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Dextroamphetamine	DBH), flavin-containing monooxygenase 3 (FMO3), butyrate-CoA ligase (XM-ligase), and glycine N-acyltransferase (GLYAT) are the enzymes known to metabolize amphetamine or its metabolites in humans. Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone. Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine, 4-hydroxynorephedrine, and norephedrine. The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination. The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following: History, society, and culture Racemic amphetamine was first synthesized under the chemical name "phenylisopropylamine" in Berlin, 1887 by the Romanian chemist Lazar Edeleanu. It was not widely marketed until 1932, when the pharmaceutical company Smith, Kline & French (now known as GlaxoSmithKline) introduced it in the form of the Benzedrine inhaler for use as a bronchodilator. Notably, the amphetamine contained in the Benzedrine inhaler was the liquid free-base, not a chloride or sulfate salt. Three years later, in 1935, the medical community became aware of the stimulant properties of amphetamine, specifically dextroamphetamine, and in 1937 Smith, Kline, and French introduced tablets under the brand name Dexedrine. In the United States, Dexedrine was approved to treat narcolepsy and attention disorders. In Canada indications once included epilepsy and parkinsonism. Dextroamphetamine was marketed in various other forms in the following decades, primarily by Smith, Kline, and French, such as several combination medications including a mixture of dextroamphetamine and amobarbital (a barbiturate) sold under the tradename Dexamyl and, in the 1950s, an extended release capsule (the "Spansule"). Preparations containing dextroamphetamine were also used in World War II as a treatment against fatigue.It quickly became apparent that dextroamphetamine and other amphetamines had a high potential for misuse, although they were not heavily controlled until 1970, when the Comprehensive Drug Abuse Prevention and Control Act was passed by the United States Congress. Dextroamphetamine, along with other sympathomimetics, was eventually classified as Schedule II, the most restrictive category possible for a drug with a government-sanctioned, recognized medical use. Internationally, it has been available under the names AmfeDyn (Italy), Curban (US), Obetrol (Switzerland), Simpamina (Italy), Dexedrine/GSK (US & Canada), Dexedrine/UCB (United Kingdom), Dextropa (Portugal), and Stild (Spain). It became popular on the mod scene in England in the early 1960s, and carried through to the Northern Soul scene in the north of England to the end of the 1970s. In October 2010, GlaxoSmithKline sold the rights for Dexedrine Spansule to Amedra Pharmaceuticals (a subsidiary of CorePharma).The U.S. Air Force uses dextroamphetamine as one of its "go pills", given to pilots on long missions to help them remain focused and alert. Conversely, "no-go pills" are used after the mission is completed, to combat the effects of the mission and "go-pills". The Tarnak Farm incident was linked by media reports to the use of this drug on long term fatigued pilots. The military did not accept this explanation, citing the lack of similar incidents. Newer stimulant medications or awakeness promoting agents with different side effect profiles, such as modafinil, are being investigated and sometimes issued for this reason. Formulations Transdermal Dextroamphetamine Patches Dextroamphetamine is available as a transdermal patch containing dextroamphetamine base under the brand name Xelstrym. It is available in four dosage forms each worn for 9 hours that deliver dextroamphetamine at rates of 4.5 mg/9 hours, 9 mg/9 hours, 13.5 mg/9 hours, and 18 mg/9 hours. Dextroamphetamine sulfate In the United States, immediate release (IR) formulations of dextroamphetamine sulfate are available generically as 5 mg and 10 mg tablets, marketed by Barr (Teva Pharmaceutical Industries), Mallinckrodt Pharmaceuticals, Wilshire Pharmaceuticals, Aurobindo Pharmaceutical USA and CorePharma. Previous IR tablets sold under the brand names Dexedrine and Dextrostat have been discontinued but in 2015, IR tablets became available by the brand name Zenzedi, offered as 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg and 30 mg tablets. Dextroamphetamine sulfate is also available as a controlled-release (CR) capsule preparation in strengths of 5 mg, 10 mg, and 15 mg under the brand name Dexedrine Spansule, with generic versions marketed by Barr and Mallinckrodt. A bubblegum flavored oral solution is available under the brand name ProCentra, manufactured by FSC Pediatrics, which is designed to be an easier method of administration in children who have difficulty swallowing tablets, each 5 mL contains 5 mg dextroamphetamine. The conversion rate between