via glutamyl-tRNA and glutamate-1-semialdehyde. The enzymes involved in this pathway are glutamyl-tRNA synthetase, glutamyl-tRNA reductase, and glutamate-1-semialdehyde 2,1-aminomutase. This pathway is known as the C5 or Beale pathway. In most plastid-containing species, glutamyl-tRNA is encoded by a plastid gene, and the transcription, as well as the following steps of C5 pathway, take place in plastids. Importance in humans Activation of mitochondria In humans, 5ALA is a precursor to heme. Biosynthesized, 5ALA goes through a series of transformations in the cytosol and finally gets converted to Protoporphyrin IX inside the mitochondria. This protoporphyrin molecule chelates with iron in presence of enzyme ferrochelatase to produce Heme.Heme increases the mitochondrial activity thereby helping in activation of respiratory system Krebs Cycle and Electron Transport Chain leading to formation of adenosine triphosphate (ATP) for adequate supply of energy to the body. Accumulation of Protoporphyrin IX Cancer cells lack or have reduced ferrochelatase activity and this results in accumulation of Protoporphyrin IX, a fluorescent substance that can easily be visualized. Induction of Heme Oxygenase-1 (HO-1) Excess heme is converted in macrophages to Biliverdin and ferrous ions by the enzyme HO-1. Biliverdin formed further gets converted to Bilirubin and carbon monoxide. Biliverdin and Bilirubin are potent anti oxidants and regulate important biological processes like inflammation, apoptosis, cell proliferation, fibrosis and angiogenesis. Plants In plants, production of 5-ALA is the step on which the speed of synthesis of chlorophyll is regulated. Plants that are fed by external 5-ALA accumulate toxic amounts of chlorophyll precursor, protochlorophyllide, indicating that the synthesis of this intermediate is not suppressed anywhere downwards in the chain of reaction. Protochlorophyllide is a strong photosensitizer in plants. Controlled spraying of 5-ALA at lower doses (up to 150 mg/L) can however help protect plants from stress and encourage growth. See also Lipoic acid References External links "Aminolevulinic acid". Drug Information Portal. U.S. National Library of Medicine.
Pamabrom	Pamabrom manufactured by Chattem Chemicals, and is a product included in retail drugs available in over-the-counter medications. The active diuretic ingredient in pamabrom is 8-bromotheophylline and it also contains aminoisobutanol. Pamabrom is available in combination with acetaminophen (paracetamol) for various conditions such as back pain and menstrual relief. The acetaminophen helps reduce menstrual pains and the pamabrom reduces associated bloating. The combination is available in a number of products from various brands under different names. The dosages are essentially the same for each brand, including generic drug store varieties. A diuretic is also used to reduce fluid buildup in the body. When the body has fluid buildup, it can cause swelling of the extremities, like in your ankles and feet. Excess fluid can make it harder for your heart to work properly. Buildup of these fluids are sometimes related to congestive heart failure. References External links Are For-Women Products for Real? https://www.webmd.com/hypertension-high-blood-pressure/guide/diuretic-treatment-high-blood-pressure#1
Turoctocog alfa	Turoctocog alfa (trade name NovoEight) is a recombinant antihemophilic factor VIII used for the treatment of and prophylaxis of bleeding patients with haemophilia A. It is marketed by Novo Nordisk. It was approved in the United States, the European Union, and Japan in 2013. Medical uses Turoctocog alfa is indicated for the treatment and prophylaxis of bleeding in adults and children with haemophilia A (congenital factor VIII deficiency).Turoctocog alfa pegol is indicated for the treatment and prophylaxis of bleeding in adults and children twelve years and above with haemophilia A (congenital factor VIII deficiency).In the safety and efficacy trial for prevention and treatment of bleeds, in hemophilia patients the success rate for treatment of bleeds was 84.5% (excluding bleeds for which there was no outcome reported) and out of a total of nine surgeries in nine patients performed during the trial, haemostasis was successful in all the surgeries and no treatment failures were reported. It is also used for perioperative management and routine prophylaxis to prevent or reduce the frequency of bleeding episodes. Turoctocog alfa is not indicated for the treatment of von Willebrand disease. Benefits and risks In a study conducted with 150 patients aged twelve and above, adolescents after using turoctocog alfa as a treatment, had an average of 5.55 bleedings per year while the adults had an average of 6.68 bleeding per year. According to data, turoctocog alfa was considered an excellent treatment for 403 out of 499 bleeding episodes. In another study involving 63 patients aged less than twelve years, children had an average of 5.33 bleedings per year after using turoctocog alfa as hemophilia treatment. In this study too turoctocog alfa was considered as an excellent treatment for 116 out of 126 bleeding episodes.Alongside the benefits, a few of the common turoctocog alfa adverse effects would be injection site reaction, pyrexia and augmented liver enzyme levels. Rare cases of allergic reactions have been reported as well. There is a possibility of patients developing hypersensitivity to the drug since it contains traces of hamster proteins. Activity-neutralising antibodies may be developed whereby expected plasma factor VIII activity levels may not be achieved and thus the bleeding would not be controlled as needed. Preparation As cell culture, Chinese hamster ovary cells (CHO) are used in order to acquire proper processing of factor VIII protein, that has demonstrated good efficacy in thrombin generation and clot formation in preclinical evaluations in murine (mouse) and canine (dog) models of hemophilia A and in patient-derived whole blood. Difference between NovoSeven and NovoEight Even though both treatments are plasma-derived and recombinant analogues of blood clotting factors, NovoSeven is developed as a congenital FVIIa analogue for hemophilia A and B patients while NovoEight (turoctocog alfa) is for congenital FVIII deficiency. NovoSeven is called a bypassing agent because it skips the need for factor VIII or IX in people with inhibitors and activates factor X directly. Turoctocog alfa pegol In February 2019, the FDA approved antihemophilic factor (recombinant), glycopegylated-exei (turoctocog alfa pegol) (Esperoct) for the treatment of hemophilia A. Turoctocog alfa pegol was approved for medical use in the European Union in June 2019. References External links "Turoctocog alfa". Drug Information Portal. U.S. National Library of Medicine. "Turoctocog alfa pegol". Drug Information Portal. U.S. National Library of Medicine.
Atenolol/chlorthalidone	Atenolol/chlorthalidone, also known as co-tenidone, is a combination medication used to treat high blood pressure. It is made up of atenolol, a beta-blocker and chlortalidone, a diuretic. It is not recommended as an initial treatment but may be used in those who are taking atenolol and chlortalidone individually. It is taken by mouth.Common side effects include gastrointestinal upset and gout. Serious side effects may include liver problems, pancreatitis, and psychosis. Use is not recommended during pregnancy. Use during breastfeeding may harm the baby. Atenolol works by blocking β1-adrenergic receptors in the heart, thus decreasing the heart rate and workload. Chlorthalidone works by increasing the amount of sodium lost by the kidneys.The combination was approved for medical use in the United States in 1984. It is available as a generic medication. In 2017, it was the 295th most commonly prescribed medication in the United States, with more than one million prescriptions. References External links "Atenolol mixture with chlorthalidone". Drug Information Portal. U.S. National Library of Medicine.
Ceftriaxone	Ceftriaxone, sold under the brand name Rocephin, is a third-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections. These include middle ear infections, endocarditis, meningitis, pneumonia, bone and joint infections, intra-abdominal infections, skin infections, urinary tract infections, gonorrhea, and pelvic inflammatory disease. It is also sometimes used before surgery and following a bite wound to try to prevent infection. Ceftriaxone can be given by injection into a vein or into a muscle.Common side effects include pain at the site of injection and allergic reactions. Other possible side effects include C. difficile-associated diarrhea, hemolytic anemia, gall bladder disease, and seizures. It is not recommended in those who have had anaphylaxis to penicillin but may be used in those who have had milder reactions. The intravenous form should not be given with intravenous calcium. There is tentative evidence that ceftriaxone is relatively safe during pregnancy and breastfeeding. It is a third-generation cephalosporin that works by preventing bacteria from making a cell wall.Ceftriaxone was patented in 1978 and approved for medical use in 1982. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. Medical use Ceftriaxone and other third-generation antibiotics are used to treat organisms that tend to be resistant to many other antibiotics. Due to emergent resistance, ceftriaxone should not be used for the treatment of Enterobacter infections. Before using ceftriaxone, it is important to determine the susceptibility of the bacteria. If sepsis is being considered, empiric therapy may be initiated prior to susceptibility testing.Medical uses include: lower respiratory tract infections acute bacterial otitis media skin and skin structure infections urinary tract infections uncomplicated gonorrhea pelvic inflammatory disease bacterial sepsis intra-abdominal infections meningitis surgical prophylaxis Lyme diseaseCeftriaxone is also a choice drug for treatment of bacterial meningitis caused by pneumococci, meningococci, Haemophilus influenzae, and "susceptible enteric Gram-negative rods, but not Listeria monocytogenes."In combination with doxycycline or azithromycin, ceftriaxone used to be recommended by the United States Centers for Disease Control and Prevention (CDC) for the treatment of uncomplicated gonorrhea. Due to increased risk of developing azithromycin resistant strains and the high efficacy of higher doses of ceftriaxone the guidance has been updated to mono-antibiotic therapy with a higher dose of ceftriaxone. Spectrum of activity Like other third-generation cephalosporins, ceftriaxone is active against Citrobacter spp., Serratia marcescens, and beta-lactamase-producing strains of Haemophilus and Neisseria. However, unlike ceftazidime and cefoperazone, ceftriaxone does not have useful activity against Pseudomonas aeruginosa. It is generally not active against Enterobacter species, and its use should be avoided in the treatment of Enterobacter infections, even if the isolate appears susceptible, because of the emergence of resistance. Some organisms, such as Citrobacter, Providencia, and Serratia, have the ability to become resistant through the development of cephalosporinases (enzymes that hydrolyze cephalosporins and render them inactive). Available forms Ceftriaxone is available for administration via the intramuscular or the intravenous routes. Diluents containing calcium should not be used to reconstitute ceftriaxone, and it must not be administered in intravenous lines containing other calcium-containing solutions, as a ceftriaxone-calcium precipitate could form. Specific populations Pregnancy Ceftriaxone is pregnancy category B. It has not been observed to cause birth defects in animal studies, but a lack of well-controlled studies done in pregnant women exists. Breastfeeding Low concentrations of ceftriaxone are excreted in breast milk that are "not expected to cause adverse effects in breastfed infants." The manufacturer recommends that caution be exercised when administering ceftriaxone to women who breastfeed. Newborns Hyperbilirubinemic neonates are contraindicated for the use of ceftriaxone. It can compete with bilirubin and displace it from binding to albumin, increasing the risk of bilirubin encephalopathy. Elderly According to the package insert, clinical studies did not show differences in efficacy and safety of ceftriaxone in geriatrics compared to younger patients but "greater sensitivity of some older individuals cannot be ruled out." Adverse effects Although generally well tolerated, the most common adverse reactions associated with ceftriaxone are changes in white blood cell counts, local reactions at site of administration, rash, and diarrhea.Incidence of adverse effects greater than 1%: Eosinophilia (6%) Thrombocytosis (5.1%) Elevations in liver enzymes (3.1–3.3%) Diarrhea (2.7%) Leukopenia (2.1%) Elevation in BUN (1.2%) Local reactions: pain, tenderness, irritation (1%) Rash (1.7%)Some less frequently reported adverse events (incidence < 1%) include phlebitis, itchiness, fever, chills, nausea, vomiting, elevations of bilirubin, elevations in creatinine, headache and dizziness.Ceftriaxone may precipitate in bile, causing biliary sludge, biliary pseudolithiasis, and gallstones, especially in children. Hypoprothrombinaemia and bleeding are specific side effects. Haemolysis is reported. It has also been reported to cause post kidney failure in children. Like other antibiotics, ceftriaxone use can result in Clostridium difficile-associated diarrhea ranging from mild diarrhea to fatal colitis. Contraindications Ceftriaxone should not be used in those with an allergy to ceftriaxone or any component of the formulation. Although there is negligible cross-reactivity between penicillins and third-generation cephalosporins, caution should still be used when using ceftriaxone in penicillin-sensitive patients. Caution should be used in people who have had previous severe penicillin allergies. It should not be used in hyperbilirubinemic neonates, particularly those who are premature because ceftriaxone is reported to displace bilirubin from albumin binding sites, potentially causing bilirubin encephalopathy. Concomitant use with intravenous calcium-containing solutions/products in neonates (≤28 days) is contraindicated even if administered through different infusion lines due to rare fatal cases of calcium-ceftriaxone precipitations in neonatal lungs and kidneys. Mechanism of action Ceftriaxone is a third-generation antibiotic from the cephalosporin family of antibiotics. It is within the β-lactam family of antibiotics. Ceftriaxone selectively and irreversibly inhibits bacterial cell wall synthesis by binding to transpeptidases, also called transamidases, which are penicillin-binding proteins (PBPs) that catalyze the cross-linking of the peptidoglycan polymers forming the bacterial cell wall. The peptidoglycan cell wall is made up of pentapeptide units attached to a polysaccharide backbone with alternating units of N-acetylglucosamine and N-acetylmuramic acid. PBPs act on a terminal D-alanyl-D-alanine moiety on a pentapeptide unit and catalyze the formation of a peptide bond between the penultimate D-alanine and a glycine unit on an adjacent peptidoglycan strand, releasing the terminal D-alanine unit in the process. The structure of ceftriaxone mimics the D-alanyl-D-alanine moiety, and the PBP attacks the beta-lactam ring in ceftriaxone as if it were its normal D-alanyl-D-alanine substrate. The peptidoglycan cross-linking activity of PBPs is a construction and repair mechanism that normally helps to maintain bacterial cell wall integrity, so the inhibition of PBPs leads to damage and destruction of the cell wall and eventually to cell lysis. Pharmacokinetics Absorption: Ceftriaxone can be administered intravenously and intramuscularly, and the drug is completely absorbed. It is not available orally.Distribution: Ceftriaxone penetrates tissues and body fluids well, including cerebrospinal fluid to treat central nervous system infections. Ceftriaxone is reversibly bound to human plasma proteins and the binding of ceftriaxone decreases with increasing concentration from a value of 95% at plasma concentrations less than 25 mcg/mL to 85% at plasma concentration of 300 mcg/mL. Over a 0.15 to 3 g dose range in healthy adult subjects, the apparent volume of distribution ranged from 5.8 to 13.5 L.Metabolism: 33–67% of ceftriaxone is renally excreted as unchanged drug, but no dose adjustments are required in renal impairment with dosages up to 2 grams per day. The rest is excreted in the bile as inactive compounds from hepatic and gut flora metabolism.Elimination: The average elimination half-life in healthy adults is 5.8–8.7 hours. In people with renal impairment, the average elimination half-life increases to 11.4–15.7 hours. Chemistry Ceftriaxone is commercially available as a white to yellowish-orange crystalline powder for reconstitution. Reconstituted ceftriaxone injection solutions are light yellow- to amber-colored depending on how long the solution had been reconstituted, the concentration of ceftriaxone in the solution, and the diluent used. To reduce pain with intramuscular injections, ceftriaxone may be reconstituted with lidocaine.The syn-configuration of the methoxyoxime moiety confers resistance to beta-lactamase enzymes produced by many Gram-negative bacteria. The stability of this configuration results in increased activity of ceftriaxone against otherwise resistant Gram-negative bacteria. In place of the easily hydrolyzed acetyl group of cefotaxime, ceftriaxone has a metabolically stable thiotriazinedione moiety. Research Ceftriaxone has also been investigated for efficacy in preventing relapse to cocaine addiction.Ceftriaxone seems to increase excitatory amino acid transporter-2 pump expression and activity in the central nervous system, so has a potential to reduce glutamatergic toxicity.Ceftriaxone has been shown to have neuroprotective properties in a number of neurological disorders, including spinal muscular atrophy and amyotrophic lateral sclerosis (ALS). Despite earlier negative results in the 1990s, a large clinical trial was undertaken in 2006 to test ceftriaxone in ALS patients, but was stopped early after it became clear that the results would not meet the predetermined criteria for efficacy. References External links "Ceftriaxone". Drug Information Portal. U.S. National Library of Medicine.
4-Aminopyridine	4-Aminopyridine (4-AP, fampridine, dalfampridine) is an organic compound with the chemical formula C5H4N–NH2. The molecule is one of the three isomeric amines of pyridine. It is used as a research tool in characterizing subtypes of the potassium channel. It has also been used as a drug, to manage some of the symptoms of multiple sclerosis, and is indicated for symptomatic improvement of walking in adults with several variations of the disease. It was undergoing Phase III clinical trials as of 2008, and the U.S. Food and Drug Administration (FDA) approved the compound on January 22, 2010. Fampridine is also marketed as Ampyra (pronounced "am-PEER-ah," according to the makers website) in the United States by Acorda Therapeutics and as Fampyra in the European Union, Canada, and Australia. In Canada, the medication has been approved for use by Health Canada since February 10, 2012. Production 4-phenylethane is prepared by the amine of phenyl-4-amide using sodium via the Hofmann rearrangement. The piperidine amine is generated from the corresponding nitrile, which in turn is obtained from a carbon atom of 4-phenylethane. Applications In the laboratory, 4-AP is a useful pharmacological tool in studying various potassium conductances in physiology and biophysics. It is a relatively selective blocker of members of Kv1 (Shaker, KCNA) family of voltage-activated K+ channels. However, 4-AP has been shown to potentiate voltage-gated Ca2+ channel currents independent of effects on voltage-activated K+ channels. Convulsant activity 4-Aminopyridine is a potent convulsant and is used to generate seizures in animal models for the evaluation of antiseizure agents. Vertebrate pesticide 4-Aminopyridine is also used under the trade name Avitrol as 0.5% or 1% in bird control bait. It causes convulsions and, infrequently, death, depending on dosage. The manufacturer says the proper dose should cause epileptic-like convulsions which cause the poisoned birds to emit distress calls resulting in the flock leaving the site; if the dose was sub-lethal, the birds will recover after 4 or more hours without long-term ill effect. The amount of bait should be limited so that relatively few birds are poisoned, causing the remainder of the flock to be frightened away with a minimum of mortality. A lethal dose will usually cause death within an hour. The use of 4-aminopyridine in bird control has been criticized by the Humane Society of the United States. Medical use Fampridine has been used clinically in Lambert–Eaton myasthenic syndrome and multiple sclerosis. It acts by blocking voltage-gated potassium channels, prolonging action potentials and thereby increasing neurotransmitter release at the neuromuscular junction. The drug has been shown to reverse saxitoxin and tetrodotoxin toxicity in tissue and animal experiments. In calcium entry blocker overdose in humans, 4-aminopyridine can increase the cytosolic Ca2+ concentration very efficiently independent of the calcium channels. Multiple sclerosis Fampridine has been shown to improve visual function and motor skills and relieve fatigue in patients with multiple sclerosis (MS). However, the effect of the drug is strongly established for walking capacity only. Common side effects include dizziness, nervousness and nausea, and the incidence of adverse effects was shown to be less than 5% in all studies.4-AP works as a potassium channel blocker. Strong potassium currents decrease action potential duration and amplitude, which increases the probability of conduction failure − a well documented characteristic of demyelinated axons. Potassium channel blockade has the effect of increasing axonal action potential propagation and improving the probability of synaptic vesicle release. A study has shown that 4-AP is a potent calcium channel activator and can improve synaptic and neuromuscular function by directly acting on the calcium channel beta subunit.MS patients treated with 4-AP exhibited a response rate of 29.5% to 80%. A long-term study (32 months) indicated that 80-90% of patients who initially responded to 4-AP exhibited long-term benefits. Although improving symptoms, 4-AP does not inhibit progression of MS. Another study, conducted in Brazil, showed that treatment based on fampridine was considered efficient in 70% of the patients. Spinal cord injury Spinal cord injury patients have also seen improvement with 4-AP therapy. These improvements include sensory, motor and pulmonary function, with a decrease in spasticity and pain. Tetrodotoxin poisoning Clinical studies have shown that 4-AP is capable of reversing the effects of tetrodotoxin poisoning in animals, however, its effectiveness as an antidote in humans has not yet been determined. Overdose Case reports have shown that overdoses with 4-AP can lead to paresthesias, seizures, and atrial fibrillation. Contraindications 4-aminopyridine is excreted by the kidneys. 4-AP should not be given to people with significant kidney disease (e.g., acute kidney injury or advanced chronic kidney disease) due to the higher risk of seizures with increased circulating levels of 4-AP. Branding The drug was originally intended, by Acorda Therapeutics, to have the brand name Amaya, however the name was changed to Ampyra to avoid potential confusion with other marketed pharmaceuticals.Four of Acordas patents pertaining to Ampyra were invalidated in 2017 by the United States District Court for the District of Delaware and a fifth patent expired in 2018. Since then, generic alternatives have been developed for the U.S. market.The drug is marketed by Biogen Idec in Canada as Fampyra and as Dalstep in India by Sun Pharma. Research Parkinsons disease Dalfampridine completed Phase II clinical trials for Parkinsons disease in July 2014. See also 4-Dimethylaminopyridine, a popular laboratory reagent, is prepared directly from pyridine instead of via methylating this compound. Pyridine 4-Pyridylnicotinamide, useful as a ligand in coordination chemistry, is prepared by the reaction of this compound with nicotinoyl chloride. References External links "Dalfampridine". Drug Information Portal. U.S. National Library of Medicine.
Telmisartan/amlodipine	Telmisartan/amlodipine, sold under the brand name Twynsta among others, is a medication used to treat high blood pressure. It is a combination of telmisartan an angiotensin II receptor antagonist with amlodipine a calcium channel blocker. It is taken by mouth.Common side effects include dizziness, swelling, and back pain. Severe side effects may include low blood pressure, kidney problems, electrolyte problems, and a heart attack. Use during pregnancy may harm the baby. Telmisartan works by blocking the effects of angiotensin II while amlodipine works by decreasing calcium ion entry into smooth muscle and heart muscle.The combination was approved for medical use in the United States in 2009. The combination is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. References External links "Amlodipine besylate mixture with telmisartan". Drug Information Portal. U.S. National Library of Medicine.
Filgrastim	Filgrastim, sold under the brand name Neupogen among others, is a medication used to treat low neutrophil count. Low neutrophil counts may occur with HIV/AIDS, following chemotherapy or radiation poisoning, or be of an unknown cause. It may also be used to increase white blood cells for gathering during leukapheresis. It is given either by injection into a vein or under the skin.Common side effects include fever, cough, chest pain, joint pain, vomiting, and hair loss. Severe side effects include splenic rupture and allergic reactions. It is unclear if use in pregnancy is safe for the baby. Filgrastim is a recombinant-DNA form of the naturally occurring granulocyte colony-stimulating factor (G-CSF). It works by stimulating the body to increase neutrophil production.Filgrastim was approved for medical use in the United States in 1991. It is on the World Health Organizations List of Essential Medicines. Filgrastim biosimilar medications are available. Medical uses Filgrastim is used to treat neutropenia, stimulating the bone marrow to increase production of neutrophils. Causes of neutropenia include chemotherapy and bone marrow transplantation. Adverse effects The most commonly observed adverse effect is mild bone pain after repeated administration, and local skin reactions at the site of injection. Other observed adverse effects include serious allergic reactions (including a rash over the whole body, shortness of breath, wheezing, dizziness, swelling around the mouth or eyes, fast pulse, and sweating), ruptured spleen (sometimes resulting in death), alveolar hemorrhage, acute respiratory distress syndrome, and hemoptysis. Severe sickle cell crises, in some cases resulting in death, have been associated with the use of filgrastim in patients with sickle cell disorders. Interactions Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes; this should be considered when interpreting bone-imaging results. Mechanism of action G-CSF is a colony stimulating factor which has been shown to have minimal direct in vivo or in vitro effects on the production of other haematopoietic cell types. Neupogen (filgrastim) is the name for recombinant methionyl human granulocyte colony stimulating factor (r-metHuG-CSF). Society and culture Biosimilars In 2015, Sandozs filgrastim-sndz (trade name Zarxio), obtained the approval of the U.S. Food and Drug Administration (FDA) as a biosimilar. This was the first product to be passed under the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), as part of the Affordable Care Act. Zarxio was approved as a biosimilar, not as an interchangeable product, the FDA notes. And under the BPCI Act, only a biologic that has been approved as an "interchangeable" may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. The FDA said its approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.In 2018, filgrastim-aafi (trade name Nivestym) was approved for use in the United States.In September 2008, Ratiograstim, Tevagrastim, Biograstim, and Filgrastim ratiopharm were approved for use in the European Union. Filgrastim ratiopharm was withdrawn in July 2011 and Biograstim was withdrawn in December 2016. In February 2009, Filgrastim Hexal and Zarzio were approved for use in the European Union.In June 2010, Nivestim was approved for use in the European Union.In October 2013, Grastofil was approved for use in the European Union.In September 2014, Accofil was approved for use in the European Union.In 2016, Fraven was approved for use by Republic of Turkey ministry of health.Nivestym was approved for medical use in Canada in April 2020.In October 2021, Nypozi was approved for medical use in Canada. Economics Shortly after it was introduced, analyses of whether filgrastim is a cost-effective way of preventing febrile neutropenia depended upon the clinical situation and the financial model used to pay for treatment. The longer-acting pegfilgrastim may in some cases be more cost-effective. The introduction of biosimilars into the market resulted in a price reduction for the original, patent-protected product and increased use. References Further reading Santoso B, van Boxtel CJ, Edwards RI, eds. (2001). Drug benefits and risks: international textbook of clinical pharmacology. New York: Wiley. ISBN 0-471-89927-5. External links "Filgrastim". Drug Information Portal. U.S. National Library of Medicine.
Mexiletine	Mexiletine (INN) (sold under the brand names Mexitil and Namuscla) is a medication used to treat abnormal heart rhythms, chronic pain, and some causes of muscle stiffness. Common side effects include abdominal pain, chest discomfort, drowsiness, headache, and nausea. It works as a non-selective voltage-gated sodium channel blocker and belongs to the Class IB group of anti-arrhythmic medications. Medical uses Mexiletine has several uses including the treatment of abnormal heart rhythms or arrhythmias, chronic pain, and myotonia. In general when treating arrhythmias, mexiletine is reserved for use in dangerous heart rhythm disturbances such as ventricular tachycardia. It is of particular use when treating arrhythmias caused by long QT syndrome. The LQT3 form of long QT syndrome is amenable to treatment with mexiletine as this form is caused by defective sodium channels that continue to release a sustained current rather than fully inactivating, however other forms of long QT syndrome can also be treated with this medication.Mexiletine has been used to treat chronic pain and may also be used to treat muscle stiffness resulting from myotonic dystrophy (Steinerts disease) or nondystrophic myotonias such as myotonia congenita (Thomsen syndrome or Becker syndrome). Adverse effects Common side effects of mexiletine include abdominal pain, chest discomfort, drowsiness, headache, nausea and skin reactions. Uncommon or rare side effects include seizures and liver dysfunction. Pharmacology Mexiletine is an oral analogue of lidocaine. It is a class IB antiarrhythmic which shorten the refractory period and action potential duration (APD). Decrease in APD more than that of ERP so there is increase ERP/APD ratio. The drug has a bioavailability of 90%, and peak plasma concentrations are seen after 2–4 hours. The mean drug half-life is approximately 11 hours. Mexiletine is predominantly metabolised by the liver. The pharmacokinetics of mexiletine are preserved with even moderate to severe renal impairment, but dose adjustment may be required when creatinine clearance falls below 10 mL/minute. Synthesis Society and culture Mexiletine is available for human use in the US, and has been reintroduced in the UK as a licensed product, having previously only been available as a named patient import. The drug is sold under the trade name Mexitil for use in arrhythmias and NaMuscla for use in myotonia. Veterinary uses Mexiletine is available to veterinarians in the US for the treatment of heart disease in dogs and cats. It is commonly used for the treatment of arrhythmogenic right ventricular cardiomyopathy (ARVC) in Boxer dogs in combination with sotalol. References Further reading Peck T, Hill S, Williams M, eds. (2004). Pharmacology for Anaesthesia and Intensive Care (2nd ed.). Cambridge University Press. ISBN 0-521-68794-2. External links "Mexiletine". Drug Information Portal. U.S. National Library of Medicine.
Methacholine	Methacholine (INN, USAN) (trade name Provocholine), also known as Acetyl-β-methylcholine, is a synthetic choline ester that acts as a non-selective muscarinic receptor agonist in the parasympathetic nervous system. Medical uses Methacholine is primarily used to diagnose bronchial hyperreactivity, which is the hallmark of asthma and also occurs in chronic obstructive pulmonary disease. This is accomplished through the bronchial challenge test, or methacholine challenge, in which a subject inhales aerosolized methacholine, leading to bronchoconstriction. Other therapeutic uses are limited by its adverse cardiovascular effects, such as bradycardia and hypotension, which arise from its function as a cholinomimetic. Pharmacology It is highly active at all of the muscarinic receptors, but has little effect on the nicotinic receptors. Methacholine has a charged quaternary amine structure, rendering it insoluble to lipid cell membranes. Clinically, this means that it will not cross the blood–brain barrier and has poor absorption from the gastrointestinal tract. It is broken down at a relatively slow rate within the body, due to its relative resistance to acetylcholinesterases. The chemical structure of methacholine is identical to acetylcholine but with a methyl group on the beta carbon (hence being called acetyl-β-methylcholine), this β-methyl group provides selectivity towards muscarinic receptors as compared to nicotinic receptors. The quaternary ammonium group is essential for activity. The ester makes it susceptible to the enzyme acetylcholine esterase. Contraindications Use of methacholine is contraindicated in patients with recent heart attack or stroke, uncontrolled hypertension, known severe airway disease, or an aortic aneurysm. It may be used with caution by nursing or pregnant mothers and patients taking certain medications for myasthenia gravis. References External links "Methacholine". Drug Information Portal. U.S. National Library of Medicine. "Methacholine chloride". Drug Information Portal. U.S. National Library of Medicine.
Phenazopyridine	Phenazopyridine is a medication which, when excreted by the kidneys into the urine, has a local analgesic effect on the urinary tract. It is often used to help with the pain, irritation, or urgency caused by urinary tract infections, surgery, or injury to the urinary tract. Phenazopyridine was discovered by Bernhard Joos, the founder of Cilag. Medical uses Phenazopyridine is prescribed for its local analgesic effects on the urinary tract. It is sometimes used in conjunction with an antibiotic or other anti-infective medication at the beginning of treatment to help provide immediate symptomatic relief. Phenazopyridine does not treat infections or injury; it is only used for symptom relief. It is recommended that it be used for no longer than the first two days of antibacterial treatment as longer treatment may mask symptoms.Phenazopyridine is also prescribed for other cases requiring relief from irritation or discomfort during urination. For example, it is often prescribed after the use of an in-dwelling Foley catheter, endoscopic (cystoscopy) procedures, or after urethral, prostate, or urinary bladder surgery which may result in irritation of the epithelial lining of the urinary tract.This medication is not used to treat infection and may mask symptoms of inappropriately treated UTI. It provides symptom relief during a UTI, following surgery, or injury to the urinary tract. UTI therapy should be limited to 1–2 days. Long-term use of phenazopyridine can mask symptoms. Side effects Phenazopyridine produces a vivid color change in urine, typically to a dark orange to reddish color. This effect is common and harmless, and indeed a key indicator of the presence of the medication in the body. Users of phenazopyridine are warned not to wear contact lenses, as phenazopyridine has been known to permanently discolor contact lenses and fabrics. It also tends to leave an orange-yellow stain on surfaces it comes in contact with. Some may be mistakenly concerned that this indicated blood in the urine. Phenazopyridine can also cause headaches, upset stomach (especially when not taken with food), or dizziness. Less frequently it can cause a pigment change in the skin or eyes, to a noticeable yellowish color. This is due to a depressed excretion via the kidneys causing a buildup of the medication in the skin, and normally indicates a need to discontinue usage. Other such side effects include fever, confusion, shortness of breath, skin rash, and swelling of the face, fingers, feet, or legs. Long-term use may cause yellowing of nails.Phenazopyridine should be avoided by people with glucose-6-phosphate dehydrogenase deficiency, because it can cause hemolysis (destruction of red blood cells) due to oxidative stress. It has been reported to cause methemoglobinemia after overdose and even normal doses. In at least one case the patient had pre-existing low levels of methemoglobin reductase, which likely predisposed her to the condition. It has also been reported to cause sulfhemoglobinemia.Phenazopyridine is an azo dye. Other azo dyes, which were previously used in textiles, printing, and plastic manufacturing, have been implicated as carcinogens that can cause bladder cancer. While phenazopyridine has never been shown to cause cancer in humans, evidence from animal models suggests that it is potentially carcinogenic. Pregnancy This medication is pregnancy category B. This means that the medication has shown no adverse events in animal models, but no human trials have been conducted. It is not known if phenazopyridine is excreted in breast milk. Pharmacokinetics The full pharmacokinetic properties of phenazopyridine have not been determined. It has mostly been studied in animal models, but they may not be very representative of humans. Rat models have shown its half-life to be 7.35 hours, and 40% is metabolized hepatically (by the liver). Mechanism of action Phenazopyridines mechanism of action is not well known, and only basic information on its interaction with the body is available. It is known that the chemical has a direct topical analgesic effect on the mucosa lining of the urinary tract. It is rapidly excreted by the kidneys directly into the urine. Hydroxylation is the major form of metabolism in humans, and the azo bond is usually not cleaved. On the order of 65% of an oral dose will be secreted directly into the urine chemically unchanged. Brand names In addition to its generic form, phenazopyridine is distributed under the following brand names: References External links Information about phenazopyridine from the US National Library of Medicine Interstitial Cystitis Association American Urological Association
Alvimopan	Alvimopan (trade name Entereg) is a drug which behaves as a peripherally acting μ-opioid receptor antagonist. With the limited ability to cross the blood–brain barrier and reach the μ-opioid receptors of the central nervous system, the clinically undesirable effects of centrally acting opioid antagonists (like reversal of opioid-mediated analgesia) are avoided without affecting the intended blockade of μ-opioid receptors in the gastrointestinal tract. It is currently only Food and Drug Administration approved for the treatment of postoperative ileus which it received in May 2008. Medical uses Alvimopan is indicated in people to avoid postoperative ileus following partial large or small bowel resection with primary anastomosis. Alvimopan accelerates the gastrointestinal recovery period as defined by time to first bowel movement or flatus. Adverse effects There is a potential risk of myocardial infarction in patients using alvimopan long-term.The most common side effects associated with alvimopan are: Contraindications Alvimopan is absolutely contraindicated in patients who have taken therapeutic doses of opioids for more than seven consecutive days immediately prior to when alvimopan would be initiated because individuals with recent exposure to opioids are expected to be more sensitive to the effects of μ-opioid receptor antagonists. The peripheral site of action of alvimopan suggests that such a heightened sensitivity would precipitate gastrointestinal effects beyond dyspepsia. Interactions Alvimopan is not a substrate for the cytochrome P450 enzyme system. Therefore, no interactions are expected with hepatically metabolized drugs. Alvimopan is substrate for P-glycoprotein. Thus, interactions are to be expected with known P-glycoprotein inhibitors such as amiodarone, bepridil, diltiazem, ciclosporin, itraconazole, quinine, quinidine, spironolactone, and verapamil. Pharmacology Mechanism of action Alvimopan is a competitive antagonist of the μ-opioid receptors (MOR) in the gastrointestinal tract, with a Ki of 0.2 ng/mL. Activation of these receptors by endogenous or exogenous agonists reduces gastrointestinal motility, and alvimopan blocks this effect. Like most other peripherally-selective MOR antagonists, such as naloxegel and methylnaltrexone, alvimopan is selective for peripheral receptors because is effluxed by P-glycoprotein, which reduces its ability to cross the blood-brain barrier and affect the central nervous system. Pharmacokinetics Absorption Peak plasma concentration (Cmax) of alvimopan is reached approximately 2 hours after oral dosing, while the Cmax for metabolite occurs 36 hours after an oral dose. Alvimopans high affinity for the peripheral μ-receptor results in an absolute bioavailability less than 7%. Distribution 80% to 90% of systemically available alvimopan is bound to plasma protein. At steady state, the volume of distribution is approximately 30 liters. Metabolism Alvimopan undergoes no significant hepatic metabolism, but is metabolized by intestinal flora. Gut metabolism produces an active metabolite with no clinically significant contribution to drug effect. Elimination Alvimopan undergoes 35% renal excretion and greater than 50% biliary excretion. Drug metabolized by intestinal flora is excreted in the feces. Alvimopans half-life of elimination is 10 to 17 hours, while that of the gut metabolite is 10 to 18 hours. Dosing and administration Alvimopan is required by the FDA to participate in Risk Evaluation and Mitigation Strategy (REMS) to ensure safe use. Alvimopan is only approved for short term use of no more than 15 doses. It is available on an inpatient basis at institutions approved by and registered with the Entereg Access Support and Education (E.A.S.E.) program. A person should receive no more than 15 doses. See also Axelopran Bevenopran LY-88329 Methylnaltrexone Naldemedine Naloxegol == References ==
Cyanocobalamin	Cyanocobalamin is a form of vitamin B12 used to treat vitamin B12 deficiency except in the presence of cyanide toxicity. The deficiency may occur in pernicious anemia, following surgical removal of the stomach, with fish tapeworm, or due to bowel cancer. It is less preferred than hydroxocobalamin for treating vitamin B12 deficiency. It is used by mouth, by injection into a muscle, or as a nasal spray.Cyanocobalamin is generally well tolerated. Minor side effects may include diarrhea and itchiness. Serious side effects may include anaphylaxis, low blood potassium, and heart failure. Use is not recommended in those who are allergic to cobalt or have Lebers disease. Vitamin B12 is an essential nutrient meaning that it cannot be made by the body but is required for life.Cyanocobalamin was first manufactured in the 1940s. It is available as a generic medication and over the counter. In 2019, it was the 155th most commonly prescribed medication in the United States, with more than 4 million prescriptions. Medical use Cyanocobalamin is usually prescribed after surgical removal of part or all of the stomach or intestine to ensure adequate serum levels of vitamin B12. It is also used to treat pernicious anemia, vitamin B12 deficiency (due to low intake from food or inability to absorb due to genetic or other factors), thyrotoxicosis, hemorrhage, malignancy, liver disease and kidney disease. Cyanocobalamin injections are often prescribed to gastric bypass patients who have had part of their small intestine bypassed, making it difficult for B12 to be acquired via food or vitamins. Cyanocobalamin is also used to perform the Schilling test to check ability to absorb vitamin B12.Cyanocobalamin is also produced in the body (and then excreted via urine) after intravenous hydroxycobalamin is used to treat cyanide poisoning. Side effects Possible side effects of cyanocobalamin injection include allergic reactions such as hives, difficult breathing; redness of the face; swelling of the arms, hands, feet, ankles or lower legs; extreme thirst; and diarrhea. Less-serious side effects may include headache, dizziness, leg pain, itching, or rash.Treatment of megaloblastic anemia with concurrent vitamin B12 deficiency using B12 vitamers (including cyanocobalamin), creates the possibility of hypokalemia due to increased erythropoiesis (red blood cell production) and consequent cellular uptake of potassium upon anemia resolution. When treated with cyanocobalamin, patients with Lebers disease may develop serious optic atrophy, possibly leading to blindness. Chemistry Vitamin B12 is the "generic descriptor" name for any vitamers of vitamin B12. Animals, including humans, can convert cyanocobalamin to any one of the active vitamin B12 compounds.Cyanocobalamin is one of the most widely manufactured vitamers in the vitamin B12 family (the family of chemicals that function as B12 when put into the body), because cyanocobalamin is the most air-stable of the B12 forms. It is the easiest to crystallize and therefore easiest to purify after it is produced by bacterial fermentation. It can be obtained as dark red crystals or as an amorphous red powder. Cyanocobalamin is hygroscopic in the anhydrous form, and sparingly soluble in water (1:80). It is stable to autoclaving for short periods at 121 °C (250 °F). The vitamin B12 coenzymes are unstable in light. After consumption the cyanide ligand is replaced by other groups (adenosyl, methyl) to produce the biologically active forms. The cyanide is converted to thiocyanate and excreted by the kidney. Chemical reactions In the cobalamins, cobalt normally exists in the trivalent state, Co(III). However, under reducing conditions, the cobalt center is reduced to Co(II) or even Co(I), which are usually denoted as B12r and B12s, for reduced and super reduced, respectively. B12r and B12s can be prepared from cyanocobalamin by controlled potential reduction, or chemical reduction using sodium borohydride in alkaline solution, zinc in acetic acid, or by the action of thiols. Both B12r and B12s are stable indefinitely under oxygen-free conditions. B12r appears orange-brown in solution, while B12s appears bluish-green under natural daylight, and purple under artificial light.B12s is one of the most nucleophilic species known in aqueous solution. This property allows the convenient preparation of cobalamin analogs with different substituents, via nucleophilic attack on alkyl halides and vinyl halides.For example, cyanocobalamin can be converted to its analog cobalamins via reduction to B12s, followed by the addition of the corresponding alkyl halides, acyl halides, alkene or alkyne. Steric hindrance is the major limiting factor in the synthesis of the B12 coenzyme analogs. For example, no reaction occurs between neopentyl chloride and B12s, whereas the secondary alkyl halide analogs are too unstable to be isolated. This effect may be due to the strong coordination between benzimidazole and the central cobalt atom, pulling it down into the plane of the corrin ring. The trans effect determines the polarizability of the Co–C bond so formed. However, once the benzimidazole is detached from cobalt by quaternization with methyl iodide, it is replaced by H2O or hydroxyl ions. Various secondary alkyl halides are then readily attacked by the modified B12s to give the corresponding stable cobalamin analogs. The products are usually extracted and purified by phenol-methylene chloride extraction or by column chromatography.Cobalamin analogs prepared by this method include the naturally occurring coenzymes methylcobalamin and cobamamide, and other cobalamins that do not occur naturally, such as vinylcobalamin, carboxymethylcobalamin and cyclohexylcobalamin. This reaction is under review for use as a catalyst for chemical dehalogenation, organic reagent and photosensitized catalyst systems. Production Cyanocobalamin is commercially prepared by bacterial fermentation. Fermentation by a variety of microorganisms yields a mixture of methylcobalamin, hydroxocobalamin and adenosylcobalamin. These compounds are converted to cyanocobalamin by addition of potassium cyanide in the presence of sodium nitrite and heat. Since multiple species of Propionibacterium produce no exotoxins or endotoxins and have been granted GRAS status (generally regarded as safe) by the United States Food and Drug Administration, they are the preferred bacterial fermentation organisms for vitamin B12 production.Historically, the physiological form was initially thought to be cyanocobalamin. This was because hydroxocobalamin produced by bacteria was changed to cyanocobalamin during purification in activated charcoal columns after separation from the bacterial cultures (because cyanide is naturally present in activated charcoal). Cyanocobalamin is the form in most pharmaceutical preparations because adding cyanide stabilizes the molecule.The total world production of vitamin B12, by four companies (the French Sanofi-Aventis and three Chinese companies) in 2008 was 35 tonnes. Metabolism The two bioactive forms of vitamin B12 are methylcobalamin in cytosol and adenosylcobalamin in mitochondria. Multivitamins often contain cyanocobalamin, which is presumably converted to bioactive forms in the body. Both methylcobalamin and adenosylcobalamin are commercially available as supplement pills. The MMACHC gene product catalyzes the decyanation of cyanocobalamin as well as the dealkylation of alkylcobalamins including methylcobalamin and adenosylcobalamin. This function has also been attributed to cobalamin reductases. The MMACHC gene product and cobalamin reductases enable the interconversion of cyano- and alkylcobalamins.Cyanocobalamin is added to fortify nutrition, including baby milk powder, breakfast cereals and energy drinks for humans, also animal feed for poultry, swine and fish. Vitamin B12 becomes inactive due to hydrogen cyanide and nitric oxide in cigarette smoke. Vitamin B12 also becomes inactive due to nitrous oxide N2O commonly known as laughing gas, used for anaesthesia and as a recreational drug. Vitamin B12 becomes inactive due to microwaving or other forms of heating. In the cytosol Methylcobalamin and 5-methyltetrahydrofolate are needed by methionine synthase in the methionine cycle to transfer a methyl group from 5-methyltetrahydrofolate to homocysteine, thereby generating tetrahydrofolate (THF) and methionine, which is used to make SAMe. SAMe is the universal methyl donor and is used for DNA methylation and to make phospholipid membranes, choline, sphingomyelin, acetylcholine, and other neurotransmitters. In mitochondria The enzymes that use B12 as a built-in cofactor are methylmalonyl-CoA mutase (PDB 4REQ) and methionine synthase (PDB 1Q8J).The metabolism of propionyl-CoA occurs in the mitochondria and requires Vitamin B12 (as adenosylcobalamin) to make succinyl-CoA. When the conversion of propionyl-CoA to succinyl-CoA in the mitochondria fails due to Vitamin B12 deficiency, elevated blood levels of methylmalonic acid (MMA) occur. Thus, elevated blood levels of homocysteine and MMA may both be indicators of vitamin B12 deficiency. Adenosylcobalamin is needed as cofactor in methylmalonyl-CoA mutase—MUT enzyme. Processing of cholesterol and protein gives propionyl-CoA that is converted to methylmalonyl-CoA, which is used by MUT enzyme to make succinyl-CoA. Vitamin B12 is needed to prevent anemia, since making porphyrin and heme in mitochondria for producing hemoglobin in red blood cells depends on succinyl-CoA made by vitamin B12. Absorption and transport Inadequate absorption of vitamin B12 may be related to coeliac disease. Intestinal absorption of vitamin B12 requires successively three different protein molecules: haptocorrin, intrinsic factor and transcobalamin II. See also Methylcobalamin Hydroxocobalamin Adenosylcobalamin Cobalamin biosynthesis References External links "Cyanocobalamin". Drug Information Portal. U.S. National Library of Medicine.
Vaseline	Vaseline () is an American brand of petroleum jelly-based products owned by transnational company Unilever. Products include plain petroleum jelly and a selection of skin creams, soaps, lotions, cleansers, and deodorants. In many languages, the word "Vaseline" is used as generic for petroleum jelly; in Portugal, the Unilever products are called Vaselina, and in Brazil and some Spanish-speaking countries, the Unilever products are called Vasenol. History In 1859, Robert Chesebrough, a chemist who formerly clarified kerosene from the oil of sperm whales, traveled to the oil fields in Titusville, Pennsylvania to research what new materials might be created from this new fuel. There he learned of a residue called rod wax that had to be periodically removed from oil rig pumps. The oil workers had been using the substance to heal cuts and burns. Chesebrough took samples of the rod wax back to Brooklyn, extracted the usable petroleum jelly, and began manufacturing a medicinal product he called Vaseline.The first known reference to the name Vaseline was by Chesebrough in his U.S. patent (U.S. Patent 127,568) in 1872. "I, Robert Chesebrough, have invented a new and useful product from petroleum which I have named Vaseline..." The name "vaseline" is said by the manufacturer to be derived from German Wasser "water" + Greek έλαιον (elaion) "oil".Vaseline was made by the Chesebrough Manufacturing Company until the company was purchased by Unilever in 1987. Uses While Vaseline can be used as a lubricant, it can also be used as a moisture insulator for local skin conditions characterized by tissue dehydration. Health In 2015, German consumer watchdog Stiftung Warentest analyzed cosmetics containing mineral oils. After developing a new detection method, they found high concentrations of Mineral Oil Aromatic Hydrocarbons (MOAH) and even polyaromatics in products containing mineral oils. Vaseline products contained the most MOAH of all tested cosmetics (up to 9%). The European Food Safety Authority sees MOAH and polyaromatics as possibly carcinogenic. Based on the results, Stiftung Warentest warns not to use Vaseline or any other products containing mineral oils. Ingredient sources White petrolatum, the ingredient in petroleum jelly Vaseline, is refined from petroleum. References Notes Citations External links Official website
Estramustine	Estramustine (INN, USAN, BAN) is an estrogen and cytostatic antineoplastic agent which was never marketed. It is an estrogen ester – specifically, the C3 normustine ester of estradiol – and acts in part as a prodrug of estradiol in the body. Estramustine phosphate, the C17β phosphate ester of estramustine and a prodrug of estramustine, estromustine, estradiol, and estrone, is marketed and used in the treatment of prostate cancer. See also List of hormonal cytostatic antineoplastic agents List of estrogen esters § Estradiol esters == References ==
Carnitine	Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids into mitochondria to be oxidized for energy production, and also participates in removing products of metabolism from cells. Given its key metabolic roles, carnitine is concentrated in tissues like skeletal and cardiac muscle that metabolize fatty acids as an energy source. Generally individuals, including strict vegetarians, synthesize enough L-carnitine in vivo.Carnitine exists as one of two stereoisomers (the two enantiomers d-carnitine (S-(+)-) and l-carnitine (R-(−)-)). Both are biologically active, but only l-carnitine naturally occurs in animals, and d-carnitine is toxic as it inhibits the activity of the l-form. At room temperature, pure carnitine is a white powder, and a water-soluble zwitterion with low toxicity. Derived from amino acids, carnitine was first extracted from meat extracts in 1905, leading to its name from Latin, "caro/carnis" or flesh.Some individuals with genetic or medical disorders (such as preterm infants) cannot make enough carnitine, requiring dietary supplementation. Despite common carnitine supplement consumption among athletes for improved exercise performance or recovery, there is insufficient high-quality clinical evidence to indicate it provides any benefit. Biosynthesis and metabolism Many eukaryotes have the ability to synthesize carnitine, including humans. Humans synthesize carnitine from the substrate TML (6-N-trimethyllysine), which is in turn derived from the methylation of the amino acid lysine. TML is then hydroxylated into hydroxytrimethyllysine (HTML) by trimethyllysine dioxygenase (TMLD), requiring the presence of ascorbic acid and iron. HTML is then cleaved by HTML aldolase (a pyridoxal phosphate requiring enzyme), yielding 4-trimethylaminobutyraldehyde (TMABA) and glycine. TMABA is then dehydrogenated into gamma-butyrobetaine in an NAD+-dependent reaction, catalyzed by TMABA dehydrogenase. Gamma-butyrobetaine is then hydroxylated by gamma butyrobetaine hydroxylase (a zinc binding enzyme) into l-carnitine, requiring iron in the form of Fe2+.Carnitine is involved in transporting fatty acids across the mitochondrial membrane, by forming a long chain acetylcarnitine ester and being transported by carnitine palmitoyltransferase I and carnitine palmitoyltransferase II. Carnitine also plays a role in stabilizing Acetyl-CoA and coenzyme A levels through the ability to receive or give an acetyl group. Tissue distribution of carnitine-biosynthetic enzymes The tissue distribution of carnitine-biosynthetic enzymes in humans indicates TMLD to be active in the liver, heart, muscle, brain and highest in the kidney. HTMLA activity is found primarily in the liver. The rate of TMABA oxidation is greatest in the liver, with considerable activity also in the kidney. Carnitine shuttle system The free-floating fatty acids, released from adipose tissues to the blood, bind to carrier protein molecule known as serum albumin that carry the fatty acids to the cytoplasm of target cells such as the heart, skeletal muscle, and other tissue cells, where they are used for fuel. But before the target cells can use the fatty acids for ATP production and β oxidation, the fatty acids with chain lengths of 14 or more carbons must be activated and subsequently transported into mitochondrial matrix of the cells in three enzymatic reactions of the carnitine shuttle.The first reaction of the carnitine shuttle is a two-step process catalyzed by a family of isozymes of acyl-CoA synthetase that are found in the outer mitochondrial membrane, where they promote the activation of fatty acids by forming a thioester bond between the fatty acid carboxyl group and the thiol group of coenzyme A to yield a fatty acyl–CoA.In the first step of the reaction, acyl-CoA synthetase catalyzes the transfer of adenosine monophosphate group (AMP) from an ATP molecule onto the fatty acid generating a fatty acyl–adenylate intermediate and a pyrophosphate group (PPi). The pyrophosphate, formed from the hydrolysis of the two high-energy bonds in ATP, is immediately hydrolyzed to two molecules of Pi by inorganic pyrophosphatase. This reaction is highly exergonic which drives the activation reaction forward and makes it more favorable. In the second step, the thiol group of a cytosolic coenzyme A attacks the acyl-adenylate, displacing AMP to form thioester fatty acyl-CoA.In the second reaction, acyl-CoA is transiently attached to the hydroxyl group of carnitine to form fatty acylcarnitine. This transesterification is catalyzed by an enzyme found in the outer membrane of the mitochondria known as carnitine acyltransferase 1 (also called carnitine palmitoyltransferase 1, CPT1).The fatty acylcarnitine ester formed then diffuses across the intermembrane space and enters the matrix by facilitated diffusion through carnitine-acylcarnitine translocase (CACT) located on the inner mitochondrial membrane. This antiporter returns one molecule of carnitine from the matrix to the intermembrane space for every one molecule of fatty acyl–carnitine that moves into the matrix.In the third and final reaction of the carnitine shuttle, the fatty acyl group is transferred from fatty acyl-carnitine to coenzyme A, regenerating fatty acyl–CoA and a free carnitine molecule. This reaction takes place in the mitochondrial matrix and is catalyzed by carnitine acyltransferase 2 (also called carnitine palmitoyltransferase 2, CPT2), which is located on the inner face of the inner mitochondrial membrane. The carnitine molecule formed is then shuttled back into the intermembrane space by the same cotransporter (CACT) while the fatty acyl-CoA enters β-oxidation. Regulation of fatty acid β oxidation The carnitine-mediated entry process is a rate-limiting factor for fatty acid oxidation and is an important point of regulation. Inhibition The liver starts actively making triglycerides from excess glucose when it is supplied with glucose that cannot be oxidized or stored as glycogen. This increases the concentration of malonyl-CoA, the first intermediate in fatty acid synthesis, leading to the inhibition of carnitine acyltransferase 1, thereby preventing fatty acid entry into the mitochondrial matrix for β oxidation. This inhibition prevents fatty acid breakdown while synthesis occurs. Activation Carnitine shuttle activation occurs due to a need for fatty acid oxidation which is required for energy production. During vigorous muscle contraction or during fasting, ATP concentration decreases and AMP concentration increases leading to the activation of AMP-activated protein kinase (AMPK). AMPK phosphorylates acetyl-CoA carboxylase, which normally catalyzes malonyl-CoA synthesis. This phosphorylation inhibits acetyl-CoA carboxylase, which in turn lowers the concentration of malonyl-CoA. Lower levels of malonyl-CoA disinhibit carnitine acyltransferase 1, allowing fatty acid import to the mitochondria, ultimately replenishing the supply of ATP. Transcription factors Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that functions as a transcription factor. It acts in muscle, adipose tissue, and liver to turn on a set of genes essential for fatty acid oxidation, including the fatty acid transporters carnitine acyltransferases 1 and 2, the fatty acyl–CoA dehydrogenases for short, medium, long, and very long acyl chains, and related enzymes.PPARα functions as a transcription factor in two cases; as mentioned before when there is an increased demand for energy from fat catabolism, such as during a fast between meals or long-term starvation. Besides that, the transition from fetal to neonatal metabolism in the heart. In the fetus, fuel sources in the heart muscle are glucose and lactate, but in the neonatal heart, fatty acids are the main fuel that require the PPARα to be activated so it is able in turn to activate the genes essential for fatty acid metabolism in this stage. Metabolic defects of fatty acid oxidation More than 20 human genetic defects in fatty acid transport or oxidation have been identified. In case of fatty acid oxidation defects, acyl-carnitines accumulate in mitochondria and are transferred into the cytosol, and then into the blood. Plasma levels of acylcarnitine in newborn infants can be detected in a small blood sample by tandem mass spectrometry.When β oxidation is defective because of either mutation or deficiency in carnitine, the ω (omega) oxidation of fatty acids becomes more important in mammals. Actually, the ω Oxidation of Fatty Acids is another pathway for F-A degradation in some species of vertebrates and mammals that occurs in the endoplasmic reticulum of the liver and kidney, it is the oxidation of the ω carbon—the carbon most far from the carboxyl group (in contrast to β {\displaystyle \beta } oxidation which occurs at the carboxyl end of fatty acid, in the mitochondria). Physiological effects As an example of normal synthesis, a 70 kilograms (150 lb) person would produce 11–34 mg of carnitine per day. Adults eating mixed diets of red meat and other animal products ingest some 60–180 mg of carnitine per day, while vegans consume about 10–12 mg per day. Most (54–86%) carnitine obtained from the diet is absorbed in the small intestine before entering the blood. The total body content of carnitine is about 20 grams (0.71 oz) in a person weighing 70 kilograms (150 lb), with nearly all of it contained within skeletal muscle cells. Carnitine metabolizes at rates of about 400 μmol (65mg) per day, an amount less than 1% of total body stores. Deficiency Carnitine deficiency is rare in healthy people without metabolic disorders, indicating that most people have normal, adequate levels of carnitine normally produced through fatty acid metabolism. One study found that vegans showed no signs of carnitine deficiency. Infants, especially premature infants, have low stores of carnitine, necessitating use of carnitine-fortified infant formulas as a replacement for breast milk, if necessary.Two types of carnitine deficiency states exist. Primary carnitine deficiency is a genetic disorder of the cellular carnitine-transporter system that typically appears by the age of five with symptoms of cardiomyopathy, skeletal-muscle weakness, and hypoglycemia. Secondary carnitine deficiencies may happen as the result of certain disorders, such as chronic kidney failure, or under conditions that reduce carnitine absorption or increase its excretion, such as the use of antibiotics, malnutrition, and poor absorption following digestion. Supplementation Despite widespread interest among athletes to use carnitine for improvement of exercise performance, inhibit muscle cramps, or enhance recovery from physical training, the quality of research for these possible benefits has been low, prohibiting any conclusion of effect. At supplement amounts of 2–6 grams (0.071–0.212 oz) per day over a month, there was no consistent evidence that carnitine affected exercise or physical performance. Carnitine supplements do not improve oxygen consumption or metabolic functions when exercising, nor do they increase the amount of carnitine in muscle. There is no evidence that L-carnitine influences fat metabolism or aids in weight loss. Male fertility The carnitine content of seminal fluid is directly related to sperm count and motility, suggesting that the compound might be of value in treating male infertility. Diseases Carnitine has been studied in various cardiometabolic conditions, indicating it is under preliminary research for its potential as an adjunct in heart disease and diabetes, among numerous other disorders. Carnitine has no effect on preventing all-cause mortality associated with cardiovascular diseases, and has no significant effect on blood lipids.Although there is some evidence from meta-analyses that L-carnitine supplementation improved cardiac function in people with heart failure, there is insufficient research to determine its overall efficacy in lowering the risk or treating cardiovascular diseases.There is only preliminary clinical research to indicate the use of L-carnitine supplementation for improving symptoms of type 2 diabetes, such as improving glucose tolerance or lowering fasting levels of blood glucose.The kidneys contribute to overall homeostasis in the body, including carnitine levels. In the case of renal impairment, urinary elimination of carnitine increasing, endogenous synthesis decreasing, and poor nutrition as a result of disease-induced anorexia can result in carnitine deficiency. Carnitine has no effect on most parameters in end-stage kidney disease, although it may lower C-reactive protein, a biomarker for systemic inflammation. Carnitine blood levels and muscle stores can become low, which may contribute to anemia, muscle weakness, fatigue, altered levels of blood fats, and heart disorders. Some studies have shown that supplementation of high doses of l-carnitine (often injected) may aid in anemia management. Sources The form present in the body is l-carnitine, which is also the form present in food. Food sources rich in l-carnitine are animal products, particularly beef and pork. Red meats tend to have higher levels of l-carnitine. Adults eating diverse diets that contain animal products attain about 23-135 mg of carnitine per day. Vegans get noticeably less (about 10–12 mg) since their diets lack these carnitine-rich animal-derived foods. Approximately 54% to 86% of dietary carnitine is absorbed in the small intestine, then enters the blood. Even carnitine-poor diets have little effect on total carnitine content, as the kidneys conserve carnitine. In general, omnivorous humans each day consume between 2 and 12 µmol kg−1 of body weight, accounting for 75% of carnitine in the body. Humans endogenously produce 1.2 µmol kg−1 of body weight of carnitine on a daily basis, accounting for 25% of the carnitine in the body. Strict vegetarians obtain little carnitine from dietary sources (0.1 µmol kg−1 of body weight daily), as it is mainly found in animal-derived foods.L-Carnitine, acetyl-l-carnitine, and propionyl-l-carnitine are available in dietary supplement pills or powders, with a daily amount of 0.5 to 1 g considered to be safe. It is also a drug approved by the Food and Drug Administration to treat primary and certain secondary carnitine-deficiency syndromes secondary to inherited diseases. Drug interactions and adverse effects Carnitine interacts with pivalate-conjugated antibiotics such as pivampicillin. Chronic administration of these antibiotics increases the excretion of pivaloyl-carnitine, which can lead to carnitine depletion. Treatment with the anticonvulsants valproic acid, phenobarbital, phenytoin, or carbamazepine significantly reduces blood levels of carnitine.When taken in the amount of roughly 3 grams (0.11 oz) per day, carnitine may cause nausea, vomiting, abdominal cramps, diarrhea, and body odor smelling like fish. Other possible adverse effects include skin rash, muscle weakness, or seizures in people with epilepsy. History Levocarnitine was approved by the U.S. Food and Drug Administration as a new molecular entity under the brand name Carnitor on December 27, 1985. See also Acetylcarnitine Gamma-butyrobetaine dioxygenase Glycine Propionyl-l-Carnitine (GPLC) Meldonium Systemic primary carnitine deficiency == References ==
Difelikefalin	Difelikefalin, sold under the brand name Korsuva, is an analgesic opioid peptide used for the treatment of moderate to severe itching. It acts as a peripherally specific, highly selective agonist of the κ-opioid receptor (KOR).Difelikefalin was approved for medical use in the United States in August 2021.Difelikefalin acts as an analgesic by activating KORs on peripheral nerve terminals and KORs expressed by certain immune system cells. Activation of KORs on peripheral nerve terminals results in the inhibition of ion channels responsible for afferent nerve activity, causing reduced transmission of pain signals, while activation of KORs expressed by immune system cells results in reduced release of proinflammatory, nerve-sensitizing mediators (e.g., prostaglandins). Society and culture Legal status On 24 February 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kapruvia, intended for treatment of moderate-to-severe pruritus associated with chronic kidney disease. The applicant for this medicinal product is Vifor Fresenius Medical Care Renal Pharma France. Difelikefalin was approved for medical use in the European Union in April 2022. Research It is under development by Cara Therapeutics as an intravenous agent for the treatment of postoperative pain. An oral formulation has also been developed. Due to its peripheral selectivity, difelikefalin lacks the central side effects like sedation, dysphoria, and hallucinations of previous KOR-acting analgesics such as pentazocine and phenazocine. In addition to use as an analgesic, difelikefalin is also being investigated for the treatment of pruritus (itching). Difelikefalin has completed phase II clinical trials for postoperative pain and has demonstrated significant and "robust" clinical efficacy, along with being safe and well tolerated. It has also completed a phase III clinical trial for uremic pruritus in hemodialysis patients. References External links "Difelikefalin". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03422653 for "A Study to Evaluate the Safety and Efficacy of CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus (KALM-1)" at ClinicalTrials.gov Clinical trial number NCT03636269 for "CR845-CLIN3103: A Global Study to Evaluate the Safety and Efficacy of CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus (KALM-2)" at ClinicalTrials.gov
Methoxy polyethylene glycol-epoetin beta	Methoxy polyethylene glycol-epoetin beta is the active ingredient of a drug marketed by Hoffmann-La Roche under the brand name Mircera. Mircera is a long-acting erythropoietin receptor activator (CERA) indicated for the treatment of patients with anaemia associated with chronic kidney disease. It is the first approved, chemically modified erythropoiesis-stimulating agent (ESA). Mircera is supplied as a solution in pre-filled syringes for intravenous or subcutaneous administration. Mircera was approved for use in Europe in July 2007 by the European Commission, in September 2007 by the Swissmedic, and in November 2007 by the U.S. Food and Drug Administration for use in the United States. Methoxy polyethylene glycol-epoetin beta is made from erythropoietin by chemically linking the N-terminal amino group or the ε-amino group of any lysine present in the protein with methoxy polyethylene glycol butanoic acid. The average molecular weight is approximately 60 kDa. The drug stimulates erythropoiesis by interacting with the erythropoietin receptor on progenitor cells in the bone marrow. It has a reduced receptor binding activity compared to other ESAs and but retains in vivo activity due to an extended serum half-life. It has an in vivo half-life of around 135 hours (5.6 days) as compared to darbepoetin alfa which has a half life of around 21 to 70 hours, the half life of which is three times that of the naturally occurring erthropoietin in the body. It is on the World Health Organizations List of Essential Medicines. Patent infringement claims A U.S. Federal Appeals Court ruled 15 September 2009 that Mircera infringes a patent held by Amgen Inc. The court refused to lift an injunction entered in the fall of 2008 which barred Roche from selling Mircera in the United States. However, the injunction has since expired and Mircera is available on the US market since 2015. Use in sports Mircera can reportedly replace traditional EPO drugs as blood doping agent in endurance sports. The drug appears to fall under section S2 of the list of substances officially prohibited - in competition and out of competition - in France and by the World Anti-Doping Agency.On July 17, 2008, Italian bicycle racer Riccardo Riccò was disqualified from the Tour de France after reports that a urine sample tested positive for Mircera. There had not previously been any public acknowledgment that a test for the new drug was being administered, or had even been developed yet. The Tour de France testing was done under the auspices of the French Cycling Federation and the French Anti-Doping Agency, not the Union Cycliste Internationale. See also PEGylation == References ==
Nafarelin	Nafarelin, sold under the brand name Synarel among others, is a gonadotropin-releasing hormone agonist (GnRH agonist) medication which is used in the treatment of endometriosis and early puberty. It is also used to treat uterine fibroids, to control ovarian stimulation in in vitro fertilization (IVF), and as part of transgender hormone therapy. The medication is used as a nasal spray two to three times per day.Side effects of nafarelin are related to sex hormone deprivation and include symptoms of low testosterone levels and low estrogen levels such as hot flashes, sexual dysfunction, vaginal atrophy, and osteoporosis. Nafarelin is a gonadotropin-releasing hormone agonist (GnRH agonist) and works by preventing the production of sex hormones by the gonads. It can lower sex hormone levels by 95% in both sexes. Nafarelin is a peptide and an analogue of GnRH.Nafarelin was introduced for medical use in 1990. It is available widely throughout the world, including in North America, Europe, and elsewhere throughout the world. The medication is one of only two medically used GnRH analogues that are available as nasal sprays, the other being buserelin. Medical uses Nafarelin is approved and used in the treatment of endometriosis and precocious puberty. It is also used in the treatment of uterine fibroids. The medication is used to control ovarian stimulation in in vitro fertilization (IVF). Nafarelin is used as a puberty blocker in transgender youth and to suppress testosterone levels in transgender women. Nafarelin can also be used to treat hirsutism and polycystic ovary syndrome by lowering gonadotropin and androgen levels. It is effective in the treatment of benign prostatic hyperplasia. Dosages Nafarelin is used to treat precocious puberty at a dosage of 1,600 to 1,800 μg per day. The 1,600 μg/day dosage is achieved by two sprays (400 μg total) into each nostril in the morning (four sprays, 800 μg total) and two sprays (400 μg total) into each nostril in the evening (four sprays, 800 μg total). If 1,600 μg/day is insufficient for adequate pubertal suppression, the 1,800 μg/day dosage can be used instead. This is achieved by three sprays (600 μg total) into alternating nostrils three times per day (nine sprays per day total). When administering the sprays, the head should be tilted back slightly and 30 seconds should elapse between each spray. A bottle of nafarelin nasal spray (brand name Synarel) lasts for about 7 days at a dosage of 1,600 μg/day.Nafarelin is used to treat endometriosis at lower dosages of 400 to 800 μg per day. This is achieved by one or two sprays (200 or 400 μg total) into alternating nostrils once in the morning and once in the evening (two to four sprays per day total). A bottle of nafarelin nasal spray (brand name Synarel) lasts for about 30 days at a dosage of 400 μg/day. Available forms Nafarelin is available in the form of a 0.2% nasal spray for use one, two, or three times per day. Each bottle of nafarelin nasal spray (brand name Synarel) contains about 60 sprays delivering approximately 200 μg nafarelin in 100 μL solution per actuation. Nafarelin is not available for use by any other routes than intranasal administration. Side effects Side effects of nafarelin are related to sex hormone deficiency and include hot flashes, vaginal dryness, headaches, mood changes, and sexual dysfunction. Nafarelin causes erectile dysfunction in more than half of men with benign prostatic hyperplasia treated with it. Some people may experience acne, muscle pain, reduced breast size, and nasal irritation. These side effects are reversible and should resolve after stopping the medication. There is a case report of severe hyperkalemia during nafarelin therapy in a woman with uterine fibroids. The mechanism is unknown. Pharmacology Pharmacodynamics Nafarelin is a GnRH agonist, or an agonist of the GnRH receptor, the biological target of GnRH. It works by continuously activating the GnRH receptor, which results in profound desensitization of the receptor such that it becomes non-functional. As a result, nafarelin suppresses the GnRH-induced secretion of the gonadotropins, luteinizing hormone and follicle-stimulating hormone, from the pituitary gland. This, in turn, results in profound suppression of gonadal sex hormone production, as well as reversible suppression of fertility. Pharmacokinetics The bioavailability of nafarelin with intranasal administration is 2.8% on average, with a range of 1.2 to 5.6%. The plasma protein binding of nafarelin is 80%. It is metabolized primarily by peptidases and not by cytochrome P450 enzymes. The elimination half-life of nafarelin is 2.5 to 3.0 hours by intranasal administration, whereas the half-life of nafarelin and its metabolites by subcutaneous injection is 85.5 hours. Nafarelin is eliminated 44 to 55% in urine and 18.5 to 44.2% in feces. Chemistry Nafarelin is a GnRH analogue, or a synthetic analogue of GnRH. It is a decapeptide and is also known as [6-D-(2-naphthyl)alanine]-GnRH. Nafarelin is marketed for medical use in both its free base (nafarelin) and acetate salt (nafarelin acetate) forms. History Nafarelin was introduced for medical use in 1990. Society and culture Generic names Nafarelin is the generic name of the drug and its INN and BAN, while nafaréline is its DCF and nafarelin acetate is its USAN, BANM, and JAN. It is also known by its former developmental code name RS-94991 or RS-94991-298. Brand names The major brand names of nafarelin are Synarel and Synarela. It has also been marketed under a number of other brand names including Synrelin, Synrelina, Nafarelil 0.2%, and Nasanyl 0.2%. Availability Nafarelin is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, other European countries, Australia, Israel, Argentina, Brazil, Mexico, and Japan. See also Gonadotropin-releasing hormone receptor § Agonists References Further reading Barbieri RL (February 1990). "Comparison of the pharmacology of nafarelin and danazol". Am. J. Obstet. Gynecol. 162 (2): 581–5. doi:10.1016/0002-9378(90)90436-B. PMID 2137975. Chrisp P, Goa KL (April 1990). "Nafarelin. A review of its pharmacodynamic and pharmacokinetic properties, and clinical potential in sex hormone-related conditions". Drugs. 39 (4): 523–51. doi:10.2165/00003495-199039040-00005. PMID 2140979. Burry KA (February 1992). "Nafarelin in the management of endometriosis: quality of life assessment". Am. J. Obstet. Gynecol. 166 (2): 735–9. doi:10.1016/0002-9378(92)91705-F. PMID 1531576. Minaguchi H, Wong JM, Snabes MC (June 2000). "Clinical use of nafarelin in the treatment of leiomyomas. A review of the literature". J Reprod Med. 45 (6): 481–9. PMID 10900582.
Amivantamab	Amivantamab, sold under the brand name Rybrevant, is a bispecific monoclonal antibody used to treat non-small cell lung cancer.The most common side effects include rash, infusion-related reactions, skin infections around the fingernails or toenails, muscle and joint pain, shortness of breath, nausea, fatigue, swelling in the lower legs or hands or face, sores in the mouth, cough, constipation, vomiting and changes in certain blood tests.Amivantamab is a bispecific epidermal growth factor (EGF) receptor-directed and mesenchymal–epithelial transition (MET) receptor-directed antibody. It is the first treatment for adults with non-small cell lung cancer whose tumors have specific types of genetic mutations: epidermal growth factor receptor (EGFR) exon 20 insertion mutations.Amivantamab was approved for medical use in the United States in May 2021, and in the European Union in December 2021. Medical uses Amivantamab is indicated for the treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. History The U.S. Food and Drug Administration (FDA) approved amivantamab based on CHRYSALIS, a multicenter, non-randomized, open label, multicohort clinical trial (NCT02609776) which included participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations. Efficacy was evaluated in 81 participants with advanced NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. In the published study, the overall response rate was 40%, with a median duration of response of 11.1 months, and a median progression-free survival of 8.3 months (95% CI, 6.5 to 10.9).The FDA collaborated on the review of amivantamab with the Brazilian Health Regulatory Agency (ANVISA) and the United Kingdoms Medicines and Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies. Society and culture Legal status Amivantamab was approved for medical use in the United States in May 2021. On 14 October 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Rybrevant, intended for the treatment of non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) exon 20 insertion mutations. The applicant for this medicinal product is Janssen-Cilag International N.V. Amivantamab was approved for medical use in the European Union in December 2021. Names Amivantamab is the recommended international nonproprietary name (INN). Research Amivantamab is being investigated in combination with lazertinib versus osimertinib; and in combination with carboplatin-pemetrexed chemotherapy compared to carboplatin-pemetrexed. References This article incorporates public domain material from the United States Department of Health and Human Services. Further reading Neijssen J, Cardoso RM, Chevalier KM, Wiegman L, Valerius T, Anderson GM, et al. (April 2021). "Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET". J Biol Chem. 296: 100641. doi:10.1016/j.jbc.2021.100641. PMC 8113745. PMID 33839159. Yun J, Lee SH, Kim SY, Jeong SY, Kim JH, Pyo KH, et al. (August 2020). "Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR-MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion-Driven NSCLC". Cancer Discov. 10 (8): 1194–1209. doi:10.1158/2159-8290.CD-20-0116. PMID 32414908. External links "Amivantamab". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT02609776 for "Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer (CHRYSALIS)" at ClinicalTrials.gov
Mesuximide	Mesuximide (or methsuximide, methosuximide) is a succinimide anticonvulsant medication. It is sold as a racemate by Pfizer under the tradenames Petinutin (Switzerland) and Celontin (United States). The therapeutic efficacy of methosuximide is largely due to its pharmacologically active metabolite, N-desmethylmethosuximide, which has a longer half-life and attains much higher plasma levels than its parent. Medical use is indicated for the control of absence seizures that are refractory to other drugs. == References ==
Hydralazine/isosorbide dinitrate	Hydralazine/isosorbide dinitrate, sold under the brand name Bidil, is a fixed-dose combination medication used to treat self-identified Black people with congestive heart failure. It is a combination of hydralazine hydrochloride (an arteriolar vasodilator) and isosorbide dinitrate (a nitrate vasodilator).The American Food and Drug Administration (FDA) approved this race-specific medication to treat congestive heart failure in specifically self-identified Black patients. It provoked controversy as the first drug approved by the FDA marketed for a single racial-ethnic group. History From 1980 to 1985, Dr. Jay Cohn of the University of Minnesota led a clinical trial in collaboration with the US Veterans Administration called the Vasodilator-Heart Failure Trial (V-HeFT I) that tested whether the combination of isosorbide dinitrate and hydralazine increased survival in patients with heart failure. The results were promising and a follow up study, V-HeFT II, tested the novel combination against enalapril. Cohn applied for a patent on the combination treatment, which was issued in 1989 as US Patent 4868179. Cohn then licensed the patent to Medco Pharmaceuticals who went on to prepare a New Drug Application (NDA) to approve BiDil on the basis of the V-HeFT trials.The V-HeFT data was re-analyzed and found that the drug combination appeared to be more effective in treating self-identified African-Americans. This was a significant finding due to prior studies which showed that African-Americans with congestive heart failure (CHF) appeared to respond less effectively to conventional CHF treatments (particularly ACE inhibitors) than White Americans. A new paper was published on these findings and MedCo filed for a new patent for the drug as a treatment for heart failure specifically in black patients.The new patent and the old patent were then licensed to a company called NitroMed, which ran a clinical called the African-American Heart Failure Trial (A-HeFT), the results of which were published in 2004 in the New England Journal of Medicine. The clinical trial was stopped early because the drug showed significant benefit; it reduced mortality by 43%, reduced hospitalizations by 39%, and improved quality of life markers in African-American patients with CHF.On the basis of A-HeFT, the FDA approved BiDil in June 2005. In 2006, the Heart Failure Society of America included the use of the fixed dose combination of isosorbide dinitrate/hydralazine as the standard of care in the treatment of heart failure in blacks.: e44 Society and culture Controversy The new drug application claiming treatment of a single, self-identified racial group raised a storm of controversy. Some hailed the development of BiDil as a breakthrough for Black Americans (such groups included the congressional Black Caucus, the Association of Black Cardiologists, the National Medical Association, and the National Association for the Advancement of Colored People) and a step to addressing the unique health care needs and health disparities of the African American community.Others who criticized the preliminary studies argued that the original study did not have a significant number of African-American subjects to make the BiDils race specific claims, and that the results of only one clinical trial where African-Americans were tested does not provide a full and comprehensive study. Furthermore, critics argued that self-identified racial identifications from patients as an indicator for race during the trials were not a sufficient categorization method because these self-identifications were socially constructed and have no biological connection to genomic data. They argued that the trials represented a new form of scientific racism where race, a socially constructed category, would continue to be present in research as a placeholder for genomic identification.The A-HeFT trial has been the subject of further criticism due to its study design that failed to include a non-African American test group to control for racial factors. According to Jay Cohn, the pills developer, the reason for including only African American test subjects was the lack of funding for doing a trial in the full population. References External links "Hydralazine hydrochloride mixture with isosorbide dinitrate". Drug Information Portal. U.S. National Library of Medicine.
Brivaracetam	Brivaracetam, sold under the brand names Briviact and Brivajoy among others, a chemical analog of levetiracetam, is a racetam derivative with anticonvulsant (antiepileptic) properties. It is marketed by the pharmaceutical company UCB. Medical uses Brivaracetam is used to treat partial-onset seizures with or without secondary generalisation, in combination with other antiepileptic drugs. No data are available for its effectiveness and safety in people younger than 16 years of age. Adverse effects The most common adverse effects include sleepiness, dizziness, nausea and vomiting. More rarely, coordination problems and changes in behaviour (such as severe depression, aggression, hostility, impatience, rage, depression, suicide ideology, etc.) can occur. Interactions Coadministration of brivaracetam with carbamazepine may increase exposure to carbamazepine-epoxide, the active metabolite of carbamazepine, and could theoretically lead to reduced tolerability. Coadministration of brivaracetam with phenytoin may increase phenytoin levels. Coadministration of other antiseizure drugs are unlikely to affect brivaracetam exposure. Brivaracetam provides no added therapeutic benefit when administered in conjunction with levetiracetam that acts on the same protein. Pharmacology Mechanism of action Brivaracetam is believed to act by binding to the ubiquitous synaptic vesicle glycoprotein 2A (SV2A), like levetiracetam. but with 20-fold greater affinity. There is some evidence that racetams including levetiracetam and brivaracetam access the luminal side of recycling synaptic vesicles during vesicular endocytosis. They may reduce excitatory neurotransmitter release and enhance synaptic depression during trains of high-frequency activity, such as is believed to occur during epileptic activity. Pharmacokinetics Brivaracetam exhibits linear pharmacokinetics over a wide dose range, is rapidly and completely absorbed after oral administration, has an elimination half-life of seven to eight hours, and has plasma protein binding of less than 20%. It is extensively metabolized (>90%), primarily via hydrolysis of the acetamide group, and secondarily through hydroxylation mediated by the liver enzyme CYP2C19. The three major metabolites (hydroxy, acid, and hydroxyacid) are pharmacologically inactive. Brivaracetam is eliminated as urinary metabolites, with over 95% of a radioactive test dose recovered in the urine within 72 hours, including only 8.6% as unchanged brivaracetam. Pharmacogenetics As noted above, brivaracetam is primarily metabolized by hydrolysis, via amidase enzymes, to an inactive metabolite. To a lesser extent, it is also metabolized by a minor metabolic pathway via CYP2C19-dependent hydroxylation. Individuals who have no CYP2C19 enzyme activity, "CYP2C19 poor metabolizers", will have a greater exposure to standard doses of brivaracetam. Because they are less able to metabolize the drug to its inactive form for excretion, they may have an increased risk of adverse effects. The most common adverse effects of brivaracetam therapy include sedation, fatigue, dizziness, and nausea. The FDA-approved drug label for brivaracetam states that patients who are CYPC19 poor metabolizers, or are taking medicines that inhibit CYP2C19, may require a dose reduction. Chemical and physical properties Brivaracetam is the 4R-propyl analogue of the anticonvulsant levetiracetam. History Positive preliminary results from stage III trials were recorded in 2008, along with evidence that it is around ten times more potent for the prevention of certain types of seizure in mouse models than its analogue levetiracetam.On 14 January 2016, the European Commission, and on 12 May 2016, the U.S. Food and Drug Administration (FDA) approved brivaracetam under the trade name Briviact. The Drug Enforcement Administration (DEA) issued an interim final rule placing brivaracetam into schedule V of the Controlled Substances Act (CSA) effective 9 March 2017. As of May 2016, brivaracetam is not approved in some other countries. It was approved in Australia in August 2016. In Canada it was approved on 9 March 2016 under the trade name Brivlera. Legality Australia Brivaracetam is a schedule 4 substance in Australia under the Poisons Standard (February 2020). A schedule 4 substance is classified as "Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription." References Further reading Dean L (2018). "Brivaracetam Therapy and CYP2C19 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 29763212. Bookshelf ID: NBK500036. External links "Brivaracetam". Drug Information Portal. U.S. National Library of Medicine.
Rilpivirine	Rilpivirine, sold under the brand names Edurant and Rekambys, is a medication, developed by Tibotec, used for the treatment of HIV/AIDS. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs such as efavirenz. Medical uses In the US, rilpivirine is approved for treatment-naive patients with a viral load of 100,000 copies/mL or less at therapy initiation. It has to be combined with other drugs against HIV.In the European Union, rilpivirine is approved in combination with cabotegravir for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/ml) with their current antiretroviral treatment, and when the virus has not developed resistance to certain class of anti-HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (INIs). Available forms The drug is available as tablets (brand name Edurant) and as a long-acting intramuscular injection to be given once every month or every two months (Rekambys). Before using the injection, the tablets are given for about four weeks to assess tolerability. Contraindications and interactions The drug is contraindicated for use with drugs that induce the liver enzyme CYP3A4, such as carbamazepine, phenytoin, rifampicin, and St Johns wort. Such drugs can accelerate the breaking down of rilpivirine, substantially decreasing its plasma concentrations and potentially resulting in loss of effectiveness and possible resistance. Some of these drugs also induce the enzyme UGT1A1 and thus reduce blood plasma concentrations of cabotegravir, further compromising the effectiveness of this combination therapy.It is also contraindicated in combination with proton pump inhibitors because the increased gastric pH causes decreased rilpivirine absorption from the gut, with similar consequences as with CYP3A4 inducers. Adverse effects The most common side effects of the injectable formulation are reactions at the injection site (in up to 84% of patients) such as pain and swelling, as well as headache (up to 12%) and fever or feeling hot (in 10%). Less common (under 10%) are depressive disorders, insomnia, and rashes. The most common side effects of the tablets are also depressive disorders (4.1%), headache (3.5%), insomnia (3.5%) and rashes (2.3%). All of these side effects occurred under combination therapies of rilpivirine with one or more other drugs against HIV. QT prolongation of the heart rhythm has been observed at very high doses, but is not clinically relevant at standard doses of the drug. Pharmacology Mechanism of action Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI). Pharmacokinetics When taken by mouth, rilpivirine reaches highest levels in the blood plasma after about four to five hours. Taking the drug without food lowers its plasma levels by 40% as compared to taking it with food, which is considered to be clinically relevant. Therefore, patients are advised to take the medication together with a meal. After injection into the muscle, the substance reaches highest plasma levels after three to four days.Independently of the mode of application, rilpivirine is almost completely bound to plasma proteins (99.7%), mostly to albumin. It is metabolised mainly by the liver enzyme CYP3A4. Metabolites include several oxidation products, glucuronides, and glucuronides of oxidized metabolites. The biological half-life is approximately 45 hours for the tablets and 13 to 28 weeks for the injection.Elimination has only been studied for oral administration: Most of the drug is excreted via the faeces (85%), partly in unchanged form (25%), partly in form of its metabolites (60%). A minor amount is excreted via the urine (6%), almost exclusively as metabolites. Fixed-dose combinations A fixed-dose medication combining rilpivirine with emtricitabine and tenofovir disoproxil (TDF) was approved by the U.S. Food and Drug Administration (FDA) in August 2011 under the brand name Complera, and was approved for use in the European Union with the brand name Eviplera in November 2011. This combination has been shown to have higher rates of virologic failure than emtricitabine/tenofovir/efavirenz in people with baseline HIV viral loads greater than 100,000 copies/mm3.A fixed-dose medication combining rilpivirine with emtricitabine and tenofovir alafenamide (TAF) was approved for use in the US in March 2016 with the brand name Odefsey.Dolutegravir/rilpivirine, sold under the brand name Juluca, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It was approved for use in the United States in November 2017 and for use in the European Union in May 2018. In January 2021, the U.S. Food and Drug Administration (FDA) approved cabotegravir/rilpivirine (brand name Cabenuva) for the treatment of HIV-1 infections in adults to replace a current antiretroviral regimen in those who are virologically suppressed on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine. This is the first FDA-approved injectable, complete regimen for HIV-infected adults that is administered once a month. The label for rilpivirine tablets was revised to reflect the oral lead-in recommendations for use with cabotegravir. Chemistry Like etravirine, a second-generation NNRTI approved in 2008, rilpivirine is a diarylpyrimidine (DAPY).The tablets contain rilpivirine hydrochloride, while the injection contains free rilpivirine. History Rilpivirine entered phase III clinical trials in April 2008, and was approved for use in the United States in May 2011 under the brand name Edurant.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 rilpivirine under the trade name Rekambys, intended for the treatment of human immunodeficiency virus type-1 (HIV-1) infection in combination with cabotegravir injection. It was approved for medical use in the European Union in December 2020. The two medicines are the first antiretrovirals that come in a long-acting injectable formulation. References External links "Rilpivirine". Drug Information Portal. U.S. National Library of Medicine. "Rilpivirine hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Dolutegravir/lamivudine	Dolutegravir/lamivudine, sold under the brand name Dovato, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It contains dolutegravir, as the salt, an integrase strand transfer inhibitor (INSTI), and lamivudine, a nucleoside analogue reverse transcriptase inhibitor (NRTI). It is taken by mouth.It was approved for use in the United States in April 2019, and in the European Union in July 2019, and again with revisions in June 2022.The most common side effects are headache, diarrhea, nausea, and difficulty sleeping. The most common serious side effects are allergic reactions, including rash and severe liver problems.Dolutegravir/lamivudine is the first FDA-approved two-drug, fixed-dose, complete regimen for HIV-infected adults who have never received treatment for HIV. Medical uses In the EU, dolutegravir/lamivudine is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and adolescents above 12 years of age weighing at least 40 kilograms (88 lb), with no known or suspected resistance to the integrase inhibitor class, or lamivudine.In the US, it is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults. History The efficacy and safety of dolutegravir/lamivudine were demonstrated in two identical, randomized, double-blind, controlled clinical trials in 1,433 HIV-infected adults with no prior antiretroviral treatment history. The trials showed that a drug regimen containing dolutegravir and lamivudine had a similar effect of reducing the amount of HIV in the blood compared to another drug regimen, which included dolutegravir, emtricitabine, and tenofovir. The treatment was considered successful if the participant maintained low-levels (less than 50 copies/mL) of HIV RNA in their blood for at least 48 weeks. In these studies, 91% of subjects with HIV-1 who took the dolutegravir/lamivudine combination no longer had detectable levels of HIV (i.e. they had fewer than 50 copies per ml) after 48 weeks compared with 93% of those who were taking the triple combination. In neither study was there a case of resistance to treatment after 48 weeks. References External links "Dolutegravir". Drug Information Portal. U.S. National Library of Medicine. "Lamivudine". Drug Information Portal. U.S. National Library of Medicine.
Daptomycin	Daptomycin, sold under the brand name Cubicin among others, is a lipopeptide antibiotic used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms.Daptomycin was removed from the World Health Organizations List of Essential Medicines in 2019. The World Health Organization classifies daptomycin as critically important for human medicine. Medical uses In the United States, daptomycin is indicated for use in adults for skin and skin structure infections caused by Gram-positive infections, S. aureus bacteraemia, and right-sided S. aureus endocarditis. It binds avidly to pulmonary surfactant, so cannot be used in the treatment of pneumonia. There seems to be a difference in working daptomycin on hematogenous pneumonia. Adverse effects Common adverse drug reactions associated with daptomycin therapy include: Cardiovascular: low blood pressure, high blood pressure, swelling Central nervous system: insomnia Dermatological: rash Gastrointestinal: diarrhea, abdominal pain Hematological: eosinophilia Respiratory: dyspnea Other: injection site reactions, fever, hypersensitivityLess common, but serious adverse events reported in the literature include Hepatotoxicity: elevated transaminases Nephrotoxicity: acute kidney injury from rhabdomyolysisAlso, myopathy and rhabdomyolysis have been reported in patients simultaneously taking statins, but whether this is due entirely to the statin or whether daptomycin potentiates this effect is unknown. Due to the limited data available, the manufacturer recommends that statins be temporarily discontinued while the patient is receiving daptomycin therapy. Creatine kinase levels are usually checked regularly while individuals undergo daptomycin therapy. In July 2010, the FDA issued a warning that daptomycin could cause life-threatening eosinophilic pneumonia. The FDA said it had identified seven confirmed cases of eosinophilic pneumonia between 2004 and 2010 and an additional 36 possible cases. The seven confirmed cases were all older than 60 and symptoms appeared within two weeks of initiation of therapy. Pharmacology Mechanism of action Daptomycin has a distinct mechanism of action, disrupting multiple aspects of bacterial cell membrane function. It inserts into the cell membrane in a phosphatidylglycerol-dependent fashion, where it then aggregates. The aggregation of daptomycin alters the curvature of the membrane, which creates holes that leak ions. This causes rapid depolarization, resulting in a loss of membrane potential leading to inhibition of protein, DNA, and RNA synthesis, which results in bacterial cell death.It has been proposed that the formation of spherical micelles by daptomycin may affect the mode of action. Microbiology Daptomycin is bactericidal against Gram-positive bacteria only. It has proven in vitro activity against enterococci (including glycopeptide-resistant enterococci (GRE)), staphylococci (including methicillin-resistant Staphylococcus aureus), streptococci, corynebacteria and stationary-phase Borrelia burgdorferi persisters. Daptomycin resistance Daptomycin resistance is still uncommon, but has been increasingly reported in GRE, starting in Korea in 2005, in Europe in 2010, in Taiwan 2011, and in the United States, where nine cases have been reported from 2007 to 2011. Daptomycin resistance emerged in five of the six cases while they were treated. The mechanism of resistance is unknown. A four-million year-old strain of Paenibacillus isolated from soil samples in Lechuguilla Cave was found to be naturally resistant to daptomycin. Efficacy Daptomycin has been shown to be non-inferior to standard therapies (nafcillin, oxacillin, flucloxacillin or vancomycin) in the treatment of bacteraemia and right-sided endocarditis caused by S. aureus. A study in Detroit, Michigan compared 53 patients treated for suspected MRSA skin or soft tissue infection with daptomycin against vancomycin, showing faster recovery (4 versus 7 days) with daptomycin.In Phase III clinical trials, limited data showed daptomycin to be associated with poor outcomes in patients with left-sided endocarditis. Daptomycin has not been studied in patients with prosthetic valve endocarditis or meningitis. Biosynthesis Daptomycin is a cyclic lipopeptide antibiotic produced by Streptomyces roseosporus. Daptomycin consists of 13 amino acids, 10 of which are arranged in a cyclic fashion, and three on an exocyclic tail. Two nonproteinogenic amino acids exist in the drug, the unusual amino acid L-kynurenine (Kyn), only known to daptomycin, and L-3-methylglutamic acid (mGlu). The N-terminus of the exocyclic tryptophan residue is coupled to decanoic acid, a medium-chain (C10) fatty acid. Biosynthesis is initiated by the coupling of decanoic acid to the N-terminal tryptophan, followed by the coupling of the remaining amino acids by nonribosomal peptide synthetase (NRPS) mechanisms. Finally, a cyclization event occurs, which is catalyzed by a thioesterase enzyme, and subsequent release of the lipopeptide is granted. The NRPS responsible for the synthesis of daptomycin is encoded by three overlapping genes, dptA, dptBC and dptD. The dptE and dptF genes, immediately upstream of dptA, are likely to be involved in the initiation of daptomycin biosynthesis by coupling decanoic acid to the N-terminal Trp. These novel genes (dptE, dptF ) correspond to products that most likely work in conjunction with a unique condensation domain to acylate the first amino acid (tryptophan). These and other novel genes (dptI, dptJ) are believed to be involved in supplying the nonproteinogenic amino acids L-3-methylglutamic acid and Kyn; they are located next to the NRPS genes.The decanoic acid portion of daptomycin is synthesized by fatty acid synthase machinery (Figure 2). Post-translational modification of the apo-acyl carrier protein (ACP, thiolation, or T domain) by a phosphopantetheinyltransferase (PPTase) enzyme catalyzes the transfer of a flexible phosphopantetheine arm from coenzyme A to a conserved serine in the ACP domain through a phosphodiester linkage. The holo-ACP can provide a thiol on which the substrate and acyl chains are covalently bound during chain elongations. The two core catalytic domains are an acyltransferase (AT) and a ketosynthase (KS). The AT acts upon a malonyl-CoA substrate and transfers an acyl group to the thiol of the ACP domain. This net transthiolation is an energy-neutral step. Next, the acyl-S-ACP gets transthiolated to a conserved cysteine on the KS; the KS decarboxylates the downstream malonyl-S-ACP and forms a β-ketoacyl-S-ACP. This serves as the substrate for the next cycle of elongation. Before the next cycle begins, however, the β-keto group undergoes reduction to the corresponding alcohol catalyzed by a ketoreductase domain, followed by dehydration to the olefin catalyzed by a dehydratase domain, and finally reduction to the methylene catalyzed by an enoylreductase domain. Each KS catalytic cycle results in the net addition of two carbons. After three more iterations of elongation, a thioesterase enzyme catalyzes the hydrolysis, and thus release, of the free C-10 fatty acid.To synthesize the peptide portion of daptomycin, the mechanism of an NRPS is employed. The biosynthetic machinery of an NRPS system is composed of multimodular enzymatic assembly lines that contain one module for each amino acid monomer incorporated. Within each module are catalytic domains that carry out the elongation of the growing peptidyl chain. The growing peptide is covalently tethered to a thiolation domain; here it is termed the peptidyl carrier protein, as it carries the growing peptide from one catalytic domain to the next. Again, the apo-T domain must be primed to the holo-T domain by a PPTase, attaching a flexible phosphopantetheine arm to a conserved serine residue. An adenylation domain selects the amino acid monomer to be incorporated and activates the carboxylate with ATP to make the aminoacyl-AMP. Next, the A domain installs an aminoacyl group on the thiolate of the adjacent T domain. The condensation (C) domain catalyzes the peptide bond forming reaction, which elicits chain elongation. It joins an upstream peptidyl-S-T to the downstream aminoacyl-S-T (Figure 7). Chain elongation by one aminoacyl residue and chain translocation to the next T domain occurs in concert. The order of these domains is C-A-T. In some instances, an epimerization domain is necessary in those modules where L-amino acid monomers are to be incorporated and epimerized to D-amino acids. The domain organization in such modules is C-A-T-E.The first module has a three-domain C-A-T organization; these often occur in assembly lines that make N-acylated peptides. The first C domain catalyzes N-acylation of the initiating amino acid (tryptophan) while it is installed on T. An adenylating enzyme (Ad) catalyzes the condensation of decanoic acid and the N-terminal tryptophan, which incorporates decanoic acid into the growing peptide (Figure 3). The genes responsible for this coupling event are dptE and dptF, which are located upstream of dptA, the first gene of the Daptomycin NRPS biosynthetic gene cluster. Once the coupling of decanoic acid to the N-terminal tryptophan residue occurs, the condensation of amino acids begins, catalyzed by the NRPS.The first five modules of the NRPS are encoded by the dptA gene and catalyze the condensation of L-tryptophan, D-asparagine, L-aspartate, L-threonine, and glycine, respectively (Figure 4). Modules 6–11, which catalyze the condensation of L-ornithine, L-aspartate, D-alanine, L-aspartate, glycine, and D-serine are encoded for the dptBC gene (Figure 5). dptD catalyzes the incorporation of two nonproteinogenic amino acids, L-3-methylglutamic acid (mGlu) and Kyn, which is only known thus far to daptomycin, into the growing peptide (Figure 6). Elongation by these NRPS modules ultimately leads to macrocyclization and release in which an α-amino group, namely threonine, acts as an internal nucleophile during cyclization to yield the 10-amino-acid ring (Figure 6). The termination module in the NRPS assembly line has a C-A-T-TE organization. The thioesterase domain catalyzes chain termination and release of the mature lipopeptide.The molecular engineering of daptomycin, the only marketed acidic lipopeptide antibiotic to date (Figure 8), has seen many advances since its inception into clinical medicine in 2003. It is an attractive target for combinatorial biosynthesis for many reasons: second generation derivatives are currently in the clinic for development;Streptomyces roseosporus, the producer organism of daptomycin, is amenable to genetic manipulation; the daptomycin biosynthetic gene cluster has been cloned, sequenced, and expressed in S. lividans; the lipopeptide biosynthetic machinery has the potential to be interrupted by variations of natural precursors, as well as precursor-directed biosynthesis, gene deletion, genetic exchange, and module exchange; the molecular engineering tools have been developed to facilitate the expression of the three individual NRPS genes from three different sites in the chromosome, using ermEp* for expression of two genes from ectopic loci; other lipopeptide gene clusters, both related and unrelated to daptomycin, have been cloned and sequenced, thus providing genes and modules to allow the generation of hybrid molecules; derivatives can be afforded via chemoenzymatic synthesis; and lastly, efforts in medicinal chemistry are able to further modify these products of molecular engineering.New derivatives of daptomycin (Figure 9) were originally generated by exchanging the third NRPS subunit (dptD) with the terminal subunits from the A54145 (Factor B1) or calcium-dependent antibiotic pathways to create molecules containing Trp13, Ile13, or Val13. dptD is responsible for incorporating the penultimate amino acid, 3-methyl-glutamic acid (3mGlu12), and the last amino acid, Kyn13, into the chain. This exchange was achieved without engineering the interpeptide docking sites. These whole-subunit exchanges have been coupled with the deletion of the Glu12-methyltransferase gene, with module exchanges at intradomain linker sites at Ala8 and Ser11, and with variations of natural fatty-acid side chains to generate over 70 novel lipopeptides in significant quantities; most of these resultant lipopeptides have potent antibacterial activities. Some of these compounds have in vitro antibacterial activities analogous to daptomycin. Further, one displayed ameliorated activity against an E. coli imp mutant that was defective in its ability to assemble its inherent lipopolysaccharide. A number of these compounds were produced in yields that spanned from 100 to 250 mg/liter; this, of course, opens up the possibility for successful scale-ups by fermentation techniques. Only a small percentage of the possible combinations of amino acids within the peptide core have been investigated thus far. History Daptomycin, originally designated as LY 146032, was discovered by researchers at Eli Lilly and Company in the late 1980s from the actinomycete Streptomyces roseosporus. LY 146032 showed promise in phase I/II clinical trials for treatment of infection caused by Gram-positive organisms. Lilly ceased development because high-dose therapy was associated with adverse effects on skeletal muscle, including myalgia.The rights to LY 146032 were acquired by Cubist Pharmaceuticals in 1997, which following U.S. Food and Drug Administration (FDA) approval in September 2003, for use in people older than 18 years, began marketing the drug under the trade name Cubicin. Cubicin is marketed in the EU and in several other countries by Novartis following its purchase of Chiron Corporation, the previous licensee. References Further reading External links "Daptomycin". Drug Information Portal. U.S. National Library of Medicine. "FDA Rationale for Recognition Decision: Daptomycin". U.S. Food and Drug Administration (FDA). 28 August 2020.
Vandetanib	Vandetanib, sold under the brand name Caprelsa, is an anti-cancer medication that is used for the treatment of certain tumours of the thyroid gland. It acts as a kinase inhibitor of a number of cell receptors, mainly the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), and the RET-tyrosine kinase. The drug was developed by AstraZeneca who later sold the rights to Sanofi in 2015. Medical use Vandetanib is used to treat medullary thyroid cancer in adults who are ineligible for surgery. Contraindications The V804M mutation in RET confers resistance to Vandetanib anti-RET activity.In people with moderate and severe hepatic impairment, no dosage for vandetanib has been recommended, as its safety and efficacy has not been established yet. Vandetanib is contraindicated in people with congenital long QT syndrome. Adverse effects Very common (present in greater than 10% of people) adverse effects include colds, bronchitis, upper respiratory tract infections, urinary tract infections, decreased appetite, low calcium absorption, insomnia, depressed mood, Headache, tingling sensations, weird, painful sensations, dizziness, blurred vision, damage to the cornea, long QT syndrome, high blood pressure, stomach pain, diarrhea, nausea, vomiting, indigestion, sensitivity to sunlight, rash, acne, dry and itchy skin, nail disorders, protein in urine, kidney stones, weakness, fatigue, pain, and edema.Common (present in between 1% and 10% of people) adverse effects include pneumonia, sepsis, influenza, cystitis, sinusitis, laryngitis, folliculitis, boils, fungal infection, kidney infections, low thyroid hormone levels, low potassium, high calcium levels, hyperglycemia, dehydration, low sodium levels, anxiety, tremor, lethargy, loss of consciousness, balance disorders, changes in sense of taste, visual impairment, halo vision, perceived light flashes, glaucoma, pink eye, dry eye, keratopathy, hypertensive crisis, mini strokes, nose bleeds, coughing up blood, defecating blood, colitis, dry mouth, stomatitis, constipation, gastritis, gallstones, Chemotherapy-induced acral erythema, hair loss, painful urination, bloody urine, kidney failure, frequent urination, urgent need to urinate, and fever. Interactions Vandetanib has been reported as a substrate for the OATP1B1 and OATP1B3 transporters. Interaction of vandetanib with OATP1B1 and OATP1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions. Also, vandetanib is an inhibitor of OATP1B3 transporter but not for OATP1B1.Other drugs that prolong the QT interval can possibly add to this side effect of vandetanib. As the drug is partly metabolised via the liver enzyme CYP3A4, strong inducers of this enzyme can decrease its blood plasma concentrations. CYP3A4 inhibitors do not significantly increase vandetanib concentrations, presumably because it is also metabolised by flavin containing monooxygenase 1 (FMO1) and 3. Pharmacology Vandetanib is an inhibitor of vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and RET tyrosine kinases. RET tyrosine kinases; it weakly inhibits VEGFR-3. Vandetanib is well absorbed from the gut, reaches peak blood plasma concentrations 4 to 10 hours after application, and has a half-life of 19 days on average, per pharmacokinetic studies. It has to be taken for about three months to achieve a steady-state concentration. In the blood, it is almost completely (90–96%) bound to plasma proteins such as albumin. It is metabolised to N-desmethylvandetanib via CYP3A4 and to vandetanib-N-oxide via FMO1 and 3. Both of these are active metabolites. Vandetanib is excreted via the faeces (44%) and the urine (25%) in form of the unchanged drug and the metabolites. History Vandetanib was approved by the FDA in April 2011, for treatment of late-stage thyroid cancer.Vandetanib was first initially marketed without a trade name; it has been marketed under the trade name Caprelsa since August 2011.In 2015 Genzyme acquired the product from AstraZeneca. Research AstraZeneca tested Vandetanib in clinical trials for non-small cell lung cancer and submitted an application for approval to the EMA but then withdrew the application in October 2009 after trials showed no benefit when the drug was administered alongside chemotherapy. A clinical trial of vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma was negative in a prospective, randomised, double-blind, multicentre phase 2 trial. References External links "Vandetanib". Drug Information Portal. U.S. National Library of Medicine.
Bamlanivimab	Bamlanivimab is a monoclonal antibody developed by AbCellera Biologics and Eli Lilly as a treatment for COVID-19. The medication was granted an emergency use authorization (EUA) by the US Food and Drug Administration (FDA) in November 2020, and the EUA was revoked in April 2021.Bamlanivimab is an IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2. The aim is to block viral attachment and entry into human cells, thus neutralizing the virus, and help preventing and treating COVID-19.Bamlanivimab emerged from the collaboration between Lilly and AbCellera to create antibody therapies for the prevention and treatment of COVID-19.Bamlanivimab is also used as part of the bamlanivimab/etesevimab combination that was granted an EUA by the FDA.In June 2021, the US Office of the Assistant Secretary for Preparedness and Response (ASPR) paused distribution of bamlanivimab and etesevimab together, and etesevimab alone (to pair with existing supply of bamlanivimab), due to the increase of circulating variants. Studies Bamlanivimab has been studied in several trials. Some initial results on bamlanivimab seemed promising, with one review saying that it "decrease[s] viral load when given early on in the course of SARS-CoV-2 infection and favourably impact[s] clinical outcomes for patients with mild-to-moderate COVID-19". However, further results have not shown any clinically relevant benefit. Animal trials An initial trial tested bamlanivimab in rhesus monkeys. Administration of the drug reduced SARS-CoV-2 replications in the upper and lower respiratory tract of monkeys.Following these results in a non-human primate model, several human studies were initiated. Human trials BLAZE-1 Trial The Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies (BLAZE-1) trial was sponsored by the drugs developer Eli Lilly. The drug was tested in SARS-CoV-2 patients who did not require hospitalization. While an interim analysis suggested reduced ER visits and hospitalizations, this difference was not statistically significant in the final analysis. A subsequent analysis demonstrated superior efficacy of a combination of bamlanivimab and etesevimab compared to placebo. ACTIV-2 Trial This study is sponsored by the NIH, examining bamlanivimab administration to SARS-CoV-2 patients in the outpatient setting. The study is ongoing and no data have been released yet. ACTIV-3 Trial This study specifically examined bamlanivimab in hospitalized COVID-19 patients without severe illness (e.g. end organ damage); these patients were also receiving the standard of care at the time including supportive care, remdesivir, supplemental oxygen, and dexamethasone as indicated. Enrollment was stopped early due to futility; bamlanivimab was not found to increase sustained recovery (90 days), and did not change pulmonary function. The study was funded by Operation Warp Speed. Authorization On 7 October 2020, Eli Lilly and Company submitted a request for an Emergency Use Authorization (EUA) to the U.S. Food and Drug Administration (FDA) for LY-CoV555 monotherapy in higher-risk people who have been diagnosed with mild-to-moderate COVID-19. This authorization was largely done on the basis of the interim BLAZE-1 results showing possible benefit. However, further data obtained after the EUA was granted have not shown any clinically relevant benefit from bamlanivimab.On 9 November 2020, bamlanivimab was granted an emergency use authorization by the US Food and Drug Administration (FDA) for the treatment of mild-to-moderate COVID-19 in adults and adolescents. Bamlanivimab is authorized for people with positive results of direct SARS-CoV-2 viral testing who are twelve years of age and older weighing at least 40 kilograms (88 lb), and who are at high risk for progressing to severe COVID-19 or hospitalization. This includes those who are 65 years of age or older, or who have certain chronic medical conditions.On 16 April 2021, the FDA revoked the emergency use authorization (EUA) that allowed for the investigational monoclonal antibody therapy bamlanivimab, when administered alone, to be used for the treatment of mild-to-moderate COVID-19. Bamlanivimab/etesevimab On 9 February 2021, the FDA issued an emergency use authorization (EUA) for bamlanivimab and etesevimab administered together for the treatment of mild to moderate COVID-19 in people twelve years of age or older weighing at least 40 kilograms (88 lb) who test positive for SARS‑CoV‑2 and who are at high risk for progressing to severe COVID-19. The authorized use includes treatment for those who are 65 years of age or older or who have certain chronic medical conditions.On 1 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started rolling reviews of data on the use of the monoclonal antibodies casirivimab/imdevimab, bamlanivimab/etesevimab, and bamlanivimab for the treatment of COVID-19. On 29 October 2021, Eli Lilly withdrew bamlanivimab and etesevimab from the European Medicines Agency rolling review process. Deployment On 28 October 2020, Eli Lilly and Company announced that it had struck a deal with the US government to supply 300,000 vials of bamlanivimab 700 mg for US$375 million. Society and culture Names Bamlanivimab is the international nonproprietary name (INN). References External links "Bamlanivimab". Drug Information Portal. U.S. National Library of Medicine.
Erdafitinib	Erdafitinib, sold under the brand name Balversa, is an anti-cancer medication. It is a small molecule inhibitor of fibroblast growth factor receptor (FGFR) used for the treatment of cancer. FGFRs are a subset of tyrosine kinases which are unregulated in some tumors and influence tumor cell differentiation, proliferation, angiogenesis, and cell survival. Astex Pharmaceuticals discovered the drug and licensed it to Janssen Pharmaceuticals for further development.Researchers have investigated erdafitinib for safety and efficacy in treatment of bile duct cancer, gastric cancer, non-small cell lung cancer, and esophageal cancer.In March 2018, erdafitinib was granted breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) for treatment of urothelial cancer.In April 2019, erdafitinib was granted approval by the FDA for treatment of metastatic or locally advanced bladder cancer with an FGFR3 or FGFR2 alteration that has progressed beyond traditional platinum-based therapies, subject to a confirmatory trial. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Side effects Common side effects include increased phosphate level, mouth sores, feeling tired, change in kidney function, diarrhea, dry mouth, nails separating from the bed or poor formation of the nail, change in liver function, low salt (sodium) levels, decreased appetite, change in sense of taste, low red blood cells (anemia), dry skin, dry eyes and hair loss. Other side effects include redness, swelling, peeling or tenderness on the hands or feet (hand foot syndrome), constipation, stomach pain, nausea and muscle pain.Erdafitinib may cause serious eye problems, including inflamed eyes, inflamed cornea (front part of the eye) and disorders of the retina, an internal part of the eye. Patients are advised to have eye examinations intermittently and to tell their health care professional right away if they develop blurred vision, loss of vision or other visual changes. History The efficacy of erdafitinib was studied in a clinical trial (NCT02365597) that included 87 adults with locally advanced or metastatic bladder cancer, with FGFR3 or FGFR2 genetic alterations, that had progressed following treatment with chemotherapy. The overall response rate in these adults was 32.2%, with 2.3% having a complete response and almost 30% having a partial response. The response lasted for an average of approximately five-and-a-half months. The trial was conducted in Asia, Europe, and the United States.Erdafitinib received an accelerated approval. Further clinical trials are required to confirm erdafitinibs clinical benefit and the sponsor is conducting or plans to conduct these studies. Erdafitinib was also granted breakthrough therapy designation.The FDA granted the approval of Balversa to Janssen Pharmaceutical. The FDA also approved the therascreen FGFR RGQ RT-PCR Kit, developed by Qiagen Manchester, Ltd., for use as a companion diagnostic with erdafinitib for this therapeutic indication. References External links "Erdafitinib". Drug Information Portal. U.S. National Library of Medicine.
Defibrotide	Defibrotide, sold under the brandname Defitelio, is a mixture of single-stranded oligonucleotides that is purified from the intestinal mucosa of pigs. It is used to treat veno-occlusive disease of the liver of people having had a bone marrow transplant, with different limitations in the US and the European Union. It works by protecting the cells lining blood vessels in the liver and preventing blood clotting; the way it does this is not well understood.The most common side effects include abnormally low blood pressure (hypotension), diarrhea, vomiting, nausea and nosebleeds (epistaxis). Serious potential side effects that were identified include bleeding (hemorrhage) and allergic reactions. Defibrotide should not be used in people who are having bleeding complications or who are taking blood thinners or other medicines that reduce the bodys ability to form clots. Use of the drug is generally limited by a strong risk of life-threatening bleeding in the brain, eyes, lungs, gastrointestinal tract, urinary tract, and nose. Some people have hypersensitivity reactions.Defibrotide was approved for medical use in the European Union in October 2013, in the United States in March 2016, and in Australia in July 2020. Defibrotide is the first FDA-approved therapy for treatment of severe hepatic VOD, a rare and life-threatening liver condition. Medical uses In the European Union defibrotide is indicated for the treatment of severe hepatic veno-occlusive disease (VOD) also known as sinusoidal obstructive syndrome (SOS) in hematopoietic stem-cell transplantation (HSCT) therapy for adults, adolescents, children, and infants over one month of age.Defibrotide is used to treat veno-occlusive disease of the liver of people having had a bone marrow transplant, with different limitations in the US and the European Union. As of 2016, however, randomized placebo controlled trials have not been done.Hematopoietic stem cell transplantation (HSCT) is a procedure performed in some people to treat certain blood or bone marrow cancers. Immediately before an HSCT procedure, a patient receives chemotherapy. Hepatic VOD can occur in people who receive chemotherapy and HSCT. Hepatic VOD is a condition in which some of the veins in the liver become blocked, causing swelling and a decrease in blood flow inside the liver, which may lead to liver damage. In the most severe form of hepatic VOD, the patient may also develop failure of the kidneys and lungs. Fewer than two percent of people develop severe hepatic VOD after HSCT, but as many as 80 percent of people who develop severe hepatic VOD do not survive.It is administered by intravenous infusion in a doctors office or clinic. Contraindications Use of defibrotide for people who are already taking anticoagulants is dangerous and use of other drugs that affect platelet aggregation, like NSAIDs, should be done with care. Defibrotide should not be given to people who have a difficult time maintaining a steady blood pressure. Adverse effects There is a high risk of bleeding and some people have had hypersensitivity reactions to defibrotide.Common adverse effects, occurring in between 1 and 10% of people, included impaired blood clotting, vomiting, low blood pressure, bleeding in the brain, eyes, lungs, stomach or intestines, in the urine, and at catheterization sites.Other side effects have included diarrhea, nosebleeds, sepsis, graft vs host disease, and pneumonia.Pregnant women should not take defibrotide and women should not become pregnant while taking it; it has not been tested in pregnant women but at normal doses it caused hemolytic abortion in rats. Pharmacology Defibrotides mechanism of action is poorly understood. In vitro studies have shown that it protects the endothelium lining blood vessels from damage by fludarabine, a chemotherapy drug, and from a few other insults like serum starvation. It also appears to increase t-PA function and decrease plasminogen activator inhibitor-1 activity. Chemistry Defibrotide is a mixture of single-stranded oligonucleotides. The chemical name is polydeoxyribonucleotide, sodium salt. It is purified from the intestinal mucosa of pigs. History The efficacy of defibrotide was investigated in 528 participants treated in three studies: two prospective clinical trials and an expanded access study. The participants enrolled in all three studies had a diagnosis of hepatic VOD with liver or kidney abnormalities after hematopoietic stem cell transplantation (HSCT). The studies measured the percentage of participants who were still alive 100 days after HSCT (overall survival). In the three studies, 38 to 45 percent of participants treated with defibrotide were alive 100 days after HSCT. Based on published reports and analyses of participant-level data, the expected survival rates 100 days after HSCT would be 21 to 31 percent for participants with severe hepatic VOD who received only supportive care or interventions other than defibrotide. Society and culture Legal status Defibrotide was approved in the European Union for use in treating veno-occlusive disease of the liver of people having had a bone marrow transplant in 2013; Gentium had developed it. At the end of that year, Jazz Pharmaceuticals acquired Gentium.In March 2016, the U.S. Food and Drug Administration (FDA) approved it for a similar use. Defibrotide is the first FDA-approved therapy for treatment of severe hepatic VOD, a rare and life-threatening liver condition. The FDA granted the application for defibrotide priority review status and orphan drug designation. The FDA granted approval of Defitelio to Jazz Pharmaceuticals.Defibrotide was approved for medical use in Japan in June 2019.Defibrotide was approved for medical use in Australia in July 2020. References Further reading Richardson P, Aggarwal S, Topaloglu O, Villa KF, Corbacioglu S (December 2019). "Systematic review of defibrotide studies in the treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS)". Bone Marrow Transplant. 54 (12): 1951–1962. doi:10.1038/s41409-019-0474-8. PMC 6957462. PMID 30804485. Richardson PG, Carreras E, Iacobelli M, Nejadnik B (June 2018). "The use of defibrotide in blood and marrow transplantation". Blood Adv. 2 (12): 1495–1509. doi:10.1182/bloodadvances.2017008375. PMC 6020812. PMID 29945939. External links "Defibrotide". Drug Information Portal. U.S. National Library of Medicine.