dextroamphetamine sulfate to amphetamine free base is.728.In Australia, dexamphetamine is available in bottles of 100 instant release 5 mg tablets as a generic drug. or slow release dextroamphetamine preparations may be compounded by individual chemists. In the United Kingdom, it is available in 5 mg instant release sulfate tablets under the generic name dexamfetamine sulfate as well as 10 mg and 20 mg strength tablets under the brand name Amfexa. It is also available in generic dexamfetamine sulfate 5 mg/ml oral sugar-free syrup. The brand name Dexedrine was available in the United Kingdom prior to UCB Pharma disinvesting the product to another pharmaceutical company (Auden Mckenzie). Lisdexamfetamine Dextroamphetamine is the active metabolite of the prodrug lisdexamfetamine (L-lysine-dextroamphetamine), available by the brand name Vyvanse (Elvanse in the European market) (Venvanse in the Brazil market) (lisdexamfetamine dimesylate). Dextroamphetamine is liberated from lisdexamfetamine enzymatically following contact with red blood cells. The conversion is rate-limited by the enzyme, which prevents high blood concentrations of dextroamphetamine and reduces lisdexamfetamines drug liking and abuse potential at clinical doses. Vyvanse is marketed as once-a-day dosing as it provides a slow release of dextroamphetamine into the body. Vyvanse is available as capsules, and chewable tablets, and in seven strengths; 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg. The conversion rate between lisdexamfetamine dimesylate (Vyvanse) to dextroamphetamine base is 29.5%. Adderall Another pharmaceutical that contains dextroamphetamine is commonly known by the brand name Adderall. It is available as immediate release (IR) tablets and extended release (XR) capsules. Adderall contains equal amounts of four amphetamine salts: One-quarter racemic (d,l-)amphetamine aspartate monohydrate One-quarter dextroamphetamine saccharate One-quarter dextroamphetamine sulfate One-quarter racemic (d,l-)amphetamine sulfateAdderall has a total amphetamine base equivalence of 63%. While the enantiomer ratio by dextroamphetamine salts to levoamphetamine salts is 3:1, the amphetamine base content is 75.9% dextroamphetamine, 24.1% levoamphetamine. Notes Image legend Reference notes References External links "Dextroamphetamine". Drug Information Portal. U.S. National Library of Medicine. Poison Information Monograph (PIM 178: Dexamphetamine Sulphate)
Metamucil	Metamucil is a fiber supplement. Introduced in 1934 by G. D. Searle & Company, Metamucil was acquired by Procter & Gamble in 1985. The name is a combination of the Greek word for change (meta) and the class of fiber that it utilizes (mucilage). In its early years, Metamucil achieved sporadic drug-store distribution as a "behind the counter" brand. Since 1974, the brand was also marketed to consumers by print and TV advertising and became available in food outlets. Flavored versions were added in 1979. Products The brand is sold as powdered drink mixes, capsules and wafers in a variety of flavors. Metamucil contains psyllium seed husks as the active ingredient. It is manufactured in Phoenix, Arizona, by Procter & Gamble. When first marketed to consumers in 1974, Metamucil was marketed as a laxative. The advertising slogan at that time was "If not nature, then Metamucil". Procter & Gamble sought to make Metamucil a household name by advertising in magazines and on television, using the claim "All fiber is not created equal".The target group was older people who are more likely to suffer from constipation. On October 4, 2013, Procter & Gamble partnered with Tony Danza to organize the “Do More Than You Think” contest to promote and fund health and wellness charities. The main prize was the chance to select the charity that would receive a $100,000 donation from Procter & Gamble. == References ==
Fluoxetine	Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorder (OCD), bulimia nervosa, panic disorder, and premenstrual dysphoric disorder. It is also approved for treatment of major depressive disorder in adolescents and children 8 years of age and over. It has also been used to treat premature ejaculation. Fluoxetine is taken by mouth.Common side effects include indigestion, trouble sleeping, sexual dysfunction, loss of appetite, dry mouth, and rash. Serious side effects include serotonin syndrome, mania, seizures, an increased risk of suicidal behavior in people under 25 years old, and an increased risk of bleeding. Antidepressant discontinuation syndrome is less likely to occur with fluoxetine than with other antidepressants, but it still happens in many cases. Fluoxetine taken during pregnancy is associated with significant increase in congenital heart defects in the newborns. It has been suggested that fluoxetine therapy may be continued during breastfeeding if it was used during pregnancy or if other antidepressants were ineffective.Fluoxetine was discovered by Eli Lilly and Company in 1972, and entered medical use in 1986. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2020, it was the 25th most commonly prescribed medication in the United States, with more than 23 million prescriptions. Lilly also markets fluoxetine in a fixed-dose combination with olanzapine as olanzapine/fluoxetine (Symbyax). Medical uses Fluoxetine is frequently used to treat major depressive disorder, obsessive–compulsive disorder (OCD), post-traumatic stress disorder (PTSD), bulimia nervosa, panic disorder, premenstrual dysphoric disorder, and trichotillomania. It has also been used for cataplexy, obesity, and alcohol dependence, as well as binge eating disorder. Fluoxetine seems to be ineffective for social anxiety disorder. Studies do not support a benefit in children with autism, though there is tentative evidence for its benefit in adult autism. Fluoxetine together with fluvoxamine has shown some initial promise as a potential treatment for reducing COVID-19 severity if given early. Depression Efficacy of fluoxetine for acute and maintenance treatment of major depressive disorder in adults as well as children and adolescents (8 to 18 years) was established in multiple clinical trials. In addition to being effective for depression in 6-week long double-blind controlled trials, fluoxetine was better than placebo for the prevention of depression recurrence, when the patients, who originally responded to fluoxetine, were treated for a further 38 weeks. Efficacy of fluoxetine for geriatric as well as pediatric depression was also demonstrated in placebo-controlled trials.Fluoxetine is as effective as tricyclic antidepressants but is better tolerated. According to a network analysis of clinical trials, fluoxetine may belong to the group of less effective antidepressants; however, its acceptability is higher than any other antidepressant, except agomelatine. Obsessive–compulsive disorder The efficacy of fluoxetine in the treatment of obsessive–compulsive disorder (OCD) was demonstrated in two randomized multicenter phase III clinical trials. The pooled results of these trials demonstrated that 47% of completers treated with the highest dose were "much improved" or "very much improved" after 13 weeks of treatment, compared to 11% in the placebo arm of the trial. The American Academy of Child and Adolescent Psychiatry state that SSRIs, including fluoxetine, should be used as first-line therapy in children, along with cognitive behavioral therapy (CBT), for the treatment of moderate to severe OCD. Panic disorder The efficacy of fluoxetine in the treatment of panic disorder was demonstrated in two 12-week randomized multicenter phase III clinical trials that enrolled patients diagnosed with panic disorder, with or without agoraphobia. In the first trial, 42% of subjects in the fluoxetine-treated arm were free of panic attacks at the end of the study, vs. 28% in the placebo arm. In the second trial, 62% of fluoxetine treated patients were free of panic attacks at the end of the study, vs. 44% in the placebo arm. Bulimia nervosa A 2011 systematic review discussed seven trials which compared fluoxetine to a placebo in the treatment of bulimia nervosa, six of which found a statistically significant reduction in symptoms such as vomiting and binge eating. However, no difference was observed between treatment arms when fluoxetine and psychotherapy were compared to psychotherapy alone. Premenstrual dysphoric disorder Fluoxetine is used to treat premenstrual dysphoric disorder, a condition where individuals have affective and somatic symptoms monthly during the luteal phase of menstruation. Taking fluoxetine 20 mg/d can be effective in treating PMDD, though doses of 10 mg/d have also been prescribed effectively. Impulsive aggression Fluoxetine is considered a first-line medication for the treatment of impulsive aggression of low intensity. Fluoxetine reduced low intensity aggressive behavior in patients in intermittent aggressive disorder and borderline personality disorder. Fluoxetine also reduced acts of domestic violence in alcoholics with a history of such behavior. Special populations In children and adolescents, fluoxetine is the antidepressant of choice due to tentative evidence favoring its efficacy and tolerability. In pregnancy, fluoxetine is considered a category C drug by the US Food and Drug Administration (FDA). Evidence supporting an increased risk of major fetal malformations resulting from fluoxetine exposure is limited, although the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK has warned prescribers and patients of the potential for fluoxetine exposure in the first trimester (during organogenesis, formation of the fetal organs) to cause a slight increase in the risk of congenital cardiac malformations