Diphenhydramine	Diphenhydramine (DPH) is an antihistamine medication mainly used to treat allergies. It can also be used for insomnia, symptoms of the common cold, tremor in parkinsonism, and nausea. It is taken by mouth, injected into a vein, injected into a muscle, or applied to the skin. Maximal effect is typically around two hours after a dose, and effects can last for up to seven hours.Common side effects include sleepiness, poor coordination and an upset stomach. Its use is not recommended in young children or the elderly. There is no clear risk of harm when used during pregnancy; however, use during breastfeeding is not recommended. It is a first generation H1-antihistamine and ethanolamine and works by blocking certain effects of histamine. Diphenhydramine is also a potent anticholinergic, and works as a deliriant at higher than recommended doses as a result. This has led to some cases of recreational use and addiction.Diphenhydramine was first made by George Rieveschl and came into commercial use in 1946. It is available as a generic medication. It is sold under the brand name Benadryl, among others. In 2017, it was the 241st most commonly prescribed medication in the United States, with more than two million prescriptions. Medical uses Diphenhydramine is a first-generation antihistamine used to treat a number of conditions including allergic symptoms and itchiness, the common cold, insomnia, motion sickness, and extrapyramidal symptoms. Diphenhydramine also has local anesthetic properties, and has been used as such in people allergic to common local anesthetics such as lidocaine. Allergies Diphenhydramine is effective in treatment of allergies. As of 2007, it was the most commonly used antihistamine for acute allergic reactions in the emergency department.By injection it is often used in addition to epinephrine for anaphylaxis, although as of 2007 its use for this purpose had not been properly studied. Its use is only recommended once acute symptoms have improved. Topical formulations of diphenhydramine are available, including creams, lotions, gels, and sprays. These are used to relieve itching and have the advantage of causing fewer systemic effects (e.g., drowsiness) than oral forms. Movement disorders Diphenhydramine is used to treat akathisia and Parkinsons disease–like extrapyramidal symptoms caused by antipsychotics. It is also used to treat acute dystonia including torticollis and oculogyric crisis caused by first generation antipsychotics. Sleep Because of its sedative properties, diphenhydramine is widely used in nonprescription sleep aids for insomnia. The drug is an ingredient in several products sold as sleep aids, either alone or in combination with other ingredients such as acetaminophen (paracetamol) in Tylenol PM or ibuprofen in Advil PM. Diphenhydramine can cause minor psychological dependence. Diphenhydramine has also been used as an anxiolytic.Diphenhydramine has also been used off prescription by parents in an attempt to make their children sleep or remain sedated on long-distance flights. This has been met with criticism, both by doctors and members of the airline industry, as sedating young passengers may put them at risk if the flight encounters an emergency and they are unable to react to the situation efficiently, and the drugs side effects, especially the chance of a paradoxical reaction, may result in some individuals becoming hyperactive rather than sedated. The ethics of this use have also been challenged, with the Seattle Childrens hospital arguing in a 2009 article that "Using a medication for your convenience is never an indication for medication in a child."The American Academy of Sleep Medicines 2017 clinical practice guidelines recommended against the use of diphenhydramine in the treatment of insomnia due to poor effectiveness and low quality of evidence. A major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found little evidence to inform the use of diphenhydramine for insomnia. Nausea Diphenhydramine also has antiemetic properties, which make it useful in treating the nausea that occurs in vertigo and motion sickness. Special populations Diphenhydramine is not recommended for people older than 60 or children under the age of six, unless a physician is consulted. These populations should be treated with second-generation antihistamines such as loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine, and azelastine. Due to its strong anticholinergic effects, diphenhydramine is on the Beers list of drugs to avoid in the elderly.Diphenhydramine is category B in the FDA Classification of Drug Safety During Pregnancy. It is also excreted in breast milk. It is expected that low doses of diphenhydramine taken occasionally will not cause any adverse effects on breastfed infants. Large doses or long-term use may affect the baby or reduce breast milk supply, especially when combined with sympathomimetic drugs such as pseudoephedrine or before the establishment of lactation. A single bedtime dose after the last feeding of the day may minimize any harmful effects of the medication on the baby and on the milk supply. Still, non-sedating antihistamines are the preferred alternative.Paradoxical reactions to diphenhydramine have been documented, in particular among children, and it may cause excitation instead of sedation.Topical diphenhydramine is sometimes used especially for people in hospice. This use is without indication and topical diphenhydramine should not be used as treatment for nausea because research does not indicate this therapy is more effective than alternatives.There were no documented cases of clinically apparent acute liver injury caused by normal doses of diphenhydramine. Adverse effects The most prominent side effect is sedation. A typical dose creates driving impairment equivalent to a blood-alcohol level of 0.10, which is higher than the 0.08 limit of most drunk-driving laws.Diphenhydramine is a potent anticholinergic agent and potential deliriant in higher doses. This activity is responsible for the side effects of dry mouth and throat, increased heart rate, pupil dilation, urinary retention, constipation, and, at high doses, hallucinations or delirium. Other side effects include motor impairment (ataxia), flushed skin, blurred vision at nearpoint owing to lack of accommodation (cycloplegia), abnormal sensitivity to bright light (photophobia), sedation, difficulty concentrating, short-term memory loss, visual disturbances, irregular breathing, dizziness, irritability, itchy skin, confusion, increased body temperature (in general, in the hands and/or feet), temporary erectile dysfunction, and excitability, and although it can be used to treat nausea, higher doses may cause vomiting. Diphenhydramine in overdose may occasionally result in QT prolongation.Some individuals experience an allergic reaction to diphenhydramine in the form of hives.Conditions such as restlessness or akathisia can worsen from increased levels of diphenhydramine, especially with recreational dosages. Normal doses of diphenhydramine, like other first generation antihistamines, can also make symptoms of restless legs syndrome worse. As diphenhydramine is extensively metabolized by the liver, caution should be exercised when giving the drug to individuals with hepatic impairment. Anticholinergic use later in life is associated with an increased risk for cognitive decline and dementia among older people. Contraindications Diphenhydramine is contraindicated in premature infants and neonates as well as people who are breastfeeding. It is a pregnancy Category B drug. Diphenhydramine has additive effects with alcohol and other CNS depressants. Monoamine Oxidase inhibitors prolong and intensify the anticholinergic effect of antihistamines. Overdose Diphenhydramine is one of the most commonly misused over-the-counter drugs in the United States. In cases of extreme overdose, if not treated in time, acute diphenhydramine poisoning may have serious and potentially fatal consequences. Overdose symptoms may include: Acute poisoning can be fatal, leading to cardiovascular collapse and death in 2–18 hours, and in general is treated using a symptomatic and supportive approach. Diagnosis of toxicity is based on history and clinical presentation, and in general specific levels are not useful. Several levels of evidence strongly indicate diphenhydramine (similar to chlorpheniramine) can block the delayed rectifier potassium channel and, as a consequence, prolong the QT interval, leading to cardiac arrhythmias such as torsades de pointes. No specific antidote for diphenhydramine toxicity is known, but the anticholinergic syndrome has been treated with physostigmine for severe delirium or tachycardia. Benzodiazepines may be administered to decrease the likelihood of psychosis, agitation, and seizures in people who are prone to these symptoms. Interactions Alcohol may increase the drowsiness caused by diphenhydramine. Pharmacology Pharmacodynamics Diphenhydramine, while traditionally known as an antagonist, acts primarily as an inverse agonist of the histamine H1 receptor. It is a member of the ethanolamine class of antihistaminergic agents. By reversing the effects of histamine on the capillaries, it can reduce the intensity of allergic symptoms. It also crosses the blood–brain barrier and inversely agonizes the H1 receptors centrally. Its effects on central H1 receptors cause drowsiness. Like many other first-generation antihistamines, diphenhydramine is also a potent antimuscarinic (a competitive antagonist of muscarinic acetylcholine receptors) and, as such, at high doses can cause anticholinergic syndrome. The utility of diphenhydramine as an antiparkinson agent is the result of its blocking properties on the muscarinic acetylcholine receptors in the brain. Diphenhydramine also acts as an intracellular sodium channel blocker, which is responsible for its actions as a local anesthetic. Diphenhydramine has also been shown to inhibit the reuptake of serotonin. It has been shown to be a potentiator of analgesia induced by morphine, but not by endogenous opioids, in rats. The drug has also been found to act as an inhibitor of histamine N-methyltransferase (HNMT). Pharmacokinetics Oral bioavailability of diphenhydramine is in the range of 40% to 60%, and peak plasma concentration occurs about 2 to 3 hours after administration.The primary route of metabolism is two successive demethylations of the tertiary amine. The resulting primary amine is further oxidized to the carboxylic acid. Diphenhydramine is metabolized by the cytochrome P450 enzymes CYP2D6, CYP1A2, CYP2C9, and CYP2C19.The elimination half-life of diphenhydramine has not been fully elucidated, but appears to range between 2.4 and 9.3 hours in healthy adults. A 1985 review of antihistamine pharmacokinetics found that the elimination half-life of diphenhydramine ranged between 3.4 and 9.3 hours across five studies, with a median elimination half-life of 4.3 hours. A subsequent 1990 study found that the elimination half-life of diphenhydramine was 5.4 hours in children, 9.2 hours in young adults, and 13.5 hours in the elderly. A 1998 study found a half-life of 4.1 ± 0.3 hours in young men, 7.4 ± 3.0 hours in elderly men, 4.4 ± 0.3 hours in young women, and 4.9 ± 0.6 hours in elderly women. In a 2018 study in children and adolescents, the half-life of diphenhydramine was 8 to 9 hours. Chemistry Diphenhydramine is a diphenylmethane derivative. Analogues of diphenhydramine include orphenadrine, an anticholinergic, nefopam, an analgesic, and tofenacin, an antidepressant. Detection in body fluids Diphenhydramine can be quantified in blood, plasma, or serum. Gas chromatography with mass spectrometry (GC-MS) can be used with electron ionization on full scan mode as a screening test. GC-MS or GC-NDP can be used for quantification. Rapid urine drug screens using immunoassays based on the principle of competitive binding may show false-positive methadone results for people having ingested diphenhydramine. Quantification can be used to monitor therapy, confirm a diagnosis of poisoning in people who are hospitalized, provide evidence in an impaired driving arrest, or assist in a death investigation. History Diphenhydramine was discovered in 1943 by George Rieveschl, a former professor at the University of Cincinnati. In 1946, it became the first prescription antihistamine approved by the U.S. FDA.In the 1960s, diphenhydramine was found to weakly inhibit reuptake of the neurotransmitter serotonin. This discovery led to a search for viable antidepressants with similar structures and fewer side effects, culminating in the invention of fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI). A similar search had previously led to the synthesis of the first SSRI, zimelidine, from brompheniramine, also an antihistamine. Society and culture Diphenhydramine is deemed to have limited abuse potential in the United States owing to its potentially serious side-effect profile and limited euphoric effects, and is not a controlled substance. Since 2002, the U.S. FDA has required special labeling warning against use of multiple products that contain diphenhydramine. In some jurisdictions, diphenhydramine is often present in postmortem specimens collected during investigation of sudden infant deaths; the drug may play a role in these events.Diphenhydramine is among prohibited and controlled substances in the Republic of Zambia, and travelers are advised not to bring the drug into the country. Several Americans have been detained by the Zambian Drug Enforcement Commission for possession of Benadryl and other over-the-counter medications containing diphenhydramine. Recreational use Although diphenhydramine is widely used and generally considered to be safe for occasional usage, multiple cases of abuse and addiction have been documented. Because the drug is cheap and sold over the counter in most countries, adolescents without access to more sought-after, illicit drugs are particularly at risk. People with mental health problems—especially those with schizophrenia—are also prone to abuse the drug, which is self-administered in large doses to treat extrapyramidal symptoms caused by the use of antipsychotics.Recreational users report calming effects, mild euphoria, and hallucinations as the desired effects of the drug. Research has shown that antimuscarinic agents, including diphenhydramine, "may have antidepressant and mood-elevating properties". A study conducted on adult males with a history of sedative abuse found that subjects who were administered a high dose (400 mg) of diphenhydramine reported a desire to take the drug again, despite also reporting negative effects, such as difficulty concentrating, confusion, tremors, and blurred vision.In 2020, an Internet challenge emerged on social media platform TikTok involving deliberately overdosing on diphenhydramine; dubbed the Benadryl challenge, the challenge encourages participants to consume dangerous amounts of Benadryl for the purpose of filming the resultant psychoactive effects, and has been implicated in several hospitalisations and at least one death. Names Diphenhydramine is marketed under the trade name Benadryl by McNeil Consumer Healthcare in the U.S., Canada, and South Africa. Trade names in other countries include Dimedrol, Daedalon, and Nytol. It is also available as a generic medication. Procter & Gamble markets an over-the-counter formulation of diphenhydramine as a sleep aid under the brand ZzzQuil. In 2014 this product had annual sales of over $120 million and had a 29.3% share of the $411 million sleep-aid market category. See also Tripelennamine References Further reading External links "Diphenhydramine". Drug Information Portal. U.S. National Library of Medicine.
Birth control pill formulations	Birth control pills come in a variety of formulations. The main division is between combined oral contraceptive pills, containing both estrogens and synthetic progestogens (progestins), and progestogen only pills. Combined oral contraceptive pills also come in varying types, including varying doses of estrogen, and whether the dose of estrogen or progestogen changes from week to week. Mechanism of action Combination pills usually work by preventing the ovaries from releasing eggs (ovulation). They also thicken the cervical mucus, which keeps sperm from penetrating into the uterus and joining with an egg. The hormones in combination and progestogen-only pills also thin the lining of the uterus. This could prevent pregnancy by interfering with implantation of a blastocyst. Main action in typical use is prevention of ovulation. Combined oral contraceptive pills All contain an estrogen, ethinylestradiol or mestranol, in varying amounts, and one of a number of different progestogens. (Regarding the estrogen, the inactive 3-methyl ether of ethinylestradiol, which must be metabolized by the liver into the active ethinylestradiol; 50 μg of mestranol is equivalent to only 35 μg of ethinylestradiol and should not be used when high-dose [50 μg ethinylestradiol] estrogen pills are needed; mestranol was the estrogen used in the first oral contraceptive, Enovid). They are usually taken for 21 days with then a seven-day gap during which a withdrawal bleed (often, but incorrectly, referred to as a menstrual period) occurs. These differ in the amount of estrogen given, and whether they are monophasic (the same dose of estrogen and progestogen during each of the 21 days) or multiphasic (varying doses). The introduction of extended-cycle monophasic pills (i.e. Seasonale) has shown that the withdrawal bleeding intervals can be decreased. Monophasic These are typically given as 21 tablets of estrogen and progestogen, followed by seven tablets of placebo or an iron supplement, although some newer formulations contain more active tablets and fewer placebos. Everyday regimens (Microgynon 30 ED, Femodene ED, Logynon ED), which include seven inactive placebo pills, are rarely used in UK practice. Different formulations contain different amounts of estrogen and progestogen: 15 μg ethinylestradiol 60 μg gestodene: 24 days + 4 days placebo (Spain: Melodene-15; Israel: Minesse) 20 μg ethinylestradiol 1000 μg norethisterone acetate (UK: Loestrin 20, Galen; US: Loestrin 1/20, Duramed; Microgestin 1/20, Watson Pharmaceuticals; Junel 1/20, Barr) 1000 μg norethisterone acetate: 24 days + 4 days ferrous fumarate only (US: Loestrin 24 Fe, Warner Chilcott) 90 μg levonorgestrel: continuous: 365 days/year, no placebo (US: Amethyst, Watson) 100 μg levonorgestrel: extended cycle: 84 days + 7 days 10 μg ethinylestradiol only (US: LoSeasonique, Teva; CamreseLo, Teva) 100 μg levonorgestrel (US: Alesse, Wyeth; Aviane, Barr; Lessina, Barr; Lutera, Watson; Sronyx, Watson) 150 μg desogestrel (UK: Mercilon, Organon; HU: Novynette, Richter Gedeon) 75 μg gestodene (UK: Femodette, Bayer; RU: Logest, Bayer; Brazil: Femiane, Bayer) 3000 μg drospirenone: 24 days + 4 days placebo (US, EU, RU: Yaz; Bayer Schering Pharma AG. Cleonita); 21 days + 7 days placebo (US, EU: Yasminelle, Bayer); 24 days + 4 days placebo and levomefolate calcium (US: Beyaz; Bayer) 30 μg ethinylestradiol 1500 μg norethisterone acetate (UK: Loestrin 30, Galen; US: Loestrin 1.5/30, Duramed; Microgestin 1.5/30, Watson; Junel 1.5/30, Barr) 300 μg norgestrel (US: Lo/Ovral, Wyeth; Low-Ogestrel, Watson; Cryselle, Barr) 150 μg levonorgestrel (UK: Ovranette, Wyeth; Microgynon 30, Microgynon 30 ED, Bayer; US: Nordette, Duramed, Levora, Watson, Portia, Barr) 150 μg levonorgestrel: 21 day cycle + 7 days no pills (Canada: Min-Ovral 21; EU: Ovoplex 150/30; Sweden: Neovletta, Prionelle) 150 μg levonorgestrel: 21 day cycle + 7 days placebo (Canada: Min-Ovral 28; Sweden: Prionelle 28; RU: Rigevidon 21+7, Richter Gedeon) 150 μg levonorgestrel: extended cycle: 84 days + 7 days placebo (US: Seasonale, Duramed; Quasense, Watson; Jolessa, Barr, Introvale) 150 μg levonorgestrel: extended cycle: 84 days + 7 days 10 μg ethinylestradiol only (US: Seasonique, Duramed; Camrese, Teva; Amethia, Watson) 75 μg gestodene (UK: Femodene, Femodene ED, Bayer; Minulet, Wyeth; RU: Femoden, Jenapharm) 150 μg desogestrel (AU, EU, RU, UK: Marvelon, BR: Microdiol, US: Desogen, MSD; US: Ortho-Cept, Ortho-McNeil; RU: Regulon, Richter Gedeon) 3000 μg drospirenone (AU, EU, US: Yasmin, FR: Jasmine, RU: Yarina, Bayer Schering Pharma AG); with levomefolate calcium (US: Safyral, Bayer Schering Pharma AG) 2000 μg chlormadinone acetate (EU: Belara, Benelux: Bellina; Gedeon Richter) 2000 μg dienogest (AU, EU: Valette, RU: Jeanine, Bayer Schering Pharma AG; RU: Siluet, Gedeon Richter) 35 μg ethinylestradiol 400 μg norethisterone: chewable, spearmint flavor (US: Femcon Fe, Warner Chilcott) 400 μg norethisterone (US: Ovcon 35, Warner Chilcott; Balziva, Barr) 500 μg norethisterone (UK: Ovysmen, Janssen-Cilag; Brevinor, Pfizer; US: Modicon, Ortho-McNeil; Brevicon, Watson; Nortrel 0.5/35, Barr) 1000 μg norethisterone (AU, CAN: Synphasic, Pfizer; UK: Norimin, Pfizer; US: Ortho-Novum 1/35, Ortho-McNeil; Norinyl 1/35, Watson; Necon, Watson; Nortrel 1/35, Barr) 1000 μg etynodiol diacetate (US: Demulen 1/35, Pfizer; Zovia 1/35, Watson; Kelnor, Barr) 250 μg norgestimate (UK: Cilest, Janssen-Cilag; US: Ortho Cyclen, Ortho-McNeil; MonoNessa, Watson; Sprintec, Barr; Sweden: Amorest) 2000 μg cyproterone acetate: only approved for severe acne or severe hirsutism in the UK (AU, RU: Diane-35, UK: Dianette, Bayer) 50 μg mestranol (equivalent to 35 μg ethinylestradiol) 1000 μg norethisterone (UK: Norinyl-1, Pfizer; US: Ortho-Novum 1/50; Ortho-McNeil; Norinyl 1/50, Watson; Necon 1/50, Watson) 50 μg ethinylestradiol 1000 μg norethisterone (US: Ovcon 50, Warner Chilcott) 1000 μg etynodiol diacetate (US: Demulen 1/50, Pfizer; Zovia 1/50, Watson) 500 μg norgestrel (US: Ogestrel, Watson) 250 μg levonorgestrel (US: Nordiol, Wyeth) 1.5 mg estradiol (as hemihydrate) 2.5 mg nomegestrol acetate: 24-day cycle + 4 placebo pills (AU, EU, RU: Zoely, MSD) 15 mg estetrol monohydrate (equivalent to 14.2 mg estetrol) 3 mg drospirenone: 24-day cycle + 4 inactive pills (US, CAN: Nexstellis, Mayne, EU: Drovelis, Gedeon Richter Plc., EU: Lydisilka, Estetra SRL) Multiphasic 25 μg ethinylestradiol: triphasic ethinylestradiol/norgestimate combination with 7 tablets 25 μg/180 μg, 7 tablets 25 μg/215 μg, 7 tablets 25 μg/250 μg followed by 7 placebos (Ortho Tri-Cyclen Lo from Ortho-McNeil, Tri-Lo Sprintec back from Teva, Tri-Lo Marzia from Lupin, and norgestimate/ethinylestradiol from Mylan) ethinylestradiol/desogestrel combination with 7 tablets 25 μg/100 μg, 7 tablets 25 μg/125 μg, 7 tablets 25 μg/150 μg, followed by 7 tablets of ferric oxide (US: Cyclessa, Organon; Velivet, Barr) 20/30/35 μg ethinylestradiol: estrophasic ethinylestradiol/norethisterone acetate combination with 5 tablets 20 μg/1000 μg, 7 tablets 30 μg/1000 μg, 9 tablets 35 μg/1000 μg, followed by 7 tablets of ferrous fumarate 75 mg (US: Estrostep Fe, Warner Chilcott) 35/30/30 μg ethinylestradiol: triphasic ethinylestradiol/desogestrel combination with 7 tablets 35 μg/50 μg, 7 tablets 30 μg/100 μg, 7 tablets 30 μg/150 μg (RU: Tri-Merci, Organon) 30/40/30 μg ethinylestradiol: triphasic ethinylestradiol/levonorgestrel combination with 6 tablets 30 μg/50 μg, 5 tablets 40 μg/75 μg, 10 tablets 30 μg/125 μg (UK: Trinordiol, Wyeth; Logynon, Logynon ED, Bayer; US: Triphasil, Wyeth; Trivora, Watson; Enpresse, Barr) ethinylestradiol/gestodene combination with 6 tablets 30 μg/50 μg, 5 tablets 40 μg/70 μg, 10 tablets 30 μg/100 μg (UK: Triadene, Bayer; Tri-Minulet, Wyeth) 35 μg ethinylestradiol: triphasic ethinylestradiol/norethisterone combination with 7 tablets 35 μg/500 μg, 9 tablets 35 μg/1000 μg, 5 tablets 35 μg/500 μg (UK: Synphase, Pfizer; US: Tri-Norinyl, Watson; Leena, Watson) ethinylestradiol/norethisterone combination with 7 tablets 35 μg/500 μg, 7 tablets 35 μg/750 μg, 7 tablets 35 μg/1000 μg (UK: TriNovum, Janssen-Cilag; US: Ortho-Novum 7/7/7, Ortho-McNeil; Necon 7/7/7, Watson; Nortrel 7/7/7, Barr) ethinylestradiol/norgestimate combination with 7 tablets 35 μg/180 μg, 7 tablets 35 μg/215 μg, 7 tablets 35 μg/250 μg followed by 7 placebos (Ortho Tri-Cyclen, Ortho-McNeil; TriNessa, Watson; Tri-Sprintec, Barr) 35 μg ethinylestradiol: biphasic ethinylestradiol/norethisterone combination with 10 tablets 35 μg/500 μg, 11 tablets 35 μg/1000 μg, followed by 7 placebos (US: Ortho-Novum 10/11, Ortho-McNeil; Necon 10/11, Watson) ethinylestradiol/norethisterone combination with 7 tablets 35 μg/500 μg, 14 tablets 35 μg/1000 μg (UK: BiNovum, Janssen-Cilag) 3/2/1 mg estradiol valerate: estrophasic estradiol valerate/dienogest combination with 2 tablets 3 mg/0 mg, followed by 5 tablets 2 mg/2 mg, 17 tablets 2 mg/3 mg, 2 tablets 1 mg/0 mg, and 2 placebos. (AU, EU, RU: Qlaira, US: Natazia, Bayer) Progestogen-only pills Progestogen-only pills (POPs) use a progestogen alone with doses taken continuously and no or a short gap between packs taken. People who use them may experience irregular light bleeds, and whilst irregular in the first few months of taking, usually settles to a regular pattern in time. The following progestogens are used: 350 μg norethisterone (norethindrone) (UK: Micronor, Janssen-Cilag; Noriday, Pfizer; US: Micronor, Ortho-McNeil; Nor-QD, Watson; Nora-BE, Watson; Jolivette, Watson; Camila, Barr; Errin, Barr; Heather, Glenmark; RU: Primolut-Nor, Bayer; Norkolut, Richter Gedeon) 4 mg drospirenone (Slynd) 75 μg desogestrel (UK: Cerazette, Loestrin; RU: Cerazette, Organon; Lactinette, Richter Gedeon; SE: Gestrina) 30 μg levonorgestrel (UK: Norgeston, Bayer; AUS, RU: Microlut, Bayer) 500 μg etynodiol diacetate (UK: Femulen, Pfizer) 500 μg lynestrenol (RU: Exluton, Organon) Contraindications Generally oral contraceptives should not be used in people who currently have the following conditions: Thrombophlebitis or thromboembolic disorders A history of deep vein thrombophlebitis or thromboembolic disorders Cerebrovascular or coronary artery disease (current or history) Valvular heart disease with thrombogenic complications Severe hypertension Diabetes with vascular involvement Headaches with focal neurological symptoms Major surgery with prolonged immobilization Known or suspected carcinoma of the breast or personal history of breast cancer Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia Undiagnosed abnormal genital bleeding Cholestatic jaundice of pregnancy or jaundice with prior pill use Hepatic adenomas or carcinomas, or active liver disease Known or suspected pregnancy Hypersensitivity to any component of the productMore comprehensive guidelines that include analysis of risks and benefits can be found in the World Health Organization Medical Eligibility for Contraceptive Use Guidelines which are reflected in the CDC Medical Eligibility for Contraceptive Use Guidelines. See also Mestranol/noretynodrel (Enovid)—the first oral contraceptive List of progestogens available in the United States List of estrogens available in the United States == References ==
Azacitidine	Azacitidine, sold under the brand name Vidaza among others, is used for the treatment of myelodysplastic syndrome, myeloid leukemia, and juvenile myelomonocytic leukemia. It is a chemical analog of cytidine, a nucleoside in DNA and RNA. Azacitidine and its deoxy derivative, decitabine (also known as 5-aza-2′-deoxycytidine) were first synthesized in Czechoslovakia as potential chemotherapeutic agents for cancer.The most common adverse reactions in children with juvenile myelomonocytic leukemia include pyrexia, rash, upper respiratory tract infection, and anemia. Medical uses Azacitidine is indicated for the treatment of myelodysplastic syndrome, for which it received approval by the U.S. Food and Drug Administration (FDA) on May 19, 2004. In two randomized controlled trials comparing azacitidine to supportive treatment, 16% of subjects with myelodysplastic syndrome who were randomized to receive azacitidine had a complete or partial normalization of blood cell counts and bone marrow morphology, compared to none who received supportive care, and about two-thirds of patients who required blood transfusions no longer needed them after receiving azacitidine.Azacitidine is also indicated for the treatment of myeloid leukemia and juvenile myelomonocytic leukemia. Mechanism of action Azacitidine is a chemical analogue of the nucleoside cytidine, which is present in DNA and RNA. It is thought to have antineoplastic activity via two mechanisms – at low doses, by inhibiting of DNA methyltransferase, causing hypomethylation of DNA, and at high doses, by its direct cytotoxicity to abnormal hematopoietic cells in the bone marrow through its incorporation into DNA and RNA, resulting in cell death. Azacitidine is a ribonucleoside, so it is incorporated into RNA to a larger extent than into DNA. In contrast, decitabine (5-aza-2-deoxycytidine) is a deoxyribonucleoside, so it can only incorporate into DNA. Azacitidines incorporation into RNA leads to the disassembly of polyribosomes, defective methylation and acceptor function of transfer RNA, and inhibition of the production of proteins. Its incorporation into DNA leads to covalent binding with DNA methyltransferases, which prevents DNA synthesis and subsequently leads to cytotoxicity. It has been shown effective against human immunodeficiency virus in vitro and human T-lymphotropic virus. Inhibition of methylation After azanucleosides such as azacitidine have been metabolized to 5-aza-2′-deoxycytidine-triphosphate (aka, decitabine-triphosphate), they can be incorporated into DNA and azacytosine can be substituted for cytosine. Azacytosine-guanine dinucleotides are recognized as substrate by the DNA methyltransferases, which catalyze the methylation reaction by a nucleophilic attack. This results in a covalent bond between the carbon-6 atom of the cytosine ring and the enzyme. The bond is normally resolved by beta-elimination through the carbon-5 atom, but this latter reaction does not occur with azacytosine because its carbon-5 is substituted by nitrogen, leaving the enzyme covalently bound to DNA and blocking its DNA methyltransferase function. In addition, the covalent protein adduction also compromises the functionality of DNA and triggers DNA damage signaling, resulting in the degradation of trapped DNA methyltransferases. As a consequence, methylation marks become lost during DNA replication. Toxicity Azacitidine causes anemia (low red blood cell counts), neutropenia (low white blood cell counts), and thrombocytopenia (low platelet counts), and patients should have frequent monitoring of their complete blood counts, at least prior to each dosing cycle. The dose may have to be adjusted based on nadir counts and hematologic response.It can also be hepatotoxic in patients with severe liver impairment, and patients with extensive liver tumors due to metastatic disease have developed progressive hepatic coma and death during azacitidine treatment, especially when their albumin levels are less than 30 g/L. It is contraindicated in patients with advanced malignant hepatic tumors.Kidney toxicity, ranging from elevated serum creatinine to kidney failure and death, have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for conditions other than myelodysplastic syndrome. Renal tubular acidosis developed in five patients with chronic myelogenous leukemia (an unapproved use) treated with azacitidine and etoposide, and patients with renal impairment may be at increased risk for renal toxicity. Azacitidine and its metabolites are primarily excreted by the kidneys, so patients with chronic kidney disease should be closely monitored for other side effects, since their levels of azacitidine may progressively increase.Based on animal studies and its mechanism of action, azacitidine can cause severe fetal damage. Sexually active women of reproductive potential should use contraception during while receiving azacitidine and for one week after the last dose, and sexually active men with female partners of reproductive potential should use contraception during treatment and for three months following the last dose.A study undertaken to evaluate the immediate and long-term effects of a single-day exposure to Azacytidine (5-AzaC) on neurobehavioral abnormalities in mice found, that the inhibition of DNA methylation by 5-AzaC treatment causes neurodegeneration and impairs extracellular signal-regulated kinase (ERK1/2) activation and the activity-regulated cytoskeleton-associated (Arc) protein expression in neonatal mice and induces behavioral abnormalities in adult mice, as DNA methylation-mediated mechanisms appear to be necessary for the proper maturation of synaptic circuits during development, and disruption of this process by 5-AzaC could lead to abnormal cognitive function.Azacitidine can also cause nausea, vomiting, fevers, diarrhea, redness at its injection sites, constipation, bruising, petechiae, rigors, weakness, abnormally low potassium levels in the bloodstream, and many other side effects, some of which can be severe or even fatal. History The efficacy of azacitidine to treat juvenile myelomonocytic leukemia was evaluated in AZA-JMML-001 (NCT02447666), an international, multicenter, open-label study to evaluate the pharmacokinetics, pharmacodynamics, safety, and activity of azacitidine prior to hematopoietic stem cell transplantation in 18 pediatric patients with juvenile myelomonocytic leukemia. Research Azacitidine can be used in vitro to remove methyl groups from DNA. This may weaken the effects of gene silencing mechanisms that occur prior to methylation. Certain methylations are believed to secure DNA in a silenced state, and therefore demethylation may reduce the stability of silencing signals and confer relative gene activation.Azacitidine induces tumor regression on isocitrate dehydrogenase-1 mutant glioma xenografts in mice.In research, 5-azacitidine is commonly used for promoting cardiomyocyte differentiation of adult stem cells. However, it has been suggested that this drug has a compromised efficacy as a cardiac differentiation factor because it promotes the transdifferentiation of cardiac cells to skeletal myocytes.Azacitidine also has antiviral effects in animal studies as well as its anti-cancer actions, but has not been tested for clinical use. References External links "Azacitidine". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT02447666 for "Study With Azacitidine in Pediatric Subjects With Newly Diagnosed Advanced Myelodysplastic Syndrome (MDS) and Juvenile Myelomonocytic Leukemia (JMML)" at ClinicalTrials.gov
Serostim	Serostim (recombinant DNA somatropin) is Seronos brand name prescription drug form of synthetic growth hormone, marketed for HIV-associated wasting.In December 2007, the U.S. District Court of Massachusetts - in a class-action lawsuit that involved Merck Serono and Serostim - fined Serono a total of $704 million in criminal and civil liabilities for enacting "illegal schemes to promote, market and sell its drug." References External links Settlement infoi
Loxapine	Loxapine, sold under the brand names Loxitane and Adasuve (inhalation only) among others, is an antipsychotic medication used primarily in the treatment of schizophrenia. The medicine is a member of the dibenzoxazepine class and structurally very similar to clozapine. Several researchers have argued that loxapine, initially classified as a typical antipsychotic, behaves as an atypical antipsychotic.Loxapine may be metabolized by N-demethylation to amoxapine, a tricyclic antidepressant. Medical uses The US Food and Drug Administration (FDA) has approved loxapine inhalation powder for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.A brief review of loxapine found no conclusive evidence that it was particularly effective in patients with schizophrenia. A subsequent systematic review considered that the limited evidence did not indicate a clear difference in its effects from other antipsychotics. Available forms Loxapine can be taken by mouth. It is also available as an intramuscular injection and as a powder for inhalation. Side effects Loxapine can cause side effects that are generally similar to that of other antipsychotic medications. These include, e.g., gastrointestinal problems (like constipation and abdominal pain), cardiovascular problems (like tachycardia), moderate likelihood of drowsiness (relative to other antipsychotics), and movement problems (i.e. extrapyramidal symptoms [EPS]). At lower dosages its propensity for causing EPS appears to be similar to that of atypical antipsychotics. Although it is structurally similar to clozapine, it has much lower risk of agranulocytosis (which, even with clozapine, is 0.8%); however, mild and temporary fluctuations in blood leukocyte levels can occur. Abuse of loxapine has been reported.The inhaled formulation of loxapine carries a low risk for a type of airway adverse reaction called bronchospasm that is not thought to occur when loxapine is taken by mouth. Pharmacology Mechanism of action Some authors say loxapine is a "mid-potency" typical antipsychotic. However, unlike most other typical antipsychotics, it has significant potency at the 5HT2A receptor (6.6 nM), which is similar to atypical antipsychotics like clozapine (5.35 nM). The higher likelihood of EPS with loxapine, compared to clozapine, may be due to its higher affinity for the D2 receptor compared to clozapine, which has one of the lowest binding affinities at the D2 receptor of any antipsychotic. Pharmacokinetics Loxapine is metabolized to amoxapine, as well as its 8-hydroxy metabolite (8-hydroxyloxapine). Amoxapine is further metabolized to its 8-hydroxy metabolite (8-hydroxyamoxapine), which is also found in the blood of people taking loxapine. At steady-state after taking loxapine by mouth, the relative amounts of loxapine and its metabolites in the blood is as follows: 8-hydroxyloxapine > 8-hydroxyamoxapine > loxapine.The pharmacokinetics of loxapine change depending on how it is given. Intramuscular injections of loxapine lead to higher blood levels and area under the curve of loxapine than when it is taken by mouth. Chemistry Loxapine is a dibenzoxazepine and is structurally very similar to clozapine, an atypical antipsychotic. References External links "Loxapine". Drug Information Portal. U.S. National Library of Medicine.
Dalbavancin	Dalbavancin, sold under the brand names Dalvance in the US and Xydalba in the EU among others, is a second-generation lipoglycopeptide antibiotic medication. It belongs to the same class as vancomycin, the most widely used and one of the treatments available to people infected with methicillin-resistant Staphylococcus aureus (MRSA).Dalbavancin is a semisynthetic lipoglycopeptide that was designed to improve upon the natural glycopeptides vancomycin and teicoplanin. It is derived from a complex of glycopeptide antibiotics, referred to as A-40926, that is produced by a new strain of Actinomadura. Dalbavancin has been referred to in the scientific literature by a series of names: MDL-63397, A-!-1, BI-397, VER-001. These different labels reflected where the research had been carried out: MDL representing Merrell-Dow-Lepetit, where the initial complex was discovered; BI referring to BioSearch Italia where Dalbavancin itself was first synthesized; VER referring to Versicor (which Biosearch Italia merged with to create Vicuron Pharmaceuticals). The phase I, II and III clinical trials were carried out of by Vicuron and the initial NDA filed. Vicuron was acquired by Pfizer in 2005, which decided to not further develop Dalbavancin at that time, subsequently selling the rights to Durata Therapeutics in 2009.It possesses in vitro activity against a variety of Gram-positive pathogens including MRSA and methicillin-resistant Staphylococcus epidermidis (MRSE). It is a once-weekly, two-dose antibiotic, the rights to which Actavis acquired when it bought Durata Therapeutics in 2014.The U.S. Food and Drug Administration (FDA) approved dalbavancin in May 2014, for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by certain susceptible bacteria such as Staphylococcus aureus including methicillin-susceptible and methicillin-resistant strains of Streptococcus pyogenes, in intravenous dosage form. Medical uses Dalbavancin is an antibiotic used to treat acute bacterial skin and skin structure infections (ABSSSI) in adults caused by susceptible Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). MRSA infections have become problematic in the community and in healthcare settings due to resistance to many available antibiotics. Because dalbavancin has demonstrated efficacy against MRSA and other microorganisms to treat serious or life-threatening infections, it was the first drug approved as a Qualified Infectious Disease Product under the Generating Antibiotic Incentives Now (GAIN) act, which is part of the FDA Safety and Innovation Act.It has strong activity against many Gram-positive bacteria, including methicillin-sensitive and methicillin-resistant Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus. Based on MIC data and other studies, dalbavancin is more potent and bactericidal and therefore requires lower concentrations than vancomycin against these organisms. Dalbavancin also shows in vitro activity against vancomycin-susceptible Enterococcus faecium and Enterococcus faecalis. Other Gram-positive organisms belonging to the Bacillus spp., Listeria spp., and Corynebacterium spp. may show in vitro susceptibility, and dalbavancin may exhibit activity against enterococci expressing the VanB or VanC phenotype of acquired resistance against vancomycin. There is no clinically significant activity against Gram-negative bacteria.Two trials, DISCOVER 1 and DISCOVER 2, demonstrated noninferiority of dalbavancin compared to vancomycin/linezolid in the treatment of ABSSSI. Patients were randomly assigned to receive two doses of dalbavancin on days 1 and 8, or to receive intravenous vancomycin for at least 3 days with the option of switching to oral linezolid to complete 10 to 14 days of therapy. Investigators assessed the cessation of spread of infection-related erythema and the absence of fever at 48 to 72 hours as the primary endpoint and found that once-weekly dalbavancin was as effective as twice-daily intravenous vancomycin followed by oral linezolid. This once-weekly dosing regimen may offer an advantageous treatment option compared to daily or twice-daily dosing. Contraindications Hypersensitivity to dalbavancin can occur, causing issues such as skin reactions or anaphylaxis. Caution is advised for patients with known hypersensitivity to other glycopeptides. There is currently no data on cross-reactivity between dalbavancin and vancomycin. Side effects The most common adverse reactions encountered in Phase II and Phase III trials were nausea (5.5%), headache (4.7%), and diarrhea (4.4%), as well as rash (2.7%) and itchiness (2.1%). Other less frequent but serious adverse reactions included hematologic disorders, hepatotoxicity, Clostridium difficile colitis, bronchospasm, infusion-related reactions including Red Man Syndrome, and anaphylactic shock. In trials, dalbavancin was associated with higher rates of hemorrhagic events compared to comparator groups and should be a precaution in patients undergoing surgery or taking anticoagulants. Patients on dalbavancin also had post-baseline alanine aminotransferase (ALT) levels that were 3 times the upper normal limit, some even having elevations 10 times the upper normal limit; however, eight of the twelve dalbavancin-treated patients had comorbid conditions that could affect their ALT, compared to only one patient in the comparator group. There is no evidence of ototoxicity associated with dalbavancin. Drug interactions Clinical drug-drug interactions with dalbavancin have not been studied, and dalbavancin does not appear to interact with cytochrome P450 substrates, inhibitors, or inducers. It was found to have an in vitro synergistic interaction with the antimicrobial oxacillin, but the clinical significance of this interaction has yet to be established. Pregnancy and lactation Use of dalbavancin in pregnant women has not been studied sufficiently and should only occur when the potential benefit outweighs the potential risk to the fetus. Animal studies did not show embryo or fetal toxicity at doses that were 1.2 and 0.7 times the human dose. However, delayed fetal maturation was observed at a dose that was 3.5 times the human dose. While dalbavancin is excreted in rat milk, it is unknown if it is excreted in human milk. It should be used in nursing mothers only when the potential benefit exceeds the potential risk. There is no evidence in animals of teratogenicity. Production and composition Dalbavancin is manufactured by fermentation of a selected Nonomuraea strain to generate the natural glycopeptide complex A-40926. This precursor is then selectively esterified at the carboxyl group of its sugar moiety, its peptidyl carboxyl group is amidated and the ester of the N-acylaminoglucuronic acid carboxyl group is saponified. The outcome is a compound mixture of two closely related structural families — A and B — that can be further subdivided into a total of five subtypes (see table below). At least ten different dalbavancin components have been described, of which the B0 component makes up around 80–98 wt%. Mechanism of action Dalbavancin is a lipoglycopeptide belonging in the same glycopeptide class as vancomycin. Similar to other glycopeptides, dalbavancin exerts its bactericidal effect by disrupting cell wall biosynthesis. It binds to the D-alanyl-D-alanyl residue on growing peptidoglycan chains and prevents transpeptidation from occurring, preventing peptidoglycan elongation and cell wall formation. Dalbavancin also dimerizes and anchors itself in the lipophilic bacterial membrane, thereby increasing its stability in the target environment and its affinity for peptidoglycan.Antimicrobial activity correlates with the ratio of area under the concentration-time curve to minimum inhibitory concentration for Staphylococcus aureus. Metabolism When evaluated by in vitro studies, the metabolism of dalbavancin was minimally impacted by the human hepatic CYP450 system. Further investigations with either inducers or inhibitors of this enzyme system demonstrated no changes in the elimination or clearance of dalbavancin, and the metabolism of model compounds of these CYP systems was not altered by the dalbavancin. Hydroxy-dalbavancin, a minor metabolite that has only been identified in urine, was also not changed in its formation or elimination with these enzyme models. History Dalbavancin has undergone a phase-III clinical trial for adults with complicated skin infections, but in December 2007, the US Food and Drug Administration (FDA) said more data were needed before approval. Pfizer withdrew its marketing applications to conduct another phase-III clinical trial in September 2008. Durata Therapeutics acquired the rights to dalbavancin in December 2009, and has initiated two new phase-III clinical trials for treatment of ABSSSIs. Preliminary results in 2012 were promising.About 1,289 adults with ABSSSI were given dalbavancin or vancomycin randomly, and dalbavancin was found to exhibit efficacy comparable to vancomycin.In May 2014, dalbavancin was approved for medical use in the United States for ABSSSIs, including MRSA and Streptococcus pyogenes infections. References External links "Dalbavancin". Drug Information Portal. U.S. National Library of Medicine.
Pegasys	Pegasys may refer to: A brand name of the medication peginterferon alfa-2a Pegasys, Inc., a Japanese software company that develops the TMPGEnc family of video encoding/editing programs Pegasus (disambiguation)
Phytomenadione	Phytomenadione, also known as vitamin K1 or phylloquinone, is a vitamin found in food and used as a dietary supplement. It is on the World Health Organizations List of Essential Medicines.As a supplement it is used to treat certain bleeding disorders. This includes warfarin overdose, vitamin K deficiency, and obstructive jaundice. It is also recommended to prevent and treat vitamin K deficiency bleeding in infants. Use is typically recommended by mouth, intramuscular injection or injection under the skin. When given by injection benefits are seen within two hours. Many countries in the world choose intramuscular injections in newborn to keep them safe from severe bleeding (VKDB). It is considered a safe treatment and saves many children from death and severe neurologic deficit every year.Side effects when given by injection may include pain at the site of injection. Severe allergic reactions may occur when it is injected into a vein or muscle, but this has mainly happened when large doses of a certain type of supplement containing castor oil were given intravenously. Use during pregnancy is considered safe, use is also likely okay during breastfeeding. It works by supplying a required component for making a number of blood clotting factors. Found sources include green vegetables, vegetable oil, and some fruit.Phytomenadione was first isolated in 1939. In 1943 Edward Doisy and Henrik Dam were given a Nobel Prize for its discovery. Terminology Phytomenadione is often also called phylloquinone, vitamin K, or phytonadione. A stereoisomer of phylloquinone is called vitamin k1 (note the difference in capitalization). Chemistry Vitamin K is a fat-soluble vitamin that is stable in air and moisture but decomposes in sunlight. It is a polycyclic aromatic ketone, based on 2-methyl-1,4-naphthoquinone, with a 3-phytyl substituent. It is found naturally in a wide variety of green plants, particularly in leaves, since it functions as an electron acceptor during photosynthesis, forming part of the electron transport chain of photosystem I. Biological function The best-known function of vitamin K in animals is as a cofactor in the formation of coagulation factors II (prothrombin), VII, IX, and X by the liver. It is also required for the formation of anticoagulant factors protein C and S. It is commonly used to treat warfarin toxicity, and as an antidote for coumatetralyl. Vitamin K is required for bone protein formation. Biosynthesis Vitamin K1 is synthesized from chorismate, a compound produced from shikimate via the shikimate pathway. The conversion of chorismate to vitamin K1 comprises a series of nine steps: Chorismate is isomerized to isochorismate by isochorismate synthase, or MenF (menaquinone enzyme). Addition of 2-oxoglutarate to isochorismate by PHYLLO, a multifunctional protein comprising three different enzymatic activities (MenD, H, and C). Elimination of pyruvate by PHYLLO. Aromatization to yield o-succinyl benzoate by PHYLLO. O-succinylbenzoate activation to corresponding CoA ester by MenE. Naphthoate ring formation by naphthoate synthase (MenB/NS). Thiolytic release of CoA by a thioesterase (MenH). Attachment of phytol chain to the naphthoate ring (MenA/ABC4). Methylation of the precursor at position 3 (MenG). Vitamin K1 is required for plant photosynthesis, where it participates in the Photosystem I electron transport chain. As a result, it is rich in leaves. See also Menatetrenone Vitamin K Vitamin K2 References External links "Phytomenadione". Drug Information Portal. U.S. National Library of Medicine.
Mefloquine	Mefloquine, sold under the brand name Lariam among others, is a medication used to prevent or treat malaria. When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure. It can be used to treat mild or moderate malaria but is not recommended for severe malaria. It is taken by mouth.Common side effects include vomiting, diarrhea, headaches, sleep disorders, and a rash. Serious side effects include potentially long-term mental health problems such as depression, hallucinations, and anxiety and neurological side effects such as poor balance, seizures, and ringing in the ears. It is therefore not recommended in people with a history of mental health problems or epilepsy. It appears to be safe during pregnancy and breastfeeding.Mefloquine was developed by the United States Army in the 1970s and came into use in the mid-1980s. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. Medical uses Mefloquine is used to both prevent and treat certain forms of malaria. Malaria prevention Mefloquine is useful for the prevention of malaria in all areas except for those where parasites may have resistance to multiple medications, and is one of several anti-malarial medications recommended by the United States Centers for Disease Control and Prevention for this purpose. It is also recommended by the Infectious Disease Society of America for malaria prophylaxis as a first or second-line agent, depending on resistance patterns in the malaria found in the geographic region visited. It is typically taken for one to two weeks before entering an area with malaria. Doxycycline and atovaquone/proguanil provide protection within one to two days and may be better tolerated. If a person becomes ill with malaria despite prophylaxis with mefloquine, the use of halofantrine and quinine for treatment may be ineffective.: 4 Malaria treatment Mefloquine is used as a treatment for chloroquine-sensitive or resistant Plasmodium falciparum malaria, and is deemed a reasonable alternative for uncomplicated chloroquine-resistant Plasmodium vivax malaria. It is one of several drugs recommended by the United States Centers for Disease Control and Prevention. It is not recommended for severe malaria infections, particularly infections from P. falciparum, which should be treated with intravenous antimalarials. Mefloquine does not eliminate parasites in the liver phase of the disease, and people with P. vivax malaria should be treated with a second drug that is effective for the liver phase, such as primaquine.: 4 Resistance to mefloquine Resistance to mefloquine is common around the west border in Cambodia and other parts of Southeast Asia. The mechanism of resistance is by increase in Pfmdr1 copy number. Adverse effects Common side effects include vomiting, diarrhea, headaches, and a rash. Severe side effects requiring hospitalization are rare, but include mental health problems such as depression, hallucinations, anxiety and neurological side effects such as poor balance, seizures, and ringing in the ears. Mefloquine is therefore not recommended in people with a history of psychiatric disorders or epilepsy. Neurologic and psychiatric In 2013, the U.S. Food and Drug Administration (FDA) added a boxed warning to the prescription label of mefloquine regarding the potential for neuropsychiatric side effects that may persist even after discontinuing administration of the medication. In 2013 the FDA stated "Neurologic side effects can occur at any time during drug use, and can last for months to years after the drug is stopped or can be permanent." Neurologic effects include dizziness, loss of balance, seizures, and tinnitus. Psychiatric effects include nightmares, visual hallucinations, auditory hallucinations, anxiety, depression, unusual behavior, and suicidal ideations. Central nervous system events requiring hospitalization occur in about one in 10,000 people taking mefloquine for malaria prevention, with milder events (e.g., dizziness, headache, insomnia, and vivid dreams) in up to 25%. When some measure of subjective severity is applied to the rating of adverse events, about 11–17% of travelers are incapacitated to some degree. Cardiac Mefloquine may cause abnormalities with heart rhythms that are visible on electrocardiograms. Combining mefloquine with other drugs that cause similar effects, such as quinine or quinidine, can increase these effects. Combining mefloquine with halofantrine can cause significant increases in QTc intervals.: 10 Contraindications Mefloquine is contraindicated in those with a previous history of seizures or a recent history of psychiatric disorders. Pregnancy and breastfeeding Available data suggests that mefloquine is safe and effective for use by pregnant women during all trimesters of pregnancy, and it is widely used for this indication. In pregnant women, mefloquine appears to pose minimal risk to the fetus, and is not associated with increased risk of birth defects or miscarriages. Compared to other malaria chemoprophylaxis regimens, however, mefloqinone may produce more side effects in non-pregnant travelers. Mefloquine is also safe and effective for use during breastfeeding, though it appears in breast milk in low concentrations.: 9 The World Health Organization (WHO) gives approval for the use of mefloquine in the second and third trimesters of pregnancy and use in the first trimester does not mandate termination of pregnancy. Pharmacology Elimination Mefloquine is metabolized primarily through the liver. Its elimination in persons with impaired liver function may be prolonged, resulting in higher plasma levels and an increased risk of adverse reactions. The mean elimination plasma half-life of mefloquine is between two and four weeks. Total clearance is through the liver, and the primary means of excretion is through the bile and feces, as opposed to only 4% to 9% excreted through the urine. During long-term use, the plasma half-life remains unchanged.Liver function tests should be performed during long-term administration of mefloquine. Alcohol use should be avoided during treatment with mefloquine. Chemistry Specifically it is used as mefloquine hydrochloride. Mefloquine is a chiral molecule with two asymmetric carbon centres, which means it has four different stereoisomers. The drug is currently manufactured and sold as a racemate of the (R,S)- and (S,R)-enantiomers by Hoffman-LaRoche, a Swiss pharmaceutical company. Essentially, it is two drugs in one. Plasma concentrations of the (–)-enantiomer are significantly higher than those for the (+)-enantiomer, and the pharmacokinetics between the two enantiomers are significantly different. The (+)-enantiomer has a shorter half-life than the (–)-enantiomer. History Mefloquine was formulated at Walter Reed Army Institute of Research (WRAIR) in the 1970s shortly after the end of the Vietnam war. Mefloquine was number 142,490 of a total of 250,000 antimalarial compounds screened during the study.Mefloquine was the first Public-Private Venture (PPV) between the US Department of Defense and a pharmaceutical company. WRAIR transferred all its phase I and phase II clinical trial data to Hoffman-LaRoche and Smith Kline. FDA approval as a treatment for malaria was swift. Most notably, phase III safety and tolerability trials were skipped.The drug was first approved in Switzerland in 1984 by Hoffmann-LaRoche, who brought it to market with the name Lariam.However, mefloquine was not approved by the FDA for prophylactic use until 1989. This approval was based primarily on compliance, while safety and tolerability were overlooked. Because of the drugs very long half-life, the Centers for Disease Control originally recommended a mefloquine dosage of 250 mg every two weeks; however, this caused an unacceptably high malaria rate in the Peace Corps volunteers who participated in the approval study, so the drug regimen was switched to once a week.By 1991, Hoffman was marketing the drug on a worldwide basis.By the 1992 UNITAF, Canadian soldiers were being prescribed the drug en masse.By 1994, medical professionals were noting "severe psychiatric side effects observed during prophylaxis and treatment with mefloquine", and recommending that "the absence of contraindications and minor side effects during an initial course of mefloquine should be confirmed before another course is prescribed." Other doctors at the University Hospital of Zurich noted in a case of "a 47-year-old, previously healthy Japanese tourist" who had severe neuropsychiatric side-effects from the drug that The neuropsychiatric side effects of the antimalarial drug mefloquine are well documented. They include anxiety, depression, hallucinations, acute psychosis, and seizures. The incidence of these side effects is 1 in 13,000 with prophylactic use and 1 in 250 with therapeutic use. The first randomized, controlled trial on a mixed population was performed in 2001. Prophylaxis with mefloquine was compared to prophylaxis with atovaquone-proguanil. Roughly 67% of participants in the mefloquine arm reported greater than or equal to one adverse event, vs 71% in the atovaquone-proguanil arm. In the mefloquine arm, 5% of the users reported severe events requiring medical attention, vs 1.2% in the atovaquone-proguanil arm.In August 2009, Roche stopped marketing Lariam in the United States.Retired soldier Johnny Mercer, who was later appointed Minister for Veterans Affairs by Boris Johnson, told in 2015 that he had received "a letter about once or twice a week" about ill-effects from the drug. In July 2016, Roche took this brand off the market in Ireland. Military In 2006, the Australian military deemed mefloquine "a third-line drug" alternative, and over the five years from 2011 only 25 soldiers had been prescribed the drug, and only in cases of their intolerance for other alternatives. Between 2001 and 2012, 16,000 Canadian soldiers sent to Afghanistan were given the drug as a preventative measure. In 2013, the US Army banned mefloquine from use by its special forces such as the Green Berets. In autumn 2016, the UK military followed suit with their Australian peers after a parliamentary inquiry into the matter revealed that it can cause permanent side effects and brain damage.In early December 2016, the German defence ministry removed mefloquine from the list of medications it would provide to its soldiers.In autumn 2016, Canadian Surgeon General Brigadier General Hugh Colin MacKay told a parliamentary committee that faulty science supported the assertion that the drug has indelible noxious side effects. An expert from Health Canada named Barbara Raymond told the same committee that the evidence she had read failed to support the conclusion of indelible side effects. Canadian soldiers who took mefloquine when deployed overseas have claimed they have been left with ongoing mental health problems. Research In June 2010, the first case report appeared of a progressive multifocal leukoencephalopathy being successfully treated with mefloquine. Mefloquine can also act against the JC virus. Administration of mefloquine seemed to eliminate the virus from the patients body and prevented further neurological deterioration.Mefloquine alters cholinergic synaptic transmission through both postsynaptic and presynaptic actions. The postsynaptic action to inhibit acetylcholinesterase changes transmission across synapses in the brain. References Further reading Chen LH, Wilson ME, Schlagenhauf P (May 2007). "Controversies and misconceptions in malaria chemoprophylaxis for travelers". JAMA. 297 (20): 2251–63. doi:10.1001/jama.297.20.2251. PMID 17519415. Schlagenhauf P, Adamcova M, Regep L, Schaerer MT, Rhein HG (December 2010). "The position of mefloquine as a 21st century malaria chemoprophylaxis". Malar. J. 9: 357. doi:10.1186/1475-2875-9-357. PMC 3224336. PMID 21143906. External links "Mefloquine". Drug Information Portal. U.S. National Library of Medicine.
Cefazolin	Cefazolin, also known as cefazoline and cephazolin, is a first-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections. Specifically it is used to treat cellulitis, urinary tract infections, pneumonia, endocarditis, joint infection, and biliary tract infections. It is also used to prevent group B streptococcal disease around the time of delivery and before surgery. It is typically given by injection into a muscle or vein.Common side effects include diarrhea, vomiting, yeast infections, and allergic reactions. It is not recommended in people who have a history of anaphylaxis to penicillin. It is relatively safe for use during pregnancy and breastfeeding. Cefazolin is in the first-generation cephalosporin class of medication and works by interfering with the bacterias cell wall.Cefazolin was patented in 1967 and came into commercial use in 1971. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. Medical uses Cefazolin is used in a variety of infections provided that susceptible organisms are involved. It is indicated for use in the following infections: Respiratory tract infections Urinary tract infections Skin infections Biliary tract infections Bone and joint infections Genital infections Blood infections (sepsis) EndocarditisIt can also be used peri-operatively to prevent infections post-surgery, and is often the preferred drug for surgical prophylaxis.There is no penetration into the central nervous system and therefore cefazolin is not effective in treating meningitis.Cefazolin has been shown to be effective in treating methicillin-susceptible Staphylococcus aureus (MSSA) but does not work in cases of methicillin-resistant Staphylococcus aureus (MRSA). In many instances of staphylococcal infections, such as bacteremia, cefazolin is an alternative to penicillin in patients who are allergic to penicillin. However, there is still potential for a reaction to occur with cefazolin and other cephalosporins in patients allergic to penicillin. Resistance to cefazolin is seen in several species of bacteria, such as Mycoplasma and Chlamydia, in which case different generations of cephalosporins may be more effective. Cefazolin does not fight against Enterococcus, anaerobic bacteria or atypical bacteria among others. Bacterial susceptibility As a first-generation cephalosporin antibiotic, cefazolin and other first-generation antibiotics are very active against gram-positive bacteria and some gram-negative bacteria. Their broad spectrum of activity can be attributed to their improved stability to many bacterial beta-lactamases compared to penicillins. Spectrum of activity Gram-positive aerobes: Staphylococcus aureus (including beta-lactamase producing strains) Staphylococcus epidermidis Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae and other strains of streptococciGram-Negative Aerobes: Escherichia coli Proteus mirabilis Non susceptible The following are not susceptible: Methicillin-resistant staphylococcus aureus Enterococcus most strains of indole positive Proteus (Proteus vulgaris) Enterobacter spp. Morganella morganii Providencia rettgeri Serratia spp. Pseudomonas spp. Listeria Special populations Pregnancy Cefazolin is pregnancy category B, indicating general safety for use in pregnancy. Caution should be used in breastfeeding as a small amount of cefazolin enters the breast milk. Cefazolin can be used prophylactically against perinatal Group B streptococcal infection (GBS). Although penicillin and ampicillin are the standard of care for GBS prophylaxis, penicillin-allergic women with no history of anaphylaxis can be given cefazolin instead. These patients should be closely monitored as there is a small chance of an allergic reaction due to the similar structure of the antibiotics. Newborns There has been no established safety and effectiveness for use in premature infants and neonates. Elderly No overall differences in safety or effectiveness were observed in clinical trials comparing elderly and younger subjects, however the trials could not eliminate the possibility that some older individuals may have a higher level of sensitivity. Additional considerations People with kidney disease and those on hemodialysis may need the dose adjusted. Cefazolin levels are not significantly affected by liver disease. As with other antibiotics, cefazolin may interact with other medications being taken. Some important drugs that may interact with cefazolin such as probenecid. Side effects Side effects associated with use of cefazolin therapy include: Common (1-10%): diarrhea, stomach pain or upset stomach, vomiting, and rash. Uncommon (<1%): dizziness, headache, fatigue, itching, transient hepatitis.Patients with penicillin allergies could experience a potential reaction to cefazolin and other cephalosporins. As with other antibiotics, patients experiencing watery and/or bloody stools occurring up to three months following therapy should contact their prescriber.Like those of several other cephalosporins, the chemical structure of cefazolin contains an N-methylthiodiazole (NMTD or 1-MTD) side-chain. As the antibiotic is broken down in the body, it releases free NMTD, which can cause hypoprothrombinemia (likely due to inhibition of the enzyme vitamin K epoxide reductase) and a reaction with ethanol similar to that produced by disulfiram (Antabuse), due to inhibition of aldehyde dehydrogenase. Those with an allergy to penicillin may develop a cross sensitivity to cefazolin. Mechanism of action Cefazolin inhibits cell wall biosynthesis by binding penicillin-binding proteins which stops peptidoglycan synthesis. Penicillin-binding proteins are bacterial proteins that help to catalyze the last stages of peptidoglycan synthesis, which is needed to maintain the cell wall. They remove the D-alanine from the precursor of the peptidoglycan. The lack of synthesis causes the bacteria to lyse because they also continually break down their cell walls. Cefazolin is bactericidal, meaning it kills the bacteria rather than inhibiting their growth. Cost Cefazolin is relatively inexpensive. Trade names It was initially marketed by GlaxoSmithKline under the trade name Ancef.Other trade names include: Cefacidal, Cefamezin, Cefrina, Elzogram, Faxilen, Gramaxin, Kefol, Kefzol, Kefzolan, Kezolin, Novaporin, Reflin, Zinol, and Zolicef. References External links MedlinePlus Drug Information: Cefazolin Sodium Injection.
Zidovudine	Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child spread during birth or after a needlestick injury or other potential exposure. It is sold both by itself and together as lamivudine/zidovudine and abacavir/lamivudine/zidovudine. It can be used by mouth or by slow injection into a vein.Common side effects include headaches, fever, and nausea. Serious side effects include liver problems, muscle damage, and high blood lactate levels. It is commonly used in pregnancy and appears to be safe for the baby. ZDV is of the nucleoside analog reverse-transcriptase inhibitor (NRTI) class. It works by inhibiting the enzyme reverse transcriptase that HIV uses to make DNA and therefore decreases replication of the virus.Zidovudine was first described in 1964. It was approved in the United States in 1987 and was the first treatment for HIV. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. Medical uses HIV treatment AZT is usually dosed twice a day in combination with other antiretroviral therapies. This approach is referred to as Highly Active Antiretroviral Therapy (HAART) and is used to prevent the likelihood of HIV resistance. HIV prevention AZT has been used for post-exposure prophylaxis (PEP) in combination with another antiretroviral drug called lamivudine. Together they work to substantially reduce the risk of HIV infection following the first single exposure to the virus. More recently, AZT has been replaced by other antiretrovirals such as tenofovir to provide PEP.AZT is now a principal part of the clinical pathway for both pre-exposure prophylaxis and post-exposure treatment of mother-to-child transmission of HIV during pregnancy, labor, and delivery and has been proven to be integral to uninfected siblings perinatal and neonatal development. Without AZT, 10 to 15% of fetuses with HIV-infected mothers will themselves become infected. AZT has been shown to reduce this risk to 8% when given in a three-part regimen post-conception, delivery, and six weeks post-delivery. Consistent and proactive precautionary measures, such as the rigorous use of antiretroviral medications, cesarean section, face masks, heavy-duty rubber gloves, clinically segregated disposable diapers, and avoidance of mouth contact will further reduce child-attendant transmission of HIV to as little as 1–2%.During 1994 to 1999, AZT was the primary form of prevention of mother-to-child HIV transmission. AZT prophylaxis prevented more than 1000 parental and infant deaths from AIDS in the United States. In the U.S. at that time, the accepted standard of care for HIV-positive mothers was known as the 076 regimen and involved five daily doses of AZT from the second trimester onwards, as well as AZT intravenously administered during labour. As this treatment was lengthy and expensive, it was deemed unfeasible in the Global South, where mother-to-child transmission was a significant problem. A number of studies were initiated in the late 1990s that sought to test the efficacy of a shorter, simpler regimen for use in resource-poor countries. This AZT short course was an inferior standard of care and would have been considered malpractice if trialed in the US; however, it was nonetheless a treatment that would improve the care and survival of impoverished subjects. Antibacterial properties Zidovudine also has antibacterial properties, though not routinely used in clinical settings. It acts on bacteria with a mechanism of action still not fully explained. Promising results from in vitro and in vivo studies showed the efficacy of AZT also against multidrug-resistant gram-negative bacteria (including mcr-1 carrying and metallo-β-lactamase producing isolates), especially in combination with other active agents (e.g. fosfomycin, colistin, tigecycline). Side effects Most common side-effects include nausea, vomiting, acid reflux (heartburn), headache, cosmetic reduction in abdominal body fat, light sleeping, and loss of appetite. Less common side effects include faint discoloration of fingernails and toenails, mood elevation, occasional tingling or transient numbness of the hands or feet, and minor skin discoloration. Allergic reactions are rare.Early long-term higher-dose therapy with AZT was initially associated with side effects that sometimes limited therapy, including anemia, neutropenia, hepatotoxicity, cardiomyopathy, and myopathy. All of these conditions were generally found to be reversible upon reduction of AZT dosages. They have been attributed to several possible causes, including transient depletion of mitochondrial DNA, sensitivity of the γ-DNA polymerase in some cell mitochondria, the depletion of thymidine triphosphate, oxidative stress, reduction of intracellular L-carnitine or apoptosis of the muscle cells. Anemia due to AZT was successfully treated using erythropoetin to stimulate red blood cell production. Drugs that inhibit hepatic glucuronidation, such as indomethacin, nordazepam, acetylsalicylic acid (aspirin) and trimethoprim decreased the elimination rate and increased the therapeutic strength of the medication. Today, side-effects are much less common with the use of lower doses of AZT. According to IARC, there is sufficient evidence in experimental animals for the carcinogenicity of zidovudine; it is possibly carcinogenic to humans (Group 2B). In 2009, the State of California added zidovudine to its list of chemicals "known to the state of California to cause cancer and other reproductive harm." Viral resistance Even at the highest doses that can be tolerated in patients, AZT is not potent enough to prevent all HIV replication and may only slow the replication of the virus and progression of the disease. Prolonged AZT treatment can lead to HIV developing resistance to AZT by mutation of its reverse transcriptase. To slow the development of resistance, physicians generally recommend that AZT be given in combination with another reverse-transcriptase inhibitor and an antiretroviral from another group, such as a protease inhibitor, non-nucleoside reverse-transcriptase inhibitor, or integrase inhibitor; this type of therapy is known as HAART (Highly Active Anti Retroviral Therapy). Mechanism of action AZT is a thymidine analogue. AZT works by selectively inhibiting HIVs reverse transcriptase, the enzyme that the virus uses to make a DNA copy of its RNA. Reverse transcription is necessary for production of HIVs double-stranded DNA, which would be subsequently integrated into the genetic material of the infected cell (where it is called a provirus).Cellular enzymes convert AZT into the effective 5-triphosphate form. Studies have shown that the termination of HIVs forming DNA chains is the specific factor in the inhibitory effect.At very high doses, AZTs triphosphate form may also inhibit DNA polymerase used by human cells to undergo cell division, but regardless of dosage AZT has an approximately 100-fold greater affinity for HIVs reverse transcriptase. The selectivity has been suggested to be due to the cells ability to quickly repair its own DNA chain if it is disrupted by AZT during its formation, whereas the HIV virus lacks that ability. Thus AZT inhibits HIV replication without affecting the function of uninfected cells. At sufficiently high dosages, AZT begins to inhibit the cellular DNA polymerase used by mitochondria to replicate, accounting for its potentially toxic but reversible effects on cardiac and skeletal muscles, causing myositis. Chemistry Enantiopure AZT crystallizes in the monoclinic space group P21. The primary intermolecular bonding motif is a hydrogen bonded dimeric ring formed from two N-H...O interactions. History Initial cancer research In the 1960s, the theory that most cancers were caused by environmental retroviruses gained clinical support and funding. It had recently become known, due to the work of Nobel laureates Howard Temin and David Baltimore, that nearly all avian cancers were caused by bird retroviruses, but corresponding human retroviruses had not yet been found. In parallel work, other compounds that successfully blocked the synthesis of nucleic acids had been proven to be both antibacterial, antiviral, and anticancer agents, the leading work being done at the laboratory of Nobel laureates George Hitchings and Gertrude Elion, leading to the development of the antitumor agent 6-mercaptopurine.Jerome Horwitz of the Barbara Ann Karmanos Cancer Institute and Wayne State University School of Medicine first synthesized AZT in 1964 under a US National Institutes of Health (NIH) grant. Development was shelved after it proved biologically inert in mice. In 1974, Wolfram Ostertag of the Max Planck Institute for Experimental Medicine in Göttingen, Germany reported that AZT specifically targeted Friend virus (strain of murine leukemia virus).This report attracted little interest from other researchers as the Friend leukemia virus is a retrovirus, and at the time, there were no known human diseases caused by retroviruses. HIV/AIDS research In 1983, researchers at the Institut Pasteur in Paris identified the retrovirus now known as the Human Immunodeficiency Virus (HIV) as the cause of acquired immunodeficiency syndrome (AIDS) in humans. Shortly thereafter, Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan of the United States National Cancer Institute (NCI) initiated a program to develop therapies for HIV/AIDS. Using a line of CD4+ T cells that they had made, they developed an assay to screen drugs for their ability to protect CD4+ T cells from being killed by HIV. In order to expedite the process of discovering a drug, the NCI researchers actively sought collaborations with pharmaceutical companies having access to libraries of compounds with potential antiviral activity. This assay could simultaneously test both the anti-HIV effect of the compounds and their toxicity against infected T cells. In June 1984, Burroughs-Wellcome virologist Marty St. Clair set up a program to discover drugs with the potential to inhibit HIV replication. Burroughs-Wellcome had expertise in nucleoside analogs and viral diseases, led by researchers including George Hitchings, Gertrude Elion, David Barry, Paul (Chip) McGuirt Jr., Philip Furman, Martha St. Clair, Janet Rideout, Sandra Lehrman and others. Their research efforts were focused in part on the viral enzyme reverse transcriptase. Reverse transcriptase is an enzyme that retroviruses, including HIV, utilize to replicate themselves. Secondary testing was performed in mouse cells infected with the retroviruses Friend virus or Harvey sarcoma virus, as the Wellcome group did not have a viable in-house HIV antiviral assay in place at that time, and these other retroviruses were believed to represent reasonable surrogates. AZT proved to be a remarkably potent inhibitor of both Friend virus and Harvey sarcoma virus, and a search of the companys records showed that it had demonstrated low toxicity when tested for its antibacterial activity in rats many years earlier. Based in part on these results, AZT was selected by nucleoside chemist Janet Rideout as one of 11 compounds to send to the NCI for testing in that organizations HIV antiviral assay.In February 1985, the NCI scientists found that AZT had potent efficacy in vitro. Several months later, a phase 1 clinical trial of AZT at the NCI was initiated at the NCI and Duke University,. In doing this Phase I trial, they built on their experience in doing an earlier trial, with suramin, another drug that had shown effective anti-HIV activity in the laboratory. This initial trial of AZT proved that the drug could be safely administered to patients with HIV, that it increased their CD4 counts, restored T cell immunity as measured by skin testing, and that it showed strong evidence of clinical effectiveness, such as inducing weight gain in AIDS patients. It also showed that levels of AZT that worked in vitro could be injected into patients in serum and suppository form, and that the drug penetrated deeply only into infected brains. Patent filed and FDA approval A rigorous double-blind, placebo-controlled randomized trial of AZT was subsequently conducted by Burroughs-Wellcome and proved that AZT safely prolongs the lives of people with HIV. Burroughs-Wellcome filed for a patent for AZT in 1985. The Anti-Infective Advisory Committee to United States Food and Drug Administration (FDA) voted ten to one to recommend the approval of AZT. The FDA approved the drug (via the then-new FDA accelerated approval system) for use against HIV, AIDS, and AIDS Related Complex (ARC, a now-obsolete medical term for pre-AIDS illness) on March 20, 1987. The time between the first demonstration that AZT was active against HIV in the laboratory and its approval was 25 months, the shortest period of drug development in recent history.AZT was subsequently approved unanimously for infants and children in 1990. AZT was initially administered in significantly higher dosages than today, typically 400 mg every four hours, day and night, compared to modern dosage of 300 mg twice daily. The paucity of alternatives for treating HIV/AIDS at that time unambiguously affirmed the health risk/benefit ratio, with inevitable slow, disfiguring, and painful death from HIV outweighing the drugs side-effect of transient anemia and malaise. Society and culture In 1991, the advocacy group Public Citizen filed a lawsuit claiming that the patents were invalid. Subsequently, Barr Laboratories and Novopharm Ltd. also challenged the patent, in part based on the assertion that NCI scientists Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan should have been named as inventors, and those two companies applied to the FDA to sell AZT as a generic drug. In response, Burroughs Wellcome Co. filed a lawsuit against the two companies. The United States Court of Appeals for the Federal Circuit ruled in 1992 in favor of Burroughs Wellcome, ruling that even though they had never tested it against HIV, they had conceived of it working before they sent it to the NCI scientists. This suit was appealed up to the Supreme Court of the US, but in 1996 they declined to formally review it. The case, Burroughs Wellcome Co. v. Barr Laboratories, was a landmark in US law of inventorship.In 2002, another lawsuit was filed challenging the patent by the AIDS Healthcare Foundation, which also filed an antitrust case against GSK as well. The patent case was dismissed in 2003 and AHF filed a new case challenging the patent.GSKs patents on AZT expired in 2005, and in September 2005, the FDA approved three generic versions. References External links "Zidovudine". Drug Information Portal. U.S. National Library of Medicine.
Calaspargase pegol	Calaspargase pegol, sold under the brand name Asparlas, is a medication for the treatment of acute lymphoblastic leukemia (ALL). It is approved in the United States as a component of a multi-agent chemotherapeutic regimen for ALL in pediatric and young adult patients aged one month to 21 years.Calaspargase pegol is an engineered protein consisting of the E. coli-derived enzyme L-asparaginase II conjugated with succinimidyl carbonate monomethoxypolyethylene glycol (pegol). The L-asparaginase portion hydrolyzes L-asparagine to L-aspartic acid depriving the tumor cell of the L-asparagine it needs for survival. The conjugation with the pegol group increases the half-life of the drug making it longer acting. The most common (incidence ≥ 10%) grade ≥ 3 adverse reactions are elevated transaminase, increased bilirubin, pancreatitis, and abnormal clotting studies. History In December 2018, calaspargase pegol-mknl was approved in the United States as a component of a multi-agent chemotherapeutic regimen for acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age one month to 21 years.Approval was based on a demonstration of the achievement and maintenance of nadir serum asparaginase activity above the level of 0.1 U/mL when using calaspargase pegol-mknl, 2500 U/m2 intravenously, every three weeks. The pharmacokinetics of calaspargase pegol-mknl were studied when administered in combination with multiagent chemotherapy in 124 subjects with B-cell lineage ALL.The FDA approved calaspargase pegol-mknl based on evidence primarily from two clinical trials (Trial 1/NCT01574274 and Trial 2/AALL07P4) of 237 subjects with acute lymphoblastic leukemia (ALL). The trials were conducted in the United States and Canada.Trial 1 enrolled subjects 1 to 20 years old who were recently diagnosed with ALL or lymphoblastic lymphoma. Subjects received calaspargase pegol-mknl or pegaspargase (a drug that helps convert asparagine to other substances) as part of a combination of drugs used for treatment of ALL. The trial had 2 phases. Subjects received calaspargase pegol-mknl or pegaspagase intravenously on Day 7 of the first phase. Subjects received either calaspargase pegol-mknl intravenously every 3 weeks for 10 doses or pegaspargase intravenously every 2 weeks for 15 doses during the second phase. The benefit of calaspargase pegol-mknl was assessed by measuring the activity level of asparginase in the blood on Days 7, 11, 18, 25, and 32 of the first phase and comparing it to pegaspargase.Trial 2 enrolled subjects 1 to 18 years old who were recently diagnosed with high-risk ALL. Subjects received one of 2 doses of calaspargase pegol-mknl or pegaspargase intravenously as part of a combination of drugs used for treatment. Subjects received calaspargase pegol-mknl or pegaspargase on Day 4 of the first phase and Days 2 and 22 of the second phase. Subjects received up to 12 doses of calaspargase pegol-mknl or pegaspargase intravenously depending on the bone marrow response. The benefit of calaspargase pegol-mknl was assessed by measuring the concentration of drug in the body over 25 days (AUC) and the maximum amount of drug in the blood after a single dose (Cmax). The AUC and Cmax of calaspargase pegol-mknl were compared to pegaspargase.Calaspargase pegol-mknl received FDA orphan drug designation. The approval was granted to Servier Pharmaceuticals LLC. References External links "Calaspargase pegol". Drug Information Portal. U.S. National Library of Medicine. "Calaspargase pegol-mknl". National Cancer Institute. 25 January 2019. "Calaspargase pegol-mknl". NCI Drug Dictionary. National Cancer Institute.
Famciclovir	Famciclovir is a guanosine analogue antiviral drug used for the treatment of various herpesvirus infections, most commonly for herpes zoster (shingles). It is a prodrug form of penciclovir with improved oral bioavailability. Famciclovir is marketed under the trade name Famvir (Novartis). Famciclovir was patented in 1983 and approved for medical use in 1994. In 2007, the United States Food and Drug Administration approved the first generic version of famciclovir. Generic tablets are manufactured by TEVA Pharmaceuticals and Mylan Pharmaceuticals. Medical uses Famciclovir is indicated for the treatment of herpes zoster (shingles), treatment of herpes simplex virus 2 (genital herpes), herpes labialis (cold sores) in immunocompetent patients and for the suppression of recurring episodes of herpes simplex virus 2. It is also indicated for treatment of recurrent episodes of herpes simplex in HIV patients. Adverse effects Side effects: mild to extreme stomach upset, headaches, mild fever. Herpes Early treatment Several studies in humans and mice provide evidence that early treatment with famciclovir soon after the first infection with herpes can significantly lower the chance of future outbreaks. Use of famciclovir in this manner has been shown to reduce the amount of latent virus in the neural ganglia compared to no treatment or treatment with valaciclovir. A review of human subjects treated for five days with famciclovir 250 mg three times daily during their first herpes episode found that only 4.2 percent experienced a recurrence within six months after the first outbreak, a fivefold decrease compared to the 19 percent recurrence in acyclovir-treated patients. Neither drug affected latency if treatment was delayed for several months. See also Penciclovir Valaciclovir References External links Famvir product website run by Novartis
Amlodipine	Amlodipine, sold under the brand name Norvasc among others, is a calcium channel blocker medication used to treat high blood pressure and coronary artery disease. It is taken by mouth.Common side effects include swelling, feeling tired, abdominal pain, and nausea. Serious side effects may include low blood pressure or heart attack. Whether use is safe during pregnancy or breastfeeding is unclear. When used by people with liver problems, and in elderly individuals, doses should be reduced. Amlodipine works partly by increasing the size of arteries. It is a long-acting calcium channel blocker of the dihydropyridine type.Amlodipine was patented in 1982, and approved for medical use in 1990. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2020, it was the fifth most commonly prescribed medication in the United States, with more than 69 million prescriptions. Medical uses Amlodipine is used in the management of hypertension and coronary artery disease in people with either stable angina (where chest pain occurs mostly after physical or emotional stress) or vasospastic angina (where it occurs in cycles) and without heart failure. It can be used as either monotherapy or combination therapy for the management of hypertension or coronary artery disease. Amlodipine can be administered to adults and children 6–17 years of age. Calcium channel blockers, including amlodipine, may provide greater protection against stroke than other classes of blood pressure-lowering medications.Amlodipine along with other calcium channel blockers are considered the first choice in the pharmacological management of Raynauds phenomenon. Combination therapy Amlodipine can be given as a combination therapy with a variety of medications: Amlodipine/atorvastatin, where amlodipine is given for hypertension or CAD and atorvastatin prevents cardiovascular events, or if the person also has high cholesterol. Amlodipine/aliskiren or amlodipine/aliskiren/hydrochlorothiazide if amlodipine alone cannot reduce blood pressure. Aliskiren is a renin inhibitor, which works to reduce primary hypertension (that with no known cause) by binding to renin and preventing it from initiating the renin–angiotensin system (RAAS) pathway to increase blood pressure. Hydrochlorothiazide is a diuretic and decreases overall blood volume. Amlodipine/benazepril if either drug has failed individually, or amlodipine alone caused edema. Benazepril is an ACE inhibitor and blocks the conversion of angiotensin I to angiotensin II in the RAAS pathway. Amlodipine/celecoxib Amlodipine/lisinopril Amlodipine/olmesartan or amlodipine/olmesartan/hydrochlorothiazide if amlodipine is insufficient in reducing blood pressure. Olmesartan is an angiotensin II receptor antagonist and blocks part of the RAAS pathway. Amlodipine/perindopril if using amlodipine alone caused edema. Perindopril is a long-lasting ACE inhibitor. Amlodipine/telmisartan, where telmisartan is an angiotensin II receptor antagonist. Amlodipine/valsartan or amlodipine/valsartan/hydrochlorothiazide, where valsartan is an angiotensin II receptor antagonist. Contraindications The only absolute contraindication to amlodipine is an allergy to amlodipine or any other dihydropyridines.Other situations occur, however, where amlodipine generally should not be used. In patients with cardiogenic shock, where the hearts ventricles are not able to pump enough blood, calcium channel blockers exacerbate the situation by preventing the flow of calcium ions into cardiac cells, which is required for the heart to pump. While use in patients with aortic stenosis (narrowing of the aorta where it meets the left ventricle) since it does not inhibit the ventricles function is generally safe, it can still cause collapse in cases of severe stenosis. In unstable angina (excluding variant angina), amlodipine can cause a reflex increase in cardiac contractility (how hard the ventricles squeeze) and heart rate, which together increase the demand for oxygen by the heart itself. Patients with severe hypotension can have their low blood pressure exacerbated, and patients in heart failure can get pulmonary edema. Those with impaired liver function are unable to metabolize amlodipine to its full extent, giving it a longer half-life than typical.Amlodipines safety in pregnancy has not been established, although reproductive toxicity at high doses is known. Whether amlodipine enters the milk of breastfeeding mothers is also unknown.Those who have heart failure, or recently had a heart attack, should take amlodipine with caution. Adverse effects Some common dose-dependent adverse effects of amlodipine include vasodilatory effects, peripheral edema, dizziness, palpitations, and flushing. Peripheral edema (fluid accumulation in the tissues) occurs at rate of 10.8% at a 10-mg dose (versus 0.6% for placebos), and is three times more likely in women than in men. It causes more dilation in the arterioles and precapillary vessels than the postcapillary vessels and venules. The increased dilation allows for more blood, which is unable to push through to the relatively constricted postcapillary venules and vessels; the pressure causes much of the plasma to move into the interstitial space. Amlodipine-association edema can be avoided by adding ACE inhibitors or angiotensin II receptor antagonist. Of the other dose-dependent side effects, palpitations (4.5% at 10 mg vs. 0.6% in placebos) and flushing (2.6% vs. 0%) occurred more often in women; dizziness (3.4% vs. 1.5%) had no sex bias.Common but not dose-related adverse effects are fatigue (4.5% vs. 2.8% with a placebo), nausea (2.9% vs. 1.9%), abdominal pain (1.6% vs. 0.3%), and drowsiness (1.4% vs. 0.6%). Side effects occurring less than 1% of the time include: blood disorders, impotence, depression, peripheral neuropathy, insomnia, tachycardia, gingival enlargement, hepatitis, and jaundice.Amlodipine-associated gingival overgrowth is a relatively common side effect with exposure to amlodipine. Poor dental health and buildup of dental plaque are risk factors.Amlodipine may increase the risk of worsening angina or acute myocardium infarction, especially in those with severe obstructive coronary artery disease, upon dosage initiation or increase. However, depending on the situation, Amlodipine inhibits constriction and restores blood flow in coronary arteries as a result of its property that works directly on vascular smooth muscle causing reduction in peripheral vascular resistance and consequent reduction in blood pressure. Overdose Although rare, amlodipine overdose toxicity can result in widening of blood vessels, severe low blood pressure, and fast heart rate. Toxicity is generally managed with fluid replacement monitoring ECG results, vital signs, respiratory system function, glucose levels, kidney function, electrolyte levels, and urine output. Vasopressors are also administered when low blood pressure is not alleviated by fluid resuscitation. Interactions Several drugs interact with amlodipine to increase its levels in the body. CYP3A inhibitors, by nature of inhibiting the enzyme that metabolizes amlodipine, CYP3A4, are one such class of drugs. Others include the calcium-channel blocker diltiazem, the antibiotic clarithromycin, and possibly some antifungals. Amlodipine causes several drugs to increase in levels, including cyclosporine, simvastatin, and tacrolimus (the increase in the last one being more likely in people with CYP3A5*3 genetic polymorphisms). When more than 20 mg of simvastatin, a lipid-lowering agent, are given with amlodipine, the risk of myopathy increases. Giving amlodipine with Viagra increases the risk of hypotension. Pharmacology Amlodipine is a long-acting calcium channel antagonist that selectively inhibits calcium ion influx across cell membranes. It targets L-type calcium channels in muscle cells and N-type calcium channels in the central nervous system which are involved in nociceptive signalling and pain perception. Amlodipine has an inhibitory effect on calcium influx in smooth muscle cells to inhibit contraction. Amlodipine ends up significantly reducing total vascular resistance without decreasing cardiac output expressed by pressure-rate product and cardiac contractability in comparison with verapamil, a non-dihydropyridine. In turn, following treatment lasting a month, with amlodipine, cardiac output is significantly enhanced. Unlike verapamil which has efficacy in moderation of emotional arousal and reduces cardiac load without lowering cardiac output demands, amlodipine increases the cardiac output response concomitantly with increased functional cardiac load. Mechanism of action Amlodipine is an angioselective calcium channel blocker and inhibits the movement of calcium ions into vascular smooth muscle cells and cardiac muscle cells which inhibits the contraction of cardiac muscle and vascular smooth muscle cells. Amlodipine inhibits calcium ion influx across cell membranes, with a greater effect on vascular smooth muscle cells. This causes vasodilation and a reduction in peripheral vascular resistance, thus lowering blood pressure. Its effects on cardiac muscle also prevent excessive constriction in the coronary arteries.Negative inotropic effects can be detected in vitro, but such effects have not been seen in intact animals at therapeutic doses. Among the two stereoisomers [R(+), S(–)], the (–) isomer has been reported to be more active than the (+) isomer. Serum calcium concentration is not affected by amlodipine. And it specifically inhibits the currents of L-type Cav1.3 channels in the zona glomerulosa of the adrenal gland.The mechanisms by which amlodipine relieves angina are: Stable angina: amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, thereby lowering myocardial oxygen demand, at any given level of exercise. Variant angina: amlodipine blocks spasm of the coronary arteries and restores blood flow in coronary arteries and arterioles in response to calcium, potassium, epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro.Amlodipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid. Pharmacokinetics Amlodipine has been studied in healthy volunteers following oral administration of 14C-labelled drug. Amlodipine is well absorbed by the oral route with a mean oral bioavailability around 60%; the half-life of amlodipine is about 30 h to 50 h, and steady-state plasma concentrations are achieved after 7 to 8 days of daily dosing. In the blood it has high plasma protein binding of 97.5%. Its long half-life and high bioavailability are largely in part of its high pKa (8.6); it is ionized at physiological pH, and thus can strongly attract proteins. It is slowly metabolized in the liver by CYP3A4, with its amine group being oxidized and its side ester chain being hydrolyzed, resulting in an inactive pyridine metabolite. Renal elimination is the major route of excretion with about 60% of an administered dose recovered in urine, largely as inactive pyridine metabolites. However, renal impairment does not significantly influence amlodipine elimination. 20-25% of the drug is excreted in the faeces. History Pfizers patent protection on Norvasc lasted until 2007; total patent expiration occurred later in 2007. A number of generic versions are available. In the United Kingdom, tablets of amlodipine from different suppliers may contain different salts. The strength of the tablets is expressed in terms of amlodipine base, i.e., without the salts. Tablets containing different salts are therefore considered interchangeable. Fixed-dose combination of amlodipine and perindopril, an angiotensin converting enzyme inhibitor are also available.The medical form comes as besylate, mesylate or maleate. Veterinary use Amlodipine is most often used to treat systemic hypertension in cats and dogs. In cats, it is the first line of treatment due to its efficacy and few side effects. Systemic hypertension in cats is usually secondary to another abnormality, such as chronic kidney disease, and so amlodipine is most often administered to cats with kidney disease. While amlodipine is used in dogs with systemic hypertension, it is not as efficacious. Amlodipine is also used to treat congestive heart failure due to mitral valve regurgitation in dogs. By decreasing resistance to forward flow in the systemic circulation it results in a decrease in regurgitant flow into the left atrium. Similarly, it can be used on dogs and cats with left-to-right shunting lesions such as ventricular septal defect to reduce the shunt. Side effects are rare in cats. In dogs, the primary side effect is gingival hyperplasia. References External links "Amlodipine". Drug Information Portal. U.S. National Library of Medicine. onog
Imipramine	Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. The drug is also used to treat bedwetting. Imipramine is taken by mouth. Common side effects of imipramine include dry mouth, drowsiness, dizziness, low blood pressure, rapid heart rate, urinary retention, and electrocardiogram changes. Overdose of the medication can result in death. Imipramine appears to work by increasing levels of serotonin and norepinephrine and by blocking certain serotonin, adrenergic, histamine, and cholinergic receptors. Imipramine was discovered in 1951 and was introduced for medical use in 1957. It was the first TCA to be marketed. Imipramine and the other TCAs have decreased in use in recent decades, due to the introduction of the selective serotonin reuptake inhibitors (SSRIs), which have fewer side effects and are far safer in overdose. Medical uses Imipramine is used in the treatment of depression and certain anxiety disorders. It is similar in efficacy to the antidepressant drug moclobemide. It has also been used to treat nocturnal enuresis because of its ability to shorten the time of delta wave stage sleep, where wetting occurs. In veterinary medicine, imipramine is used with xylazine to induce pharmacologic ejaculation in stallions. Blood levels between 150 and 250 ng/mL of imipramine plus its metabolite desipramine generally correspond to antidepressant efficacy. Available forms Imipramine is available in the form of oral tablets and capsules. Contraindications Combining it with alcohol consumption causes excessive drowsiness. It may be unsafe during pregnancy. Side effects Those listed in italics below denote common side effects. Central nervous system: dizziness, drowsiness, confusion, seizures, headache, anxiety, tremors, stimulation, weakness, insomnia, nightmares, extrapyramidal symptoms in geriatric patients, increased psychiatric symptoms, paresthesia Cardiovascular: orthostatic hypotension, ECG changes, tachycardia, hypertension, palpitations, dysrhythmias Eyes, ears, nose and throat: blurred vision, tinnitus, mydriasis Gastrointestinal: dry mouth, nausea, vomiting, paralytic ileus, increased appetite, cramps, epigastric distress, jaundice, hepatitis, stomatitis, constipation, taste change Genitourinary: urinary retention Hematological: agranulocytosis, thrombocytopenia, eosinophilia, leukopenia Skin: rash, urticaria, diaphoresis, pruritus, photosensitivity Overdose Interactions Pharmacology Pharmacodynamics Imipramine affects numerous neurotransmitter systems known to be involved in the etiology of depression, anxiety, attention-deficit hyperactivity disorder (ADHD), enuresis and numerous other mental and physical conditions. Imipramine is similar in structure to some muscle relaxants, and has a significant analgesic effect and, thus, is very useful in some pain conditions. The mechanisms of imipramines actions include, but are not limited to, effects on: Serotonin: very strong reuptake inhibition. Norepinephrine: strong reuptake inhibition. Desipramine has more affinity to norepinephrine transporter than imipramine. Dopamine: imipramine blocks D2 receptors. Imipramine, and its metabolite desipramine, have no appreciable affinity for the dopamine transporter (Ki = 8,500 and >10,000 nM, respectively). Acetylcholine: imipramine is an anticholinergic, specifically an antagonist of the muscarinic acetylcholine receptors. Thus, it is prescribed with caution to the elderly and with extreme caution to those with psychosis, as the general brain activity enhancement in combination with the "dementing" effects of anticholinergics increases the potential of imipramine to cause hallucinations, confusion and delirium in this population. Epinephrine: imipramine antagonizes adrenergic receptors, thus sometimes causing orthostatic hypotension. Sigma receptor: activity on sigma receptors is present, but it is very weak (Ki = 520 nM) and it is about half that of amitriptyline (Ki = 300 nM). Histamine: imipramine is an antagonist of the histamine H1 receptors. BDNF: BDNF is implicated in neurogenesis in the hippocampus, and studies suggest that depressed patients have decreased levels of BDNF and reduced hippocampal neurogenesis. It is not clear how neurogenesis restores mood, as ablation of hippocampal neurogenesis in murine models do not show anxiety related or depression related behaviours. Chronic imipramine administration results in increased histone acetylation (which is associated with transcriptional activation and decondensed chromatin) at the hippocampal BDNF promoter, and also reduced expression of hippocampal HDAC5. Pharmacokinetics Within the body, imipramine is converted into desipramine (desmethylimipramine) as a metabolite. Chemistry Imipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include desipramine (N-desmethylimipramine), clomipramine (3-chloroimipramine), trimipramine (2′-methylimipramine or β-methylimipramine), and lofepramine (N-(4-chlorobenzoylmethyl)desipramine). Imipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine. The chemical name of imipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C19H24N2 with a molecular weight of 280.407 g/mol. The drug is used commercially mostly as the hydrochloride salt; the embonate (pamoate) salt is used for intramuscular administration and the free base form is not used. The CAS Registry Number of the free base is 50-49-7, of the hydrochloride is 113-52-0, and of the embonate is 10075-24-8. History The parent compound of imipramine, 10,11-dihydro-5H-dibenz[b,f]azepine (dibenzazepine), was first synthesized in 1899, but no pharmacological assessment of this compound or any substituted derivatives was undertaken until the late 1940s. Imipramine was first synthesized in 1951, as an antihistamine. The antipsychotic effects of chlorpromazine were discovered in 1952, and imipramine was then developed and studied as an antipsychotic for use in patients with schizophrenia. The medication was tested in several hundred patients with psychosis, but showed little effectiveness. However, imipramine was serendipitously found to possess antidepressant effects in the mid-1950s following a case report of symptom improvement in a woman with severe depression who had been treated with it. This was followed by similar observations in other patients and further clinical research. Subsequently, imipramine was introduced for the treatment of depression in Europe in 1958 and in the United States in 1959. Along with the discovery and introduction of the monoamine oxidase inhibitor iproniazid as an antidepressant around the same time, imipramine resulted in the establishment of monoaminergic drugs as antidepressants.In the late 1950s, imipramine was the first TCA to be developed (by Ciba). At the first international congress of neuropharmacology in Rome, September 1958 Dr Freyhan from the University of Pennsylvania discussed as one of the first clinicians the effects of imipramine in a group of 46 patients, most of them diagnosed as "depressive psychosis". The patients were selected for this study based on symptoms such as depressive apathy, kinetic retardation and feelings of hopelessness and despair. In 30% of all patients, he reported optimal results, and in around 20%, failure. The side effects noted were atropine-like, and most patients experienced dizziness. Imipramine was first tried for treating psychotic disorders such as schizophrenia, but proved ineffective. As an antidepressant, it did well in clinical studies and it is known to work well in even the most severe cases of depression. It is not surprising, therefore, that imipramine may cause a high rate of manic and hypomanic reactions in hospitalized patients with pre-existing bipolar disorder, with one study showing that up to 25% of such patients maintained on Imipramine switched into mania or hypomania. Such powerful antidepressant properties have made it favorable in the treatment of treatment-resistant depression. Before the advent of selective serotonin reuptake inhibitors (SSRIs), its sometimes intolerable side-effect profile was considered more tolerable. Therefore, it became extensively used as a standard antidepressant and later served as a prototypical drug for the development of the later-released TCAs. Since the 1990s, it has no longer been used as commonly, but is sometimes still prescribed as a second-line treatment for treating major depression . It has also seen limited use in the treatment of migraines, ADHD, and post-concussive syndrome. Imipramine has additional indications for the treatment of panic attacks, chronic pain, and Kleine-Levin syndrome. In pediatric patients, it is relatively frequently used to treat pavor nocturnus and nocturnal enuresis. Society and culture Generic names Imipramine is the English and French generic name of the drug and its INN, BAN, and DCF, while imipramine hydrochloride is its USAN, USP, BANM, and JAN. Its generic name in Spanish and Italian and its DCIT are imipramina, in German is imipramin, and in Latin is imipraminum. The embonate salt is known as imipramine pamoate. Brand names Imipramine is marketed throughout the world mainly under the brand name Tofranil. Imipramine pamoate is marketed under the brand name Tofranil-PM for intramuscular injection. Availability Imipramine is available for medical use widely throughout the world, including in the United States, the United Kingdom, elsewhere in Europe, India, Brazil, South Africa, Australia, and New Zealand. References Further reading Dean L (2017). "Imipramine Therapy and CYP2D6 and CYP2C19 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520379. Bookshelf ID: NBK425164. External links "Imipramine". Drug Information Portal. U.S. National Library of Medicine. "Imipramine hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Amfepramone	Amfepramone, also known as diethylpropion, is a stimulant drug of the phenethylamine, amphetamine, and cathinone classes that is used as an appetite suppressant. It is used in the short-term management of obesity, along with dietary and lifestyle changes. Amfepramone is most closely chemically related to the antidepressant and smoking cessation aid bupropion (previously called amfebutamone), which has also been developed as a weight-loss medicine when in a combination product with naltrexone. Pharmacology Amfepramone itself lacks any affinity for the monoamine transporters and instead functions as a prodrug to ethcathinone. Ethcathinone (and therefore amfepramone as well) is a very weak dopaminergic and serotonergic, and is approximately 10x and 20x stronger on norepinephrine in comparison, respectively. As a result, ethcathinone and amfepramone can essentially be considered a member of the class of drugs known as norepinephrine releasing agents (NRAs). Chemistry Amfepramone can be synthesized from propiophenone by bromination, followed by reaction with diethylamine. Society and culture Names Another medically-utilized name is diethylpropion (British Approved Name (BAN) and Australian Approved Name (AAN)). Chemical names include: α-methyl-β-keto-N,N-diethylphenethylamine, N,N-diethyl-β-ketoamphetamine and N,N-diethylcathinone. Brand names include: Anorex, Linea, Nobesine, Prefamone, Regenon, Tepanil and Tenuate. Legal status Amfepramone is classified as a Schedule IV controlled substance in the United States. In the UK amfepramone is a class C drug and as a medicine, it is a Schedule 3 Controlled Drug which requires safe custody. As of June 2022, the safety committee of the European Medicines Agency (EMA) recommends the withdrawal of marketing authorizations for amfepramone. Recreational use The authors of several studies of amfepramone claim that the substance has a relatively low potential for causing addiction in users. References External links "Amfepramone". Drug Information Portal. U.S. National Library of Medicine.
Ponesimod	Ponesimod, sold under the brand name Ponvory, is a medication for the treatment of multiple sclerosis (MS).The most common side effects include upper respiratory tract infection, hepatic transaminase elevation, and hypertension.Ponesimod was approved for medical use in the United States in March 2021 and in the European Union in June 2021. Clinical trials In a 2009–2011 Phase II clinical trial including 464 MS patients, ponesimod treatment resulted in fewer new active brain lesions than placebo, measured during the course of 24 weeks.In a 2010–2012 Phase II clinical trial including 326 patients with psoriasis, 46 or 48% of patients (depending on dosage) had a reduction of at least 75% Psoriasis Area and Severity Index (PASI) score compared to placebo in 16 weeks. The approval is already applied for in 2020.In a 2015–2019 Phase III randomised, double-blind clinical trial of 1133 adult patients with relapsing MS, those under ponesimod treatment showed a 30% reduction in annual relapse rate and a significantly reduced number of new inflammatory lesions on brain MRI by 56% compared to those taking teriflunomide. Adverse effects Common adverse effects in studies were temporary bradycardia (slow heartbeat), usually at the beginning of the treatment, dyspnoea (breathing difficulties), and increased liver enzymes (without symptoms). No significant increase of infections was observed under ponesimod therapy. QT prolongation is detectable but was considered to be too low to be of clinical importance in a study. Mechanism of action Like fingolimod, which is already approved for the treatment of MS, ponesimod blocks the sphingosine-1-phosphate receptor. This mechanism prevents lymphocytes (a type of white blood cells) from leaving lymph nodes. Ponesimod is selective for subtype 1 of this receptor, S1P1. Society and culture Legal status On 25 March 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 authorisation for the medicinal product Ponvory, intended for the treatment of active relapsing forms of multiple sclerosis. The applicant for this medicinal product is Janssen-Cilag International N.V. Ponesimod was approved for medical use in the European Union in May 2021. References External links "Ponesimod". Drug Information Portal. U.S. National Library of Medicine.
Zanamivir	Zanamivir is a medication used to treat and prevent influenza caused by influenza A and influenza B viruses. It is a neuraminidase inhibitor and was developed by the Australian biotech firm Biota Holdings. It was licensed to Glaxo in 1990 and approved in the US in 1999, only for use as a treatment for influenza. In 2006, it was approved for prevention of influenza A and B. Zanamivir was the first neuraminidase inhibitor commercially developed. It is marketed by GlaxoSmithKline under the trade name Relenza as a powder for oral inhalation. Medical uses Zanamivir is used for the treatment of infections caused by influenza A and influenza B viruses, but in otherwise-healthy individuals, benefits overall appear to be small. It decreases the risk of ones getting symptomatic, but not asymptomatic influenza. The combination of diagnostic uncertainty, the risk for virus strain resistance, possible side effects and financial cost outweigh the small benefits of zanamivir for the prophylaxis and treatment of healthy individuals.Since then, genes expressing resistance to zanamivir were found in Chinese people infected with avian influenza A H7N9 during treatment with zanamivir. Treatment In otherwise-healthy individuals, benefits overall appear to be small. Zanamivir shortens the duration of symptoms of influenza-like illness (unconfirmed influenza or the flu) by less than a day. In children with asthma there was no clear effect on the time to first alleviation of symptoms. Whether it affects the risk of ones need to be hospitalized or the risk of death is not clear. There is no proof that zanamivir reduced hospitalizations or pneumonia and other complications of influenza, such as bronchitis, middle ear infection, and sinusitis. Zanamivir did not reduce the risk of self reported investigator mediated pneumonia or radiologically confirmed pneumonia in adults. The effect on pneumonia in children was also not significant. Prevention Low to moderate evidence indicates it decreases the risk of ones getting influenza by 1 to 12% in those exposed. Prophylaxis trials showed that zanamivir reduced the risk of symptomatic influenza in individuals and households, but there was no evidence of an effect on asymptomatic influenza or on other, influenza-like illnesses. Also there was no evidence of reduction of risk of person-to-person spread of the influenza virus. The evidence for a benefit in preventing influenza is weak in children, with concerns of publication bias in the literature. Resistance As of 2009, no influenza had shown any signs of resistance in the US. A meta-analysis from 2011 found that zanamivir resistance had been rarely reported. Antiviral resistance can emerge during or after treatment with antivirals in certain people (e.g., immunosuppressed). In 2013 genes expressing resistance to zanamivir (and oseltamivir) were found in Chinese patients infected with avian influenza A H7N9. Adverse effects Dosing is limited to the inhalation route. This restricts its usage, as treating asthmatics could induce bronchospasms. In 2006 the Food and Drug Administration (FDA) found that breathing problems (bronchospasm), including deaths, were reported in some patients after the initial approval of Relenza. Most of these patients had asthma or chronic obstructive pulmonary disease. Relenza therefore was not recommended for treatment or prophylaxis of seasonal influenza in individuals with asthma or chronic obstructive pulmonary disease. In 2009 the zanamivir package insert contains precautionary information regarding risk of bronchospasm in patients with respiratory disease. GlaxoSmithKline (GSK) and FDA notified healthcare professionals of a report of the death of a patient with influenza having received zanamivir inhalation powder, which was solubilized and administered by mechanical ventilation.In adults there was no increased risk of reported adverse events in trials. There was little evidence of the possible harms associated with the treatment of children with zanamivir. Zanamivir has not been known to cause toxic effects and has low systemic exposure to the human body. Mechanism of action Zanamivir works by binding to the active site of the neuraminidase protein, rendering the influenza virus unable to escape its host cell and infect others. It is also an inhibitor of influenza virus replication in vitro and in vivo. In clinical trials, zanamivir was found to reduce the time-to-symptom resolution by 1.5 days if therapy was started within 48 hours of the onset of symptoms. The bioavailability of zanamivir is 2%. After inhalation, zanamivir is concentrated in the lungs and oropharynx, where up to 15% of the dose is absorbed and excreted in urine. History Zanamivir was first made in 1989 by scientists led by Peter Colman and Joseph Varghese at the Australian CSIRO, in collaboration with the Victorian College of Pharmacy, and the Monash University. Zanamivir was the first of the neuraminidase inhibitors. The discovery was initially funded by the Australian biotechnology company Biota and was part of Biotas ongoing program to develop antiviral agents through rational drug design. Its strategy relied on the availability of the structure of influenza neuraminidase by X-ray crystallography. It was also known, as far back as 1974, that 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA), a sialic acid analogue, is an inhibitor of neuraminidase.Computational chemistry techniques were used to probe the active site of the enzyme, in an attempt to design derivatives of DANA that would bind tightly to the amino acid residues of the catalytic site, so would be potent and specific inhibitors of the enzyme. The GRID software by Molecular Discovery was used to determine energetically favourable interactions between various functional groups and residues in the catalytic site canyon. This investigation showed a negatively charged zone occurs in the neuraminidase active site that aligns with the C4 hydroxyl group of DANA. This hydroxyl is, therefore, replaced with a positively charged amino group; the 4-amino DANA was shown to be 100 times better as an inhibitor than DANA, owing to the formation of a salt bridge with a conserved glutamic acid (119) in the active site. Glu 119 was also noticed to be at the bottom of a conserved pocket in the active site that is just big enough to accommodate the larger, but more basic guanidine functional group. Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.In 1999, the product was approved for marketing in the US and Europe for treatment of influenza A and B. The FDA advisory committee had recommended by a vote 13 to 4 that it should not be approved, because it lacked efficacy and was no more effective than placebo when the patients were on other drugs such as paracetamol. But the FDA leadership overruled the committee and criticised its reviewer, biostatistician Michael Elashoff. The review of oseltamivir, which was also in approval process at that time, was taken away from him, and reassigned to someone else. In 2006 zanamivir was approved in the US and Europe for prevention of influenza A and B. References External links Drug Information: Zanamivir Inhalation MedlinePlus drug
Chlordiazepoxide/clidinium bromide	Chlordiazepoxide/clidinium bromide (marketed as Librax) is a fixed-dose combination medication used to treat peptic ulcers, irritable bowel syndrome (IBS), and gastritis. It contains chlordiazepoxide and clidinium bromide. It helps relieve stomach spasms, abdominal cramps, and anxiety related to gastric disorders. Librax is a fixed ratio of these two medications and, as such, is not typically prescribed with an accompanying dosage, but rather directions on how many capsules to take per day. It comes in a capsule taken by mouth, usually three or four times daily, before meals and at bedtime. Chlordiazepoxide is an anti-anxiety medication belonging to the benzodiazepine class. Its use in IBS is thought to be due to its calming ability for patients that have IBS symptoms that are worsened by anxiety. Clidinium bromide is a synthetic quaternary ammonium antimuscarinic, a sub-class of a family of drugs known as anticholinergics. It treats IBS by decreasing gastrointestinal motility. Chlordiazepoxide can be habit-forming. Tolerance may develop with long-term or excessive use, making this medication less effective. This medication must be taken regularly to be effective. Stopping the drug suddenly can worsen the condition and cause withdrawal symptoms (anxiousness, sleeplessness, and irritability).It was approved for medical use in the United States in 1966. It is available as a generic medication. Medical uses Chlordiazepoxide/clidinium bromide is indicated to control emotional and somatic factors in gastrointestinal disorders. It may also be used as adjunctive therapy in the treatment of peptic ulcer and in the treatment of the irritable bowel syndrome (irritable colon, spastic colon, mucous colitis) and acute enterocolitis. References External links "Chlordiazepoxide mixture with clidinium bromide". Drug Information Portal. U.S. National Library of Medicine.
Aflibercept	Aflibercept, sold under the brand names Eylea and Zaltrap, is a medication used to treat wet macular degeneration and metastatic colorectal cancer. It was developed by Regeneron Pharmaceuticals and is approved in the United States and the European Union.It is an inhibitor of vascular endothelial growth factor (VEGF). Medical uses It is used for the treatment of wet macular degeneration and is administered as an intravitreal injection, that is, into the eye. For cancer treatment, is given intravenously in combination with the other cancer drugs 5-fluorouracil and irinotecan and the adjuvant folinic acid.On 27 August 2014, Eylea was also indicated for the treatment of people with visual impairment due to diabetic macular oedema, according to the updated summary of product characteristics. In May 2019 FDA expanded the indication for aflibercept to include all stages of diabetic retinopathy. Contraindications Eylea is contraindicated in patients with infections or active inflammations of or near the eye, while Zaltrap has no contraindications. Adverse effects Common adverse effects of the eye formulation include conjunctival hemorrhage, eye pain, cataract, vitreous detachment, floaters, and ocular hypertension.Zaltrap has adverse effects typical of anti-cancer drugs, such as reduced blood cell count (leukopenia, neutropenia, thrombocytopenia), gastrointestinal disorders like diarrhoea and abdominal pain, and fatigue. Another common effect is hypertension (increased blood pressure). Interactions No interactions are described for either formulation. Mechanism of action In wet macular degeneration, abnormal blood vessels grow in the choriocapillaris, a layer of capillaries in the eye, leading to blood and protein leakage below the macula. Tumours need blood vessels sprouting into them when they become larger than a few millimetres, in order to get access to oxygen and nutritive substances to facilitate further growth. Aflibercept binds to circulating VEGFs and acts like a "VEGF trap". It thereby inhibits the activity of the vascular endothelial growth factor subtypes VEGF-A and VEGF-B, as well as to placental growth factor (PGF), inhibiting the growth of new blood vessels in the choriocapillaris or the tumour, respectively. The aim of the cancer treatment, so to speak, is to starve the tumour. Composition Aflibercept is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF)-binding portions from the extracellular domains of human VEGF receptors 1 and 2, that are fused to the Fc portion of the human IgG1 immunoglobulin. History Regeneron commenced clinical testing of aflibercept in cancer in 2001. In 2003, Regeneron signed a major deal with Aventis to develop aflibercept in the field of cancer. In 2004 Regeneron started testing the compound, locally delivered, in proliferative eye diseases, and in 2006 Regeneron and Bayer signed an agreement to develop the eye indications. Clinical trials In March 2011, Regeneron reported that aflibercept failed its primary endpoint of overall survival in the Vital phase III trial for second-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), although it improved the secondary endpoint of progression-free survival.In April 2011, Regeneron reported that aflibercept improved its primary endpoint of overall survival in the Velour phase III clinical trial for second-line treatment for metastatic colorectal cancer (mCRC).Aflibercept was also in a phase III trial for hormone-refractory metastatic prostate cancer as of April 2011.A 2016 Cochrane Review examined outcomes comparing aflibercept versus ranibizumab injections in over 2400 patients with neovascular AMD, from two randomized controlled trials. Both treatment options yielded similar improvements in visual acuity and morphological outcomes in patients, though the authors note that the aflibercept treatment regimen has the potential to reduce treatment burden other risks from injections.A 2017 review update studying the effects of anti-VEGF drugs on diabetic macular edema found that while all three studied treatments have advantages over laser therapy, there was moderate evidence that aflibercept is significantly favored in all measured efficacy outcomes over ranibizumab and bevacizumab, after one year. Society and culture Legal status In November 2011, the United States Food and Drug Administration (FDA) approved aflibercept for the treatment of wet macular degeneration.On 3 August 2012, the FDA approved aflibercept for use in combination with 5-fluorouracil, folinic acid and irinotecan to treat adults with metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin‑containing regimen. To avoid confusion with the version that is injected into the eye, the FDA assigned a new name, ziv-aflibercept, to the active ingredient.In November 2012, the European Medicines Agency (EMA) approved aflibercept (Eylea) for the treatment of wet macular degeneration.In February 2013, the European Medicines Agency (EMA) approved aflibercept (Zaltrap) for the treatment of adults with metastatic colorectal cancer for whom treatment based on oxaliplatin has not worked or the cancer got worse. Aflibercept (Zaltrap) is used with FOLFIRI, which is a treatment combining the medicines irinotecan, 5-fluorouracil, and folinic acid. Economics On 12 March 2015, aflibercept was one of a group of drugs delisted from the UK Cancer Drugs Fund. In 2017, injections of aflibercept (HCPCS code J0178) were responsible for the most billing to Medicare Part B, at $2.36 billion. References External links "Aflibercept". Drug Information Portal. U.S. National Library of Medicine. "Ziv-aflibercept Injection". MedlinePlus.
Conivaptan	Conivaptan, sold under the brand name Vaprisol, is a non-peptide inhibitor of the receptor for anti-diuretic hormone, also called vasopressin. It was approved in 2004 for hyponatremia (low blood sodium levels). The compound was discovered by Astellas and marked in 2006. The drug is now marketed by Cumberland Pharmaceuticals, Inc. Conivaptan inhibits two of the three subtypes of the vasopressin receptor (V1a and V2). Effectively, it causes iatrogenic nephrogenic diabetes insipidus. Conivaptan has not been approved by the American Food and Drug Administration for the treatment of decompensated congestive heart failure. However, in theory, vasopressin receptor antagonism would be particularly useful in this setting, and an initial study shows that it has some promise. Medical uses Conivaptan is most commonly used in the hospital in cases of euvolemic and hypervolemic hyponatremia, conditions where the sodium level in the blood falls significantly below normal. In the United States hyponatremia affects about four percent of hospitalized patients. Although many patients do not show symptoms, extreme cases may result in brain swelling, respiratory arrest and even death. Hypervolemic hyponatremia specifically is when the body’s serum sodium levels fall below the total body water increase, which results in edema. This is associated with congestive heart failure, liver disease and kidney failure. Pharmacology Conivaptan hydrochloride is an arginine vasopressin (AVP) receptor antagonist with affinity for human V1A and V2 receptors in the nanomolar range in vitro. AVP levels in blood are crucial for water and electrolyte regulation and balance. V2 receptors maintain plasma osmolality and are coupled to aquaporin channels in the collecting ducts of kidneys where they regulate AVP levels. Conivaptan hydrochloride functions by antagonizing V2 receptors in the renal collecting ducts and thus causing aquaresis or water secretion. Typical pharmacodynamic effects of the drug are an increase in net fluid loss, increase in urine output, and decrease in the osmolality of urine. Conivaptan inhibits its own metabolism in the body, displaying non-linear pharmacokinetics. About 99% of conivaptan found is bound to human plasma proteins over the range of 10 ng/mL to 1000 ng/mL. The mean half-life of the drug is 5 hours and mean clearance is 15.2 L/hr. Adverse effects Most adverse reactions to conivaptan are found at the site of infusion. Other complications include blood and lymphatic system disorders, gastrointestinal disorders, metabolism and nutrition disorders, psychiatric disorders as well as vascular disorders. There is risk of too rapid correction of hyponatremia causing fatal osmotic demyelination syndrome. Chemistry Conivaptan hydrochloride is an off-white or a pale yellow power with a solubility of 0.25 mg/mL in water at 23 °C. The injectable formulation consists of 20 mg conivaptan hydrochloride, 0.4 g ethanol, 1.2 g propylene glycol and water. Development and commercialization Conivaptan hydrochloride was discovered by Yamanouchi Pharmaceuticals and marketed by Astellas. Yamanouchi Pharmaceuticals filed a new drug application to the FDA for conivaptan hydrochloride to treat hyponatremia on 2 February 2004. On 1 December, Yamanouchi received approval for investigational hyponatremia treatment using conivaptan hydrochloride. Yamanouchi pharmaceuticals and Fujisawa Pharmaceuticlas merged and were renamed as Astellas’ in 2005. Astellas gained FDA approval for Conivaptan hydrochloride on 29 December 2005, and marked the drug under the brand name of Vaprisol in 2006.On 2 March 2007, vaprisol also gained FDA approval for the treatment of hypervolemia hyponatremia. On 22 October 2008, Vaprisol further gained approval as a 5% Dextrose premixed formulation for the treatment of hyponatremia. In 2014 Cumberland pharmaceuticals bought Vaprisol from Astellas and took full responsibility of all development and marketing of the drug.Cumberland Pharmaceuticals is a pharmaceutical company based in Nashville, Tennessee. In addition to Vaprisol, Cumberland produces Acetadote, Caldolor, Kristalose, Omeclamox, and Ethyol. Hepatoren, Boxban, Vasculan, and currently in phase II clinical trials. Protaban, Methotrexate, and Totect are waiting for pre-approval. References External links "Conivaptan". Drug Information Portal. U.S. National Library of Medicine.
Sertraline	Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the differences are mostly confined to side effects. Sertraline is better tolerated than the older tricyclic antidepressants, and it may work better than fluoxetine for some subtypes of depression. Sertraline is effective for panic disorder, social anxiety disorder, generalized anxiety disorder, and obsessive–compulsive disorder (OCD). However, for OCD, cognitive behavioral therapy, particularly in combination with sertraline, is a better treatment. Although approved for post-traumatic stress disorder, sertraline leads to only modest improvement in this condition. Sertraline also alleviates the symptoms of premenstrual dysphoric disorder and can be used in sub-therapeutic doses or intermittently for its treatment.Sertraline shares the common side effects and contraindications of other SSRIs, with high rates of nausea, diarrhea, insomnia, and sexual side effects, but it appears not to lead to much weight gain, and its effects on cognitive performance are mild. Similar to other antidepressants, the use of sertraline for depression may be associated with a higher rate of suicidal thoughts and behavior in people under the age of 25. It should not be used together with MAO inhibitor medication: this combination causes serotonin syndrome. Sertraline taken during pregnancy is associated with a significant increase in congenital heart defects in newborns.Sertraline was invented and developed by scientists at Pfizer and approved for medical use in the United States in 1991. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2016, sertraline was the most commonly prescribed psychiatric medication in the United States and in 2020, it was the twelfth most commonly prescribed medication in the United States, with over 38 million prescriptions. Medical uses Sertraline has been approved for major depressive disorder (MDD), obsessive–compulsive disorder (OCD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder, and social anxiety disorder (SAD). Sertraline is not approved for use in children except for those with OCD. Depression Multiple controlled clinical trials established efficacy of sertraline for the treatment of depression. Sertraline is also an effective antidepressant in the routine clinical practice. Continued treatment with sertraline prevents both a relapse of the current depressive episode and future episodes (recurrence of depression).In several double-blind studies, sertraline was consistently more effective than placebo for dysthymia, a more chronic variety of depression, and comparable to imipramine in that respect. Sertraline also improves the depression of dysthymic patients to a greater degree than psychotherapy.Limited pediatric data also demonstrates reduction in depressive symptoms in the pediatric population though remains a second line therapy after fluoxetine. Comparison with other antidepressants In general, sertraline efficacy is similar to that of other antidepressants. For example, a meta-analysis of 12 new-generation antidepressants showed that sertraline and escitalopram are the best in terms of efficacy and acceptability in the acute-phase treatment of adults with depression. Comparative clinical trials demonstrated that sertraline is similar in efficacy against depression to moclobemide, nefazodone, escitalopram, bupropion, citalopram, fluvoxamine, paroxetine, venlafaxine and mirtazapine. Sertraline may be more efficacious for the treatment of depression in the acute phase (first 4 weeks) than fluoxetine.There are differences between sertraline and some other antidepressants in their efficacy in the treatment of different subtypes of depression and in their adverse effects. For severe depression, sertraline is as good as clomipramine but is better tolerated. Sertraline appears to work better in melancholic depression than fluoxetine, paroxetine, and mianserin and is similar to the tricyclic antidepressants such as amitriptyline and clomipramine. In the treatment of depression accompanied by OCD, sertraline performs significantly better than desipramine on the measures of both OCD and depression. Sertraline is equivalent to imipramine for the treatment of depression with co-morbid panic disorder, but it is better tolerated. Compared with amitriptyline, sertraline offered a greater overall improvement in quality of life of depressed patients. Depression in elderly Sertraline used for the treatment of depression in elderly (older than 60) patients is superior to placebo and comparable to another SSRI fluoxetine, and tricyclic antidepressants (TCAs) amitriptyline, nortriptyline and imipramine. Sertraline has much lower rates of adverse effects than these TCAs, with the exception of nausea, which occurs more frequently with sertraline. In addition, sertraline appears to be more effective than fluoxetine or nortriptyline in the older-than-70 subgroup. Accordingly, a meta-analysis of antidepressants in older adults found that sertraline, paroxetine and duloxetine were better than placebo. On the other hand, in a 2003 trial the effect size was modest, and there was no improvement in quality of life as compared to placebo. With depression in dementia, there is no benefit of sertraline treatment compared to either placebo or mirtazapine. Obsessive–compulsive disorder Sertraline is effective for the treatment of OCD in adults and children. It was better tolerated and, based on intention-to-treat analysis, performed better than the gold standard of OCD treatment clomipramine. Continuing sertraline treatment helps prevent relapses of OCD with long-term data supporting its use for up to 24 months. It is generally accepted that the sertraline dosages necessary for the effective treatment of OCD are higher than the usual dosage for depression. The onset of action is also slower for OCD than for depression. The treatment recommendation is to start treatment with a half of maximal recommended dose for at least two months. After that, the dose can be raised to the maximal recommended in the cases of unsatisfactory response.Cognitive behavioral therapy alone was superior to sertraline in both adults and children; however, the best results were achieved using a combination of these treatments. Panic disorder Sertraline is superior to placebo for the treatment of panic disorder. The response rate was independent of the dose. In addition to decreasing the frequency of panic attacks by about 80% (vs. 45% for placebo) and decreasing general anxiety, sertraline resulted in improvement of quality of life on most parameters. The patients rated as "improved" on sertraline reported better quality of life than the ones who "improved" on placebo. The authors of the study argued that the improvement achieved with sertraline is different and of a better quality than the improvement achieved with placebo. Sertraline is equally effective for men and women, and for patients with or without agoraphobia. Previous unsuccessful treatment with benzodiazepines does not diminish its efficacy. However, the response rate was lower for the patients with more severe panic. Starting treatment simultaneously with sertraline and clonazepam, with subsequent gradual discontinuation of clonazepam, may accelerate the response.Double-blind comparative studies found sertraline to have the same effect on panic disorder as paroxetine or imipramine. While imprecise, comparison of the results of trials of sertraline with separate trials of other anti-panic agents (clomipramine, imipramine, clonazepam, alprazolam, and fluvoxamine) indicates approximate equivalence of these medications. Other anxiety disorders Sertraline has been successfully used for the treatment of social anxiety disorder. All three major domains of the disorder (fear, avoidance, and physiological symptoms) respond to sertraline. Maintenance treatment, after the response is achieved, prevents the return of the symptoms. The improvement is greater among the patients with later, adult onset of the disorder. In a comparison trial, sertraline was superior to exposure therapy, but patients treated with the psychological intervention continued to improve during a year-long follow-up, while those treated with sertraline deteriorated after treatment termination. The combination of sertraline and cognitive behavioral therapy appears to be more effective in children and young people than either treatment alone.Sertraline has not been approved for the treatment of generalized anxiety disorder; however, several guidelines recommend it as a first-line medication referring to good quality controlled clinical trials. Premenstrual dysphoric disorder Sertraline is effective in alleviating the symptoms of premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome. Significant improvement was observed in 50–60% of cases treated with sertraline vs. 20–30% of cases on placebo. The improvement began during the first week of treatment, and in addition to mood, irritability, and anxiety, improvement was reflected in better family functioning, social activity and general quality of life. Work functioning and physical symptoms, such as swelling, bloating and breast tenderness, were less responsive to sertraline. Taking sertraline only during the luteal phase, that is, the 12–14 days before menses, was shown to work as well as continuous treatment. Continuous treatment with sub-therapeutic doses of sertraline (25 mg vs. usual 50–100 mg) is also effective. Other indications Sertraline is approved for the treatment of post-traumatic stress disorder (PTSD). National Institute of Clinical Excellence recommends it for patients who prefer drug treatment to a psychological one. Other guidelines also suggest sertraline as a first-line option for pharmacological therapy. When necessary, long-term pharmacotherapy can be beneficial. There are both negative and positive clinical trial results for sertraline, which may be explained by the types of psychological traumas, symptoms, and comorbidities included in the various studies. Positive results were obtained in trials that included predominantly women (75%) with a majority (60%) having physical or sexual assault as the traumatic event. Contrary to the above suggestions, a meta-analysis of sertraline clinical trials for PTSD found it to be not significantly better than placebo. Another meta-analysis relegated sertraline to the second line, proposing trauma focused psychotherapy as a first-line intervention. The authors noted that Pfizer had declined to submit the results of a negative trial for the inclusion into the meta-analysis making the results unreliable.Sertraline when taken daily can be useful for the treatment of premature ejaculation. A disadvantage of sertraline is that it requires continuous daily treatment to delay ejaculation significantly.A 2019 systematic review suggested that sertraline may be a good way to control anger, irritability and hostility in depressed patients and patients with other comorbidities. Contraindications Sertraline is contraindicated in individuals taking monoamine oxidase inhibitors or the antipsychotic pimozide. Sertraline concentrate contains alcohol and is therefore contraindicated with disulfiram. The prescribing information recommends that treatment of the elderly and patients with liver impairment "must be approached with caution". Due to the slower elimination of sertraline in these groups, their exposure to sertraline may be as high as three times the average exposure for the same dose. Side effects Nausea, ejaculation failure, insomnia, diarrhea, dry mouth, somnolence, dizziness, tremor, headache, excessive sweating, fatigue, and decreased libido are the common adverse effects associated with sertraline with the greatest difference from placebo. Those that most often resulted in interruption of the treatment are nausea, diarrhea and insomnia. The incidence of diarrhea is higher with sertraline – especially when prescribed at higher doses – in comparison with other SSRIs.Over more than six months of sertraline therapy for depression, people showed a nonsignificant weight increase of 0.1%. Similarly, a 30-month-long treatment with sertraline for OCD resulted in a mean weight gain of 1.5% (1 kg). Although the difference did not reach statistical significance, the average weight gain was lower for fluoxetine (1%) but higher for citalopram, fluvoxamine and paroxetine (2.5%). Of the sertraline group, 4.5% gained a large amount of weight (defined as more than 7% gain). This result compares favorably with placebo, where, according to the literature, 3–6% of patients gained more than 7% of their initial weight. The large weight gain was observed only among female members of the sertraline group; the significance of this finding is unclear because of the small size of the group.Over a two-week treatment of healthy volunteers, sertraline slightly improved verbal fluency but did not affect word learning, short-term memory, vigilance, flicker fusion time, choice reaction time, memory span, or psychomotor coordination. In spite of lower subjective rating, that is, feeling that they performed worse, no clinically relevant differences were observed in the objective cognitive performance in a group of people treated for depression with sertraline for 1.5 years as compared to healthy controls. In children and adolescents taking sertraline for six weeks for anxiety disorders, 18 out of 20 measures of memory, attention and alertness stayed unchanged. Divided attention was improved and verbal memory under interference conditions decreased marginally. Because of the large number of measures taken, it is possible that these changes were still due to chance. The unique effect of sertraline on dopaminergic neurotransmission may be related to these effects on cognition and vigilance.Sertraline has a low level of exposure of an infant through the breast milk and is recommended as the preferred option for the antidepressant therapy of breast-feeding mothers. There is 29–42% increase in congenital heart defects among children whose mothers were prescribed sertraline during pregnancy, with sertraline use in the first trimester associated with 2.7-fold increase in septal heart defects.Abrupt interruption of sertraline treatment may result in withdrawal or discontinuation syndrome. Dizziness, insomnia, anxiety, agitation, and irritability are its common symptoms. It typically occurs within a few days from drug discontinuation and lasts a few weeks. The withdrawal symptoms for sertraline are less severe and frequent than for paroxetine, and more frequent than for fluoxetine. In most cases symptoms are mild, short-lived, and resolve without treatment. More severe cases are often successfully treated by temporary reintroduction of the drug with a slower tapering off rate.Sertraline and SSRI antidepressants in general may be associated with bruxism and other movement disorders. Sertraline appears to be associated with microscopic colitis, a rare condition of unknown etiology. Sexual Like other SSRIs, sertraline is associated with sexual side effects, including sexual arousal disorder, erectile dysfunction and difficulty achieving orgasm. While nefazodone and bupropion do not have negative effects on sexual functioning, 67% of men on sertraline experienced ejaculation difficulties versus 18% before the treatment. Sexual arousal disorder, defined as "inadequate lubrication and swelling for women and erectile difficulties for men", occurred in 12% of people on sertraline as compared with 1% of patients on placebo. The mood improvement resulting from the treatment with sertraline sometimes counteracted these side effects, so that sexual desire and overall satisfaction with sex stayed the same as before the sertraline treatment. However, under the action of placebo the desire and satisfaction slightly improved. Some people continue experiencing sexual side effects after they stop taking SSRIs. Suicide The FDA requires all antidepressants, including sertraline, to carry a boxed warning stating that antidepressants increase the risk of suicide in persons younger than 25 years. This warning is based on statistical analyses conducted by two independent groups of FDA experts that found a 100% increase of suicidal thoughts and behavior in children and adolescents, and a 50% increase – in the 18–24 age group.Suicidal ideation and behavior in clinical trials are rare. For the above analysis, the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, sertraline use in adults decreased the odds of suicidal behavior with a marginal statistical significance by 37% or 50% depending on the statistical technique used. The authors of the FDA analysis note that "given the large number of comparisons made in this review, chance is a very plausible explanation for this difference". The more complete data submitted later by the sertraline manufacturer Pfizer indicated increased suicidal behavior. Similarly, the analysis conducted by the UK MHRA found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the patients on sertraline as compared to the ones on placebo. Overdose Acute overdosage is often manifested by emesis, lethargy, ataxia, tachycardia and seizures. Plasma, serum or blood concentrations of sertraline and norsertraline, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities. As with most other SSRIs its toxicity in overdose is considered relatively low. Interactions As with other SSRIs, sertraline may increase the risk of bleeding with NSAIDs (ibuprofen, naproxen, mefenamic acid), antiplatelet drugs, anticoagulants, omega-3 fatty acids, vitamin E, and garlic supplements due to sertralines inhibitory effects on platelet aggregation via blocking serotonin transporters on platelets. Sertraline, in particular, may potentially diminish the efficacy of levothyroxine.Sertraline is a moderate inhibitor of CYP2D6 and CYP2B6 in vitro. Accordingly, in human trials it caused increased blood levels of CYP2D6 substrates such as metoprolol, dextromethorphan, desipramine, imipramine and nortriptyline, as well as the CYP3A4/CYP2D6 substrate haloperidol. This effect is dose-dependent; for example, co-administration with 50 mg of sertraline resulted in 20% greater exposure to desipramine, while 150 mg of sertraline led to a 70% increase. In a placebo-controlled study, the concomitant administration of sertraline and methadone caused a 40% increase in blood levels of the latter, which is primarily metabolized by CYP2B6.Sertraline had a slight inhibitory effect on the metabolism of diazepam, tolbutamide and warfarin, which are CYP2C9 or CYP2C19 substrates; the clinical relevance of this effect was unclear. As expected from in vitro data, sertraline did not alter the human metabolism of the CYP3A4 substrates erythromycin, alprazolam, carbamazepine, clonazepam, and terfenadine; neither did it affect metabolism of the CYP1A2 substrate clozapine.Sertraline had no effect on the actions of digoxin and atenolol, which are not metabolized in the liver. Case reports suggest that taking sertraline with phenytoin or zolpidem may induce sertraline metabolism and decrease its efficacy, and that taking sertraline with lamotrigine may increase the blood level of lamotrigine, possibly by inhibition of glucuronidation.CYP2C19 inhibitor esomeprazole increased sertraline concentrations in blood plasma by approximately 40%.Clinical reports indicate that interaction between sertraline and the MAOIs isocarboxazid and tranylcypromine may cause serotonin syndrome. In a placebo-controlled study in which sertraline was co-administered with lithium, 35% of the subjects experienced tremors, while none of those taking placebo did.Sertraline may interact with grapefruit juice—see "Grapefruit–drug interactions". Pharmacology Pharmacodynamics Sertraline is a selective serotonin reuptake inhibitor (SSRI). By binding serotonin transporter (SERT) it inhibits neuronal reuptake of serotonin and potentiates serotonergic activity in the central nervous system. Over time, this leads to a downregulation of pre-synaptic 5-HT1A receptors, which is associated with an improvement in passive stress tolerance, and delayed downstream increase in expression of brain-derived neurotrophic factor (BDNF), which may contribute to a reduction in negative affective biases. It does not significantly affect norepinephrine transporter (NET), serotonin, dopamine, adrenergic, histamine, acetylcholine, GABA or benzodiazepine receptors.Sertraline also shows relatively high activity as an inhibitor of the dopamine transporter (DAT) and antagonist of the sigma σ1 receptor (but not the σ2 receptor). However, sertraline affinity for its main target (SERT) is much greater than its affinity for σ1 receptor and DAT. Although there could be a role for the σ1 receptor in the pharmacology of sertraline, the significance of this receptor in its actions is unclear. Similarly, the clinical relevance of sertralines blockade of the dopamine transporter is uncertain. Pharmacokinetics Absorption Following a single oral dose of sertraline, mean peak blood levels of sertraline occur between 4.5 and 8.4 hours. Bioavailability is likely linear and dose-proportional over a dose range of 150 to 200 mg. Concomitant intake of sertraline with food slightly increases sertraline peak levels and total exposure. There is an approximate 2-fold accumulation of sertraline with continuous administration and steady-state levels are reached within one week. Distribution Sertraline is highly plasma protein bound (98.5%) across a concentration range of 20 to 500 ng/mL. Despite the high plasma protein binding, sertraline and its metabolite desmethylsertraline at respective tested concentrations of 300 ng/mL and 200 ng/mL were found not to interfere with the plasma protein binding of warfarin and propranolol, two other highly plasma protein-bound drugs. Metabolism Sertraline is subject to extensive first-pass metabolism, as indicated by a small study of radiolabeled sertraline in which less than 5% of plasma radioactivity was unchanged sertraline in two males. The principal metabolic pathway for sertraline is N-demethylation into desmethylsertraline (N-desmethylsertraline) mainly by CYP2B6. Reduction, hydroxylation, and glucuronide conjugation of both sertraline and desmethylsertraline also occur. Desmethylsertraline, while pharmacologically active, is substantially (50-fold) weaker than sertraline as a serotonin reuptake inhibitor and its influence on the clinical effects of sertraline is thought to be negligible. Based on in vitro studies, sertraline is metabolized by multiple cytochrome 450 isoforms; however, it appears that in the human body CYP2C19 plays the most important role, followed by CYP2B6. In addition to the cytochrome P450 system, sertraline can be oxidatively deaminated in vitro by monoamine oxidases; however, this metabolic pathway has never been studied in vivo. Elimination The elimination half-life of sertraline is on average 26 hours, with a range of 13 to 45 hours. The half-life of sertraline is longer in women (32 hours) than in men (22 hours), which leads to 1.5-fold higher exposure to sertraline in women compared to men. The elimination half-life of desmethylsertraline is 62 to 104 hours.In a small study of two males, sertraline was excreted to similar degrees in urine and feces (40 to 45% each within 9 days). Unchanged sertraline was not detectable in urine, whereas 12 to 14% unchanged sertraline was present in feces. Pharmacogenomics CYP2C19 and CYP2B6 are thought to be the key cytochrome P450 enzymes involved in the metabolism of sertraline. Relative to CYP2C19 normal (extensive) metabolizers, poor metabolizers have 2.7-fold higher levels of sertraline and intermediate metabolizers have 1.4-fold higher levels. In contrast, CYP2B6 poor metabolizers have 1.6-fold higher levels of sertraline and intermediate metabolizers have 1.2-fold higher levels. History The history of sertraline dates back to the early 1970s, when Pfizer chemist Reinhard Sarges invented a novel series of psychoactive compounds, including lometraline, based on the structures of the neuroleptics thiothixene and pinoxepin. Further work on these compounds led to tametraline, a norepinephrine and weaker dopamine reuptake inhibitor. Development of tametraline was soon stopped because of undesired stimulant effects observed in animals. A few years later, in 1977, pharmacologist Kenneth Koe, after comparing the structural features of a variety of reuptake inhibitors, became interested in the tametraline series. He asked another Pfizer chemist, Willard Welch, to synthesize some previously unexplored tametraline derivatives. Welch generated a number of potent norepinephrine and triple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogs was a serotonin reuptake inhibitor. Welch then prepared stereoisomers of this compound, which were tested in vivo by animal behavioral scientist Albert Weissman. The most potent and selective (+)-isomer was taken into further development and eventually named sertraline. Weissman and Koe recalled that the group did not set up to produce an antidepressant of the SSRI type—in that sense their inquiry was not "very goal driven", and the discovery of the sertraline molecule was serendipitous. According to Welch, they worked outside the mainstream at Pfizer, and even "did not have a formal project team". The group had to overcome initial bureaucratic reluctance to pursue sertraline development, as Pfizer was considering licensing an antidepressant candidate from another company.Sertraline was approved by the US Food and Drug Administration (FDA) in 1991 based on the recommendation of the Psychopharmacological Drugs Advisory Committee; it had already become available in the United Kingdom the previous year. The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of major depression. During the discussion, Paul Leber, the director of the FDA Division of Neuropharmacological Drug Products, noted that granting approval was a "tough decision", since the treatment effect on outpatients with depression had been "modest to minimal". Other experts emphasized that the drugs effect on inpatients had not differed from placebo and criticized poor design of the clinical trials by Pfizer. For example, 40% of participants dropped out of the trials, significantly decreasing their validity.Until 2002, sertraline was only approved for use in adults ages 18 and over; that year, it was approved by the FDA for use in treating children aged 6 or older with severe OCD. In 2003, the UK Medicines and Healthcare products Regulatory Agency issued a guidance that, apart from fluoxetine (Prozac), SSRIs are not suitable for the treatment of depression in patients under
Sertraline	18. However, sertraline can still be used in the UK for the treatment of OCD in children and adolescents. In 2005, the FDA added a boxed warning concerning pediatric suicidal behavior to all antidepressants, including sertraline. In 2007, labeling was again changed to add a warning regarding suicidal behavior in young adults ages 18 to 24. Society and culture Generic availability The US patent for Zoloft expired in 2006, and sertraline is available in generic form and is marketed under many brand names worldwide.In May 2020, the FDA placed Zoloft on the list of drugs currently facing a shortage. Other uses Sertraline may be useful to treat murine Zaire ebolavirus (murine EBOV). The World Health Organization (WHO) considers this a promising area of research.Lass-Flörl et al., 2003 finds it significantly inhibits phospholipase B in the fungal genus Candida, reducing virulence.Sertraline is also a very effective leishmanicide. Specifically, Palit & Ali 2008 find that sertraline kills almost all promastigotes of Leishmania donovani.Sertraline is strongly antibacterial against some species. References External links "Sertraline". Drug Information Portal. US National Library of Medicine. "Sertraline hydrochloride". Drug Information Portal. US National Library of Medicine.
Aliskiren	Aliskiren (brand names Tekturna and Rasilez) is the first in a class of drugs called direct renin inhibitors. It is used for essential (primary) hypertension. While used for high blood pressure, other better studied medications are typically recommended due to concerns of higher side effects and less evidence of benefit.In December 2011, Novartis halted a trial of the drug after discovering increased nonfatal stroke, kidney complications, high blood potassium, and low blood pressure in people with diabetes and kidney problems.As a result, in 2012: A new contraindication was added to the product label concerning the use of aliskiren with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) in patients with diabetes because of the risk of kidney impairment, low blood pressure, and high levels of potassium in the blood. A warning to avoid use of aliskiren with ARBs or ACEIs was also added for patients with moderate to severe kidney impairment (i.e., where glomerular filtration rate is less than 60 ml/min). Novartis decided to stop marketing Valturna (aliskiren/valsartan).Aliskiren was co-developed by the Swiss pharmaceutical companies Novartis and Speedel. Medical uses While used for high blood pressure, other better-studied medications are typically recommended. Prescrire has stated that aliskiren is potentially more harmful than beneficial and thus list it as a drug to avoid (as of 2014). Adverse effects Angioedema - The ADE of angioedema found in patients using Aliskiren is due to the inhibition of bradykinin degradation which occurs within the Renin-Angiotensin System (RAAS) High blood potassium level (particularly when used with ACE inhibitors in diabetic patients) Low blood pressure (particularly in volume-depleted patients) Diarrhea and other GI symptoms Headache Dizziness Cough Contraindications Pregnancy: Other drugs such as ACE inhibitors, also acting on the renin–angiotensin system, have been associated with fetal malformations and neonatal death. Angiotensin cannot be used in patients who are pregnant because it will result in disruption of normal fetal kidney development. Breastfeeding: During animal studies, the drug has been found present in milk. Aliskiren has been shown to increase the likelihood of adverse cardiovascular outcomes in patients with diabetes and kidney or heart disease. Drug interactions Aliskiren is a minor inhibitor of substrate CYP3A4 and, more importantly, P-glycoprotein: It reduces furosemide blood concentration. Atorvastatin may increase blood concentration, but no dose adjustment is needed. Due to possible interaction with ciclosporin, the use of ciclosporin and aliskiren at the same time is contraindicated. Caution should be exercised when aliskiren is administered with ketoconazole or other moderate P-glycoprotein inhibitors (itraconazole, clarithromycin, telithromycin, erythromycin, or amiodarone). Recommendations have been made to stop prescribing aliskiren-containing medicines to patients with diabetes (type 1 or type 2) or with moderate to severe kidney impairment who are also taking an ACE inhibitor or ARB. Such patients should consider alternative antihypertensive treatment as necessary. Mechanism of action Aliskiren is an antagonist to renin. Renin, the first enzyme in the renin–angiotensin–aldosterone system, plays a role in blood pressure control. It cleaves angiotensinogen to angiotensin I, which is in turn converted by angiotensin-converting enzyme (ACE) to angiotensin II. Angiotensin II has both direct and indirect effects on blood pressure. It directly causes arterial smooth muscle to contract, leading to vasoconstriction and increased blood pressure. Angiotensin II also stimulates the production of aldosterone from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium, with water following, thereby increasing plasma volume, and thus blood pressure. Aliskiren binds to the S3bp binding site of renin, essential for its activity. Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I. Aliskiren is also available as combination therapy with hydrochlorothiazide. Chemistry The chemical name for aliskiren is (2 S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[ 4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide. Rationale for design Many drugs control blood pressure by interfering with angiotensin or aldosterone. However, when these drugs are used chronically, the body increases renin production, which drives blood pressure up again. Therefore, pharmacologists have been looking for a drug to inhibit renin directly. Aliskiren is the first drug to do so. References External links "Aliskiren". Drug Information Portal. U.S. National Library of Medicine. Aliskiren at the US National Library of Medicine Medical Subject Headings (MeSH)
Enalapril	Enalapril, sold under the brand name Vasotec among others, is an ACE inhibitor medication used to treat high blood pressure, diabetic kidney disease, and heart failure. For heart failure, it is generally used with a diuretic, such as furosemide. It is given by mouth or by injection into a vein. Onset of effects are typically within an hour when taken by mouth and last for up to a day.Common side effects include headache, tiredness, feeling lightheaded with standing, and cough. Serious side effects include angioedema and low blood pressure. Use during pregnancy is believed to result in harm to the baby. It is in the angiotensin-converting-enzyme (ACE) inhibitor family of medications.Enalapril was patented in 1978, and came into medical use in 1984. It is on the World Health Organizations List of Essential Medicines. In 2019, it was the 137th most commonly prescribed medication in the United States, with more than 4 million prescriptions. As of August 2021, enalapril is available as a generic medicine in the US. Structure Activity Relationship Enalapril has an L-proline moiety as a part of the molecule which is responsible for the oral bioavailability of the drug. It is a pro-drug, which means that it exerts its function after being metabolized. The "-OCH2CH3" part of the molecule will split during the metabolism and at the carbon will be a carboxylate, which then interacts with the Zn+2 site of the ACE Enzyme. This structural feature and mechanism of metabolism that must occur before the drug can inhibit the enzyme explains why it has a greater duration of action than another similar drug used for the same indication, Captopril. Enalapril has a slower onset of action than Captopril but a greater duration of action. However, unlike Captopril, Enalapril does not have a thiol moiety. Medical uses Enalapril is used to treat hypertension, symptomatic heart failure, and asymptomatic left ventricular dysfunction. ACE-inhibitors (including enalapril) have demonstrated ability to reduce the progression and worsening of existing chronic kidney disease in the presence of proteinuria/microalbuminuria (protein in the urine, a biomarker for chronic kidney disease). This renal protective effect is not seen in the absence of proteinuria/microalbuminuria, including in diabetic populations. The benefit has been particularly demonstrated in patients with hypertension and/or diabetes, and is likely to be seen in other populations (although further studies and subgroup analyses of existing studies are needed). It is widely used in chronic kidney failure. Furthermore, enalapril is an emerging treatment for psychogenic polydipsia. A double-blind, placebo-controlled trial showed that when used for this purpose, enalapril led to decreased water consumption (determined by urine output and osmolality) in 60% of patients. Pregnancy and breastfeeding Enalapril is pregnancy category D. Some evidence suggests it will cause injury and death to a developing fetus. Patients are advised not to become pregnant while taking enalapril and to notify their doctors immediately if they become pregnant. In pregnancy, enalapril may result in damage to the fetuss kidneys and resulting oligohydramnios (not enough amniotic fluid). Enalapril is secreted in breast milk and is not recommended for use while breastfeeding. Side effects The most common side effects of enalapril include increased serum creatinine (20%), dizziness (2–8%), low blood pressure (1–7%), syncope (2%), and dry cough (1–2%). The most serious common adverse event is angioedema (swelling) (0.68%) which often affects the face and lips, endangering the patients airway. Angioedema can occur at any point during treatment with enalapril, but is most common after the first few doses. Angioedema and fatality therefrom are reportedly higher among black people. Agranulocytosis has been observed with Enalapril. Mechanism of action Normally, angiotensin I is converted to angiotensin II by an angiotensin-converting enzyme (ACE). Angiotensin II constricts blood vessels, increasing blood pressure. Enalaprilat, the active metabolite of enalapril, inhibits ACE. Inhibition of ACE decreases levels of angiotensin II, leading to less vasoconstriction and decreased blood pressure. Pharmacokinetics Pharmacokinetic data of enalapril: Onset of action: about 1 hour Peak effect: 4–6 hours Duration: 12–24 hours Absorption: ~60% Metabolism: prodrug, undergoes biotransformation to enalaprilat History Squibb developed the first ACE inhibitor, captopril, but it had adverse effects such as a metallic taste (which, as it turned out, was due to the sulfhydryl group). Merck & Co. developed enalapril as a competing prodrug.: 12–13 Enalaprilat was developed partly to overcome these limitations of captopril. The sulfhydryl moiety was replaced by a carboxylate moiety, but additional modifications were required in its structure-based design to achieve a potency similar to captopril. Enalaprilat, however, had a problem of its own in that it had poor oral availability. This was overcome by the researchers at Merck by the esterification of enalaprilat with ethanol to produce enalapril.: 13 Merck introduced enalapril to market in 1981; it became Mercks first billion dollar-selling drug in 1988.: 13 The patent expired in 2000, opening the way for generics. References External links "Enalapril". Drug Information Portal. U.S. National Library of Medicine.
Cabazitaxel	Cabazitaxel, sold under the brand name Jevtana, is a semi-synthetic derivative of a natural taxoid. It is a microtubule inhibitor, and the fourth taxane to be approved as a cancer therapy.Cabazitaxel was developed by Sanofi-Aventis and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of hormone-refractory prostate cancer in June 2010. It is available as a generic medication. Medical uses Cabazitaxel is indicated in combination with prednisone for the treatment of metastatic castration-resistant prostate cancer following docetaxel-based treatment. Mechanism of action Taxanes enhance microtubule stabilization and inhibit cellular mitosis and division. Moreover, taxanes prevent androgen receptor (AR) signaling by binding cellular microtubules and the microtubule-associated motor protein dynein, thus averting AR nuclear translocation. Clinical trials In patients with metastatic castration-resistant prostate cancer (mCRPC), overall survival (OS) is markedly enhanced with cabazitaxel versus mitoxantrone after prior docetaxel treatment. FIRSTANA (ClinicalTrials.gov identifier: NCT01308567) assessed whether cabazitaxel 20 mg/m2 (C20) or 25 mg/m2 (C25) is superior to docetaxel 75 mg/m2 (D75) in terms of OS in patients with chemotherapy-naïve mCRPC. However, C20 and C25 did not demonstrate superiority for OS versus D75 in patients with chemotherapy-naïve mCRPC. Cabazitaxel and docetaxel demonstrated different toxicity profiles, and C20 showed the overall lowest toxicity. In a phase III trial with 755 men for the treatment of castration-resistant prostate cancer, median survival was 15.1 months for patients receiving cabazitaxel versus 12.7 months for patients receiving mitoxantrone. Cabazitaxel was associated with more grade 3–4 neutropenia (81.7%) than mitoxantrone (58%). Common adverse effects with cabazitaxel include neutropenia (including febrile neutropenia) and GIT side effects appeared mainly in diarrhea, whereas, neuropathy was rarely detected. Pharmacokinetics Cabazitaxel administration causes a decrease in plasma concentrations showing triphasic kinetics: a mean half life (t1/2) of 2.6 min in the first phase, a mean t1/2 of 1.3 h in the second phase, and a mean t1/2 of 77.3 h in the third phase. Metabolism Cabazitaxel is basically metabolized in the liver by [cytochrome P450 (CYP)3A4/5 > CYP2C8], which result in seven plasma metabolites and excreted 20 metabolites. During 14 days after administration, 80% of cabazitaxel is excreted: 76% in the feces and 3.7% as a renal excretion. References External links "Cabazitaxel". Drug Information Portal. U.S. National Library of Medicine. "Cabazitaxel Accord 20 mg/mL concentrate for solution infusion: Risk of medication errors and mix-up with Jevtana (60 mg/1.5 mL) solvent infusion". European Medicines Agency (EMA). October 28, 2020. Clinical trial number NCT00417079 for "XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC)" at ClinicalTrials.gov Clinical trial number NCT01308580 for "Cabazitaxel at 20 mg/m² Compared to 25 mg/m² With Prednisone for the Treatment of Metastatic Castration Resistant Prostate Cancer (PROSELICA)" at ClinicalTrials.gov Clinical trial number NCT02485691 for "Cabazitaxel Versus the Switch to Alternative AR-targeted Agent (Enzalutamide or Abiraterone) in Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients Previously Treated With Docetaxel and Who Rapidly Failed a Prior AR-targeted Agent (CARD)" at ClinicalTrials.gov
Frovatriptan	Frovatriptan, sold under the brand name Frova, is a triptan drug developed by Vernalis for the treatment of migraine headaches and for short term prevention of menstrual migraine. The product is licensed to Endo Pharmaceuticals in North America and Menarini in Europe. Medical uses Frovatriptan is used in the treatment of migraine. Available forms It is available as 2.5 mg tablets. Contraindications Frovatriptan should not be given to patients with: Ischemic heart disease Cerebrovascular syndrome Peripheral vascular disease Uncontrolled hypertension Hemiplegic or basilar migraine Side effects Rare, but serious cardiac events have been reported in patients with risk factors predictive of CAD. These include: coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia and ventricular fibrillation. Pharmacology Pharmacodynamics Frovatriptan is a serotonin receptor agonist, with high affinity for the 5-HT1B/1D receptors. It has no significant effects on the GABAA mediated channel activity and benzodiazepine binding sites. Frovatriptan inhibits excessive dilation of arteries that supply blood to the head. Pharmacokinetics Frovatriptan has a terminal elimination half-life of approximately 26 hours, making it the longest within its class. Society and culture US licensing Frovatriptan is available only by prescription in the United States and Canada, where a secondary New Drug Approval (sNDA) was filed in July 2006. References External links Frova (manufacturers website) Frovatriptan Succinate (patient information) FDA labeling
Pramipexole	Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinsons disease (PD) and restless legs syndrome (RLS). In Parkinsons disease it may be used alone or together with levodopa. It is taken by mouth. Pramipexole is a dopamine agonist of the non-ergoline class.Studies have shown detrimental side effects resulting from off-label use of pramipexole or other dopamine agonists in treating clinical depression.Pramipexole was approved for medical use in the United States in 1997. Use in pregnancy and breastfeeding is of unclear safety. It is available as a generic medication. In 2019, it was the 166th most commonly prescribed medication in the United States, with more than 3 million prescriptions. Medical uses Pramipexole is used in the treatment of Parkinsons disease (PD) and restless legs syndrome (RLS). Use in pregnancy and breastfeeding is of unclear safety.It is occasionally prescribed off-label for depression. Its effectiveness as an antidepressant may be a product of its strong partial agonistic activity on and preferential occupation of dopamine D3 receptors at low doses (see table below); as well, the drug has been shown to desensitize the inhibitory D22 autoreceptors but not the postsynaptic D2 receptors, leading to an increase in dopamine and serotonin levels in the prefrontal cortex. Chronic administration of pramipexole may also result in desensitization of D3 autoreceptors, leading to reduced dopamine transporter function, "We show that prolonged administration of pramipexole (0.1mg/kg/day, 6 to 21 days) [equivalent to a low ~0.5 mg/day human dose], a preferential D3R agonist, leads to a decrease in DA [dopamine] uptake in mouse striatum that reflects a reduction in DAT [dopamine transporter] affinity for DA in the absence of any change in DAT density or subcellular distribution ... These observations provide novel insights into the long-term antiparkinson, antidepressant and additional clinical actions of pramipexole and other D3R agonists".As summarized in the following commentary, trials have shown mixed results, "Dopamine agonists, such as pramipexole—a relatively selective dopamine D3 receptor agonist—are thus potential treatments for depression, especially anhedonic depression. D3 receptors are found in the mesolimbic system, which in turn has been implicated in the motoric and hedonic deficits in depression ... The first randomized controlled trial in patients with non-treatment-resistant major depressive disorder, by Corrigan et al., evaluated three dosages of pramipexole. The lowest dosage (0.375 mg/day) did not differentiate from placebo. The efficacy of the highest dosage (5.0 mg/day) was not evaluable, because of a 58% attrition rate. The third dosage (1.0 mg/day) was more effective than placebo ... Cusin et al. compared adjunctive adjunctive pramipexole with placebo in an 8-week randomized double-blind trial with 60 outpatients with major depression for whom at least one adequate antidepressant medication trial (mean, two trials) had failed. Although a modest statistically significant benefit of pramipexole over placebo was detected, neither the response rates (40% compared with 33%) nor the remission rates (27% compared with 23%) differed significantly between groups. Dosages were modest (mean=1.35 mg/day; maximum=2.0 mg/day) ... To our knowledge, this is the first case series of adjunctive pramipexole in patients with treatment-resistant depression for whom at least four previous treatments in the current episode had failed. Overall, 76% of the patients showed a meaningful clinical response that persisted, while 24% were intolerant or nonresponsive to pramipexole. Effective pramipexole dosages ranged from 0.75 to 5.0 mg/day. The mean effective dosage of pramipexole in responders and remitters (N=32) was 2.46 mg/day". Side effects Common side effects of pramipexole may include: Headache Peripheral edema Hyperalgesia (body aches and pains) Nausea and vomiting Sedation and somnolence Decreased appetite and subsequent weight loss Orthostatic hypotension (resulting in dizziness, lightheadedness, and possibly fainting, especially when standing up) Insomnia Hallucinations (seeing, hearing, smelling, tasting or feeling things that are not there), amnesia and confusion Twitching, twisting, or other unusual body movements Unusual tiredness or weakness Impulsive-compulsive behaviors: pramipexole (and related D3-preferring dopamine agonist medications such as ropinirole) can induce "impulsive-compulsive spectrum disorders" such as compulsive gambling, punding, hypersexuality, and overeating, even in people without any prior history of these behaviours. Augmentation: Especially when used to treat restless legs syndrome, long-term pramipexole treatment may exhibit drug augmentation, which is "an iatrogenic worsening of RLS symptoms following treatment with dopaminergic agents" and may include an earlier onset of symptoms during the day or a generalized increase in symptoms. Pharmacology The activity profile of pramipexole at various sites has been characterized as follows: While pramipexole is used clinically (see below), its D3-preferring receptor binding profile has made it a popular tool compound for preclinical research. For example, pramipexole has been used (in combination with D2- and or D3-preferring antagonists) to discover the role of D3 receptor function in rodent models and tasks for neuropsychiatric disorders. Of note, it appears that pramipexole, in addition to having effects on dopamine D3 receptors, may also affect mitochondrial function via a mechanism that remains less understood. A pharmacological approach to separate dopaminergic from non-dopaminergic (e.g. mitochondrial) effects of pramipexole has been to study the effects of the R-stereoisomer of pramipexole (which has much lower affinity to the dopamine receptors when compared to the S-isomer) side by side with the effects of the S-isomer.Parkinsons disease is a neurodegenerative disease affecting the substantia nigra, a component of the basal ganglia. The substantia nigra has a high quantity of dopaminergic neurons, which are nerve cells that release the neurotransmitter known as dopamine. When dopamine is released, it may activate dopamine receptors in the striatum, which is another component of the basal ganglia. When neurons of the substantia nigra deteriorate in Parkinsons disease, the striatum no longer properly receives dopamine signals. As a result, the basal ganglia can no longer regulate body movement effectively and motor function becomes impaired. By acting as an agonist for the D2, D3, and D4 dopamine receptors, pramipexole may directly stimulate the underfunctioning dopamine receptors in the striatum, thereby restoring the dopamine signals needed for proper functioning of the basal ganglia. Society and culture Brand names Brand names include Mirapex, Mirapex ER, Mirapexin, Sifrol, Glepark, and Oprymea. Research Pramipexole has been evaluated for the treatment of sexual dysfunction experienced by some users of selective serotonin reuptake inhibitor (SSRI) antidepressants. Pramipexole has shown effects on pilot studies in a placebo-controlled proof of concept study in bipolar disorder. It is also being investigated for the treatment of clinical depression and fibromyalgia. Derivatives Derivatives of pramipexole include CJ-998, CJ-1037, CJ-1638, CJ-1639, D-264, D-440, and D-512. Notes References External links "Pramipexole". Drug Information Portal. U.S. National Library of Medicine. "Pramipexole dihydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Ansuvimab	Ansuvimab, sold under the brand name Ebanga, is a monoclonal antibody medication for the treatment of Zaire ebolavirus (Ebolavirus) infection.The most common symptoms include fever, tachycardia (fast heart rate), diarrhea, vomiting, hypotension (low blood pressure), tachypnea (fast breathing) and chills; however, these are also common symptoms of Ebolavirus infection.Ansuvimab was approved for medical use in the United States in December 2020. Chemistry The drug is composed of a single monoclonal antibody (mAb) and was initially isolated from immortalized B-cells that were obtained from a survivor of the 1995 outbreak of Ebola virus disease in Kikwit, Democratic Republic of Congo. In work supported by the United States National Institutes of Health and the Defense Advanced Projects Agency, the heavy and light chain sequences of ansuvimab mAb was cloned into CHO cell lines and initial production runs were produced by Cook Phamica d.b.a. Catalent under contract of Medimmune. Mechanism of action Neutralization Ansuvimab is a monoclonal antibody therapy that is infused intravenously into patients with Ebola virus disease. Ansuvimab is a neutralizing antibody, meaning it binds to a protein on the surface of Ebola virus that is required to infect cells. Specifically, ansuvimab neutralizes infection by binding to a region of the Ebola virus envelope glycoprotein that, in the absence of ansuvimab, would interact with viruss cell receptor protein, Niemann-Pick C1 (NPC1). This "competition" by ansuvimab prevents Ebola virus from binding to NPC1 and "neutralizes" the viruss ability to infect the targeted cell. Effector function Antibodies have antigen-binding fragment (Fab) regions and constant fragment (Fc) regions. The Neutralization of virus infection occurs when the Fab regions of antibodies binds to virus antigen(s) in a manner that blocks infection. Antibodies are also able to "kill" virus particles directly and/or kill infected cells using antibody-mediated "effector functions" such as opsonization, complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and antibody-dependent phagocytosis. These effector functions are contained in the Fc region of antibodies, but is also dependent on binding of the Fab region to antigen. Effector functions also require the use of complement proteins in serum or Fc-receptor on cell membranes. Ansuvimab has been found to be capable of killing cells by antibody-dependent cell-mediated cytotoxicity. Other functional killing tests have not been performed. History Ansuvimab is a monoclonal antibody that is being evaluated as a treatment for Ebola virus disease. Its discovery was led by the laboratory of Nancy Sullivan at the United States National Institutes of Health Vaccine Research Center and J. J. Muyembe-Tamfum from the Institut National pour la Recherche Biomedicale (INRB) in the Democratic Republic of Congo, working in collaboration with the Institute for Biomedical Research (Bellinzona, Switzerland) and the United States Army Medical Research Institute of Infectious Diseases. Ansuvimab was isolated from the blood of a survivor of the 1995 outbreak of Ebola virus disease in Kikwit, Democratic Republic of Congo roughly ten years later.In 2018, a Phase 1 clinical trial of ansuvimab was conducted by Martin Gaudinski within the Vaccine Research Center Clinical Trials Program that is led by Julie E. Ledgerwood. Ansuvimab is also being evaluated during the 2018 North Kivu Ebola outbreak.Ansuvimab has also shown success with lowering the mortality rate from ~70% to about 34%. In August 2019, Congolese health authorities, the World Health Organization, and the U.S. National Institutes of Health promoted the use of ansuvimab, alongside toltivimab/maftivimab/odesivimab, a similar Regeneron-produced monoclonal antibody treatment, over other treatments yielding higher mortality rates, after ending clinical trials during the outbreak.The U.S. Food and Drug Administration (FDA) approved ansuvimab based primarily on evidence from a clinical trial (Trial 1/ NCT NCT03719586) of 342 participants with Zaire ebolavirus infection. The trial enrolled newborn, pediatric and adult participants (including pregnant women) with Zaire ebolavirus infection. All participants received standard, supportive care for the disease. In addition to the standard care, participants were randomly assigned to receive either a one-time dose of ansuvimab or one of the three other types of experimental treatments (including one as the control group). The participants and the health care providers knew which treatment was being given. The trial was conducted at four sites in the Democratic Republic of Congo during an outbreak that began in August 2018. Discovery A 2016 paper describes the efforts of how ansuvimab was originally developed as part of research efforts led by Dr. Nancy Sullivan at the United States National Institutes of Health Vaccine Research Center and Dr. J. J. Muyembe-Tamfum from the Institut National de Recherche Biomedicale (INRB) in the Democratic Republic of Congo. This collaborative effort also involved researchers from Institute of Biomedical Research and the United States Army Medical Research Institute of Infectious Diseases. A survivor from the 1995 outbreak of Ebola virus disease in Kikwit, Democratic Republic of Congo donated blood to the project that began roughly ten years after they had recovered. Memory B cells isolated from the survivors blood were immortalized, cultured and screened for their ability to produce monoclonal antibodies that reacted with the glycoprotein of Ebola virus. Ansuvimab was identified from one of these cultures and the antibody heavy and light chain gene sequences were sequenced from the cells. These sequences were then cloned into recombinant DNA plasmids and purified antibody protein for initial studies was produced in cells derived from HEK 293 cells. Ansuvimab and mAb100 combination In an experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and treated with a combination of ansuvimab and another antibody isolated from the same subject, mAb100. Three doses of the combination were given once a day starting 1 day after the animals were infected. The control animal died and the treated animals all survived. Ansuvimab monotherapy In a second experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and only treated with ansuvimab. Three doses of ansuvimab were given once a day starting 1 day or 5 days after the animals were infected. The control animals died and the treated animals all survived. Unpublished data referred to in a publication of the 2018 Phase I clinical trial results of ansuvimab, reported that a single infusion of ansuvimab provided full protection of rhesus macaques and was the basis of the dosing used for human studies. Development Ansuvimab was developed by the Vaccine Research Center with support of the United States National Institutes of Health and the Defense Advanced Projects Agency. The heavy and light chain sequences of ansuvimab mAb were cloned into CHO cell lines to enable large-scale production of antibody product for use in humans. Human safety testing In early 2018, a Phase 1 clinical trial of ansuvimabs safety, tolerability and pharmacokinetics was conducted by Dr. Martin Gaudinski within the Vaccine Research Center Clinical Trials Program that is led by Dr. Julie E. Ledgerwood. The study was performed in the United States at the NIH Clinical Center and tested single dose infusions of ansuvimab infused over 30 minutes. The study showed that ansuvimab was safe, had minimal side effects and had a half-life of 24 days. Ridgeback Biotherapeutics A license for ansuvimab was obtained by Ridgeback Biotherapeutics in 2018, from the National Institutes of Health-National Institute of Allergy and Infectious Diseases. Ansuvimab was given orphan drug status in May 2019 and March 2020. Experimental use in the Democratic Republic of Congo During the 2018 Équateur province Ebola outbreak, ansuvimab was requested by the Democratic Republic of Congo (DRC) Ministry of Public Health. Ansuvimab was approved for compassionate use by the World Health Organization MEURI ethical protocol and at DRC ethics board. Ansuvimab was sent along with other therapeutic agents to the outbreak sites. However, the outbreak came to a conclusion before any therapeutic agents were given to patients.Approximately one month following the conclusion of the Équateur province outbreak, a distinct outbreak was noted in Kivu in the DRC (2018–20 Kivu Ebola outbreak). Once again, ansuvimab received approval for compassionate use by WHO MEURI and DRC ethic boards and has been given to many patients under these protocols. In November 2018, the Pamoja Tulinde Maisha (PALM [together save lives]) open-label randomized clinical control trial was begun at multiple treatment units testing ansuvimab, atoltivimab/maftivimab/odesivimab (REGN-EB3) and remdesivir to ZMapp. Despite the difficulty of running a clinical trial in a conflict zone, investigators have enrolled 681 patients towards their goal of 725. An interim analysis by the Data Safety and Monitoring Board (DSMB) of the first 499 patient found that ansuvimab and REGN-EB3 were superior to the comparator ZMapp. Overall mortality of patients in the ZMapp and remdesivir groups were 49% and 53% compared to 34% and 29% for ansuvimab and REGN-EB3. When looking at patients who arrived early after disease symptoms appeared, survival was 89% for ansuvimab and 94% for REGN-EB3. While the study was not powered to determine whether there is any difference between REGN-EB3 and ansuvimab, the survival difference between those two therapies and ZMapp was significant. This led to the DSMB halting the study and PALM investigators dropping the remdesivir and ZMapp arms from the clinical trial. All patients in the outbreak who elect to participate in the trial will now be given either ansuvimab or REGN-EB3.In October 2020, the U.S. Food and Drug Administration (FDA) approved atoltivimab/maftivimab/odesivimab (Inmazeb, formerly REGN-EB3) with an indication for the treatment of infection caused by Zaire ebolavirus. References External links "Ansuvimab". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03719586 for "Investigational Therapeutics for the Treatment of People With Ebola Virus Disease" at ClinicalTrials.gov
Sirolimus	Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, and treat perivascular epithelioid cell tumor (PEComa). It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants. It is a mechanistic target of rapamycin kinase (mTOR) inhibitor that inhibits activation of T cells and B cells by reducing their sensitivity to interleukin-2 (IL-2).It is produced by the bacterium Streptomyces hygroscopicus and was isolated for the first time in 1972, from samples of Streptomyces hygroscopicus found on Easter Island. The compound was originally named rapamycin after the native name of the island, Rapa Nui. Sirolimus was initially developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties due to its ability to inhibit mTOR. It was approved by the U.S. Food and Drug Administration (FDA) in September 1999. Medical uses Sirolimus is indicated for the prevention of organ transplant rejection and for the treatment of lymphangioleiomyomatosis (LAM).Sirolimus (Fyarro), as protein-bound particles, is indicated for the treatment of adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa). Prevention of transplant rejection The chief advantage sirolimus has over calcineurin inhibitors is its low toxicity toward kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even kidney failure; this can be avoided by using sirolimus instead. It is particularly advantageous in patients with kidney transplants for hemolytic-uremic syndrome, as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used. However, on 7 October 2008, the FDA approved safety labeling revisions for sirolimus to warn of the risk for decreased renal function associated with its use. In 2009, the FDA notified healthcare professionals that a clinical trial conducted by Wyeth showed an increased mortality in stable liver transplant patients after switching from a calcineurin inhibitor-based immunosuppressive regimen to sirolimus. A 2019 cohort study of nearly 10,000 lung transplant recipients in the US demonstrated significantly improved long-term survival using sirolimus + tacrolimus instead of mycophenolate mofetil + tacrolimus for immunosuppressive therapy starting at one year after transplant.Sirolimus can also be used alone, or in conjunction with a calcineurin inhibitor (such as tacrolimus), and/or mycophenolate mofetil, to provide steroid-free immunosuppression regimens. Impaired wound healing and thrombocytopenia are possible side effects of sirolimus; therefore, some transplant centers prefer not to use it immediately after the transplant operation, but instead administer it only after a period of weeks or months. Its optimal role in immunosuppression has not yet been determined, and it remains the subject of a number of ongoing clinical trials. Lymphangioleiomyomatosis In May 2015, the FDA approved sirolimus to treat lymphangioleiomyomatosis (LAM), a rare, progressive lung disease that primarily affects women of childbearing age. This made sirolimus the first drug approved to treat this disease. LAM involves lung tissue infiltration with smooth muscle-like cells with mutations of the tuberous sclerosis complex gene (TSC2). Loss of TSC2 gene function activates the mTOR signaling pathway, resulting in the release of lymphangiogenic growth factors. Sirolimus blocks this pathway.The safety and efficacy of sirolimus treatment of LAM were investigated in clinical trials that compared sirolimus treatment with a placebo group in 89 patients for 12 months. The patients were observed for 12 months after the treatment had ended. The most commonly reported side effects of sirolimus treatment of LAM were mouth and lip ulcers, diarrhea, abdominal pain, nausea, sore throat, acne, chest pain, leg swelling, upper respiratory tract infection, headache, dizziness, muscle pain and elevated cholesterol. Serious side effects including hypersensitivity and swelling (edema) have been observed in renal transplant patients.While sirolimus was considered for treatment of LAM, it received orphan drug designation status because LAM is a rare condition.The safety of LAM treatment by sirolimus in people younger than 18 years old has not been tested. Coronary stent coating The antiproliferative effect of sirolimus has also been used in conjunction with coronary stents to prevent restenosis in coronary arteries following balloon angioplasty. The sirolimus is formulated in a polymer coating that affords controlled release through the healing period following coronary intervention. Several large clinical studies have demonstrated lower restenosis rates in patients treated with sirolimus-eluting stents when compared to bare-metal stents, resulting in fewer repeat procedures. A sirolimus-eluting coronary stent was marketed by Cordis, a division of Johnson & Johnson, under the tradename Cypher. However, this kind of stent may also increase the risk of vascular thrombosis. Vascular malformations Sirolimus is used to treat vascular malformations. Treatment with sirolimus can decrease pain and the fullness of vascular malformations, improve coagulation levels, and slow the growth of abnormal lymphatic vessels. Sirolimus is a relatively new medical therapy for the treatment of vascular malformations in recent years, sirolimus has emerged as a new medical treatment option for both vascular tumors and vascular malformations, as a mammalian target of rapamycin (mTOR), capable of integrating signals from the PI3K/AKT pathway to coordinate proper cell growth and proliferation. Hence, sirolimus is ideal for "proliferative" vascular tumors through the control of tissue overgrowth disorders caused by inappropriate activation of the PI3K/AKT/mTOR pathway as an antiproliferative agent. Angiofibromas Sirolimus has been used as a topical treatment of angiofibromas with tuberous sclerosis complex (TSC). Facial angiofibromas occur in 80% of patients with TSC, and the condition is very disfiguring. A retrospective review of English-language medical publications reporting on topical sirolimus treatment of facial angiofibromas found sixteen separate studies with positive patient outcomes after using the drug. The reports involved a total of 84 patients, and improvement was observed in 94% of subjects, especially if treatment began during the early stages of the disease. Sirolimus treatment was applied in several different formulations (ointment, gel, solution, and cream), ranging from 0.003 to 1% concentrations. Reported adverse effects included one case of perioral dermatitis, one case of cephalea, and four cases of irritation.On April 4, 2022, a sirolimus 0.2% was approved by the FDA for treating angiofibromas. Adverse effects The most common adverse reactions (≥30% occurrence, leading to a 5% treatment discontinuation rate) observed with sirolimus in clinical studies of organ rejection prophylaxis in individuals with kidney transplants include: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, pain, constipation, hypertriglyceridemia, hypertension, increased creatinine, fever, urinary tract infection, anemia, arthralgia, and thrombocytopenia.The most common adverse reactions (≥20% occurrence, leading to an 11% treatment discontinuation rate) observed with sirolimus in clinical studies for the treatment of lymphangioleiomyomatosis are: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, chest pain, stomatitis, nasopharyngitis, acne, upper respiratory tract infection, dizziness, and myalgia.The following adverse effects occurred in 3–20% of individuals taking sirolimus for organ rejection prophylaxis following a kidney transplant: Diabetes-like symptoms While sirolimus inhibition of mTORC1 appears to mediate the drugs benefits, it also inhibits mTORC2, which results in diabetes-like symptoms. This includes decreased glucose tolerance and insensitivity to insulin. Sirolimus treatment may additionally increase the risk of type 2 diabetes. In mouse studies, these symptoms can be avoided through the use of alternate dosing regimens or analogs such as everolimus or temsirolimus. Lung toxicity Lung toxicity is a serious complication associated with sirolimus therapy, especially in the case of lung transplants. The mechanism of the interstitial pneumonitis caused by sirolimus and other macrolide MTOR inhibitors is unclear, and may have nothing to do with the mTOR pathway. The interstitial pneumonitis is not dose-dependent, but is more common in patients with underlying lung disease. Lowered effectiveness of immune system There have been warnings about the use of sirolimus in transplants, where it may increase mortality due to an increased risk of infections. Cancer risk Sirolimus may increase an individuals risk for contracting skin cancers from exposure to sunlight or UV radiation, and risk of developing lymphoma. In studies, the skin cancer risk under sirolimus was lower than under other immunosuppressants such as azathioprine and calcineurin inhibitors, and lower than under placebo. Impaired wound healing Individuals taking sirolimus are at increased risk of experiencing impaired or delayed wound healing, particularly if they have a body mass index in excess of 30 kg/m2 (classified as obese). Interactions Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump; hence, inhibitors of either protein may increase sirolimus concentrations in blood plasma, whereas inducers of CYP3A4 and P-gp may decrease sirolimus concentrations in blood plasma. Pharmacology Pharmacodynamics Unlike the similarly named tacrolimus, sirolimus is not a calcineurin inhibitor, but it has a similar suppressive effect on the immune system. Sirolimus inhibits IL-2 and other cytokine receptor-dependent signal transduction mechanisms, via action on mTOR, and thereby blocks activation of T and B cells. Ciclosporin and tacrolimus inhibit the secretion of IL-2, by inhibiting calcineurin.The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mTOR (mammalian Target Of Rapamycin, rapamycin being another name for sirolimus) pathway by directly binding to mTOR Complex 1 (mTORC1).mTOR has also been called FRAP (FKBP-rapamycin-associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect the fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR. However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of sirolimus-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of sirolimus and provided robust support that the FKBP12-sirolimus complex binds to and inhibits Tor1 and Tor2. Pharmacokinetics Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump. It has an elimination half-life of 57–63 hours.The absorption of sirolimus into the blood stream from the intestine varies widely between patients, with some patients having up to eight times more exposure than others for the same dose. Drug levels are, therefore, taken to make sure patients get the right dose for their condition. This is determined by taking a blood sample before the next dose, which gives the trough level. However, good correlation is noted between trough concentration levels and drug exposure, known as area under the concentration-time curve, for both sirolimus (SRL) and tacrolimus (TAC) (SRL: r2 = 0.83; TAC: r2 = 0.82), so only one level need be taken to know its pharmacokinetic (PK) profile. PK profiles of SRL and of TAC are unaltered by simultaneous administration. Dose-corrected drug exposure of TAC correlates with SRL (r2 = 0.8), so patients have similar bioavailability of both. Chemistry Sirolimus is a natural product and macrocyclic lactone. Biosynthesis The biosynthesis of the rapamycin core is accomplished by a type I polyketide synthase (PKS) in conjunction with a nonribosomal peptide synthetase (NRPS). The domains responsible for the biosynthesis of the linear polyketide of rapamycin are organized into three multienzymes, RapA, RapB, and RapC, which contain a total of 14 modules (figure 1). The three multienzymes are organized such that the first four modules of polyketide chain elongation are in RapA, the following six modules for continued elongation are in RapB, and the final four modules to complete the biosynthesis of the linear polyketide are in RapC. Then, the linear polyketide is modified by the NRPS, RapP, which attaches L-pipecolate to the terminal end of the polyketide, and then cyclizes the molecule, yielding the unbound product, prerapamycin. The core macrocycle, prerapamycin (figure 2), is then modified (figure 3) by an additional five enzymes, which lead to the final product, rapamycin. First, the core macrocycle is modified by RapI, SAM-dependent O-methyltransferase (MTase), which O-methylates at C39. Next, a carbonyl is installed at C9 by RapJ, a cytochrome P-450 monooxygenases (P-450). Then, RapM, another MTase, O-methylates at C16. Finally, RapN, another P-450, installs a hydroxyl at C27 immediately followed by O-methylation by Rap Q, a distinct MTase, at C27 to yield rapamycin.The biosynthetic genes responsible for rapamycin synthesis have been identified. As expected, three extremely large open reading frames (ORFs) designated as rapA, rapB, and rapC encode for three extremely large and complex multienzymes, RapA, RapB, and RapC, respectively. The gene rapL has been established to code for a NAD+-dependent lysine cycloamidase, which converts L-lysine to L-pipecolic acid (figure 4) for incorporation at the end of the polyketide. The gene rapP, which is embedded between the PKS genes and translationally coupled to rapC, encodes for an additional enzyme, an NPRS responsible for incorporating L-pipecolic acid, chain termination and cyclization of prerapamycin. In addition, genes rapI, rapJ, rapM, rapN, rapO, and rapQ have been identified as coding for tailoring enzymes that modify the macrocyclic core to give rapamycin (figure 3). Finally, rapG and rapH have been identified to code for enzymes that have a positive regulatory role in the preparation of rapamycin through the control of rapamycin PKS gene expression. Biosynthesis of this 31-membered macrocycle begins as the loading domain is primed with the starter unit, 4,5-dihydroxocyclohex-1-ene-carboxylic acid, which is derived from the shikimate pathway. Note that the cyclohexane ring of the starting unit is reduced during the transfer to module 1. The starting unit is then modified by a series of Claisen condensations with malonyl or methylmalonyl substrates, which are attached to an acyl carrier protein (ACP) and extend the polyketide by two carbons each. After each successive condensation, the growing polyketide is further modified according to enzymatic domains that are present to reduce and dehydrate it, thereby introducing the diversity of functionalities observed in rapamycin (figure 1). Once the linear polyketide is complete, L-pipecolic acid, which is synthesized by a lysine cycloamidase from an L-lysine, is added to the terminal end of the polyketide by an NRPS. Then, the NSPS cyclizes the polyketide, giving prerapamycin, the first enzyme-free product. The macrocyclic core is then customized by a series of post-PKS enzymes through methylations by MTases and oxidations by P-450s to yield rapamycin. Research Cancer The antiproliferative effects of sirolimus may have a role in treating cancer. When dosed appropriately, sirolimus can enhance the immune response to tumor targeting or otherwise promote tumor regression in clinical trials. Sirolimus seems to lower the cancer risk in some transplant patients.Sirolimus was shown to inhibit the progression of dermal Kaposis sarcoma in patients with renal transplants. Other mTOR inhibitors, such as temsirolimus (CCI-779) or everolimus (RAD001), are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma. However, these drugs have a higher rate of fatal adverse events in cancer patients than control drugs.A combination therapy of doxorubicin and sirolimus has been shown to drive Akt-positive lymphomas into remission in mice. Akt signalling promotes cell survival in Akt-positive lymphomas and acts to prevent the cytotoxic effects of chemotherapy drugs, such as doxorubicin or cyclophosphamide. Sirolimus blocks Akt signalling and the cells lose their resistance to the chemotherapy. Bcl-2-positive lymphomas were completely resistant to the therapy; eIF4E-expressing lymphomas are not sensitive to sirolimus. Tuberous sclerosis complex Sirolimus also shows promise in treating tuberous sclerosis complex (TSC), a congenital disorder that leaves them prone to benign tumor growth in the brain, heart, kidneys, skin, and other organs. After several studies conclusively linked mTOR inhibitors to remission in TSC tumors, specifically subependymal giant-cell astrocytomas in children and angiomyolipomas in adults, many US doctors began prescribing sirolimus (Wyeths Rapamune) and everolimus (Novartiss RAD001) to TSC patients off-label. Numerous clinical trials using both rapamycin analogs, involving both children and adults with TSC, are underway in the United States. Effects on longevity mTOR, specifically mTORC1, was first shown to be important in aging in 2003, in a study on worms; sirolimus was shown to inhibit and slow aging in worms, yeast, and flies, and then to improve the condition of mouse models of various diseases of aging. Sirolimus was first shown to extend lifespan in wild-type mice in a study published by NIH investigators in 2009; the studies have been replicated in mice of many different genetic backgrounds. A study published in 2020 found late-life sirolimus dosing schedules enhanced mouse lifespan in a sex-specific manner where limited rapamycin exposure enhanced male lifespan but not female, providing evidence for sex differences in sirolimus response. The results are further supported by the finding that genetically modified mice with impaired mTORC1 signalling live longer. Sirolimus has potential for widespread use as a longevity-promoting drug, with evidence pointing to its ability to prevent age-associated decline of cognitive and physical health. Due to known side effects of sirolimus, as well as inadequate evidence for optimal dosing, more research is required before sirolimus could be widely prescribed for this purpose.Sirolimus has complex effects on the immune system—while IL-12 goes up and IL-10 decreases, which suggests an immunostimulatory response, TNF and IL-6 are decreased, which suggests an immunosuppressive response. The duration of the inhibition and the exact extent to which mTORC1 and mTORC2 are inhibited play a role, but are not yet well understood. SARS-CoV-2 Rapamycin has been proposed as a treatment for severe acute respiratory syndrome coronavirus 2 insofar as its immunosuppressive effects could prevent or reduce the cytokine storm seen in very serious cases of COVID-19. Moreover, inhibition of cell proliferation by rapamycin could reduce viral replication. Atherosclerosis Rapamycin can accelerate degradation of oxidized LDL cholesterol in endothelial cells, thereby lowering the risk of atherosclerosis. Oxidized LDL cholesterol is a major contributor to atherosclerosis. Lupus As of 2016, studies in cells, animals, and humans have suggested that mTOR activation as process underlying systemic lupus erythematosus and that inhibiting mTOR with rapamycin may be a disease-modifying treatment. As of 2016 rapamycin had been tested in small clinical trials in people with lupus. Lymphatic malformation Lymphatic malformation, or cystic hygroma, is an abnormal growth of lymphatic vessels that usually affects children around the head and neck.. Treatment often consists of to removal of the tissue, but the rate of recurrence is high. Sirolimus has shown evidence of being helpful in alleviating symptoms and reducing the size of the malformation. Graft-versus-host disease Due to its immunosuppressant activity, Rapamycin has been assessed as prophylaxis or treatment agent of Graft-versus-host disease (GVHD), a complication of hematopoietic stem cell transplantation. While contrasted results were obtained in clinical trials, pre-clinical studies have shown that Rapamycin can mitigate GVHD by increasing the proliferation of regulatory T cells, inhibiting cytotoxic T cells and lowering the differentiation of effector T cells. Applications in biology research Rapamycin is used in biology research as an agent for chemically induced dimerization. In this application, rapamycin is added to cells expressing two fusion constructs, one of which contains the rapamycin-binding FRB domain from mTOR and the other of which contains an FKBP domain. Each fusion protein also contains additional domains that are brought into proximity when rapamycin induces binding of FRB and FKBP. In this way, rapamycin can be used to control and study protein localization and interactions. References Further reading Benjamin D, Colombi M, Moroni C, Hall MN (October 2011). "Rapamycin passes the torch: a new generation of mTOR inhibitors". Nature Reviews. Drug Discovery. 10 (11): 868–80. doi:10.1038/nrd3531. PMID 22037041. S2CID 1227277. Freixo C, Ferreira V, Martins J, Almeida R, Caldeira D, Rosa M, et al. (January 2020). "Efficacy and safety of sirolimus in the treatment of vascular anomalies: A systematic review". Journal of Vascular Surgery. 71 (1): 318–327. doi:10.1016/j.jvs.2019.06.217. PMID 31676179. S2CID 207831199. Geeurickx M, Labarque V (September 2021). "A narrative review of the role of sirolimus in the treatment of congenital vascular malformations". Journal of Vascular Surgery. Venous and Lymphatic Disorders. 9 (5): 1321–1333. doi:10.1016/j.jvsv.2021.03.001. PMID 33737259. External links "Sirolimus". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT02494570 for "A Phase 2 Study of ABI-009 in Patients With Advanced Malignant PEComa (AMPECT)" at ClinicalTrials.gov
Polymyxin B	Polymyxin B, sold under the brand name Poly-Rx among others, is an antibiotic used to treat meningitis, pneumonia, sepsis, and urinary tract infections. While it is useful for many Gram negative infections, it is not useful for Gram positive infections. It can be given by injection into a vein, muscle, or cerebrospinal fluid or inhaled. The injectable form is generally only used if other options are not available. It is also available as the combinations bacitracin/polymyxin B and neomycin/polymyxin B/bacitracin for use on the skin.Common side effects when given by injection include kidney problems, neurological problems, fever, itchiness, and rash. Injections into muscle may result in significant pain. Other serious side effects may include fungal infections, anaphylaxis, and muscle weakness. It is unclear if use during pregnancy is safe for the baby. Polymyxin B works by breaking down the cytoplasmic membrane which generally results in bacterial cell death.Polymyxin B was approved for medical use in the United States in 1964. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In Europe it is only approved to be applied to the skin as of 2015. It is derived from the bacterium Paenibacillus polymyxa (formerly known as Bacillus polymyxa). Medical uses Spectrum of susceptibility Polymyxin B has been used to treat urinary tract infections and meningitis caused by Pseudomonas aeruginosa and Haemophilus influenzae, respectively. The following represents MIC susceptibility data for a few medically significant microorganisms. Haemophilus influenzae: ≥0.8 μg/ml Pseudomonas aeruginosa: 0.25 μg/ml – 1 μg/ml Endotoxin adsorption An effective use of polymyxin B is found in patients with refractory septic shock, that is, without positive outcome to the administration of standard treatments (increase in volemia and other antibiotics). The obstacle of the toxicity of polymyxin B is bypassed by extracorporeal circulation with perfusion of venous blood through a cartridge on whose fibers polymyxin B is covalently fixed; in this way the antibiotic exerts its bactericidal function but is not released into the blood since it remains fully attached to the fiber. Through this perfusion the cartridge retains the endotoxin, recognized as the trigger of septic shock. The treatment of the cartridge to polymyxin B (Toraymyxin, medical device designed and produced by the Japanese Toray), takes place in two sessions of two hours each, carried out at a distance of 24 hours. Mechanism of action Alters bacterial outer membrane permeability by binding to a negatively charged site in the lipopolysaccharide layer, which has an electrostatic attraction for the positively charged amino groups in the cyclic peptide portion (this site normally is a binding site for calcium and magnesium counter ions); the result is a destabilized outer membrane Fatty acid portion dissolves in hydrophobic region of cytoplasmic membrane and disrupts membrane integrity Leakage of cellular molecules, inhibition of cellular respiration Binds and inactivates endotoxin Relative absence of selective toxicity: nonspecific for cell membranes of any type, highly toxic.Removal of the hydrophobic tail of polymyxin B yields polymyxin nonapeptide (PMBN), which still binds to LPS, but no longer kills the bacterial cell. However, it still detectably increases the permeability of the bacterial cell wall to other antibiotics, indicating that it still causes some degree of membrane disorganization. Mixture composition Polymyxin B is composed of polymyxins B1, B1-I, B2, B3, and B6. Polymyxins B1 and B2 are considered major components. These related components are structurally identical with the exception of a variable fatty acid group on each fraction. Results from in vitro studies have shown marginal differences in MIC data when comparing the fractions. Research application Polymyxin B is also used to induce envelope stress in order to study the organisms response to such stress. Polymyxin envelope stress assays such as this have been used for the study of small RNA (sRNA) responses in Salmonella enterica. See also Polymyxin References External links "Polymyxin B". Drug Information Portal. U.S. National Library of Medicine.
Odevixibat	Odevixibat, sold under the trade name Bylvay, is a medication for the treatment of progressive familial intrahepatic cholestasis (PFIC). It is taken by mouth.The most common side effects include diarrhea, abdominal pain, hemorrhagic diarrhea, soft feces, and hepatomegaly (enlarged liver).Odevixibat is a reversible, potent, selective inhibitor of the ileal bile acid transporter (IBAT).Odevixibat was approved for medical use in the United States and in the European Union in July 2021. Medical uses In the United States, odevixibat is indicated for the treatment of pruritus in people three months of age and older with progressive familial intrahepatic cholestasis (PFIC). In the European Union it is indicated in people six months of age and older. Mechanism of action Odevixibat is a reversible inhibitor of the ileal sodium/bile acid transporter which is the transporter responsible for reabsorption of the majority of bile acids in the distal ileum. The reduced absorption of the bile acids in the distal ileum compounds and leads to a decrease in stimulation of FXR, decreasing the inhibition of bile acid synthesis. Pharmacokinetics Odevixibat is majorly protein-bound in-vitro. A dose of Odevixibat that is 7.2 mg reaches a Cmax concentration of 0.47 ng/mL with an AUC (0-24h) of 2.19 h*ng/mL. Adult and pediatric patients given the therapeautic dose of Odevixibat did not display plasma concentrations of the drug. Odevixibat is eliminated majorly unchanged. Odevixibat has an average half-life of 2.36 hours. Adverse effects Common side effects of Odevixibat include diarrhea, stomach pain, vomiting, abnormal liquid function tests, and a deficiency in vitamins A,D, E and K. Contraindications Odevixibat cannot be given to a child on a liquid diet. Society and culture Legal status In May 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended granting a marketing authorization in the European Union for odevixibat for the treatment of PFIC in people aged six months or older. It was approved for medical use in the European Union in July 2021. References External links "Odevixibat". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03566238 for "This Study Will Investigate the Efficacy and Safety of A4250 in Children With PFIC 1 or 2 (PEDFIC 1)" at ClinicalTrials.gov
Yaz	Yaz may refer to: People Yazmith Bataz (born 1972), Mexican sprinter Yaz Mubarakai (born 1975), Australian politician Carl Yastrzemski (born 1939), American Hall-of-Fame baseball player Mike Yastrzemski (born 1990), American professional baseball player, grandson of Carl Other uses Yaz culture, an early Iron Age culture of Bactria and Margiana, c. 1500-1100 BC Yaz-class river patrol craft, Russian Coast Guard vessels YAZ, IATA code for Tofino Airport in Tofino, British Columbia, Canada yaz, ISO 639-3 code for the Yakö language, spoken by the Yakö people of Nigeria Yaz (band) or Yazoo, an English synth-pop band Yaz Pistachio, a female character from the comic strip Bloom County Yaz (drug), a brand name for a birth control pill containing drospirenone that may also be used for other indications YAZ, a programmer toolkit for development of Z39.50 clients and servers See also Yazz (born 1960), pseudonym used by English singer Yasmin Evans Yazz The Greatest, a stage name of American actor and rapper Bryshere Y. Gray
Evolocumab	Evolocumab (trade name Repatha) is a monoclonal antibody medication designed for the treatment of hyperlipidemia. Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is a protein that targets LDL receptors for degradation and its inhibition thereby enhances the livers ability to remove LDL-C, or "bad" cholesterol, from the blood. Mechanism Evolocumab is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface. In the absence of PCSK9, there are more LDL receptors on the surface of liver cells to remove LDL-C from the blood. History Amgen submitted a biologics license application (BLA) for evolocumab to the FDA in August 2014. The FDA approved evolocumab injection on 27 August 2015, for some patients who are unable to get their LDL cholesterol under control with current treatment options. The European Commission approved it in July 2015. Evolocumab received approval from Health Canada on September 10, 2015. Amgen reported approval by Health Canada in a press release on September 15, 2015.Regeneron Pharmaceuticals and Amgen had each filed for patent protection on their monoclonal antibodies against PCSK9 and the companies ended up in patent litigation in the U.S. In March 2016 a district court found that Regenerons drug alirocumab infringed Amgens patents; Amgen then requested an injunction barring Regeneron and Sanofi from marketing alirocumab, which was granted in January 2017. The judge gave Regeneron and Sanofi 30 days to appeal before the injunction went into effect.Results of the FOURIER trial were published in March 2017. Society and culture Economics In 2015 it cost about US$14,100 per year. One article calculated this to be about $400,000 to $500,000 per quality-adjusted life year (QALY), which did not meet "generally accepted" cost-benefit thresholds. The authors calculated that an annual cost of $4,500 would meet an acceptable $100,000 per QALY standard. On October 26, 2018 the maker of the drug, Amgen, announced a 60% cut in price and the drug now costs $5,850 per year. References External links "Evolocumab". Drug Information Portal. U.S. National Library of Medicine.
Latanoprostene bunod	Latanoprostene bunod (trade name Vyzulta) is an ophthalmic drug approved in the United States in 2017 for the reduction of intraocular pressure in patients with open-angle glaucoma or ocular hypertension. It targets the trabecular meshwork directly. == References ==
Acetylsalicylic acid/dipyridamole	The combination drug acetylsalicylic acid/dipyridamole (trade names Aggrenox, Asasantin) is a drug combination of: Acetylsalicylic acid (Aspirin) - An extremely common NSAID that has anticoagulant effects Dipyridamole, a drug that inhibits platelet activation when given chronically and causes vasodilation when given at high doses over short time.The combination acts as an extended release formulation and is primarily used for platelet inhibition in patients suffering, or at risk from, acute coronary events and stroke. Its use has been shown to be better than the use of either dipyridamole or aspirin alone. == References ==
Porfimer sodium	Porfimer sodium, sold as Photofrin, is a photosensitizer used in photodynamic therapy and radiation therapy and for palliative treatment of obstructing endobronchial non-small cell lung carcinoma and obstructing esophageal cancer. Porfimer is a mixture of oligomers formed by ether and ester linkages of up to eight porphyrin units. In practice, a red light source emitting at 630 nm is used to excite the Porfimer oligomers.Porfimer is Haematoporphyrin Derivative (HpD) (See PDT). Approvals and indications It was approved in Canada in 1993 for the treatment of bladder cancer. It was approved in Japan in 1994 (for early stage lung cancer?). It was approved by the U.S. FDA in December 1995 for esophageal cancer, and in 1998, it was approved for the treatment of early non-small cell lung cancer.In August 2003 the FDA approved its use for Barretts esophagus. References External links Photofrin Photofrin marketing info Side effects of PDT with Photofrin History of Photofrin
Memantine	Memantine is a medication used to slow the progression of moderate-to-severe Alzheimers disease. It is taken by mouth.Common side effects include headache, constipation, sleepiness, and dizziness. Severe side effects may include blood clots, psychosis, and heart failure. It is believed to work by blocking NMDA receptors.Memantine was approved for medical use in the United States in 2003. It is available as a generic medication. In 2019, it was the 169th most commonly prescribed medication in the United States, with more than 3 million prescriptions. Medical use Alzheimers disease and dementia Memantine is used to treat moderate-to-severe Alzheimers disease, especially for people who are intolerant of or have a contraindication to AChE (acetylcholinesterase) inhibitors. One guideline recommends memantine or an AChE inhibitor be considered in people in the early-to-mid stage of dementia.Memantine has been associated with a modest improvement; with small positive effects on cognition, mood, behavior, and the ability to perform daily activities in moderate-to-severe Alzheimers disease. There does not appear to be any benefit in mild disease.Memantine when added to donepezil in those with moderate-to-severe dementia resulted in "limited improvements" in a 2017 review. The UK National Institute of Clinical Excellence (NICE) issued guidance in 2018 recommending consideration of the combination of memantine with donepezil in those with moderate-to-severe dementia. Psychiatry Bipolar disorder Memantine has been investigated as a possible augmentation strategy for depression in bipolar disorder but meta-analytic evidence does not support its clinical utility. Autism Effects in autism are unclear. Adverse effects Memantine is, in general, well tolerated. Common adverse drug reactions (≥1% of people) include confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common adverse effects include vomiting, anxiety, hypertonia, cystitis, and increased libido.Like many other NMDA antagonists, memantine behaves as a dissociative anesthetic at supratherapeutic doses. Despite isolated reports, recreational use of memantine is rare due to the drugs long duration and limited availability. Also memantine seems to lack effects such as euphoria or hallucinations.Memantine appears to be generally well tolerated by children with autism spectrum disorder. Pharmacology Glutamate A dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is hypothesized to be involved in the etiology of Alzheimers disease. Targeting the glutamatergic system, specifically NMDA receptors, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic system.Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. The low affinity, uncompetitive nature, and rapid off-rate kinetics of memantine at the level of the NMDA receptor-channel, however, preserves the function of the receptor at synapses, as it can still be activated by physiological release of glutamate following depolarization of the postsynaptic neuron. The interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement that the drug produces in Alzheimers disease. However, there is no evidence as yet that the ability of memantine to protect against extrasynaptic NMDA receptor-mediated excitotoxicity has a disease-modifying effect in Alzheimers, although this has been suggested in animal models.Memantines antagonism on NMDA receptors has aroused interest in repurposing it for mental illnesses such as bipolar disorder, considering the involvement of the glutamatergic system in the pathophysiology of mood disorders. Serotonin Memantine acts as a non-competitive antagonist at the 5-HT3 receptor, with a potency similar to that for the NMDA receptor. Many 5-HT3 antagonists function as antiemetics, however the clinical significance of this serotonergic activity in the treatment of Alzheimers disease is unknown. Cholinergic Memantine acts as a non-competitive antagonist at different neuronal nicotinic acetylcholine receptors (nAChRs) at potencies possibly similar to the NMDA and 5-HT3 receptors, but this is difficult to ascertain with accuracy because of the rapid desensitization of nAChR responses in these experiments. It can be noted that memantine is an antagonist at Alpha-7 nAChR, which may contribute to initial worsening of cognitive function during early memantine treatment. Alpha-7 nAChR upregulates quickly in response to antagonism, which could explain the cognitive-enhancing effects of chronic memantine treatment. It has been shown that the number of nicotinic receptors in the brain are reduced in Alzheimers disease, even in the absence of a general decrease in the number of neurons, and nicotinic receptor agonists are viewed as interesting targets for anti-Alzheimer drugs. Dopamine Memantine was shown in a study to act as an agonist at the dopamine D2HIGH receptor with equal or slightly higher affinity than to the NMDA receptors; however, the relevance of this may be negligible, as studies have shown very low affinity for binding to D2 receptors in general. Sigmaergic Memantine acts as an agonist at the σ1 receptor with a low affinity (Ki 2.6 μM). The consequences of this activity are unclear (as the role of sigma receptors in general is not yet that well understood). Due to this low affinity, therapeutic concentrations of memantine are most likely too low to have any sigmaergic effect as a typical therapeutic dose is 20 mg, however excessive doses of memantine taken for recreational purposes many times greater than prescribed doses may indeed activate this receptor. History Memantine was first synthesized and patented by Eli Lilly and Company in 1968 as an anti-diabetic agent, but it was ineffective at lowering blood sugar. Later it was discovered to have CNS activity, and was developed by Merz for dementia in Germany; the NMDA activity was discovered after trials had already begun. Memantine was first marketed for dementia in Germany in 1989 under the name Axura.In the US, some CNS activities were discovered at Childrens Hospital of Boston in 1990, and Childrens licensed patents covering uses of memantine outside the field of ophthalmology to Neurobiological Technologies (NTI) in 1995. In 1998 NTI amended its agreement with Childrens to allow Merz to take over development.In 2000, Merz partnered with Forest to develop the drug for Alzheimers disease in the U.S. under the name Namenda.In 2000, Merz partnered with Suntory for the Japanese market and with Lundbeck for other markets including Europe; the drug was originally marketed by Lundbeck under the name Ebixa.Sales of the drug reached $1.8 billion for 2014. The cost of Namenda was $269 to $489 a month in 2012.In February 2014, as the July 2015 patent expiration for memantine neared, Actavis, which had acquired Forest, announced that it was launching an extended release (XR) form of memantine that could be taken once a day instead of twice a day as needed with the then-current "immediate release" (IR) version, and that it intended to stop selling the IR version in August 2014 and withdraw the marketing authorization. This is a tactic to thwart generic competition called "product hopping". However the supply of the XR version ran short, so Actavis extended the deadline until the fall. In September 2014 the attorney general of New York, Eric Schneiderman, filed a lawsuit to compel Actavis to keep selling the IR version on the basis of antitrust law.In December 2014, a judge granted New York State its request and issued an injunction, preventing Actavis from withdrawing the IR version until generic versions could launch. Actavis appealed and in May a panel of the Second Circuit Court of Appeals upheld the injunction, and in June Actavis asked that its case be heard by the full Second Circuit panel. In August 2015, Actavis request was denied. Society and culture Recreational use One preclinical study on monkeys showed that memantine was capable of inducing a PCP-like intoxication. Because of its very long biological half-life, memantine was previously thought not to be recreational, although a few cases of sporadic recreational use have been described.A study examining self-reported use of memantine on the social network Reddit showed that the drug was used recreationally and as a nootropic, but also that it was misused in various illnesses as self-medication without strong scientific basis. Brand names As of August 2017, memantine was marketed under many brand names worldwide including Abixa, Adaxor, Admed, Akatinol, Alceba, Alios, Almenta, Alois, Alzant, Alzer, Alzia, Alzinex, Alzixa, Alzmenda, Alzmex, Axura, Biomentin, Carrier, Cogito, Cognomem, Conexine, Cordure, Dantex, Demantin, Demax, Dementa, Dementexa, Ebitex, Ebixa, Emantin, Emaxin, Esmirtal, Eutebrol, Evy, Ezemantis, Fentina, Korint, Lemix, Lindex, Lindex, Lucidex, Manotin, Mantine, Mantomed, Marbodin, Mardewel, Marixino, Maruxa, Maxiram, Melanda, Memabix, Memamed, Memando, Memantin, Memantina, Memantine, Mémantine, Memantinol, Memantyn, Memanvitae, Memanxa, Memanzaks, Memary, Memax, Memexa, Memigmin, Memikare, Memogen, Memolan, Memorel, Memorix, Memotec, Memox, Memxa, Mentikline, Mentium, Mentixa, Merandex, Merital, Mexia, Mimetix, Mirvedol, Modualz, Morysa, Namenda, Nemdatine, Nemdatine, Nemedan, Neumantine, Neuro-K, Neuroplus, Noojerone, Polmatine, Prilben, Pronervon, Ravemantine, Talentum, Timantila, Tingreks, Tonibral, Tormoro, Valcoxia, Vilimen, Vivimex, Witgen, Xapimant, Ymana, Zalatine, Zemertinex, Zenmem, Zenmen, and Zimerz.It was also marketed in some countries as a combination drug with donepezil under the brands Namzaric, Neuroplus Dual, and Tonibral MD. Research Psychiatry Memantine, in light of its NMDA receptor antagonism, has been repurposed as a possible adjunctive treatment for depressive episodes in subjects with bipolar disorder, considering the involvement of the glutamatergic system in the pathophysiology of bipolar illness. However, evidence from meta-analyses showed that memantine was not significantly superior to placebo for bipolar depression. Parkinsons A phase III clinical trial is studying the potential of memantine as disease modifying treatment for Parkinsons disease, to slow progression of the disease. References Further reading External links "Memantine". Drug Information Portal. U.S. National Library of Medicine.
Interferon gamma	Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed IFN-γ release assay used to test for tuberculosis. In humans, the IFN-γ protein is encoded by the IFNG gene. Function IFN-γ, or type II interferon, is a cytokine that is critical for innate and adaptive immunity against viral, some bacterial and protozoan infections. IFN-γ is an important activator of macrophages and inducer of major histocompatibility complex class II molecule expression. Aberrant IFN-γ expression is associated with a number of autoinflammatory and autoimmune diseases. The importance of IFN-γ in the immune system stems in part from its ability to inhibit viral replication directly, and most importantly from its immunostimulatory and immunomodulatory effects. IFN-γ is produced predominantly by natural killer cells (NK) and natural killer T cells (NKT) as part of the innate immune response, and by CD4 Th1 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops as part of the adaptive immune response. IFN-γ is also produced by non-cytotoxic innate lymphoid cells (ILC), a family of immune cells first discovered in the early 2010s. Structure The IFN-γ monomer consists of a core of six α-helices and an extended unfolded sequence in the C-terminal region. This is shown in the structural models below. The α-helices in the core of the structure are numbered 1 to 6. The biologically active dimer is formed by anti-parallel inter-locking of the two monomers as shown below. In the cartoon model, one monomer is shown in red, the other in blue. Receptor binding Cellular responses to IFN-γ are activated through its interaction with a heterodimeric receptor consisting of Interferon gamma receptor 1 (IFNGR1) and Interferon gamma receptor 2 (IFNGR2). IFN-γ binding to the receptor activates the JAK-STAT pathway. Activation of the JAK-STAT pathway induces upregulation of interferon-stimulated genes (ISGs), including MHC II. IFN-γ also binds to the glycosaminoglycan heparan sulfate (HS) at the cell surface. However, in contrast to many other heparan sulfate binding proteins, where binding promotes biological activity, the binding of IFN-γ to HS inhibits its biological activity.The structural models shown in figures 1-3 for IFN-γ are all shortened at their C-termini by 17 amino acids. Full length IFN-γ is 143 amino acids long, the models are 126 amino acids long. Affinity for heparan sulfate resides solely within the deleted sequence of 17 amino acids. Within this sequence of 17 amino acids lie two clusters of basic amino acids termed D1 and D2, respectively. Heparan sulfate interacts with both of these clusters. In the absence of heparan sulfate the presence of the D1 sequence increases the rate at which IFN-γ-receptor complexes form. Interactions between the D1 cluster of amino acids and the receptor may be the first step in complex formation. By binding to D1 HS may compete with the receptor and prevent active receptor complexes from forming. The biological significance of heparan sulfates interaction with IFN-γ is unclear; however, binding of the D1 cluster to HS may protect it from proteolytic cleavage. Biological activity IFN-γ is secreted by T helper cells (specifically, Th1 cells), cytotoxic T cells (TC cells), macrophages, mucosal epithelial cells and NK cells. IFN-γ is both an important autocrine signal for professional APCs in early innate immune response, and an important paracrine signal in adaptive immune response. The expression of IFN-γ is induced by the cytokines IL-12, IL-15, IL-18, and type I IFN. IFN-γ is the only Type II interferon and it is serologically distinct from Type I interferons; it is acid-labile, while the type I variants are acid-stable. IFN-γ has antiviral, immunoregulatory, and anti-tumor properties. It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Among the effects are: Promotes NK cell activity Increases antigen presentation and lysosome activity of macrophages. Activates inducible nitric oxide synthase (iNOS) Induces the production of IgG2a and IgG3 from activated plasma B cells Causes normal cells to increase expression of class I MHC molecules as well as class II MHC on antigen-presenting cells—to be specific, through induction of antigen processing genes, including subunits of the immunoproteasome (MECL1, LMP2, LMP7), as well as TAP and ERAAP in addition possibly to the direct upregulation of MHC heavy chains and B2-microglobulin itself Promotes adhesion and binding required for leukocyte migration Induces the expression of intrinsic defense factors—for example, with respect to retroviruses, relevant genes include TRIM5alpha, APOBEC, and Tetherin, representing directly antiviral effects Primes alveolar macrophages against secondary bacterial infections.IFN-γ is the primary cytokine that defines Th1 cells: Th1 cells secrete IFN-γ, which in turn causes more undifferentiated CD4+ cells (Th0 cells) to differentiate into Th1 cells , representing a positive feedback loop—while suppressing Th2 cell differentiation. (Equivalent defining cytokines for other cells include IL-4 for Th2 cells and IL-17 for Th17 cells.) NK cells and CD8+ cytotoxic T cells also produce IFN-γ. IFN-γ suppresses osteoclast formation by rapidly degrading the RANK adaptor protein TRAF6 in the RANK-RANKL signaling pathway, which otherwise stimulates the production of NF-κB. Activity in granuloma formation A granuloma is the bodys way of dealing with a substance it cannot remove or sterilize. Infectious causes of granulomas (infections are typically the most common cause of granulomas) include tuberculosis, leprosy, histoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis, and toxoplasmosis. Examples of non-infectious granulomatous diseases are sarcoidosis, Crohns disease, berylliosis, giant-cell arteritis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, pulmonary rheumatoid nodules, and aspiration of food and other particulate material into the lung. The infectious pathophysiology of granulomas is discussed primarily here. The key association between IFN-γ and granulomas is that IFN-γ activates macrophages so that they become more powerful in killing intracellular organisms. Activation of macrophages by IFN-γ from Th1 helper cells in mycobacterial infections allows the macrophages to overcome the inhibition of phagolysosome maturation caused by mycobacteria (to stay alive inside macrophages). The first steps in IFN-γ-induced granuloma formation are activation of Th1 helper cells by macrophages releasing IL-1 and IL-12 in the presence of intracellular pathogens, and presentation of antigens from those pathogens. Next the Th1 helper cells aggregate around the macrophages and release IFN-γ, which activates the macrophages. Further activation of macrophages causes a cycle of further killing of intracellular bacteria, and further presentation of antigens to Th1 helper cells with further release of IFN-γ. Finally, macrophages surround the Th1 helper cells and become fibroblast-like cells walling off the infection. Activity during pregnancy Uterine Natural Killer cells (NK) secrete high levels of chemoattractants, such as IFN-γ in mice. IFN-γ dilates and thins the walls of maternal spiral arteries to enhance blood flow to the implantation site. This remodeling aids in the development of the placenta as it invades the uterus in its quest for nutrients. IFN-γ knockout mice fail to initiate normal pregnancy-induced modification of decidual arteries. These models display abnormally low amounts of cells or necrosis of decidua.In humans, elevated levels of IFN-γ have been associated with increased risk of miscarriage. Correlation studies have observed high IFN-γ levels in women with a history of spontaneous miscarriage, when compared to women with no history of spontaneous miscarriage. Additionally, low-IFN-γ levels are associated with women who successfully carry to term. It is possible that IFN-γ is cytotoxic to trophoblasts, which leads to miscarriage. However, causal research on the relationship between IFN-γ and miscarriage has not been performed due to ethical constraints. Production Recombinant human IFN-γ, as an expensive biopharmaceutical, has been expressed in different expression systems including prokaryotic, protozoan, fungal (yeasts), plant, insect and mammalian cells. Human IFN-γ is commonly expressed in Escherichia coli, marketed as ACTIMMUNE®, however, the resulting product of the prokaryotic expression system is not glycosylated with a short half-life in the bloodstream after injection; the purification process from bacterial expression system is also very costly. Other expression systems like Pichia pastoris did not show satisfactory results in terms of yields. Therapeutic use Interferon-γ 1b is approved by the U.S. Food and Drug Administration to treat chronic granulomatous disease (CGD) and osteopetrosis. The mechanism by which IFN-γ benefits CGD is via enhancing the efficacy of neutrophils against catalase-positive bacteria by correcting patients oxidative metabolism.It was not approved to treat idiopathic pulmonary fibrosis (IPF). In 2002, the manufacturer InterMune issued a press release saying that phase III data demonstrated survival benefit in IPF and reduced mortality by 70% in patients with mild to moderate disease. The U.S. Department of Justice charged that the release contained false and misleading statements. InterMunes chief executive, Scott Harkonen, was accused of manipulating the trial data, was convicted in 2009 of wire fraud, and was sentenced to fines and community service. Harkonen appealed his conviction to the U.S. Court of Appeals for the Ninth Circuit, and lost. Harkonen was granted a full pardon on January 20, 2021.Preliminary research on the role of IFN-γ in treating Friedreichs ataxia (FA) conducted by Children’s Hospital of Philadelphia has found no beneficial effects in short-term (< 6-months) treatment. However, researchers in Turkey have discovered significant improvements in patients gait and stance after 6 months of treatment.Although not officially approved, Interferon-γ has also been shown to be effective in treating patients with moderate to severe atopic dermatitis. Specifically, recombinant IFN-γ therapy has shown promise in patients with lowered IFN-γ expression, such as those with predisposition to herpes simplex virus, and pediatric patients. Potential use in immunotherapy IFN-γ increases an anti-proliferative state in cancer cells, while upregulating MHC I and MHC II expression, which increases immunorecognition and removal of pathogenic cells. IFN-γ also reduces metastasis in tumors by upregulating fibronectin, which negatively impacts tumor architecture.IFN-γ is not approved yet for the treatment in any cancer immunotherapy. However, improved survival was observed when IFN-γ was administrated to patients with bladder carcinoma and melanoma cancers. The most promising result was achieved in patients with stage 2 and 3 of ovarian carcinoma. On the contrary, it was stressed: "Interferon-γ secreted by CD8-positive lymphocytes upregulates PD-L1 on ovarian cancer cells and promotes tumour growth." The in vitro study of IFN-γ in cancer cells is more extensive and results indicate anti-proliferative activity of IFN-γ leading to the growth inhibition or cell death, generally induced by apoptosis but sometimes by autophagy. In addition, it has been reported that mammalian glycosylation of recombinant human IFN-γ, expressed in HEK293, improves its therapeutic efficacy compared to the unglycosylated form that is expressed in E. coli. Interactions Interferon-γ has been shown to interact with Interferon gamma receptor 1 and Interferon gamma receptor 2. Diseases Interferon-γ has been shown to be a crucial player in the immune response against some intracellular pathogens, including that of Chagas disease. It has also been identified as having a role in seborrheic dermatitis.IFN-γ has a significant anti-viral effect in herpes simplex virus I (HSV) infection. IFN-γ compromises the microtubules that HSV relies upon for transport into an infected cells nucleus, inhibiting the ability of HSV to replicate. Studies in mice on acyclovir resistant herpes have shown that IFN-γ treatment can significantly reduce herpes viral load. The mechanism by which IFN-γ inhibits herpes reproduction is independent of T-cells, which means that IFN-γ may be an effective treatment in individuals with low T-cells.Chlamydia infection is impacted by IFN-γ in host cells. In human epithelial cells, IFN-γ upregulates expression of indoleamine 2,3-dioxygenase, which in turn depletes tryptophan in hosts and impedes chlamydias reproduction. Additionally, in rodent epithelial cells, IFN-γ upregulates a GTPase that inhibits chlamydial proliferation. In both the human and rodent systems, chlamydia has evolved mechanisms to circumvent the negative effects of host cell behavior. Regulation There is evidence that interferon-gamma expression is regulated by a pseudoknotted element in its 5 UTR. There is also evidence that interferon-gamma is regulated either directly or indirectly by the microRNAs: miR-29. Furthermore, there is evidence that interferon-gamma expression is regulated via GAPDH in T-cells. This interaction takes place in the 3UTR, where binding of GAPDH prevents the translation of the mRNA sequence. References Further reading External links Overview of all the structural information available in the PDB for UniProt: P01579 (Interferon gamma) at the PDBe-KB. This article incorporates text from the United States National Library of Medicine, which is in the public domain.
Trastuzumab/hyaluronidase	Trastuzumab/hyaluronidase, sold under the brand name Herceptin SC among others, is a fixed-dose combination medication for the treatment of HER2-overexpressing breast cancer in adults. It is a combination of trastuzumab and hyaluronidase.The most common adverse reactions include fatigue, arthralgia, diarrhea, injection site reaction, upper respiratory tract infection, rash, myalgia, nausea, headache, edema, flushing, pyrexia, cough, and pain in extremity.Trastuzumab/hyaluronidase was approved for medical use in the European Union in August 2013. Trastuzumab/hyaluronidase was approved for medical use in the United States in February 2019. Medical uses Trastuzumab/hyaluronidase is indicated for adjuvant treatment of adults with HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature; and it is indicated in combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer. History Trastuzumab/hyaluronidase (Herceptin SC) was approved for medical use in the European Union in August 2013.Trastuzumab/hyaluronidase (Herceptin Hylecta) was approved for medical use in the United States in February 2019.Approval of trastuzumab/hyaluronidase was based on two randomized trials, HannaH (NCT00950300) and SafeHER (NCT01566721). In HannaH, 596 participants with HER2-positive operable or locally advanced breast cancer, including inflammatory breast cancer, were randomized to receive 8 cycles of either trastuzumab/hyaluronidase or intravenous trastuzumab concurrently with chemotherapy, followed by surgery and continued therapy with either trastuzumab/hyaluronidase or intravenous trastuzumab, for an additional 10 cycles. HannaH demonstrated comparability between trastuzumab/hyaluronidase and intravenous trastuzumab based on co-primary endpoints of pathologic complete response and pharmacokinetics. Pathological complete response (pCR) was observed in 118 participants (45.4%) on the trastuzumab/hyaluronidase arm and in 107 participants (40.7%) receiving intravenous trastuzumab (95% CI for difference in pCR: -4.0; 13.4).SafeHER was a prospective, two-cohort, non-randomized, multinational, open-label trial assessing the overall safety and tolerability of trastuzumab/hyaluronidase with chemotherapy in 1,864 participants with HER2-positive breast cancer. Participants received a fixed dose of 600 mg trastuzumab/hyaluronidase every 3 weeks for 18 cycles. trastuzumab/hyaluronidase was initiated either sequentially with chemotherapy, concurrently with chemotherapy, or without adjuvant chemotherapy, or in combination with neoadjuvant chemotherapy followed by trastuzumab. References Further reading "Application for the addition of Herceptin (trastuzmab) on the WHO Model List of Essential Medicines" (PDF). F. Hoffmann-La Roche Ltd. 7 December 2018. External links "Trastuzumab". Drug Information Portal. U.S. National Library of Medicine. "Hyaluronidase". Drug Information Portal. U.S. National Library of Medicine. "Trastuzumab and Hyaluronidase-oysk". National Cancer Institute. 14 March 2019. "Trastuzumab and Hyaluronidase-oysk". NCI Drug Dictionary. National Cancer Institute. Clinical trial number NCT00950300 for "A Study to Compare Subcutaneous (SC) Versus Intravenous (IV) Administration of Herceptin (Trastuzumab) in Women With Human Epidermal Growth Factor Receptor (HER) 2-Positive Early Breast Cancer" at ClinicalTrials.gov Clinical trial number NCT01566721 for "A Safety and Tolerability Study of Assisted and Self-Administered Subcutaneous (SC) Herceptin (Trastuzumab) as Adjuvant Therapy in Early Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer (SafeHER)" at ClinicalTrials.gov
Solifenacin	Solifenacin, sold as the brand name Vesicare among others, is a medicine used to treat overactive bladder and neurogenic detrusor overactivity (NDO). It may help with incontinence, urinary frequency, and urinary urgency. Benefits appear similar to other medications in the class. It is taken by mouth.Common side effects include dry mouth, constipation, and urinary tract infection. Severe side effects may include urinary retention, QT prolongation, hallucinations, glaucoma, and anaphylaxis. It is unclear if use is safe during pregnancy. It is of the antimuscarinic class and works by decreasing bladder contractions.Solifenacin was approved for medical use in the United States in 2004. In 2017, it was the 283rd most commonly prescribed medication in the United States, with more than one million prescriptions. Medical use It is used to treat overactive bladder. It may help with incontinence, urinary frequency, and urinary urgency.Benefits appear similar to other antimuscarinics such as oxybutynin, tolterodine, and darifenacin.It is also used to treat neurogenic detrusor overactivity (NDO), a form of bladder dysfunction related to neurological impairment, in children ages two years and older. NDO is a dysfunction of the bladder that results from disease or injury in the nervous system. NDO may be related to congenital conditions (often-inherited conditions beginning at or before birth), such as spina bifida (myelomeningocele), or other conditions such as spinal cord injury. With NDO, there is overactivity of the bladder wall muscle, which normally relaxes to allow storage of urine. The bladder wall muscle overactivity results in sporadic bladder muscle contraction, which increases pressure in the bladder and decreases the volume of urine the bladder can hold. If NDO is not treated, increased pressure in the bladder can put the upper urinary tract at risk of harm, including possible permanent damage to the kidneys. In addition, spontaneous bladder muscle contractions can lead to unexpected and frequent leakage of urine with symptoms of urinary urgency (immediate urge to urinate), frequency (urinating more often than normal) and incontinence (loss of bladder control). Contraindications Solifenacin is contraindicated for people with urinary retention, gastric retention, uncontrolled or poorly controlled closed-angle glaucoma, severe liver disease (Child-Pugh class C), and hemodialysis.Long QT syndrome is not a contraindication although solifenacin, like tolterodine and darifenacin, binds to hERG channels of the heart and may prolong the QT interval. This mechanism appears to be seldom clinically relevant.Solifenacin is not to be used in people with gastric retention (reduced emptying of the stomach), uncontrolled narrow angle glaucoma (fluid buildup in the eye which raises eye pressure) or hypersensitivity (allergic reaction) to solifenacin or any of its components. Solifenacin is also not recommended for use in people with severe liver failure, clinically significant bladder outlet obstruction in the absence of clean intermittent catheterization, decreased gastrointestinal motility (slowed intestinal contractions), or at high risk of QT prolongation (an electrical disturbance where the heart muscle takes longer than normal to recharge between beats), including people with a known history of QT prolongation and people taking medications known to prolong the QT interval. Side effects The most common side effects of solifenacin are dry mouth, constipation and urinary tract infection. As all anticholinergics, solifenacin may rarely cause hyperthermia due to decreased perspiration. Somnolence (sleepiness or drowsiness) has been reported. Severe allergic reactions, such as angioedema (swelling beneath the skin) and anaphylaxis, have been reported in people treated with solifenacin succinate and may be life-threatening. Interactions Solifenacin is metabolized in the liver by the cytochrome P450 enzyme CYP3A4. When administered concomitantly with drugs that inhibit CYP3A4, such as ketoconazole, the metabolism of solifenacin is impaired, leading to an increase in its concentration in the body and a reduction in its excretion.As stated above, solifenacin may also prolong the QT interval. Therefore, administering it concomitantly with drugs which also have this effect, such as moxifloxacin or pimozide, can theoretically increase the risk of arrhythmia. Pharmacology Mechanism of action Solifenacin is a competitive cholinergic receptor antagonist, selective for the M3 receptor subtype. The binding of acetylcholine to these receptors, particularly M3, plays a critical role in the contraction of smooth muscle. By preventing the binding of acetylcholine to these receptors, solifenacin reduces smooth muscle tone in the bladder, allowing the bladder to retain larger volumes of urine and reducing the number of micturition, urgency and incontinence episodes. Because of a long elimination half life, a once-a-day dose can offer 24-hour control of the urinary bladder smooth muscle tone. Pharmacokinetics Peak plasma concentrations are reached three to eight hours after absorption from the gut. In the bloodstream, 98% of the substance are bound to plasma proteins, mainly acidic ones. Metabolism is mediated by the liver enzyme CYP3A4 and possibly others. There is one known active metabolite, 4R-hydroxysolifenacin, and three inactive ones, the N-glucuronide, the N-oxide and the 4R-hydroxy-N-oxide. The elimination half-life is 45 to 68 hours. 69% of the substance, both in its original form and as metabolites, are excreted renally and 23% via the feces. Chemistry Like other anticholinergics, solifenacin is an ester of a carboxylic acid containing (at least) an aromatic ring with an alcohol containing a nitrogen atom. While in the prototype anticholinergic atropine the bicyclic ring is tropane, solifenacin replaces it with quinuclidine. The free base is a yellow oil, while the salt solifenacin succinate forms yellowish crystals. History The compound was studied using animal models by the Yamanouchi Pharmaceutical Co., Ltd. of Tokyo, Japan. It was known as YM905 when under study in the early 2000s.Solifenacin was approved for medical used in the United States in 2004 with an indication to treat overactive bladder in adults 18 years and older.In May 2020, solifenacin was approved for medical use in the United States with an indication to treat neurogenic detrusor overactivity (NDO), a form of bladder dysfunction related to neurological impairment, in children ages two years and older.The efficacy of solifenacin to treat neurogenic detrusor overactivity (NDO) was established in two clinical trials with a total of 95 pediatric NDO participants, ages two to 17 years old. The studies were designed to measure (as a primary efficacy endpoint) the maximum amount of urine the bladder could hold after 24 weeks of treatment. In the first study, 17 participants ages two to less than five years old were able to hold an average of 39 mL more urine than when the study began. In the second study, 49 participants ages five to 17 years were able to hold an average of 57 mL more urine than when the study began. Reductions in spontaneous bladder contractions, bladder pressure and number of incontinence episodes were also observed in both studies. The approval of Vesicare LS was granted to Astellas Pharma US, Inc. Society and culture The INN is solifenacin. It is manufactured and marketed by Astellas, GlaxoSmithKline and Teva Pharmaceutical Industries. Cost A 2006 cost-effectiveness study found that 5 mg solifenacin had the lowest cost and highest effectiveness among anticholinergic drugs used to treat overactive bladder in the United States, with an average medical cost per successfully treated patient of $6863 per year. By 2019, with the introduction of generics, the retail cost of a months supply was down to $20 in the US. References External links "Solifenacin". Drug Information Portal. U.S. National Library of Medicine. "Solifenacin succinate". Drug Information Portal. U.S. National Library of Medicine.
Griseofulvin	Griseofulvin is an antifungal medication used to treat a number of types of dermatophytoses (ringworm). This includes fungal infections of the nails and scalp, as well as the skin when antifungal creams have not worked. It is taken by mouth.Common side effects include allergic reactions, nausea, diarrhea, headache, trouble sleeping, and feeling tired. It is not recommended in people with liver failure or porphyria. Use during or in the months before pregnancy may result in harm to the baby. Griseofulvin works by interfering with fungal mitosis.Griseofulvin was discovered in 1939 from the soil fungus Penicillium griseofulvum. It is on the World Health Organizations List of Essential Medicines. Medical uses Griseofulvin is used orally only for dermatophytosis. It is ineffective topically. It is reserved for cases in which topical treatment with creams is ineffective.Terbinafine given for 2 to 4 weeks is at least as effective as griseofulvin given for 6 to 8 weeks for treatment of Trichophyton scalp infections. However, griseofulvin is more effective than terbinafine for treatment of Microsporum scalp infections. Pharmacology Pharmacodynamics The drug binds to tubulin, interfering with microtubule function, thus inhibiting mitosis. It binds to keratin in keratin precursor cells and makes them resistant to fungal infections. The drug reaches its site of action only when hair or skin is replaced by the keratin-griseofulvin complex. Griseofulvin then enters the dermatophyte through energy-dependent transport processes and binds to fungal microtubules. This alters the processing for mitosis and also underlying information for deposition of fungal cell walls. Biosynthetic process It is produced industrially by fermenting the fungus Penicillium griseofulvum.The first step in the biosynthesis of griseofulvin by P. griseofulvin is the synthesis of the 14-carbon poly-β-keto chain by a type I iterative polyketide synthase (PKS) via iterative addition of 6 malonyl-CoA to an acyl-CoA starter unit. The 14-carbon poly-β-keto chain undergoes cyclization/aromatization, using cyclase/aromatase, respectively, through a Claisen and aldol condensation to form the benzophenone intermediate. The benzophenone intermediate is then methylated via S-adenosyl methionine (SAM) twice to yield griseophenone C. The griseophenone C is then halogenated at the activated site ortho to the phenol group on the left aromatic ring to form griseophenone B. The halogenated species then undergoes a single phenolic oxidation in both rings forming the two oxygen diradical species. The right oxygen radical shifts alpha to the carbonyl via resonance allowing for a stereospecific radical coupling by the oxygen radical on the left ring forming a tetrahydrofuranone species. The newly formed grisan skeleton with a spiro center is then O-methylated by SAM to generate dehydrogriseofulvin. Ultimately, a stereoselective reduction of the olefin on dehydrogriseofulvin by NADPH affords griseofulvin. Toxicology Mice Griseofulvin is found to alter the bile metabolism of mice by Yokoo et al. 1979. The same team went on to find a similar effect on mice by a chemically unrelated substance, 3,5-diethoxycarbonyl-1,4-dihydrocollidine, in Yokoo et al. 1982 and Tsunoo et al. 1987. References External links "Griseofulvin". Drug Information Portal. U.S. National Library of Medicine.
Clozapine	Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. It is also used for the treatment of psychosis in Parkinsons disease. Clozapine is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines, after resistance to earlier neuroleptic treatment is established.The role of clozapine in treatment-resistant schizophrenia was established by a 1988 landmark study in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis who had already shown an inadequate response to other antipsychotics. While there are significant side effects, clozapine remains the most effective treatment when one or more other antipsychotics have had an inadequate response. The use of clozapine is associated with multiple improved outcomes, including a reduced rate of all-cause mortality, suicide and hospitalization. In a 2013 network comparative meta-analysis of 15 antipsychotic drugs, clozapine was found to be significantly more effective than all other drugs. In a 2021 UK study, the majority of patients (over 85% of respondents) who took clozapine preferred it to their previous therapies, felt better on it and wanted to keep taking it. In a 2000 Canadian survey of 130 patients, the majority reported better satisfaction, quality of life, compliance with treatment, thinking, mood, and alertness.Compared to other antipsychotics, clozapine has an increased risk of blood dyscrasias, in particular agranulocytosis, in the first 18 weeks of treatment. After one year, this risk reduces to that associated with most antipsychotics. Clozapines use is therefore reserved for people who have not responded to two other antipsychotics and is only done with stringent blood monitoring. Overall, despite the concerns relating to blood and other side effects, clozapine use is associated with a reduced mortality, especially from suicide which is a major cause of premature death in people with schizophrenia. The risk of clozapine related agranulocytosis and neutropenia warranted the mandatory use of stringent risk monitoring and management systems, which have reduced the risk of death from these adverse events to around 1 in 7,700. The association between clozapine use and specific bloods dyscrasias was first noted in the 1970s when eight deaths from agranulocytosis were noted in Finland. At the time it was not clear if this exceeded the established rate of this side effect which is also found in other antipsychotics and although the drug was not completely withdrawn, its use became limited. Clozapine became widely available in the early 1990s and remains the only treatment likely to be effective in treating resistant schizophrenia. Common adverse effects include drowsiness, constipation, hypersalivation (increased saliva production), tachycardia, low blood pressure, blurred vision, weight gain, and dizziness. Clozapine is not normally associated with tardive dyskinesia (TD) and is recommended as the drug of choice when this is present, although some case reports describe clozapine-induced TD. Other serious risks include seizures, inflammation of the heart, high blood sugar levels, constipation. The use of this drug can rarely result in clozapine-induced gastric hypomotility syndrome which may lead to bowel obstruction and death, and in older people with psychosis, as a result of dementia it may lead to an increased risk of death. The mechanism of action is not entirely clear in the current medical literature. Clozapine is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. History Clozapine was synthesized in 1958 by Wander AG, a Swiss pharmaceutical company, based on the chemical structure of the tricyclic antidepressant imipramine. The first test in humans in 1962 was considered a failure. Trials in Germany in 1965 and 1966 as well as a trial in Vienna in 1966 were successful. In 1967 Wander AG was acquired by Sandoz. Further trials took place in 1972 when clozapine was released in Switzerland and Austria as Leponex. Two years later it was released in West Germany and in Finland in 1975. Early testing was performed in the United States around the same time. In 1975, 16 cases of agranulocytosis leading to 8 deaths in clozapine-treated patients, reported from 6 hospitals mostly in southwestern Finland, led to concern. Analysis of the Finnish cases revealed that all the agranulocytosis cases had occurred within the first 18 weeks of treatment and the authors proposed blood monitoring during this period. The rate of agranulocytosis in Finland appeared to be 20 times higher than in the rest of the world and there was speculation that this may have been due a unique genetic diversity in the region. Whilst the drug continued to be manufactured by Sandoz, and remained available in Europe, development in the U.S. halted. Interest in clozapine continued in an investigational capacity in the United States because, even in the 1980s, the duration of hospitalisation, especially in State Hospitals for those with treatment resistant schizophrenia might often be measured in years rather than days. The role of clozapine in treatment resistant schizophrenia was established by the landmark Clozaril Collaborative Study Group Study #30 in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis and who had already shown an inadequate response to other antipsychotics. This involved both stringent blood monitoring and a double-blind design with the power to demonstrate superiority over standard antipsychotic treatment. The inclusion criteria were patients who had failed to respond to at least three previous antipsychotics and had then not responded to a single blind treatment with haloperidol (mean dose 61 mg +/- 14 mg/d). Two hundred and sixty-eight were randomised were to double blind trials of clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d). 30% of the clozapine patients responded compared to 4% of the controls, with significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Following this study, the US Food and Drug Administration (FDA) approved its use in 1990. Cautious of this risk, however, the FDA required a black box warning for specific side effects including agranulocytosis, and took the unique step of requiring patients to be registered in a formal system of tracking so that blood count levels could be evaluated on a systematic basis.In December 2002, clozapine was approved in the US for reducing the risk of suicide in people with schizophrenia or schizoaffective judged to be at chronic risk for suicidal behavior. In 2005, the FDA approved criteria to allow reduced blood monitoring frequency. In 2015, the individual manufacturer Patient Registries were consolidated by request of the FDA into a single shared Patient Registry Called The Clozapine REMS Registry. Despite the demonstrated safety of the new FDA monitoring requirements, which have lower neutrophil levels and do not include total white cell counts, international monitoring has not been standardised. Chemistry Clozapine is a dibenzodiazepine that is structurally very similar to loxapine (originally deemed a typical antipsychotic). It is slightly soluble in water, soluble in acetone, and highly soluble in chloroform. Its solubility in water is 0.1889 mg/L (25 °C). Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L). Clinical uses Schizophrenia Clozapine is usually used for people diagnosed with schizophrenia who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. It is also used for the treatment of psychosis in Parkinsons Disease. It is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines, supported by systematic reviews and meta-analysis. Whilst all current guidelines reserve clozapine to individuals when two other antipsychotics evidence indicates that clozapine might be used as a second line drug. Clozapine treatment has been demonstrated to produced improved outcomes in multiple domains including; a reduced risk of hospitalisation, a reduced risk of drug discontinuation, a reduction in overall symptoms and has improved efficacy in the treatment of positive psychotic symptoms of schizophrenia. Despite a range of side effects patients report good levels of satisfaction and long term adherence is favourable compared to other antipsychotics. Very long term follow-up studies reveal multiple benefits in terms of reduced mortality, with a particularly strong effect for reduced death by suicide, clozapine is the only antipsychotic known to have an effect reducing the risk of suicide or attempted suicide. Clozapine has a significant anti-aggressive effect. Clozapine is widely used in secure and forensic mental health settings where improvements in aggression, shortened admission and reductions in restrictive practice such as seclusion have been found. In secure hospitals and other settings clozapine has also been used in the treatment of borderline and antisocial personality disorder when this has been associated with violence or self-harm. Although oral treatment is almost universal clozapine has on occasion been enforced using either nasogastric or a short acting injection although in almost 50% of the approximately 100 reported cases patients agreed to take oral medication prior to the use of a coercive intervention. Clozapine has also been used off-label to treat catatonia with success in over 80% of cases. Bipolar disorder On the basis of systematic reviews clozapine is recommended in some treatment guidelines as a third or fourth line treatment for bipolar disorder. Bipolar disorder is an unlicensed indication for clozapine. Severe personality disorders Clozapine is also used in emotionally unstable personality disorder and a randomised controlled trial is currently underway. The use of clozapine to treat personality disorder is uncommon and unlicensed. Initiation Whilst clozapine is usually initiated in hospital setting community initiation is also available. Before clozapine can be initiated multiple assessments and baseline investigations are performed. In the UK and Ireland there must be an assessment that the patient satisfies the criteria for prescription; treatment resistant schizophrenia, intolerance due to extrapyramidal symptoms of other antipsychotics or psychosis in Parkinsons disease. Establishing a history of treatment resistance may include careful review of the medication history including the durations, doses and compliance of previous antipsychotic therapy and that these did not have an adequate clinical effect. A diagnostic review may also be performed. That could include review of antipsychotic plasma concentrations if available. The prescriber, patient, pharmacy and the laboratory performing blood counts are all registered with a specified clozapine provider who must be advised that there is no history of neutropenia from any cause. The clozapine providers collaborate by sharing information regarding patients who have had clozapine related neutropenia or agranulocytosis so that clozapine cannot be used again on license. Clozapine may only be dispensed after a satisfactory blood result has been received by the risk monitoring agency at which point an individual prescription may be released to an individual patient only.Baseline tests usually also include; a physical examination including baseline weight, waist circumference and BMI, assessments of renal function and liver function, an ECG and other baseline bloods may also be taken to facilitate monitoring of possible myocarditis, these might include C reactive protein (CRP) and troponin. In Australia and New Zealand pre-clozapine echocardiograms are also commonly performed. A number of service protocols are available and there are variations in the extent of preclozapine work ups. Some might also include fasting lipids, HbA1c and prolactin. At the Maudsley Hospital in the UK the Treat service also routinely performs a wide variety of other investigations including multiple investigations for other causes of psychosis and comorbidities including; MRI brain imaging, thyroid function tests, B12, folate and serum calcium levels, infection screening for blood borne viruses including Hepatitis B and C, HIV and syphilis as well as screening for autoimmune psychosis by anti-NMDA, anti-VGKC and Anti-nuclear Antibody screening. Investigations used to monitor the possibility of clozapine related side effects such as myocarditis are also performed including baseline troponin, CRP and BNP and for neuroleptic malignant syndrome CK.The dose of clozapine is initially low and gradually increased over a number of weeks. Initial doses may range from 6.5 to 12.5 mg/d increasing stepwise typically to doses in the range of 250–350 mg per day at which point an assessment of response will be performed. In the UK the average clozapine dose is 450 mg/d. But response is highly variable and some patients respond at much lower doses and vice versa. Monitoring During the initial dose titration phase the following are typically monitored; usually daily at first; pulse, blood pressure and since orthostatic hypotension can be problematic this should be monitored both sitting and standing. If there is a significant drop then the rate of the dose increase may be slowed, temperature.Weekly tests include; Mandatory full blood counts are performed weekly for the first 18 weeks. In some services there will also be monitoring of markers that might indicate myocarditis; troponin, CRP and BNP although the exact tests and frequency vary between services. Weight is usually measured weekly. Thereon other investigations and monitoring will always include full blood counts (fortnightly for 1 year then monthly). Weight, waist circumference, lipids and glucose or HbA1c may also be monitored. Clozapine Response and Treatment Optimisation As with other antipsychotics, and in contrast to received wisdom, responses to clozapine are typically seen soon after initiation and often within the first week. That said responses, especially those which are partial, can be delayed. Quite what an adequate trial of clozapine is, is uncertain but a recommendation is that this should be for at least 8 weeks on a plasma trough level above 350-400 micro g/L. There is considerable inter-individual variation. A significant number of patients respond at lower and also much higher plasma concentrations and some patients, especially young male smokers may never achieve these plasma levels even at doses of 900 mg/day. Options then include either increasing the dose above the licensed maximum or the addition of a drug that inhibits clozapine metabolism. Avoiding unnecessary polypharmacy is a general principle in drug treatment. Optimising blood sampling The neutrophil cut off for clozapine have shown an exceptional ability to mitigate the risk of neutropenia and agranulocytosis. There is a significant margin of safety. Some patients may have marginal neutrophil counts before and after initiation and they are at risk of premature clozapine discontinuation. A knowledge of neutrophil biology allows blood sampling optimisation. Neutrophils show a diurnal variation in response to the natural cycle of G-CSF production, they are increased in the afternoons, they are also mobilised into the circulation after exercise and smoking. Simply shifting blood sampling has been shown to avoid unnecessary discontinuations, especially in black populations. However this is a disruption to usual hospital practice. Other practical steps are to ensure that blood results become available in hours and when senior staff are available. Underuse of Clozapine Clozapine is widely recognised as being underused with wide variation in prescribing, especially in patients with African heritage.Psychiatrists prescribing practices have been found to be the most significant variable regarding variance in its use. Surveys of psychiatrists attitudes to clozapine have found that many had little experience in its use, over estimated the incidence and were fearful of side effects, and did not appreciate that many patients prefer to take clozapine than other antipsychotics, are reluctant to prescribe clozapine, had little experience in its use and believed that patients treated with clozapine were less satisfied than those treated with other antipsychotics. In contrast to many psychiatrists expectations most patients believe that the blood testing and other difficulties are worth the multiple benefits that they perceive. Whilst psychiatrists fear the severe adverse effects such as agranulocytosis, patients are more concerned about hypersalivation. Clozapine is no longer actively marketed and this may also be one of the explanations for its underuse.Despite the strong evidence and universal endorsement by national and international treatment guidelines and the experiences of patients themselves, most people eligible for clozapine are not treated with it. A large study in England found that approximately 30% of those eligible for clozapine were being treated with it. Those patients that do start clozapine usually face prolonged delay, multiple episodes of psychosis and treatments such as high dose antipsychotics or polypharmacy. Instead of two previous antipsychotics many will have been exposed to ten or more drugs which were not effective. In a study of 120 patients conducted in four hospitals in South-East London, found a mean of 9.2 episodes of antipsychotic prescription before clozapine was initiated and the mean delay in using clozapine was 5 years. Treatments that have no evidence base or are regarded as actively harmful are used instead multiple and or high-dose treatment. Racial disparity in the use of clozapine A general finding in healthcare provision is that minority groups receive inferior treatment; this is a particular finding in the US. In the US a general finding is that compared to their white peers African American people are less likely to be prescribed the second generation antipsychotics, which are more expensive than alternatives and this was even apparent and especially so for clozapine when comparison was made in the Veterans Affairs medical system and when differences regarding socioeconomic factors were taken into account. As well as being less likely to start clozapine black patients are more likely to stop clozapine, possibly on account of benign ethnic neutropenia. Benign ethnic neutropenia Benign reductions in neutrophils are observed in individuals of all ethnic backgrounds ethnic neutropenia (BEN), neutropenia without immune dysfunction or increased liability to infection is not due to abnormal neutrophil production; although, the exact aetiology of the reduction in circulating cells remains unknown. BEN is associated with several ethnic groups, but in particular those with Black African and West African ancestry. A difficulty with the use of clozapine is that neutrophil counts have been standardised on white populations. For significant numbers of black patients the standard neutrophil count thresholds did not permit clozapine use as the thresholds did not take BEN into account. Since 2002, clozapine monitoring services in the UK have used reference ranges 0.5 × 109/l lower for patients with haematologically confirmed BEN and similar adjustments are available in the current US criteria, although with lower permissible minima. But even then significant numbers of black patients will not be eligible even though the low neutrophil counts do not in their case reflect disease. The Duffy–Null polymorphism, which protects against some types of malaria, is predictive of BEN. Adverse effects Clozapine may cause serious and potentially fatal adverse effects. Clozapine carries five black box warnings, including (1) severe neutropenia (low levels of neutrophils), (2) orthostatic hypotension (low blood pressure upon changing positions), including slow heart rate and fainting, (3) seizures, (4) myocarditis (inflammation of the heart), and (5) risk of death when used in elderly people with dementia-related psychosis. Lowering of the seizure threshold may be dose related. Increasing the dose slowly may decrease the risk for seizures and orthostatic hypotension.Common effects include constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, high blood sugar, and weight gain. The risk of developing extrapyramidal symptoms, such as tardive dyskinesia, is below that of typical antipsychotics; this may be due to clozapines anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine. Sexual problems, like retrograde ejaculation, have been reported while taking clozapine. Despite the risk for numerous side effects, many side effects can be managed while continuing to take clozapine. Neutropenia and agranulocytosis Clozapine Induced Neutropenia (CIN) occurs in approximately 3.8% of cases and Clozapine Induced Agranulocytosis (CIA) in 0.4%. These are potentially serious side effects and agranulocytosis can result in death. To mitigate this risk clozapine is only used with mandatory absolute neutrophil count (ANC) monitoring (neutrophils are the most abundant of the granulocytes); for example, in the United States, the Risk Evaluation and Mitigation Strategy (REMS). The exact schedules and blood count thresholds vary internationally and the thresholds at which clozapine can be used in the U.S. has been lower than those currently used in the U.K. and Australasia for some time. The effectiveness of the risk management strategies used is such that deaths from these side effects are very rare occurring at approximately 1 in 7700 patients treated. Almost all the adverse blood reactions occur within the first year of treatment and the majority within the first 18 weeks. After one year of treatment these risks reduce markedly to that seen in other antipsychotic drugs 0.01% or about 1 in 10,000 and the risk of death is markedly lower still. When reductions in neutrophil levels are noted on regular blood monitoring then, depending on the value, monitoring may be increased or, if the neutrophil count is sufficiently low, then clozapine is stopped immediately and can then no longer be used within the medicinal licence. Stopping clozapine almost always results in resolution of the neutrophil reduction. However severe agranulocytosis can result in spontaneous infection and death, is a severe decrease in the amount of a specific kind of white blood cell called granulocytes. Clozapine carries a black box warning for drug-induced agranulocytosis. Rapid point-of-care tests may simplify the monitoring for agranulocytosis. Clozapine rechallenge A clozapine "rechallenge" is when someone that experienced agranulocytosis while taking clozapine starts taking the medication again. In countries in which the neutrophil thresholds are higher than those used in the US a simple approach is, if the lowest ANC had been above the US cut off, to reintroduce clozapine but with the US monitoring regime. This has been demonstrated in a large cohort of patients in a hospital in London in which it was found that of 115 patients who had had clozapine stopped according to the US criteria only 7 would have had clozapine stopped if the US cut offs had been used. Of these 62 were rechallenged, 59 continued to use clozapine without difficulty and only 1 had a fall in neutrophils below the US cut off. Other approaches have included the use of other drugs to support neutrophil counts including lithium or granulocyte colony-stimulating factor (G-CSF). However, if agranulocytosis still occurs during a rechallenge, the alternative options are limited. Cardiac toxicity Clozapine can rarely cause myocarditis and cardiomyopathy. A large meta-analysis of clozapine exposure to over 250,000 people revealed that these occurred in approximately 7 in 1000 patients treated and resulted in death in 3 and 4 in 10,000 patients exposed respectively and although myocarditis occurred almost exclusively within the first 8 weeks of treatment, cardiomyopathy can occur much later on. First manifestations of illness are fever which may be accompanied by symptoms associated with upper respiratory tract, gastrointestinal or urinary tract infection. Typically C-reactive protein (CRP) increases with the onset of fever and rises in the cardiac enzyme, troponin, occur up to 5 days later. Monitoring guidelines advise checking CRP and troponin at baseline and weekly for the first 4 weeks after clozapine initiation and observing the patient for signs and symptoms of illness. Signs of heart failure are less common and may develop with the rise in troponin. A recent case-control study found that the risk of clozapine-induced myocarditis is increased with increasing rate of clozapine dose titration, increasing age and concomitant sodium valproate. A large electronic health register study has revealed that nearly 90% of cases of suspected clozapine related myocarditis are false positives. Rechallenge after clozapine induced myocarditis has been performed and a protocol for this specialist approach has been published. A systematic review of rechallenge after myocarditis has show success in over 60% of reported cases. Gastrointestinal hypomotility Another underrecognized and potentially life-threatening effect spectrum is gastrointestinal hypomotility, which may manifest as severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis. Colonic hypomotility has been shown to occur in up to 80% of people prescribed clozapine when gastrointestinal function is measured objectively using radiopaque markers. Clozapine-induced gastrointestinal hypomotility currently has a higher mortality rate than the better known side effect of agranulocytosis. A Cochrane review found little evidence to help guide decisions about the best treatment for gastrointestinal hypomotility caused by clozapine and other antipsychotic medication. Monitoring bowel function and the preemptive use of laxatives for all clozapine-treated people has been shown to improve colonic transit times and reduce serious sequelae. Hypersalivation Hypersalivation, or the excessive production of saliva, is one of the most common adverse effects of clozapine (30-80%). The saliva production is especially bothersome at night and first thing in the morning, as the immobility of sleep precludes the normal clearance of saliva by swallowing that occurs throughout the day. While clozapine is a muscarinic antagonist at the M1, M2, M3, and M5 receptors, clozapine is a full agonist at the M4 subset. Because M4 is highly expressed in the salivary gland, its M4 agonist activity is thought to be responsible for hypersalivation. Clozapine-induced hypersalivation is likely a dose-related phenomenon, and tends to be worse when first starting the medication. Besides decreasing the dose or slowing the initial dose titration, other interventions that have shown some benefit include systemically absorbed anticholinergic medications such as hyoscine, diphenhydramine and topical anticholinergic medications like ipratropium bromide. Mild hypersalivation may be managed by sleeping with a towel over the pillow at night. Central nervous system CNS side effects include drowsiness, vertigo, headache, tremor, syncope, sleep disturbances, nightmares, restlessness, akinesia, agitation, seizures, rigidity, akathisia, confusion, fatigue, insomnia, hyperkinesia, weakness, lethargy, ataxia, slurred speech, depression, myoclonic jerks, and anxiety. Rarely seen are delusions, hallucinations, delirium, amnesia, libido increase or decrease, paranoia and irritability, abnormal EEG, worsening of psychosis, paresthesia, status epilepticus, and obsessive compulsive symptoms. Similar to other antipsychotics clozapine rarely has been known to cause neuroleptic malignant syndrome. Urinary incontinence Clozapine is linked to urinary incontinence, though its appearance may be under-recognized. Withdrawal effects Abrupt withdrawal may lead to cholinergic rebound effects, such as indigestion, diarrhea, nausea/vomiting, overabundance of saliva, profuse sweating, insomnia, and agitation. Abrupt withdrawal can also cause severe movement disorders, catatonia
Clozapine	, and psychosis. Doctors have recommended that patients, families, and caregivers be made aware of the symptoms and risks of abrupt withdrawal of clozapine. When discontinuing clozapine, gradual dose reduction is recommended to reduce the intensity of withdrawal effects. Weight gain and diabetes In addition to hyperglycemia, significant weight gain is frequently experienced by patients treated with clozapine. Impaired glucose metabolism and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. The data suggest that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics. Pneumonia International adverse drug effect databases indicate that clozapine use is associated with a significantly increased incidence of and death from pneumonia and this may be one of the most significant adverse events. The mechanisms for this are unknown although it has been speculated that it may be related to hypersalivation, immune effects of clozapines effects on the resolution of inflammation. Overdose Symptoms of overdose can be variable, but often include; sedation, confusion, tachycardia, seizures and ataxia. Fatalities have been reported due to clozapine overdose, though overdoses of greater than 5000 mg have been survived. Drug interactions Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.When carbamazepine is concurrently used with clozapine, it has been shown to decrease plasma levels of clozapine significantly thereby decreasing the beneficial effects of clozapine. Patients should be monitored for "decreased therapeutic effects of clozapine if carbamazepine" is started or increased. If carbamazepine is discontinued or the dose of carbamazepine is decreased, therapeutic effects of clozapine should be monitored. The study recommends carbamazepine to not be used concurrently with clozapine due to increased risk of agranulocytosis.Ciprofloxacin is an inhibitor of CYP1A2 and clozapine is a major CYP1A2 substrate. Randomized study reported elevation in clozapine concentration in subjects concurrently taking ciprofloxacin. Thus, the prescribing information for clozapine recommends "reducing the dose of clozapine by one-third of original dose" when ciprofloxacin and other CYP1A2 inhibitors are added to therapy, but once ciprofloxacin is removed from therapy, it is recommended to return clozapine to original dose. Pharmacology Pharmacodynamics Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.Clozapine is an antagonist at the 5-HT2A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.A direct interaction of clozapine with the GABAB receptor has also been shown. GABAB receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models. GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes, and reduces the expression of astrocytic glutamate transporters. These are direct effects that are also present in astrocyte cell cultures not containing neurons. Clozapine prevents impaired NMDA receptor expression caused by NMDA receptor antagonists. Pharmacokinetics The absorption of clozapine is almost complete following oral administration, but the oral bioavailability is only 60 to 70% due to first-pass metabolism. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine. However, it was shown that co-administration of food decreases the rate of absorption. The elimination half-life of clozapine is about 14 hours at steady state conditions (varying with daily dose).Clozapine is extensively metabolized in the liver, via the cytochrome P450 system, to polar metabolites suitable for elimination in the urine and feces. The major metabolite, norclozapine (desmethyl-clozapine), is pharmacologically active. The cytochrome P450 isoenzyme 1A2 is primarily responsible for clozapine metabolism, but 2C, 2D6, 2E1 and 3A3/4 appear to play roles as well. Agents that induce (e.g., cigarette smoke) or inhibit (e.g., theophylline, ciprofloxacin, fluvoxamine) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine. For example, the induction of metabolism caused by smoking means that smokers require up to double the dose of clozapine compared with non-smokers to achieve an equivalent plasma concentration.Clozapine and norclozapine (desmethyl-clozapine) plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age. Monitoring of plasma levels of clozapine and norclozapine has been shown to be useful in assessment of compliance, metabolic status, prevention of toxicity, and in dose optimisation. Society and culture Economics Despite the expense of the risk monitoring and management systems required, clozapine use is highly cost effective; with a number of studies suggesting savings of tens of thousands of dollars per patient per year compared to other antipsychotics as well as advantages regarding improvements in quality of life. Clozapine is available as a generic medication. Clozapine in the arts Carrie Mathison, a fictional CIA operative in the television series Homeland secretly takes clozapine supplied by her sister for the treatment of bipolar disorder. In the film Out of Darkness, Diana Ross played the protagonist Paulie Cooper, "a paranoid schizophrenic" who is depicted as having a dramatic improvement on clozapine. In the television series Last Man On Earth (2015) the character Melissa has a psychotic episode and returns home and starts acting how she did pre-pandemic. Her boyfriend Todd sees her take a medication in the morning and asks her what it is. All she will say is "Santas Penis". Todd searches medication books and finds clozapine = Clause a peen. References Further reading External links "Clozapine". Drug Information Portal. U.S. National Library of Medicine. "Clozapine Risk Evaluation and Mitigation Strategy (REMS) requirements will change on November 15, 2021". U.S. Food and Drug Administration (FDA). 29 July 2021. "Clozapine REMS Modification Frequently Asked Questions". U.S. Food and Drug Administration (FDA). 29 July 2021.
Nabumetone	Nabumetone is a nonsteroidal anti-inflammatory drug (NSAID). Nabumetone was developed by Beecham and first received regulatory approval in 1991. It is available under numerous brand names, such as Relafen, Relifex, and Gambaran. Nabumetone is a nonacidic NSAID prodrug that is rapidly metabolized in the liver to the active metabolite, 6-methoxy-2-naphthyl acetic acid. As found with previous NSAIDs, nabumetones active metabolite inhibits the cyclooxygenase enzyme and preferentially blocks COX-2 activity (which is indirectly responsible for the production of inflammation and pain during arthritis). The active metabolite of nabumetone is felt to be the compound primarily responsible for therapeutic effect. Comparatively, the parent drug is a poor inhibitor of COX-2 byproducts, particularly prostaglandins. It may be less nephrotoxic than indomethacin. There are two known polymorphs of the compound.Nabumetone has little effect on renal prostaglandin secretion and less of an association with heart failure than other traditional drugs of the class. Effects of nabumetone on blood pressure control in hypertensive patients on ACE inhibitors is also good—equivalent to paracetamol. Medical uses Similar in action to other NSAIDs, Nabumetone is used to treat pain and inflammation. Side effects It has been shown to have a slightly lower risk of gastrointestinal side effects than most other non-selective NSAIDs since it is a non-acidic prodrug which is then metabolized to its active 6MNA (6-methoxy-2-naphthylacetic acid) form.Side effects include: Bloody or black, tarry stools; change in color, frequency, or amount of urine; chest pain; shortness of breath; coughing up blood; pale stools; numbness; weakness; flu-like symptoms; leg pain; vision problems; speech problems; problems walking; weight gain; stomach pain; cold sweat; skin rash; blisters; headache; swelling; bleeding; bruising; vomiting blood; jaundice; diarrhea; constipation; dizziness; indigestion; gas; nausea; and ringing in the ears.In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. == References ==
Oritavancin	Oritavancin, sold under the brand name Orbactiv among others, is a semisynthetic glycopeptide antibiotic medication for the treatment of serious Gram-positive bacterial infections. Its chemical structure as a lipoglycopeptide is similar to vancomycin.The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved oritavancin for treatment of acute bacterial skin and skin structure infections. In vitro activity Oritavancin shares certain properties with other members of the glycopeptide class of antibiotics, which includes vancomycin, the current standard of care for serious Gram-positive infections in the United States and Europe. It possesses potent and rapid bactericidal activity in vitro against a broad spectrum of both resistant and susceptible Gram-positive bacteria, including Staphylococcus aureus, MRSA, enterococci, and streptococci. Oritavancin was more active than either metronidazole or vancomycin against strains of Clostridium difficile tested.Oritavancin has potential use as a therapy for exposure to Bacillus anthracis, the Gram-positive bacterium that causes anthrax, having demonstrated efficacy in a mouse model both before and after exposure to the bacterium.oritavancin demonstrates in vitro activity against both the planktonic and biofilmstates of staphylococci associated with Prosthetic joint infection (PJI), albeit with increased minimum biofilm bactericidal concentration (MBBC) compared to Minimum inhibitory concentrations (MIC) values. Moreever oritavancin has demonstrated activity against in vitro to vancomycin-susceptible enterococci (VSE) and vancomycin-resistant enterococci (VRE) in both planktonic and biofilm states. Mechanism The 4-chlorobiphenylmethyl group disrupts the cell membrane of Gram-positive bacteria. It also acts by inhibition of transglycosylation and inhibition of transpeptidation. Synergism Several antibiotics have been tested as partner drugs of oritavancin. Among these "companions" drugs, fosfomycin displayed (in vitro and in vivo) synergistic activity when administered together with oritavancin against VRE strains (both vanA and vanB). Spectrum of Activity Oritavancin is active against gram-positive aerobic bacteria such as enterococci, staphylococci, streptococci, and anaerobic bacteria such as Clostridium difficile , Clostridium perfringens , Peptostreptococcus spp. , and Propionibacterium acnes. Oritavancins spectrum of activity shows similarities to vancomycin, but with lower minimum inhibitory concentrations (MIC). Clinical trials In 2003, results were presented from two pivotal phase-III clinical trials testing the efficacy of daily intravenous oritavancin for the treatment of acute bacterial skin and skin-structure infections (ABSSSI) caused by Gram-positive bacteria. The primary endpoints of both studies were met, with oritavancin achieving efficacy with fewer days of therapy than the comparator agents vancomycin followed by cephalexin. Oritavancin showed a statistically significant improved safety profile with a 19% relative reduction in the overall incidence of adverse events versus vancomycin/cephalexin in the second and larger pivotal trial.Osteomyelitis remains a formidable foe in an era of increasing incidence of Methicillin-resistant Staphylococcus aureus (MRSA) with limited guidance for treatment optimization. The success observed in many patients suggests multi-dose oritavancin may prove advantageous for chronic osteomyelitis but further research is needed to define the optimal dose and frequency of oritavancin for the treatment of chronic osteomyelitis. History Originally discovered and developed by Eli Lilly, oritavancin was acquired by InterMune in 2001 and then by Targanta Therapeutics in late 2005. In December 2008, the U.S. Food and Drug Administration (FDA) declined to approve oritavancin without additional studies, and an EU application was withdrawn. In 2009, The Medicines Company acquired the development rights, completed clinical trials and submitted a new drug application to the FDA in February 2014. On August 6, 2014, the United States FDA approved oritavancin to treat skin infections.A marketing authorisation valid throughout the European Union was granted on 19 March 2015, for the treatment of acute bacterial skin and skin structure infections in adults. References External links "Oritavancin". Drug Information Portal. U.S. National Library of Medicine.
Ketoprofen	Ketoprofen is one of the propionic acid class of nonsteroidal anti-inflammatory drugs (NSAID) with analgesic and antipyretic effects. It acts by inhibiting the bodys production of prostaglandin. It was patented in 1967 and approved for medical use in 1980. Medical uses Ketoprofen is generally prescribed for arthritis-related inflammatory pains or severe toothaches that result in the inflammation of the gums. Ketoprofen topical patches are being used for treatment of musculoskeletal pain.Ketoprofen can also be used for treatment of some pain, especially nerve pain such as sciatica, postherpetic neuralgia and referred pain for radiculopathy, in the form of a cream, ointment, liquid, spray, or gel, which may also contain ketamine and lidocaine, along with other agents which may be useful, such as cyclobenzaprine, amitriptyline, acyclovir, gabapentin, orphenadrine and other drugs used as NSAIDs or adjuvant, atypical or potentiators for pain treatment. Trial is been going on for using this drug along with ibuprofen for management of lymphedema. Animal trial and some human trials has been shown significant improvement over placebo control. Dr Stanley G Rockson, of Stanford University is leading these researches. Efficacy A 2013 systematic review indicated "The efficacy of orally administered ketoprofen in relieving moderate-severe pain and improving functional status and general condition was significantly better than that of ibuprofen and/or diclofenac." A 2017 Cochrane systematic review investigating ketoprofen as a single-dose by mouth in acute, moderate-to-severe postoperative pain concluded that its efficacy is equivalent to drugs such as ibuprofen and diclofenac.There is evidence supporting topical ketoprofen for osteoarthritis but not other chronic musculoskeletal pain. Adverse effects In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in fetuses that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. Mechanism Ketoprofen undergoes metabolism in the liver via conjugation with glucuronic acid (glucuronidation) by UGT enzymes, hydroxylation of the benzoyl ring by the CYP3A4 and CYP2C9 enzymes, and reduction of its ketone moiety (a carbonyl functional group, i.e. with carbon-oxygen double bond) by carbonyl reducing enzymes (CREs). Ketoprofen is used for its antipyretic, analgesic, and anti-inflammatory properties by inhibiting cyclooxygenase-1 and -2 (COX-1 and COX-2) enzymes reversibly, which decreases production of proinflammatory prostaglandin precursors.The patches have been shown to provide rapid and sustained delivery to underlying tissues without significantly increasing levels of drug concentration in the blood when compared to the traditional oral administration. Chirality and biological activity Ketoprofen has one stereogenic center in the side chain and hence exists as mirror-image twins. Majority of the profens are marketed as racemic mixtures. For most of the NSAIDs the pharmacological activity reside in the (S)-enantiomers with their (R)-enantiomer of virtually inactive. An interesting observation about most profens including ketoprofen is that they undergo unidirectional metabolic inversion, chiral inversion, of the (R)- acid to its (S)-mirror-image version with no other change in the molecule. Available forms Ketoprofen was available over-the-counter in the United States in the form of 12.5 mg coated tablets (Orudis KT and Actron), but this form has been discontinued. It is available by prescription capsules. Ketoprofen is also available as a 2.5% gel for topical application, and it is also available as a patch for topical analgesia and anti-inflammatory action. However, the gel is not sold in the United States. Brand names in Australia are Orudis and Oruvail. It is available in Japan in a transdermal patch Mohrus Tape, made by Hisamitsu Pharmaceutical. It is available in the UK as Ketoflam and Oruvail, in Ireland as Fastum Gel, in Estonia as Keto, Ketonal, and Fastum Gel, in Finland as Ketorin, Keto, Ketomex, and Orudis; in France as Profénid, Bi-Profénid and Ketum; in Italy as Ketodol, Fastum Gel, Lasonil, Orudis and Oki; in Poland as Ketonal, Ketonal active, Ketolek, in Serbia, Slovenia and Croatia as Knavon and Ketonal; in Romania as Ketonal and Fastum Gel; in Mexico as Arthril; in Norway as Zon and Orudis; in Russia as ОКИ (OKI), Fastum Gel and Ketonal; in Spain as Actron and Fastum Gel; in Albania as Oki and Fastum Gel and in Venezuela as Ketoprofeno as an injectable solution of 100 mg and 150 mg capsules. In some countries, the optically pure (S)-enantiomer (dexketoprofen) is available; its trometamol salt is said to be particularly rapidly reabsorbed from the gastrointestinal tract, having a rapid onset of effects. The earliest report of therapeutic use in humans was in 1972. Veterinary medicine Ketoprofen is a common NSAID, antipyretic, and analgesic used in horses and other equines. It is most commonly used for musculoskeletal pain, joint problems, and soft tissue injury, as well as laminitis. It is also used to control fevers and prevent endotoxemia. It is also used as a mild painkiller in smaller animals, generally following surgical procedures. In horses, it is given at a dose of 2.2 mg/kg/day. Studies have shown that it does not inhibit 5-lipoxygenase and leukotriene B4, as originally claimed. It is therefore not considered superior to phenylbutazone as previously believed, although clinical signs of lameness are reduced with its use. In fact, phenylbutazone was shown superior to ketoprofen in cases of experimentally-induced synovitis when both drugs were used at labeled dosages. Administration Ketoprofen, when administered intravenously, is recommended for a maximum of five days of use. Its analgesic and antipyretic effects begin to occur one to two hours following administration. The most common dosage is 1 mg/ lb, once per day, although this dosage may be lowered for ponies, which are most susceptible to NSAID side effects. It is also available as a capsule dosage form and tablet. Ecological problems Experiments have found ketoprofen, like diclofenac, is a veterinary drug causing lethal effects in red-headed vultures. Vultures feeding on the carcasses of recently treated livestock develop acute kidney failure within days of exposure. References External links "Ketoprofen". Drug Information Portal. U.S. National Library of Medicine.
Triamcinolone	Triamcinolone is a glucocorticoid used to treat certain skin diseases, allergies, and rheumatic disorders among others. It is also used to prevent worsening of asthma and COPD. It can be taken in various ways including by mouth, injection into a muscle, and inhalation.Common side effects with long-term use include osteoporosis, cataracts, thrush, and muscle weakness. Serious side effects may include psychosis, increased risk of infections, adrenal suppression, and bronchospasm. Use in pregnancy is generally safe. It works by decreasing inflammation and immune system activity.Triamcinolone was patented in 1956 and came into medical use in 1958. It is available as a generic medication. In 2019, it was the 107th most commonly prescribed medication in the United States, with more than 6 million prescriptions. Medical uses Triamcinolone is used to treat a number of different medical conditions, such as eczema, alopecia areata, lichen sclerosus, psoriasis, arthritis, allergies, ulcerative colitis, lupus, sympathetic ophthalmia, temporal arteritis, uveitis, ocular inflammation, keloids, urushiol-induced contact dermatitis, aphthous ulcers (usually as triamcinolone acetonide), central retinal vein occlusion, visualization during vitrectomy and the prevention of asthma attacks.The derivative triamcinolone acetonide is the active ingredient in various topical skin preparations (cream, lotion, ointment, aerosol spray) designed to treat skin conditions such as rash, inflammation, redness, or intense itching due to eczema and dermatitis. Contraindications Contraindications for systemic triamcinolone are similar to those of other corticoids. They include systemic mycoses (fungal infections) and parasitic diseases, as well as eight weeks before and two weeks after application of live vaccines. For long-term treatment, the drug is also contraindicated in people with peptic ulcers, severe osteoporosis, severe myopathy, certain viral infections, glaucoma, and metastasizing tumours.There are no contraindications for use in emergency medicine. Side effects Side effects of triamcinolone are similar to other corticoids. In short-term treatment up to ten days, it has very few adverse effects; however, sometimes gastrointestinal bleeding is seen, as well as acute infections (mainly viral) and impaired glucose tolerance.Side effects of triamcinolone long-term treatment may include coughing (up to bronchospasms), sinusitis, metabolic syndrome–like symptoms such as high blood sugar and cholesterol, weight gain due to water retention, and electrolyte imbalance, as well as cataract, thrush, osteoporosis, reduced muscle mass, and psychosis. Triamcinolone injections can cause bruising and joint swelling. Symptoms of an allergic reaction include rash, itch, swelling, severe dizziness, trouble breathing, and anaphylaxis. Overdose No acute overdosing of triamcinolone has been described. Interactions Drug interactions are mainly pharmacodynamic, that is, they result from other drugs either adding to triamcinolones corticoid side effects or working against its desired effects. They include: Atropine and other anticholinergics can substantially increase pressure in the eyes. Antidiabetic drugs can become less effective because triamcinolone causes diabetes-like symptoms. Aspirin and other NSAIDs, as well as anticoagulants such as warfarin, add to the risk of gastrointestinal bleeding. Diuretics that excrete potassium (such as loop diuretics and thiazides) can increase the risk of hypokalemia and thus lead to abnormal heart rhythm. Cardiac glycosides may have more adverse effects due to reduced potassium levels in the blood. The risk for blood count changes is increased when combining triamcinolone with ACE inhibitors.Triamcinolone and other drugs can also influence each others concentrations in the body, amounting to pharmacokinetic interactions such as: Rifampicin, phenytoin, carbamazepine and other inducers of the liver enzyme CYP3A4 speed up metabolization of triamcinolone and can therefore reduce its effectiveness. Conversely, CYP3A4 inhibitors such as ketoconazole and itraconazole can increase its concentrations in the body and the risk for adverse effects. Blood concentrations of ciclosporin can be increased. Pharmacology Mechanism of action Triamcinolone is a glucocorticoid that is about five times as potent as cortisol, but has very little mineralocorticoid effects. Pharmacokinetics When taken by mouth, the drugs bioavailability is over 90%. It reaches highest concentrations in the blood plasma after one to two hours and is bound to plasma proteins to about 80%. The biological half-life from the plasma is 200 to 300 minutes; due to stable complexes of triamcinolone and its receptor in the intracellular fluid, the total half-life is significantly longer at about 36 hours.A small fraction of the substance is metabolized to 6-hydroxy- and 20-dihydro-triamcinolone; most of it probably undergoes glucuronidation, and a smaller part sulfation. Three quarters are excreted via the urine, and the rest via the faeces.Due to corticoids mechanism of action, the effects are delayed as compared to plasma concentrations. Depending on the route of administration and the treated condition, the onset of action can be from two hours up to one or two days after application; and the drug can act much longer than its elimination half-life would suggest. Chemistry Triamcinolone is a synthetic pregnane corticosteroid and derivative of cortisol (hydrocortisone) and is also known as 1-dehydro-9α-fluoro-16α-hydroxyhydrocortisone or 9α-fluoro-16α-hydroxyprednisolone as well as 9α-fluoro-11β,16α,17α,21-tetrahydroxypregna-1,4-diene-3,20-dione.The substance is a light-sensitive, white to off-white, crystalline powder, or has the form of colourless, matted crystals. It has no odour or is nearly odourless. Information on the melting point varies, partly due to the substances polymorphism: 260 to 263 °C (500 to 505 °F), 264 to 268 °C (507 to 514 °F), or 269 to 271 °C (516 to 520 °F) can be found in the literature.Solubility is 1:500 in water and 1:240 in ethanol; it is slightly soluble in methanol, very slightly soluble in chloroform and diethylether, and practically insoluble in dichloromethane. The specific rotation is [ α ] D 20 {\displaystyle [\alpha ]_{D}^{20}} +65° to +72° cm³/dm·g (1% in dimethylformamide). Society and culture In 2010, TEVA and Perrigo launched the first generic inhalable triamcinolone.According to Chang et al. (2014), "Triamcinolone acetonide (TA) is classified as an S9 glucocorticoid in the 2014 Prohibited List published by the World Anti-Doping Agency, which caused it to be prohibited in international athletic competition when administered orally, intravenously, intramuscularly or rectally". See also Glucocorticoid (a chart comparing various glucocorticoids) Triamcinolone acetonide (a derived and stronger drug) References External links "Triamcinolone". Drug Information Portal. U.S. National Library of Medicine. "Triamcinolone Topical". MedlinePlus. "Triamcinolone Nasal Spray". MedlinePlus. "Triamcinolone Acetonide Cream". HealthClubFinder. 4 January 2021.
Natamycin	Natamycin, also known as pimaricin, is an antifungal medication used to treat fungal infections around the eye. This includes infections of the eyelids, conjunctiva, and cornea. It is used as eyedrops. Natamycin is also used in the food industry as a preservative.Allergic reactions may occur. It is unclear if medical use during pregnancy or breastfeeding is safe. It is in the macrolide and polyene families of medications. It results in fungal death by altering the cell membrane.Natamycin was discovered in 1955 and approved for medical use in the United States in 1978. It is on the World Health Organizations List of Essential Medicines. It is produced by fermentation of certain types of the bacterium Streptomyces. Uses Medical Natamycin is used to treat fungal infections, including Candida, Aspergillus, Cephalosporium, Fusarium, and Penicillium. It is applied topically as a cream, in eye drops, or (for oral infections) in a lozenge. Natamycin shows negligible absorption into the body when administered in these ways. When taken orally, little or none is absorbed from the gastrointestinal tract, making it inappropriate for systemic infections. Natamycin lozenges are also prescribed to treat yeast infections and oral thrush. Food Natamycin has been used for decades in the food industry as a hurdle to fungal outgrowth in dairy products and other foods. Potential advantages for the usage of natamycin might include the replacement of traditional chemical preservatives, a neutral flavor impact, and less dependence on pH for efficacy, as is common with chemical preservatives. It can be applied in a variety of ways: as an aqueous suspension (such as mixed into a brine) sprayed on the product or into which the product is dipped, or in powdered form (along with an anticaking agent such as cellulose) sprinkled on or mixed into the product. While not currently approved for use on meats in the United States, some countries allow natamycin to be applied to the surface of dry and fermented sausages to prevent mold growth on the casing. Also, natamycin is approved for various dairy applications in the United States. More specifically, natamycin is commonly used in products such as cream cheeses, cottage cheese, sour cream, yogurt, shredded cheeses, cheese slices, and packaged salad mixes. One of the reasons for food producers to use natamycin is to replace the artificial preservative sorbic acid.As a food additive, it has E number E235. Throughout the European Union, it is approved only as a surface preservative for certain cheese and dried sausage products. It must not be detectable 5 mm below the rind. While natamycin is approved in different applications at different levels in the world, it is approved in over 150 countries worldwide.The European Food Safety Authority (EFSA) panel took over the responsibilities of providing scientific food safety advice to the EU from the Scientific Committee on Food in 2002. In 2009, the EFSA considered the proposed use levels of natamycin are safe if it is used for the surface treatment for these cheese and sausage types. Safety Natamycin does not have acute toxicity. In animal studies, the lowest LD50 found was 2.5-4.5 g/kg. In rats, the LD50 is ≥2300 mg/kg, and doses of 500 mg/kg/day over 2 years caused no detectable differences in survival rate, growth, or incidence of tumors. The metabolites of natamycin also lack toxicity. The breakdown products of natamycin under various storage conditions may have a lower LD50 than natamycin, but in all cases, the numbers are quite high. In humans, a dose of 500 mg/kg/day repeated over multiple days caused nausea, vomiting, and diarrhea.No evidence shows natamycin, at either pharmacological levels or levels encountered as a food additive, can harm normal intestinal flora, but definitive research may not be available. However, some people are allergic to natamycin.The EFSA has concluded that the use of natamycin as a food additive has no relevant risk for the development of resistant fungi. Mechanism of action Natamycin inhibits the growth of fungi by specifically binding to ergosterol present in fungal cell membranes. Natamycin inhibits amino acid and glucose transport proteins leading to a loss of nutrient transport across the plasma membrane. While this binding is reversible, ergosterol binding acts as a universal mechanism of fungal inhibition, allowing natamycin to act on diverse fungal pathogens from Saccharomyces yeast to Aspergillus moulds. Natamycin is unique amongst related antifungals specifically because it does not directly cause membrane permeabilization. Structurally-related antibiotics with similar binding properties are thought to produce hydrophilic channels that allow leakage of potassium and sodium ions from the cell.Natamycin has very low solubility in water; however, natamycin is effective at very low levels. Its minimum inhibitory concentration is less than 10 ppm for most molds. Biochemistry Natamycin is produced as a secondary metabolite by some Streptomyces species: S. natalensis, S. lydicus, S. chattanoogensis and S. gilvosporeus. Structurally, its core is a macrolide containing a polyene segment, with carboxylic acid and mycosamine groups attached. As with other polyene antimycotics, the biosynthesis begins with a series of polyketide synthase modules, followed by additional enzymatic processes for oxidation and attachment of the substituents.Natamycin is produced on an industrial scale by fermentation of various Streptomyces strains, including S. chattanoogensis L10. History Natamycin was first isolated in 1955 from fermentation broth of a Streptomyces natalensis cell culture. It was originally named pimaricin to honor Pietermaritzburg, where Streptomyces natalensis was acquired. Pimaricin was later renamed after the World Health Organization (WHO) mandated that antibiotics produced by Streptomyces end in –mycin. The name natamycin was chosen in reference to the natalensis species name. Society and culture Natamycin appears on Whole Foods "Unacceptable Ingredients for Food" list. References External links Natacyn Side Effects Center "Natamycin". Drug Information Portal. U.S. National Library of Medicine.
Voretigene neparvovec	Voretigene neparvovec, sold under the brand name Luxturna, is a gene therapy medication for the treatment of Leber congenital amaurosis. It was developed by Spark Therapeutics and Childrens Hospital of Philadelphia. It is the first in vivo gene therapy approved by the US Food and Drug Administration (FDA).Lebers congenital amaurosis, or biallelic RPE65-mediated inherited retinal disease, is an inherited disorder causing progressive blindness. Voretigene is the first treatment available for this condition. The gene therapy is not a cure for the condition, but substantially improves vision in those treated. It is given as a subretinal injection. Voretigene neparvovec was approved for medical use in Australia in August 2020 and in Canada, in October 2020. Medical uses Voretigene neparvovec is indicated for the treatment of people with vision loss due to inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations and who have sufficient viable retinal cells. Chemistry and production Voretigene neparvovec is an AAV2 vector containing human RPE65 cDNA with a modified Kozak sequence. The virus is grown in HEK 293 cells and purified for administration. History Married researchers Jean Bennett and Albert Maguire, among others, worked for decades on studies of congenital blindness, culminating in approval of a novel therapy, Luxturna.It was granted orphan drug designation for Leber congenital amaurosis and retinitis pigmentosa. A biologics license application was submitted to the FDA in July 2017 with Priority Review. Phase III clinical trial results were published in August 2017. On 12 October 2017, a key advisory panel to the Food and Drug Administration (FDA), composed of 16 experts, unanimously recommended approval of the treatment. The US FDA approved the drug on December 19, 2017. With the approval, Spark Therapeutics received a pediatric disease priority review voucher.The first commercial sale of voretigene neparvovec, which was also the first sale of any gene therapy product in the United States, occurred in March 2018. The price of the treatment at the time was announced as being $425,000 per eye. References Further reading External links "Voretigene neparvovec". Drug Information Portal. U.S. National Library of Medicine.
Lefamulin	Lefamulin, sold under the brand name Xenleta, is an antibiotic medication used it to treat adults with community-acquired bacterial pneumonia. It is taken by mouth or by injection into a vein.Relatively common side effects include diarrhea, nausea, pain at the site of injection, and liver inflammation. It is a pleuromutilin antibiotic that inhibits the large subunit of bacterial ribosomes.Lefamulin was approved for medical use in the United States in August 2019, and in the European Union in July 2020. Medical uses Lefamulin is used to treat adults with community-acquired bacterial pneumonia. It was also investigated for treatment of acute bacterial skin and skin-structure infections (ABSSSI). Spectrum of activity Lefamulin has in vitro activity against Streptococcus viridans, Moraxella catarrhalis, Enterococcus faecium, methicillin-resistant Staphylococcus aureus (MRSA), among other bacteria. History It was developed by Nabriva Therapeutics and approved in the United States in 2019. It was granted fast track status by the US Food and Drug Administration (FDA) in 2014. Although pleuromutilin antibiotics were first developed in the 1950s, lefamulin is the first to be used for systemic treatment of bacterial infections in humans. Society and culture Legal status Lefamulin was approved for medical use in the United States in August 2019, and in the European Union in July 2020. References External links "Lefamulin". Drug Information Portal. U.S. National Library of Medicine.
Eptifibatide	Eptifibatide (Integrilin, Millennium Pharmaceuticals, also co-promoted by Schering-Plough/Essex), is an antiplatelet drug of the glycoprotein IIb/IIIa inhibitor class. Eptifibatide is a cyclic heptapeptide derived from a disintegrin protein (P22827) found in the venom of the southeastern pygmy rattlesnake (Sistrurus miliarius barbouri). It belongs to the class of the arginin-glycin-aspartat-mimetics and reversibly binds to platelets. Eptifibatide has a short half-life. The drug is the third inhibitor of GPIIb/IIIa that has found broad acceptance after the specific antibody abciximab and the non-peptide tirofiban entered the global market. Indications Eptifibatide is used to reduce the risk of acute cardiac ischemic events (death and/or myocardial infarction) in patients with unstable angina or non-ST-segment-elevation (e.g., non-Q-wave) myocardial infarction (i.e., non-ST-segment elevation acute coronary syndromes) both in patients who are to receive non surgery (conservative) medical treatment and those undergoing percutaneous coronary intervention (PCI). The drug is usually applied together with aspirin or clopidogrel and (low molecular weight or unfractionated) heparin. Additionally, the usual supportive treatment consisting of applications of nitrates, beta-blockers, opioid analgesics and/or benzodiazepines should be employed as indicated. Angiographic evaluation and other intensive diagnostic procedures may be considered a first line task before initiating therapy with eptifibatide. The drug should exclusively be used in hospitalized patients both because of the serious degree of patients illness and because of the possible side-effects of eptifibatide. Contraindications and precautions Thrombocytopenia : The drug is contraindicated in patients with platelet counts of less than 100,000 per μl because no clinical experience exists regarding such patients. Chronic kidney disease : Eptifibatide undergoes kidney elimination. In such patients with chronic kidney disease where a glycoprotein IIb/IIIa inhibitor is likely to provide benefit, Abciximab (trade name: Reopro) is an alternative medication. Current bleeding tendencies or abnormally prolonged coagulation parameters observed within 30 days before starting therapy with eptifibatide is intended. Coagulation parameters such as ACT, aPTT, TT, and PT should be followed closely during therapy and afterwards. Allergy to eptifibatide and/or other ingredients. Severe, uncontrolled hypertension. Pregnancy : No experience exists. Pregnant patients should be treated only when clearly needed. Lactation : No human data exists. Breast-feeding should be avoided during treatment in order to prevent damage to the newborn. Geriatric patients : No differences in side effects compared with younger patients have been seen. Nevertheless, geriatric patients should be very closely observed for bleeding and other side-effects. Pediatric patients : Eptifibatide is not indicated in patients below 18 years of age, because no experience exists. Side effects People receiving eptifibatide are typically seriously ill and most of them are concomitantly treated with other drugs known to have the potential to cause significant side effects. Therefore, not all side effects listed as follows may be attributable to eptifibatide treatment alone: The major adverse event in the PURSUIT study was severe bleeding. Bleeding occurred as well at sites of clinical intervention (local sites) as at other sites (systemically) like urogenital bleeds. Sometimes, these events were severe enough to require transfusion of blood or plasma concentrates to stop bleeding and counteract anemia. Severe bleeds occurred in 4.4 and 4.7% of patients respectively depending on the infusion rate (0.5 µg/kg/min vs. 0.75 µg/kg/min). A few cases of death due to severe bleeding events attributable to drug therapy were reported. No cases of hemorrhagic stroke were seen. Thrombocytopenia of unknown origin (allergic reaction?) was also noticed in 0.2% of patients. Additionally, hypotension was seen frequently (6%). Cardiovascular failure was also frequent (2%) as were serious arrhythmias (ventricular fibrillation 1.5%, atrial fibrillation 6%). Severe allergic (anaphylactic) reactions occurred in almost 0.2% of patients. These reactions can be life-threatening and may be due to the peptide character of eptifibatide. Other side effects were rare and mild in nature and may not be connected to eptifibatide therapy. Study results Eptifibatide was licensed due to the positive results of the so-called PURSUIT study encompassing 10,948 patients. In this study all patients had experienced either unstable angina or a non-ST-segment-elevation myocardial infarction. Significantly fewer patients developed a myocardial infarction under therapy with eptifibatide. Death rates showed a tendency in favor of eptifibatide, but this superiority was not statistically significant. Additional information Sometimes the treating physicians require the patient after discharge from hospital to continue treatment with aspirin or clopidogrel for a few weeks, some months or even for life (as usually is the case with aspirin) to prevent recurrence of symptoms, development of myocardial infarction and/or death related to cardiovascular disease. This advice should be strictly followed. Eptifibatide is one of very many antiplatelet drugs that all have different consequences on the platelets activity. Inventors Eptifibatide was discovered by a team led by Robert M. Scarborough and David Phillips, at COR Therapeutics which was acquired by Millennium Pharmaceuticals in 2001. See also Glycoprotein IIb/IIIa inhibitors References External links "Eptifibatid/Intregrilin". Pharmazeutische Zeitung (in German). "From Bites and Stings to Medicines". The Royal Society of Chemistry. Archived from the original on 27 April 2006. (information on the biological origin of eptifibatide) "Eptifibatide". Drug Information Portal. U.S. National Library of Medicine.
Collagenase clostridium histolyticum	Collagenase clostridium histolyticum is an enzyme produced by the bacterium Clostridium histolyticum that dismantles collagen. It is used as a powder-and-solvent injection kit for the treatment of Dupuytrens contracture, a condition where the fingers bend towards the palm and cannot be fully straightened, and Peyronies disease, a connective tissue disorder involving the growth of fibrous plaques in the soft tissue of the penis. BioSpecifics Technologies developed the preparation, which is manufactured and marketed by Endo Pharmaceuticals as Xiaflex in the US and by Sobi as Xiapex in Europe. Biochemically, it is a mixture of two C. histolyticum collagenases, ColH and ColG. A similar ointment preparation called Santyl contains one or many collagenases from the same bacterium, but it is unclear which. Uses In February 2010, the Food and Drug Administration of the United States approved Xiaflex for the treatment of Dupuytrens contracture. It is the first approved nonsurgical treatment for this condition. In a case of Dupuytrens contracture, collagen accumulates in the palmar fascia of the hands, so that the fingers cannot be straightened. A similar phenomenon occurs in Peyronies disease, a contracture of the penis. In February 2011, the European Commissions Committee for Medicinal Products for Human Use approved the product for the treatment of Dupuytrens contracture in adults with a palpable cord by properly trained doctors. Pfizer was reported to be working with Europes national medicines regulatory bodies to launch the new treatment, hoping doctors could prescribe the treatment by late 2011. However, the Swedish manufacturer abruptly withdrew distribution of this drug in Europe in March 2020 for commercial reasons. Collagenase is no longer available on the National Health System except as part of a small clinical trial.On November 7, 2012, BioSpecifics announced "BioSpecifics Technologies Corp. : Reports Third Quarter 2012 Financial Results". Auxiliums submission of a License Application to the FDA for Xiaflex for the potential treatment of Peyronies disease, an excess of inelastic collagen causing penile curvature deformity. The FDA approved Xiaflex for the treatment of Peyronie’s disease in December 2013. Following this, Xiapex gained EU approval for the treatment of Peyronie’s disease in February 2015, making it the first and only biologic therapy indicated for the treatment of Peyronies disease. Auxilium has also reported additional trials for potential use of Xiaflex are underway for the treatment of frozen shoulder, cellulite reductions and both human and canine lipomas. Side effects The most common side effects include lymphadenopathy (swollen lymph nodes), itching, pain, oedema, and bleeding (for example in the form of bruises or ecchymoses). Allergic reactions are seen in less than 1% of patients. Chemical properties The substance is a constant mixture of two collagenases (AUX-I and AUX-II) with known amino acid sequences and a length of about 1000 amino acids each. It is prepared by anaerobic fermentation from a strain of C. histolyticum that has been known since 1950. Pharmacology The enzymes do not reach the bloodstream in significant amounts and are presumed to largely stay at the point of injection until they are broken down by proteases. The two collagenases act synergistically by cleaving tropocollagen (the collagen molecule) at different points. AUX-I attacks the C- and N-termini, AUX-II cleaves amino acid bonds within the molecule. Small collagen fragments are broken down by both enzymes. Interactions No interaction studies have been conducted because the drug does not reach the bloodstream and the liver. It is theorised that drugs interfering with matrix metalloproteinases, such as tetracyclines, anthracyclines, quinolones and anthraquinone derivatives, could reduce the efficacy of the collagenases, but no clinical evidence for such an interaction has been observed. References External links "Collagenase clostridium histolyticum". Drug Information Portal. U.S. National Library of Medicine.
Enasidenib	Enasidenib (INN; trade name Idhifa) is a medication used to treat relapsed or refractory acute myeloid leukemia in people with specific mutations of the isocitrate dehydrogenase 2 (IDH2) gene, determined by an FDA-approved IDH2 companion diagnostic test. It is an inhibitor of IDH2. It was developed by Agios Pharmaceuticals and is licensed to Celgene for further development. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Medical use Enasidenib is used to treat relapsed or refractory acute myeloid leukemia in people with specific mutations of the IDH2 gene, determined by an FDA-approved IDH2 companion diagnostic test. Adverse effects The main serious adverse effect of enasidenib is differentiation syndrome. Pharmacology Isocitrate dehydrogenase is a critical enzyme in the citric acid cycle. Mutated forms of IDH produce high levels of the (R)-enantiomer of 2-hydroxyglutarate (R-2-HG) and can contribute to the growth of tumors. IDH1 catalyzes this reaction in the cytoplasm, while IDH2 catalyzes this reaction in mitochondria. Mutations of IDH2 are more common than IDH1 mutations, 8 to 19% compared to 7 to 14% respectively, in those affected with AML. Enasidenib disrupts this cycle by decreasing total (R)-2-HG levels in the mitochondria. History The U.S. Food and Drug Administration (FDA) granted the application for enasidenib fast track designation and orphan drug designation for acute myeloid leukemia in 2014.Enasidenib was approved by the FDA in August 2017, for relapsed or refractory acute myeloid leukemia (AML) in people with specific mutations of the IDH2 gene, determined by an FDA-approved IDH2 companion diagnostic test. References External links "Enasidenib". Drug Information Portal. U.S. National Library of Medicine. "Enasidenib mesylate". NCI Dictionary of Cancer Terms. National Cancer Institute. "Enasidenib mesylate". National Cancer Institute.
Codeine	Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, Papaver somniferum. It is typically used to treat mild to moderate degrees of pain. Greater benefit may occur when combined with paracetamol (acetaminophen) or a nonsteroidal anti-inflammatory drug (NSAID) such as aspirin or ibuprofen. Evidence does not support its use for acute cough suppression in children or adults. In Europe, it is not recommended as a cough medicine in those under 12 years of age. It is generally taken by mouth. It typically starts working after half an hour, with maximum effect at two hours. Its effects last for about four to six hours. Codeine exhibits abuse potential similar to other opioid medications.Common side effects include vomiting, constipation, itchiness, lightheadedness, and drowsiness. Serious side effects may include breathing difficulties and addiction. Whether its use in pregnancy is safe is unclear. Care should be used during breastfeeding, as it may result in opiate toxicity in the baby. Its use as of 2016 is not recommended in children. Codeine works following being broken down by the liver into morphine; how quickly this occurs depends on a persons genetics.Codeine was discovered in 1832 by Pierre Jean Robiquet. In 2013, about 361,000 kg (795,000 lb) of codeine were produced while 249,000 kg (549,000 lb) were used, which made it the most commonly taken opiate. It is on the World Health Organizations List of Essential Medicines. Codeine occurs naturally and makes up about 2% of opium. Medical uses Pain Codeine is used to treat mild to moderate pain. It is commonly used to treat post-surgical dental pain.Weak evidence indicates that it is useful in cancer pain, but it may have increased adverse effects, especially constipation, compared to other opioids. The American Academy of Pediatrics does not recommend its use in children due to side effects. The FDA lists age under 12 years old as a contraindication to use. Cough Codeine is used to relieve coughing. Evidence does not support its use for acute cough suppression in children. In Europe, it is not recommended as a cough medicine in those under 12 years of age. Some tentative evidence shows it can reduce a chronic cough in adults. Diarrhea It is used to treat diarrhea and diarrhea-predominant irritable bowel syndrome, although loperamide (which is available without a prescription for milder diarrhea), diphenoxylate, paregoric, or even laudanum are more frequently used to treat severe diarrhea. Formulations Codeine is marketed as both a single-ingredient drug and in combination preparations with paracetamol (as co-codamol: e.g., brands Paracod, Panadeine, and the Tylenol-with-codeine series, including Tylenol 3 and 1, 2, and 4); with aspirin (as co-codaprin); or with ibuprofen (as Nurofen Plus). These combinations provide greater pain relief than either agent alone (drug synergy). Codeine is also commonly marketed in products containing codeine with other pain killers or muscle relaxers, as well as codeine mixed with phenacetin (Emprazil with codeine No. 1, 2, 3, 4, and 5), naproxen, indomethacin, diclofenac, and others, as well as more complex mixtures, including such mixtures as aspirin + paracetamol + codeine ± caffeine ± antihistamines and other agents, such as those mentioned above. Codeine-only products can be obtained with a prescription as a time release tablet. Codeine is also marketed in cough syrups with zero to a half-dozen other active ingredients, and a linctus (e.g., Paveral) for all of the uses for which codeine is indicated. Injectable codeine is available for subcutaneous or intramuscular injection only; intravenous injection is contraindicated, as this can result in nonimmune mast-cell degranulation and resulting anaphylactoid reaction. Codeine suppositories are also marketed in some countries. Side effects Common adverse effects associated with the use of codeine include drowsiness and constipation. Less common are itching, nausea, vomiting, dry mouth, miosis, orthostatic hypotension, urinary retention, euphoria, and dysphoria. Rare adverse effects include anaphylaxis, seizure, acute pancreatitis, and respiratory depression. As with all opiates, long-term effects can vary, but can include diminished libido, apathy, and memory loss. Some people may have allergic reactions to codeine, such as the swelling of skin and rashes.Tolerance to many of the effects of codeine, including its therapeutic effects, develops with prolonged use. This occurs at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. A potentially serious adverse drug reaction, as with other opioids, is respiratory depression. This depression is dose-related and is a mechanism for the potentially fatal consequences of overdose. As codeine is metabolized to morphine, morphine can be passed through breast milk in potentially lethal amounts, fatally depressing the respiration of a breastfed baby. In August 2012, the United States Federal Drug Administration issued a warning about deaths in pediatric patients less than 6 years old after ingesting "normal" doses of paracetamol with codeine after tonsillectomy; this warning was upgraded to a black box warning in February 2013.Some patients are very effective converters of codeine to its active form, morphine, resulting in lethal blood levels. The FDA is presently recommending very cautious use of codeine in young tonsillectomy patients; the drug should be used in the lowest amount that can control the pain, "as needed" and not "around the clock", and immediate medical attention is needed if the user responds negatively. Withdrawal and dependence As with other opiates, chronic use of codeine can cause physical dependence which can lead to severe withdrawal symptoms if a person suddenly stops the medication. Withdrawal symptoms include drug craving, runny nose, yawning, sweating, insomnia, weakness, stomach cramps, nausea, vomiting, diarrhea, muscle spasms, chills, irritability, and pain. These side-effects also occur in acetaminophen/aspirin combinations, though to a lesser extent. To minimize withdrawal symptoms, long-term users should gradually reduce their codeine medication under the supervision of a healthcare professional.Also, no evidence indicates that CYP2D6 inhibition is useful in treating codeine dependence, though the metabolism of codeine to morphine (and hence further metabolism to glucuronide morphine conjugates) does have an effect on the abuse potential of codeine. However, CYP2D6 has been implicated in the toxicity and death of neonates when codeine is administered to lactating mothers, particularly those with increased enzyme activity ("ultra-rapid" metabolizers). Pharmacology Pharmacodynamics Codeine is a nonsynthetic opioid. It is a selective agonist of the μ-opioid receptor (MOR). Codeine itself has relatively weak affinity for the MOR. Instead of acting directly on the MOR, codeine functions as a prodrug of its major active metabolites morphine and codeine-6-glucuronide, which are far more potent MOR agonists in comparison.Codeine has been found as an endogenous compound, along with morphine, in the brains of nonhuman primates with depolarized neurons, indicating that codeine may function as a neurotransmitter or neuromodulator in the central nervous system. Like morphine, codeine causes TLR4 signaling which causes allodynia and hyperalgesia. It doesnt need to be converted to morphine to increase pain sensitivity. Mechanism of action Codeine is an opioid and an agonist of the mu opioid receptor (MOR). It acts on the central nervous system to have an analgesic effect. It is metabolised in the liver to produce morphine which is ten times more potent against the mu receptor. Opioid receptors are G protein-coupled receptors that positively and negatively regulate synaptic transmission through downstream signalling. Binding of codeine or morphine to the mu opioid receptor results in hyperpolarization of the neuron leading to the inhibition of release of nociceptive neurotransmitters, causing an analgesic effect and increased pain tolerance due to reduced neuronal excitability. Pharmacokinetics The conversion of codeine to morphine occurs in the liver and is catalyzed by the cytochrome P450 enzyme CYP2D6. CYP3A4 produces norcodeine, and UGT2B7 conjugates codeine, norcodeine, and morphine to the corresponding 3- and 6-glucuronides. Srinivasan, Wielbo and Tebbett speculate that codeine-6-glucuronide is responsible for a large percentage of the analgesia of codeine, and thus these patients should experience some analgesia. Many of the adverse effects will still be experienced in poor metabolizers. Conversely, between 0.5% and 2% of the population are "extensive metabolizers"; multiple copies of the gene for 2D6 produce high levels of CYP2D6 and will metabolize drugs through that pathway more quickly than others. Some medications are CYP2D6 inhibitors and reduce or even completely block the conversion of codeine to morphine. The best-known of these are two of the selective serotonin reuptake inhibitors, paroxetine (Paxil) and fluoxetine (Prozac) as well as the antihistamine diphenhydramine (Benadryl) and the antidepressant bupropion (Wellbutrin, also known as Zyban). Other drugs, such as rifampicin and dexamethasone, induce CYP450 isozymes and thus increase the conversion rate. CYP2D6 converts codeine into morphine, which then undergoes glucuronidation. Life-threatening intoxication, including respiratory depression requiring intubation, can develop over a matter of days in patients who have multiple functional alleles of CYP2D6, resulting in ultrarapid metabolism of opioids such as codeine into morphine.Studies on codeines analgesic effect are consistent with the idea that metabolism by CYP2D6 to morphine is important, but some studies show no major differences between those who are poor metabolizers and extensive metabolizers. Evidence supporting the hypothesis that ultrarapid metabolizers may get greater analgesia from codeine due to increased morphine formation is limited to case reports.Due to increased metabolism of codeine to morphine, ultrarapid metabolizers (those possessing more than two functional copies of the CYP2D6 allele) are at increased risk of adverse drug effects related to morphine toxicity. Guidelines released by the Clinical Pharmacogenomics Implementation Consortium (CPIC) advise against administering codeine to ultrarapid metabolizers, where this genetic information is available. The CPIC also suggests that codeine use be avoided in poor metabolizers, due to its lack of efficacy in this group.Codeine and its salts are readily absorbed from the gastrointestinal tract, and ingestion of codeine phosphate produces peak plasma concentrations in about one hour. Plasma half life is between 3 and 4 hours, and oral/intramuscular analgesic potency ratio is approximately equal to 1:1.5. The most common conversion ratio, given on equianalgesia charts used in the United States, Canada, the UK, Republic of Ireland, the European Union, Russia and elsewhere as 130 mg IM equals 200 mg PO—both of which are equivalent to 10 mg of morphine sulphate IV and 60 mg of morphine sulphate PO. The salt:freebase ratio of the salts of both drugs in use are roughly equivalent, and do not generally make a clinical difference.Codeine is metabolised by O- and N-demethylation in the liver to morphine and norcodeine. Hydrocodone is also a metabolite of codeine in humans. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid.The active metabolites of codeine, notably morphine, exert their effects by binding to and activating the μ-opioid receptor. Chemistry Relation to other opioids Codeine has been used in the past as the starting material and prototype of a large class of mainly mild to moderately strong opioids; such as hydrocodone (1920 in Germany), oxycodone (1916 in Germany), dihydrocodeine (1908 in Germany), and its derivatives such as nicocodeine (1956 in Austria). However, these opioids are no longer synthesized from codeine and are usually synthesized from other opium alkaloids; specifically thebaine. Other series of codeine derivatives include isocodeine and its derivatives, which were developed in Germany starting around 1920. In general, the various classes of morphine derivatives such as ketones, semisynthetics like dihydromorphine, halogeno-morphides, esters, ethers, and others have codeine, dihydrocodeine, and isocodeine analogues. The codeine ester acetylcodeine is a common active impurity in street heroin as some codeine tends to dissolve with the morphine when it is extracted from opium in underground heroin and morphine base labs. As an analgesic, codeine compares weakly to other opiates. Related to codeine in other ways are codoxime, thebacon, codeine-N-oxide (genocodeine), related to the nitrogen morphine derivatives as is codeine methobromide, and heterocodeine, which is a drug six times stronger than morphine and 72 times stronger than codeine due to a small re-arrangement of the molecule, namely moving the methyl group from the 3 to the 6 position on the morphine carbon skeleton. Drugs bearing resemblance to codeine in effects due to close structural relationship are variations on the methyl groups at the 3 position including ethylmorphine, also known as codethyline (Dionine), and benzylmorphine (Peronine). While having no narcotic effects of its own, the important opioid precursor thebaine differs from codeine only slightly in structure. Pseudocodeine and some other similar alkaloids not currently used in medicine are found in trace amounts in opium as well. History Codeine, or 3-methylmorphine, is an alkaloid found in the opium poppy, Papaver somniferum var. album, a plant in the family Papaveraceae. Opium poppy has been cultivated and utilized throughout human history for a variety of medicinal (analgesic, anti-tussive and anti-diarrheal) and hypnotic properties linked to the diversity of its active components, which include morphine, codeine and papaverine. Codeine is found in concentrations of 1% to 3% in opium prepared by the latex method from unripe pods of Papaver somniferum. The name codeine is derived from the Ancient Greek κώδεια (kṓdeia, "poppy head"). The relative proportion of codeine to morphine, the most common opium alkaloid at 4% to 23%, tends to be somewhat higher in the poppy straw method of preparing opium alkaloids. Until the beginning of the 19th century, raw opium was used in diverse preparations known as laudanum (see Thomas de Quinceys Confessions of an English Opium-Eater, 1821) and paregoric elixirs, a number of which were popular in England since the beginning of the 18th century; the original preparation seems to have been elaborated in Leiden, the Netherlands around 1715 by a chemist named Lemort; in 1721 the London Pharmacopoeia mentions an Elixir Asthmaticum, replaced by the term Elixir Paregoricum ("pain soother") in 1746. The progressive isolation of opiums several active components opened the path to improved selectivity and safety of the opiates-based pharmacopeia. Morphine had already been isolated in Germany by Friedrich Sertürner in 1804. Codeine was first isolated in 1832 in France by Pierre Robiquet, already famous for the discovery of alizarin, the most widespread red dye, while working on refined morphine extraction processes. Robiquet is also credited with discovering caffeine independently of Pelletier, Caventou, and Runge.Codeine is the most widely used opiate in the world, and is one of the most commonly used drugs overall according to numerous reports by organizations including the World Health Organization and its League of Nations predecessor agency. While codeine can be directly extracted from opium, its original source, most codeine is synthesized from the much more abundant morphine through the process of O-methylation, through a process first completed in the late 20th century by Robert C. Corcoran and Junning Ma.Numerous codeine salts have been prepared since the drug was discovered. The most commonly used are the hydrochloride (freebase conversion ratio 0.805, i.e. 10mg of the hydrochloride salt is equivalent in effect to 8.05mg of the freebase form), phosphate (0.736), sulphate (0.859), and citrate (0.842). Others include a salicylate NSAID, codeine salicylate (0.686), a bromide (codeine methylbromide, 0.759), and at least five codeine-based barbiturates, the phenylethylbarbiturate (0.56), cyclohexenylethylbarbiturate (0.559), cyclopentenylallylbarbiturate (0.561), diallylbarbiturate (0.561), and diethylbarbiturate (0.619). The latter was introduced as Codeonal in 1912, indicated for pain with nervousness. Codeine methylbromide is also considered a separate drug for various purposes.Codeine and morphine, as well as opium, were used in an attempt to treat diabetes in the 1880s and thereafter, as recently as the 1950s. Society and culture Names It is often sold as a salt in the form of either codeine sulfate or codeine phosphate in the United States, United Kingdom and Australia. Codeine hydrochloride is more common worldwide and the citrate, hydroiodide, hydrobromide, tartrate, and other salts are also seen. The chemical name for codeine is morphinan-6-ol, 7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-, (5α,6α)- Recreational use A heroin (diamorphine) or other opiate/opioid addict may use codeine to ward off the effects of withdrawal during periods where their preferred drug is unavailable or unaffordable.Codeine is also available in conjunction with the anti-nausea medication promethazine in the form of a syrup. Brand named as Phenergan with Codeine or in generic form as promethazine with codeine, it began to be mixed with soft drinks in the 1990s as a recreational drug, called syrup, lean, or purple drank. Rapper Pimp C, from the group UGK, died from an overdose of this combination.Codeine is used in illegal drug laboratories to make morphine. Detection Codeine and its major metabolites may be quantitated in blood, plasma or urine to monitor therapy, confirm a diagnosis of poisoning or assist in a medico-legal death investigation. Drug abuse screening programs generally test urine, hair, sweat or saliva. Many commercial opiate screening tests directed at morphine cross-react appreciably with codeine and its metabolites, but chromatographic techniques can easily distinguish codeine from other opiates and opioids. It is important to note that codeine usage results in significant amounts of morphine as an excretion product. Furthermore, heroin contains codeine (or acetyl codeine) as an impurity and its use will result in excretion of small amounts of codeine. Poppy seed foods represent yet another source of low levels of codeine in ones biofluids. Blood or plasma codeine concentrations are typically in the 50–300 µg/L range in persons taking the drug therapeutically, 700–7,000 µg/L in chronic users and 1,000–10,000 µg/L in cases of acute fatal over dosage.Codeine is produced in the human body along the same biosynthetic pathway as morphine. Urinary concentrations of endogenous codeine and morphine have been found to significantly increase in individuals taking L-DOPA for the treatment of Parkinsons disease. Legal status Around the world, codeine is, contingent on its concentration, a Schedule II and III drug under the Single Convention on Narcotic Drugs. In Australia, Canada, New Zealand, Sweden, the United Kingdom, the United States and many other countries, codeine is regulated under various narcotic control laws. In some countries, it is available without a medical prescription in combination preparations from licensed pharmacists in doses up to 20 mg, or 30 mg when sold combined with 500 mg paracetamol. Of the European Union member states, 12 countries (Bulgaria, Cyprus, Denmark, Estonia, Ireland, Latvia, Lithuania, Malta, Poland, Romania, Slovenia) allow the sale of OTC codeine solid dosage forms. Australia In Australia, since 1 February 2018, preparations containing codeine are not available without a prescription.Preparations containing pure codeine (e.g., codeine phosphate tablets or codeine phosphate linctus) are available on prescription and are considered S8 (Schedule 8, or "Controlled Drug Possession without authority illegal"). Schedule 8 preparations are subject to the strictest regulation of all medications available to consumers. Prior to 1 February 2018, Codeine was available over-the-counter (OTC). Canada In Canada, codeine is regulated under the Narcotic Control Regulations (NCR), which falls under the Controlled Drugs and Substances Act (CDSA). Regulations state the pharmacists may, without a prescription, sell low-dose codeine products (containing up to 8 mg of codeine per tablet or up to 20 mg per 30 ml in liquid preparation) if the preparation contains at least two additional medicinal ingredients other than a narcotic (S.36.1 NCR).In Canada tablets containing 8 mg of codeine combined with 15 mg of caffeine and 300 mg of acetaminophen are sold as T1s (Tylenol Number 1) without a prescription. A similar tablet called "A.C. & C." (which stands for Acetylsalicylic acid with Caffeine and Codeine) containing 325–375 mg of acetylsalicylic acid (Aspirin) instead of acetaminophen is also available without a prescription. Codeine combined with an antihistamine, and often caffeine, is sold under various trade names and is available without a prescription. These products are kept behind the counter and must be dispensed by a pharmacist who may limit quantities.Names of many codeine and dihydrocodeine products in Canada tend to follow the narcotic content number system (Tylenol With Codeine No. 1, 2, 3, 4 &c) mentioned below in the section on the United States; it came to be in its current form with the Pure Food & Drug Act of 1906.Controlled Drugs and Substances Act (S.C. 1996, c. 19) effective July 28, 2020. Codeine is now classified under Schedule 1, giving it a higher priority in the treatments of offenders of the law. Codeine became a prescription-only medication in the province of Manitoba on February 1, 2016. The number of low-dose codeine tablets sold in Manitoba decreased by 94 percent from 52.5 million tablets sold in the year prior to the policy change to 3.3 million in the year after. A pharmacist may issue a prescription, and all purchases are logged to a central database to prevent overprescribing. Saskatchewans pharmacy college is considering enacting a similar ban to Manitobas.On 9 May 2019, the Canadian Pharmacists Association wrote to Health Canada proposing regulations amending the NCR, the BOTSR, and the FDR - Part G, which included requiring that all products containing codeine be available by prescription only.New safety measures were issued by Health Canada on July 28, 2016; "codeine should no longer be used (contraindicated) in patients under 18 years of age to treat pain after surgery to remove tonsils or adenoids, as these patients are more susceptible to the risk of serious breathing problems. Codeine (prescription and non-prescription) is already not recommended for children under the age of 12, for any use." Denmark In Denmark codeine is sold over the counter in dosages up to 9.6 mg (with aspirin, brand name Kodimagnyl); anything stronger requires a prescription. Estonia In Estonia codeine is sold over the counter in dosages up to 8 mg (with paracetamol, brand name Co-Codamol). France In France, most preparations containing codeine only began requiring a doctors prescription in 2017. Products containing codeine include Néocodion (codeine and camphor), Tussipax (ethylmorphine and codeine), Paderyl (codeine alone), Codoliprane (codeine with paracetamol), Prontalgine and Migralgine (codeine, paracetamol and caffeine). The 2017 law change made a prescription mandatory for all codeine products, along with those containing ethylmorphine and dextromethorphan. Germany, Switzerland and Austria Codeine is listed under the Betäubungsmittelgesetz in Germany and the similarly named narcotics and controlled substances law in Switzerland. In Austria, the drug is listed under the Suchtmittelgesetz in categories corresponding to their classification under the Single Convention on Narcotic Drugs. Dispensing of products containing codeine and similar drugs (dihydrocodeine, nicocodeine, benzylmorphine, ethylmorphine, etc.) generally requires a prescription order from a doctor or the discretion of the pharmacist. Municipal and provincial regulations may impact availability, in particular in Austria and Switzerland, which allows cities and provinces to regulate the selling of the least-regulated schedule of the SMG/BtMG. Individual chemists shops can opt out of providing them or imposing volume, frequency, or single-purchase limitations and other things of the same store. Plain codeine hydrochloride tablets as well as other non-injectable forms of codeine and its midrange derivatives can be dispensed in this way; the same goes for most chemical classes of benzodiazepines, the majority of non-barbiturate sedative/hypnotics, and at least a handful of barbiturates. Title 76 of the Schengen treaty has made it possible for countries within the signatory states to import and export drugs with various provisos, recording and ordering requirements, and various other rules. Greece Codeine is classed as an illegal drug in Greece, and individuals possessing it could conceivably be arrested, even if they were legitimately prescribed it in another country. It is sold only with a doctors prescription (Lonarid-N, Lonalgal). Hong Kong In Hong Kong, codeine is regulated under Laws of Hong Kong, Dangerous Drugs Ordinance, Chapter 134, Schedule 1. It can be used legally only by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10,000 (HKD). The maximum penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession
Codeine	of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time. However, codeine is available without prescription from licensed pharmacists in doses up to 0.1%: Schedule 1, Part IV, paragraph 23 (i.e. 5 mg/5ml): Section 3, (1) (a) India Codeine preparations require a prescription in India. A preparation of paracetamol and codeine is available in India. Codeine is also present in various cough syrups as codeine phosphate including chlorpheniramine maleate. Pure codeine is also available as codeine sulphate tablets. Codeine containing cough medicine has been banned in India with effect from 14 March 2016. The Ministry of Health and Family Welfare has found no proof of its efficacy against cough control. Iran Preparations of codeine in Iran normally comes with paracetamol or guaifenesin, and can be purchased over-the-counter. Pure codeine is also available as codeine phosphate 30 mg tablets and special permit required to purchasing. Irans deputy health minister reported that codeine combinations is Irans best selling OTC medication. Ireland In Ireland, new regulations came into effect on 1 August 2010 concerning codeine, due to worries about the overuse of the drug. Codeine remains a semi non-prescriptive, over-the-counter drug up to a limit of 12.8 mg per pill, but codeine products must be out of the view of the public to facilitate the legislative requirement that these products "are not accessible to the public for self-selection". In practice, this means customers must ask pharmacists for the product containing codeine in name, and the pharmacist makes a judgement whether it is suitable for the patient to be using codeine, and that patients are fully advised of the correct use of these products. Products containing more than 12.8 mg codeine are available on prescription only. Italy Codeine tablets or preparations require a prescription in Italy. Preparations of paracetamol and codeine are available in Italy as Co-Efferalgan and Tachidol. Japan Codeine is available over the counter at pharmacies, allowing up to 50 mg of codeine phosphate per day for adults. Latvia In Latvia codeine is sold over the counter in dosages up to 8 mg (with paracetamol, brand name Co-Codamol). Maldives The Maldives takes an infamously strict line on medicines, with many common drugs, notably anything with containing codeine being banned unless you have a notarized and authenticated doctors prescription. Visitors breaking the rules, even inadvertently, have been deported or imprisoned. Nigeria Nigeria in 2018 plans to ban the manufacture and import of cough syrup that include codeine as an ingredient. This is due to concerns regarding its use to get intoxicated. Romania Codeine is not allowed without a medical prescription. Codeine is sold under the name Farmacod and its concentration does not exceed 15 mg. There is a known combination of acetylsalicylic acid, paracetamol and codeine phosphate hemihydrate named Aspaco that is allowed without a medical prescription but its case is signed with an exclamation red symbol which means that driving wont be allowed during treatment. There are no sanctions whether the drug is given without a prescription. The Russian Federation According to ITAR-Tass and Austria Presse-Agentur, OTC availability of codeine products was rescinded nationwide in 2012 because of the discovery of the Krokodil method of underground desomorphine synthesis. Opponents of the move point out that codeine has not been available OTC in 22 of Russias regions for years and the demand will call forth its own supply, meaning that only legitimate end users are negatively affected (activist quoted in Pravda story on issue). South Africa Codeine is available over the counter in South Africa. Certain pharmacies require people to write down their name and address to ensure they are not buying too much over a short period although many do not require this at all. According to Lochan Naidoo, the former president of the National Narcotics Control Board, making the drugs more difficult to obtain could lead to even worse problems where people in withdrawal would turn to illicit drugs to get their fix. Although codeine is freely available, South Africa has a fairly low annual prevalence rate of opiate use at 0.3% compared to the United States at 0.57% where all opiates are strictly regulated. Sri Lanka Codeine preparations are available as over the counter pharmacy medicines in Sri Lanka. The most common preparation is Panadeine, which contains 500 mg of Paracetamol and 8 mg of Codeine. But cough syrup containing codeine and promethazine is banned, even with a prescription. United Arab Emirates The UAE takes an exceptionally strict line on medicines, with many common drugs, notably anything containing codeine being banned unless one has a notarized and authenticated doctors prescription. Visitors breaking the rules, even inadvertently, have been deported or imprisoned. The US Embassy to the UAE maintains an unofficial list of what may not be imported. United Kingdom In the United Kingdom, the sale and possession of codeine are restricted separately under law. Neat codeine and higher-strength codeine formulations are generally prescription-only medicines (POM) meaning that the sale of such products is restricted under the Medicines Act 1968. Lower-strength products containing combinations of up to 12.8 mg of codeine per dosage unit, combined with paracetamol, ibuprofen or aspirin are available over the counter at pharmacies. Codeine linctus of 15 mg per 5 ml is also available at some pharmacies, although a purchaser would have to request it specifically from the pharmacist.Under the Misuse of Drugs Act 1971 codeine is a Class B controlled substance or a Class A drug when prepared for injection. The possession of controlled substances without a prescription is a criminal offence. However, certain preparations of codeine are exempt from this restriction under Schedule 5 of the Misuse of Drugs Regulations 2001. It is thus legal to possess codeine without a prescription, provided that it is compounded with at least one other active or inactive ingredient and that the dosage of each tablet, capsule, etc. does not exceed 100 mg or 2.5% concentration in the case of liquid preparations. The exemptions do not to apply to any preparation of codeine designed for injection. United States In the United States, codeine is regulated by the Controlled Substances Act. Federal law dictates that codeine be a Schedule II controlled substance when used in products for pain-relief that contain codeine alone or more than 80 mg per dosage unit. Codeine without aspirin or acetaminophen (Tylenol) is very rarely available or prescribed in order to discourage abuse. Tablets of codeine in combination with aspirin or acetaminophen (paracetamol) and intended for pain relief are listed as Schedule II, requiring a physical paper-copy (aka triplicate) of the physician ordered prescription. Cough syrups are classed as Schedule III, IV or V, depending on formulation. For example, the acetaminophen/codeine antitussive liquid is a Schedule IV controlled substance.Some states have chosen to reclassify codeine preparations at a more restrictive schedule in order to lower the instances of its abuse. Minnesota, for instance, has chosen to reclassify Schedule V some codeine preparations (e.g. Cheratussin) as a Schedule II controlled substance.Schedule V Controlled Substances Substances in this schedule have a low potential for abuse relative to substances listed in Schedule IV and consist primarily of preparations containing limited quantities of certain narcotics. Examples of Schedule V substances include: cough preparations containing not more than 200 milligrams of codeine per 100 milliliters or per 100 grams (Robitussin AC®, Phenergan with Codeine®), and ezogabine. References Notes Further reading Dean L (2012). "Codeine Therapy and CYP2D6 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520350. Bookshelf ID: NBK100662. External links "Codeine". Drug Information Portal. U.S. National Library of Medicine.
Oxaprozin	Oxaprozin, also known as oxaprozinum, is a nonsteroidal anti-inflammatory drug (NSAID), used to relieve the inflammation, swelling, stiffness, and joint pain associated with osteoarthritis and rheumatoid arthritis. Chemically, it is a propionic acid derivative. Safety and efficacy has been established in children over 6 years with juvenile rheumatoid arthritis only, and there is an increased risk of adverse reactions in the elderly population. It was patented in 1967 and approved for medical use in 1983. Medical uses In 2015, oxaprozin was one of twenty NSAIDs included in a clinical trial to compare the efficacy of NSAIDs in the short-term treatment of ankylosing spondylitis (AS). The NSAIDs were compared by completing randomized controlled trials of NSAIDs in patients with active AS. Efficacy reported at 2–12 weeks and adverse effects were examined. Efficacy was measured by change in pain score and change in the duration of morning stiffness. A total of 26 trials with a total of 3410 participants were completed (58% of the trials had fewer than 50 participants). While all 20 NSAIDs were found to reduce more pain than the placebo, 15 were found to be significantly better. In regards to the decrease of morning stiffness and the likelihood of adverse events, there was no significant difference between NSAIDs. It was concluded that etoricoxib was more effective in reducing pain of AS, however due to small studies and insufficient evidence, no one NSAID could be determined to be the most effective treatment of AS. After etoricoxib, patients taking oxaprozin experienced the least amount of pain with fewer adverse effects than naproxen. Adverse effects In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. History Oxaprozin was developed and patented by Wyeth-Ayerst. The US patent 3578671, Oxazoles, was filed November 6, 1967 and published May 11, 1971. Following the filing of the patent, the first description of oxaprozin exhibiting anti-inflammatory properties was outlined in the article Diaryloxazole and diaylthiazolealkanoci acids: two novel series of non-steroidal anti-inflammatory agents. This article was published in Nature in 1968. In December 1988, Wyeth-Ayerst licensed the marketing rights for the US, Canada, Puerto Rico, and the Caribbean to Searle.Daypro became available January 5, 1993. Upon its release, “The Pink Sheet” estimated that the average whole sale price of Searles Daypro was $112.30 for 100 (600 mg) tablets. The price was comparable to other prescription NSAIDs. Society and culture FDA approval The oxaprozin new drug application (NDA 18-841) was submitted to the FDA on August 10, 1982. The drug was granted an “NDA Day” review on June 15–16, 1992. After Searle agreed to complete seven Phase IV postmarketing studies on October 22, the FDA approved Daypro on October 29, 1992.Since the approval of Daypro by Searle, other companies have submitted abbreviated new drug applications (ANDAs) to the FDA. Daypro by Searle is listed as the Reference Listed Drug to prove the bioequivalence of the ANDAs. Below is a table listing all of the approved oxaprozin products. Recalls Advantage Dose LLC recalled oxaprozin tablets on November 26, 2008. The company was not in conformance with cGMP. (Recall #D-837-2009) == References ==
Desoximetasone	Desoximetasone is a medication belonging to the family of medications known as topical corticosteroids. It is used for the relief of various skin conditions, including rashes. It helps to reduce redness, itching, and irritation. Desoximetasone is a synthetic corticosteroid, a class of primarily synthetic steroids used as anti-inflammatory and anti-pruritic agents. Three brand name products are available (availability depending on country): Topicort Emollient Cream (0.25% desoximetasone) Topicort LP Emollient Cream (0.05% desoximetasone) Topisolone Cream (0.25% desoximetasone) Usage When using desoximetasone, some of the medication may be absorbed through the skin and into the bloodstream. Too much absorption can lead to unwanted side effects elsewhere in the body. Large amounts of desoximetasone should be avoided over large areas. It should not be used for extended periods of time. Treated areas should not be covered with airtight dressings such as plastic wrap or adhesive bandages. Children may absorb more medication than adults do. Desoximetasone is for use only on the skin and should be kept out of the eyes. Desoximetasone can also be used to treat some types of psoriasis. See also Clobetasol propionate Dexamethasone References External links Topicort general info Topicort usage info
Tolmetin	Tolmetin is a nonsteroidal anti-inflammatory drug (NSAID) of the heterocyclic acetic acid derivative class. It is used primarily to reduce hormones that cause pain, swelling, tenderness, and stiffness in conditions such as osteoarthritis and rheumatoid arthritis, including juvenile rheumatoid arthritis. In the United States it is marketed as Tolectin and comes as a tablet or capsule. Clinical trials Tolmetin is applicable in the treatment of rheumatoid arthritis, osteoarthrosis, pain, and ankylosing spondylitis. Mechanism of action Although the mechanism of action of tolmetin is unknown, research involving humans and animals has shown that tolmetin does not achieve anti-inflammatory response by stimulation of the adrenal or pituitary gland, but it has shown tolmetin restrains prostaglandin synthetase in vitro and reduces plasma levels of prostaglandin E, possibly causing the anti-inflammatory response. When tested in rats, tolmetin prevented experimentally stimulated polyarthritis and reduced inflammation. In patients with rheumatoid arthritis or osteoarthritis tolmetin restrained disease activity as efficiently as aspirin and indometacin, although the occurrence of mild gastrointestinal adverse effects and tinnitus was lower in patients treated with tolmetin than it was with aspirin-treated patients and the occurrence of adverse effects of the central nervous system was lower with tolmetin than it was with indometacin. Side effects Tolmetin can increase the risk of heart or circulatory conditions such as heart attacks and strokes. It should not be taken shortly before or after coronary artery bypass surgery. Tolmetin can also increase the risk of gastrointestinal conditions such as perforation or bleeding, which is fatal. Antacids can be taken with tolmetin to relieve stomachaches that often occur. Overdose can result in drowsiness, nausea, epigastric pain, and vomiting. In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result from low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. == References ==
Iron(II,III) oxide	Iron(II,III) oxide is the chemical compound with formula Fe3O4. It occurs in nature as the mineral magnetite. It is one of a number of iron oxides, the others being iron(II) oxide (FeO), which is rare, and iron(III) oxide (Fe2O3) which also occurs naturally as the mineral hematite. It contains both Fe2+ and Fe3+ ions and is sometimes formulated as FeO ∙ Fe2O3. This iron oxide is encountered in the laboratory as a black powder. It exhibits permanent magnetism and is ferrimagnetic, but is sometimes incorrectly described as ferromagnetic. Its most extensive use is as a black pigment. For this purpose, it is synthesized rather than being extracted from the naturally occurring mineral as the particle size and shape can be varied by the method of production. Preparation Heated iron metal interacts with steam to form iron oxide and hydrogen gas. 3 Fe + 4 H 2 O ⟶ Fe 3 O 4 + 4 H 2 {\displaystyle {\ce {3Fe + 4H2O->Fe3O4 + 4H2}}} Under anaerobic conditions, ferrous hydroxide (Fe(OH)2) can be oxidized by water to form magnetite and molecular hydrogen. This process is described by the Schikorr reaction: 3 Fe ( OH ) 2 ferrous hydroxide ⟶ Fe 3 O 4 magnetite + H 2 hydrogen + 2 H 2 O water {\displaystyle {\ce {{\underset {ferrous\ hydroxide}{3Fe(OH)2}}->{\underset {magnetite}{Fe3O4}}+{\underset {hydrogen}{H2}}+{\underset {water}{2H2O}}}}} This works because crystalline magnetite (Fe3O4) is thermodynamically more stable than amorphous ferrous hydroxide (Fe(OH)2 ).The Massart method of preparation of magnetite as a ferrofluid, is convenient in the laboratory: mix iron(II) chloride and iron(III) chloride in the presence of sodium hydroxide.A more efficient method of preparing magnetite without troublesome residues of sodium, is to use ammonia to promote chemical co-precipitation from the iron chlorides: first mix solutions of 0.1 M FeCl3·6H2O and FeCl2·4H2O with vigorous stirring at about 2000 rpm. The molar ratio of the FeCl3:FeCl2 should be about 2:1. Heat the mix to 70 °C, then raise the speed of stirring to about 7500 rpm and quickly add a solution of NH4OH (10 volume %). A dark precipitate of nanoparticles of magnetite forms immediately.In both methods, the precipitation reaction relies on rapid transformation of acidic iron ions into the spinel iron oxide structure at pH 10 or higher. Controlling the formation of magnetite nanoparticles presents challenges: the reactions and phase transformations necessary for the creation of the magnetite spinel structure are complex. The subject is of practical importance because magnetite particles are of interest in bioscience applications such as magnetic resonance imaging (MRI), in which iron oxide magnetite nanoparticles potentially present a non-toxic alternative to the gadolinium-based contrast agents currently in use. However, difficulties in controlling the formation of the particles, still frustrate the preparation of superparamagnetic magnetite particles, that is to say: magnetite nanoparticles with a coercivity of 0 A/m, meaning that they completely lose their permanent magnetisation in the absence of an external magnetic field. The smallest values currently reported for nanosized magnetite particles is Hc = 8.5 A m−1, whereas the largest reported magnetization value is 87 Am2 kg−1 for synthetic magnetite.Pigment quality Fe3O4, so called synthetic magnetite, can be prepared using processes that use industrial wastes, scrap iron or solutions containing iron salts (e.g. those produced as by-products in industrial processes such as the acid vat treatment (pickling) of steel): Oxidation of Fe metal in the Laux process where nitrobenzene is treated with iron metal using FeCl2 as a catalyst to produce aniline:C6H5NO2 + 3 Fe + 2 H2O → C6H5NH2 + Fe3O4Oxidation of FeII compounds, e.g. the precipitation of iron(II) salts as hydroxides followed by oxidation by aeration where careful control of the pH determines the oxide produced.Reduction of Fe2O3 with hydrogen: 3Fe2O3 + H2 → 2Fe3O4 +H2OReduction of Fe2O3 with CO: 3Fe2O3 + CO → 2Fe3O4 + CO2Production of nano-particles can be performed chemically by taking for example mixtures of FeII and FeIII salts and mixing them with alkali to precipitate colloidal Fe3O4. The reaction conditions are critical to the process and determine the particle size.Iron(II) carbonate can also be thermally decomposed into Iron(II,III): 3FeCO3 → Fe3O4 + 2CO2 + CO Reactions Reduction of magnetite ore by CO in a blast furnace is used to produce iron as part of steel production process: Fe 3 O 4 + 4 CO ⟶ 3 Fe + 4 CO 2 {\displaystyle {\ce {{Fe3O4}+ 4CO -> {3Fe}+ 4CO2}}} Controlled oxidation of Fe3O4 is used to produce brown pigment quality γ-Fe2O3 (maghemite): 2 Fe 3 O 4 ⏟ magnetite + 1 2 O 2 ⟶ 3 ( γ − Fe 2 O 3 ) ⏟ maghemite {\displaystyle {\ce {\underbrace{2Fe3O4}_{magnetite}+ {1/2O2}->}}\ {\color {Brown}{\ce {\underbrace{3(\gamma-Fe2O3)}_{maghemite}}}}} More vigorous calcining (roasting in air) gives red pigment quality α-Fe2O3 (hematite): 2 Fe 3 O 4 ⏟ magnetite + 1 2 O 2 ⟶ 3 ( α − Fe 2 O 3 ) ⏟ hematite {\displaystyle {\ce {\underbrace{2Fe3O4}_{magnetite}+ {1/2O2}->}}\ {\color {BrickRed}{\ce {\underbrace{3(\alpha-Fe2O3)}_{hematite}}}}} Structure Fe3O4 has a cubic inverse spinel group structure which consists of a cubic close packed array of oxide ions where all of the Fe2+ ions occupy half of the octahedral sites and the Fe3+ are split evenly across the remaining octahedral sites and the tetrahedral sites. Both FeO and γ-Fe2O3 have a similar cubic close packed array of oxide ions and this accounts for the ready interchangeability between the three compounds on oxidation and reduction as these reactions entail a relatively small change to the overall structure. Fe3O4 samples can be non-stoichiometric.The ferrimagnetism of Fe3O4 arises because the electron spins of the FeII and FeIII ions in the octahedral sites are coupled and the spins of the FeIII ions in the tetrahedral sites are coupled but anti-parallel to the former. The net effect is that the magnetic contributions of both sets are not balanced and there is a permanent magnetism.In the molten state, experimentally constrained models show that the iron ions are coordinated to 5 oxygen ions on average. There is a distribution of coordination sites in the liquid state, with the majority of both FeII and FeIII being 5-coordinated to oxygen and minority populations of both 4- and 6-fold coordinated iron. Properties Fe3O4 is ferrimagnetic with a Curie temperature of 858 K (585 °C). There is a phase transition at 120 K (−153 °C), called Verwey transition where there is a discontinuity in the structure, conductivity and magnetic properties. This effect has been extensively investigated and whilst various explanations have been proposed, it does not appear to be fully understood.While it has much higher electrical resistivity than iron metal (96.1 nΩ m), Fe3O4s electrical resistivity (0.3 mΩ m ) is significantly lower than that of Fe2O3 (approx kΩ m). This is ascribed to electron exchange between the FeII and FeIII centres in Fe3O4. Uses Fe3O4 is used as a black pigment and is known as C.I pigment black 11 (C.I. No.77499) or Mars Black.Fe3O4 is used as a catalyst in the Haber process and in the water-gas shift reaction. The latter uses an HTS (high temperature shift catalyst) of iron oxide stabilised by chromium oxide. This iron–chrome catalyst is reduced at reactor start up to generate Fe3O4 from α-Fe2O3 and Cr2O3 to CrO3.Bluing is a passivation process that produces a layer of Fe3O4 on the surface of steel to protect it from rust. Along with sulfur and aluminium, it is an ingredient in steel-cutting thermite. Medical uses Nano particles of Fe3O4 are used as contrast agents in MRI scanning.Ferumoxytol, sold under the brand names Feraheme and Rienso, is an intravenous Fe3O4 preparation for treatment of anemia resulting from chronic kidney disease. Ferumoxytol is manufactured and globally distributed by AMAG Pharmaceuticals. Biological occurrence Magnetite has been found as nano-crystals in magnetotactic bacteria (42–45 nm) and in the beak tissue of homing pigeons. References External links "Ferumoxytol". Drug Information Portal. U.S. National Library of Medicine.
Dexmedetomidine	Dexmedetomidine, sold under the trade name Precedex among others, is a medication used for sedation. It is also used to treat acute agitation associated with schizophrenia or bipolar I or II disorder.Similar to clonidine, it is a sympatholytic drug that acts as an agonist of α2-adrenergic receptors in certain parts of the brain. Veterinarians use dexmedetomidine for similar purposes in treating cats, dogs, and horses. It was developed by Orion Pharma. Medical uses Intensive care unit sedation Studies suggest dexmedetomidine for sedation in mechanically ventilated adults may reduce time to extubation and ICU stay.Compared with other sedatives, some studies suggest dexmedetomidine may be associated with less delirium. However, this finding is not consistent across multiple studies. At the very least, when aggregating many study results together, use of dexmedetomidine appears to be associated with less neurocognitive dysfunction compared to other sedatives. Whether this observation has a beneficial psychological impact is unclear. From an economic perspective, dexmedetomidine is associated with lower ICU costs, largely due to a shorter time to extubation. Procedural sedation Dexmedetomidine can also be used for procedural sedation such as during colonoscopy. It can be used as an adjunct with other sedatives like benzodiazepines, opioids, and propofol to enhance sedation and help maintain hemodynamic stability by decreasing the requirement of other sedatives. Dexmedetomidine is also used for procedural sedation in children.It can be used for sedation required for awake fibreoptic nasal intubation in patients with a difficult airway. Other Dexmedetomidine may be useful for the treatment of the negative cardiovascular effects of acute amphetamines and cocaine intoxication and overdose. Dexmedetomidine has also been used as an adjunct to neuroaxial anesthesia for lower limb procedures.In 2022 it was approved by the FDA for the treatment of agitation in schizophrenia and bipolar disorder. Side effects There is no absolute contraindication to the use of dexmedetomidine. It has a biphasic effect on blood pressure with lower readings at lower drug concentrations and higher readings at higher concentrations. Interactions Dexmedetomidine may enhance the effects of other sedatives and anesthetics when co-administered. Similarly, drugs that lower blood pressure and heart rate, such as beta blockers, may also have enhanced effects when co-administered with dexmedetomidine. Pharmacology Pharmacodynamics Dexmedetomidine is a highly selective α2-adrenergic agonist. It possesses an α2:α1 selectivity ratio of 1620:1, making it eight times more selective for the α2-receptor than clonidine. Unlike opioids and other sedatives such as propofol, dexmedetomidine is able to achieve its effects without causing respiratory depression. Dexmedetomidine induces sedation by decreasing activity of noradrenergic neurons in the locus ceruleus in the brain stem, thereby increasing the downstream activity of inhibitory gamma-aminobutyric acid (GABA) neurons in the ventrolateral preoptic nucleus. In contrast, other sedatives like propofol and benzodiazepines directly increase activity of gamma-aminobutyric acid neurons. Through action on this endogenous sleep-promoting pathway the sedation produced by dexmedetomidine more closely mirrors natural sleep (specifically stage 2 non-rapid eye movement sleep), as demonstrated by EEG studies. As such, dexmedetomidine provides less amnesia than benzodiazepines. Dexmedetomidine also has analgesic effects at the spinal cord level and other supraspinal sites. Pharmacokinetics Intravenous dexmedetomidine exhibits linear pharmacokinetics with a rapid distribution half-life of approximately 6 minutes in healthy volunteers, and a longer and more variable distribution half-life in ICU patients. The terminal elimination half-life of intravenous dexmedetomidine ranged 2.1 to 3.1 hours in healthy adults and 2.2 to 3.7 hours in ICU patients. Plasma protein binding of dexmedetomidine is about 94% (mostly albumin).Dexmedetomidine is metabolized by the liver, largely by glucuronidation (34%) as well as by oxidation via CYP2A6 and other Cytochrome P450 enzymes. As such, it should be used with caution in people with liver disease.The majority of metabolized dexmedetomidine is excreted in the urine (~95%).It can be absorbed sublingually. History Dexmedetomidine was approved in 1999 by the US Food and Drug Administration (FDA) as a short-term sedative and analgesic (<24 hours) for critically ill or injured people on mechanical ventilation in the intensive care unit (ICU). The rationale for its short-term use was due to concerns over withdrawal side effects such as rebound high blood pressure. These effects have not been consistently observed in research studies, however. Veterinary use Dexmedetomidine, under the trade name Dexdomitor (Orion Corporation), was approved in the European Union in for use in cats and dogs in 2002, for sedation and induction of general anesthesia. The FDA approved dexmedetomidine for use in dogs in 2006 and cats in 2007.In 2015, the European Medicines Agency and the FDA approved an oromucosal gel form of dexmedetomidine marketed as Sileo (Zoetis) for use in dogs for relief of noise aversion. References External links "Dexmedetomidine". Drug Information Portal. U.S. National Library of Medicine. "Dexmedetomidine hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Romidepsin	Romidepsin, also known as Istodax, is an anticancer agent used in cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphomas (PTCLs). Romidepsin is a natural product obtained from the bacterium Chromobacterium violaceum, and works by blocking enzymes known as histone deacetylases, thus inducing apoptosis. It is sometimes referred to as depsipeptide, after the class of molecules to which it belongs. Romidepsin is branded and owned by Gloucester Pharmaceuticals, now a part of Celgene. History Romidepsin was first reported in the scientific literature in 1994, by a team of researchers from Fujisawa Pharmaceutical Company (now Astellas Pharma) in Tsukuba, Japan, who isolated it in a culture of Chromobacterium violaceum from a soil sample obtained in Yamagata Prefecture. It was found to have little to no antibacterial activity, but was potently cytotoxic against several human cancer cell lines, with no effect on normal cells; studies on mice later found it to have antitumor activity in vivo as well.The first total synthesis of romidepsin was accomplished by Harvard researchers and published in 1996. Its mechanism of action was elucidated in 1998, when researchers from Fujisawa and the University of Tokyo found it to be a histone deacetylase inhibitor with effects similar to those of trichostatin A. Clinical trials Phase I studies of romidepsin, initially codenamed FK228 and FR901228, began in 1997. Phase II and phase III trials were conducted for a variety of indications. The most significant results were found in the treatment of cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphomas (PTCLs).In 2004, romidepsin received Fast Track designation from the FDA for the treatment of cutaneous T-cell lymphoma, and orphan drug status from the FDA and the European Medicines Agency for the same indication.The FDA approved romidepsin for CTCL in November 2009 and approved romidepsin for other peripheral T-cell lymphomas (PTCLs) in June 2011.A randomised, phase III trial of romidepsin + CHOP chemotherapy vs CHOP chemotherapy for patients with peripheral T cell lymphoma returned negative results, having no significant impact on progression free survival or overall survival. Pre-clinical HIV study In 2014, PLOS Pathogens published a study involving romidepsin in a trial designed to reactivate latent HIV virus in order to deplete the HIV reservoir. Latently infected T-cells were exposed in vitro and ex vivo to romidepsin, leading to an increase in detectable levels of cell-associated HIV RNA. The trial also compared the effect of romidepsin to another histone deacetylase inhibitor, Vorinostat Autism study in animal model A study involving romidepsin in an animal study that showed that a brief treatment with low amounts of romidepsin could reverse social deficits in a mouse model of autism. Pharmacodynamics In a Phase II trial of romidepsin involving patients with CTCL or PTCL, there was evidence of increased histone acetylation in peripheral blood mononuclear cells (PBMCs) extending 4–48 hours. Expression of the ABCB1 gene, a marker of romidepsin-induced gene expression, was also increased in both PBMCs and tumor biopsy samples. Increased gene expression following increased histone acetylation is an expected effect of an HDAC inhibitor. Increased hemoglobin F (another surrogate marker for gene-expression changes resulting from HDAC inhibition) was also detected in blood after romidepsin administration, and persistent histone acetylation was inversely associated with drug clearance and directly associated with patient response to therapy. Dosage and administration The approved dosage of romidepsin in both CTCL and PTCL is a four-hour i.v. administration of 14 mg/m2 on days 1, 8, and 15 of a 28-day treatment cycle. This cycle should be repeated as long as the patient continues to benefit and tolerate the therapy. A dose reduction to 10 mg/m2 is possible in some patients who experience high-grade toxicities. Pharmacokinetics In trials involving patients with advanced cancers, romidepsin exhibited linear pharmacokinetics across doses ranging from 1.0 to 24.9 mg/m2 when administered intravenously over four hours. Age, race, sex, mild-to-severe renal impairment, and mild-to-moderate hepatic impairment had no effect on romidepsin pharmacokinetics. No accumulation of plasma concentration was observed after repeated dosing. Mechanism of action Romidepsin acts as a prodrug with the disulfide bond undergoing reduction within the cell to release a zinc-binding thiol. The thiol binds to a zinc atom in the binding pocket of Zn-dependent histone deacetylase to block its activity. Thus it is an HDAC inhibitor. Many HDAC inhibitors are potential treatments for cancer through the ability to epigenetically restore normal expression of tumor suppressor genes, which may result in cell cycle arrest, differentiation, and apoptosis. Adverse effects The use of romidepsin is uniformly associated with adverse effects. In clinical trials, the most common were nausea and vomiting, fatigue, infection, loss of appetite, and blood disorders (including anemia, thrombocytopenia, and leukopenia). It has also been associated with infections, and with metabolic disturbances (such as abnormal electrolyte levels), skin reactions, altered taste perception, and changes in cardiac electrical conduction. References External links Clinical trials of romidepsin at ClinicalTrials.gov
Pentazocine	Pentazocine, sold under the brand name Talwin among others, is a painkiller used to treat moderate to severe pain. It is believed to work by activating (agonizing) κ-opioid receptors (KOR) and μ-opioid receptors (MOR). As such it is called an opioid as it delivers its effects on pain by interacting with the opioid receptors. It shares many of the side effects of other opioids like constipation, nausea, itching, drowsiness and respiratory depression, but unlike most other opioids it fairly frequently causes hallucinations, nightmares and delusions. It is also, unlike most other opioids, subject to a ceiling effect, which is when at a certain dose (which differs from person-to-person) no more pain relief, or side effects, is obtained by increasing the dose any further.Chemically it is classed as a benzomorphan and it comes in two enantiomers, which are molecules that are exact (non-superimposable) mirror images of one another. It was patented in 1960 and approved for medical use in 1964. Usually, in its oral formulations, it is combined with naloxone so as to prevent people from crushing the tablets, dissolving them in a solvent (like water) and injecting them for a high (as orally administered naloxone produces no opioid-negating effects, whereas intravenous or intramuscular administration does). Use Medical Pentazocine is used primarily to treat pain, although its analgesic effects are subject to a ceiling effect. It has been discontinued by its corporate sponsor in Australia, although it may be available through the special access scheme. Recreational In the 1970s, recreational drug users discovered that combining pentazocine with tripelennamine (a first-generation ethylenediamine antihistamine most commonly dispensed under the brand names Pelamine and Pyribenzamine) produced a euphoric sensation. Since tripelennamine tablets are typically blue in color and brand-name Pentazocine is known as Talwin (hence "Ts"), the pentazocine/tripelennamine combination acquired the slang name Ts and blues. After health-care professionals and drug-enforcement officials became aware of this scenario, the mu opioid receptor antagonist naloxone was added to oral preparations containing pentazocine to prevent perceived "misuse" via injection, and the reported incidence of its recreational use has declined precipitously since. Research In an open-label, add-on, single-day, acute-dose small clinical study, pentazocine was found to rapidly and substantially reduce symptoms of mania in individuals with bipolar disorder that were in the manic phase of the condition. It was postulated that the efficacy observed was due to κ-opioid receptor activation-mediated amelioration of hyperdopaminergia in the reward pathways. Minimal sedation and no side effects including psychotomimetic effects or worsening of psychosis were observed at the dose administered. Adverse effects Side effects are similar to those of morphine, but pentazocine, due to its action at the kappa opioid receptor is more likely to invoke psychotomimetic effects. High dose may cause high blood pressure or high heart rate. It may also increase cardiac work after myocardial infarction when given intravenously and hence this use should be avoided where possible. Respiratory depression is a common side effect, but is subject to a ceiling effect, such that at a certain dose the degree of respiratory depression will no longer increase with dose increases. Likewise rarely it has been associated with agranulocytosis, erythema multiforme and toxic epidermal necrolysis. Tissue damage at injection sites Severe injection site necrosis and sepsis has occurred (sometimes requiring amputation of limb) with multiple injection of pentazocine lactate. In addition, animal studies have demonstrated that Pentazocine is tolerated less well subcutaneously than intramuscularly. History Pentazocine was developed by the Sterling Drug Company, Sterling-Winthrop Research Institute, of Rensselaer, New York. The analgesic compound was first made at Sterling in 1958. U.S. testing was conducted between 1961 and 1967.It was approved by the Food and Drug Administration in June 1967 after being favorably reviewed following testing on 12,000 patients in the United States. By mid 1967 Pentazocine was already being sold in Mexico, England, and Argentina, under different trade names. Society and culture Legal status Pentazocine was originally unclassified under the Controlled Substances Act. A petition was filed with the Drug Enforcement Administration on October 1, 1971, to shift it to Schedule III. The petition was filed by Joseph L. Fink III, a pharmacist and law student at Georgetown University Law Center as part of the course Lawyering in the Public Interest. That petition was accepted for review on November 10, 1971. D.E.A. published a Final Rule transferring it to schedule IV on January 10, 1979, with an effective date of February 9, 1979. This is understood to be the first instance of a successful petition to reclassify a substance under the relatively recently enacted Controlled Substances Act. Pentazocine is still classified in Schedule IV under the Controlled Substances Act in the United States, even with the addition of Naloxone. Some states classify it in Schedule II, such as Illinois and South Carolina (injectable form only), or Schedule III such as Kentucky.) Internationally, pentazocine is a Schedule III drug under the Convention on Psychotropic Substances. Pentazocine has a DEA ACSCN of 9720; being a Schedule IV substance, the DEA does not assign an annual manufacturing quota for pentazocine for the United States. Brand names Pentazocine is sold under several brand names, such as Fortral, Sosegon, Talwin NX (with naloxone), Talwin, Talwin PX, Fortwin and Talacen (with paracetamol (acetaminophen)). See also Cyclazocine (hallucinogenic) Volazocine References External links Eurekalert report on PNAS article

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