in the newborn. Furthermore, an association between fluoxetine use during the first trimester and an increased risk of minor fetal malformations was observed in one study.However, a systematic review and meta-analysis of 21 studies – published in the Journal of Obstetrics and Gynaecology Canada – concluded, "the apparent increased risk of fetal cardiac malformations associated with maternal use of fluoxetine has recently been shown also in depressed women who deferred SSRI therapy in pregnancy, and therefore most probably reflects an ascertainment bias. Overall, women who are treated with fluoxetine during the first trimester of pregnancy do not appear to have an increased risk of major fetal malformations."Per the FDA, infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn. Limited data support this risk, but the FDA recommends physicians consider tapering SSRIs such as fluoxetine during the third trimester. A 2009 review recommended against fluoxetine as a first-line SSRI during lactation, stating, "Fluoxetine should be viewed as a less-preferred SSRI for breastfeeding mothers, particularly with newborn infants, and in those mothers who consumed fluoxetine during gestation." Sertraline is often the preferred SSRI during pregnancy due to the relatively minimal fetal exposure observed and its safety profile while breastfeeding. Adverse effects Side effects observed in fluoxetine-treated persons in clinical trials with an incidence >5% and at least twice as common in fluoxetine-treated persons compared to those who received a placebo pill include abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, decreased libido, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilation, and yawning. Fluoxetine is considered the most stimulating of the SSRIs (that is, it is most prone to causing insomnia and agitation). It also appears to be the most prone of the SSRIs for producing dermatologic reactions (e.g. urticaria (hives), rash, itchiness, etc.). Sexual dysfunction Sexual dysfunction, including loss of libido, erectile dysfunction, lack of vaginal lubrication, and anorgasmia, are some of the most commonly encountered adverse effects of treatment with fluoxetine and other SSRIs. While early clinical trials suggested a relatively low rate of sexual dysfunction, more recent studies in which the investigator actively inquires about sexual problems suggest that the incidence is >70%.On 11 June 2019, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency concluded that there is a possible causal association between SSRI use and long-lasting sexual dysfunction that persists despite discontinuation of SSRI, including fluoxetine, and that the labels of these drugs should be updated to include a warning. Antidepressant discontinuation syndrome Fluoxetines longer half-life makes it less common to develop antidepressant discontinuation syndrome following cessation of therapy, especially when compared to antidepressants with shorter half-lives such as paroxetine. Although gradual dose reductions are recommended with antidepressants with shorter half-lives, tapering may not be necessary with fluoxetine. Pregnancy Antidepressant exposure (including fluoxetine) is associated with shorter average duration of pregnancy (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points). There is 30–36% increase in congenital heart defects among children whose mothers were prescribed fluoxetine during pregnancy, with fluoxetine use in the first trimester associated with 38–65% increase in septal heart defects. Suicide In October 2004, the FDA added a black box warning to all antidepressant drugs regarding use in children. In 2006, the FDA included adults aged 25 or younger. Statistical analyses conducted by two independent groups of FDA experts found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group. The suicidality was slightly decreased for those older than 24, and statistically significantly lower in the 65 and older group. This analysis was criticized by Donald Klein, who noted that suicidality, that is suicidal ideation and behavior, is not necessarily a good surrogate marker for suicide, and it is still possible, while unproven, that antidepressants may prevent actual suicide while increasing suicidality. In February 2018, the FDA ordered an update to the warnings based on statistical evidence from twenty four trials in which the risk of such events increased from two percent to four percent relative to the placebo trials.On 14 September 1989, Joseph T. Wesbecker killed eight people and injured twelve before committing suicide. His relatives and victims blamed his actions on the Prozac medication he had begun taking a month prior. The incident set off a chain of lawsuits and public outcries. Lawyers began using Prozac to justify the abnormal behaviors of their clients. Eli Lilly was accused of not doing enough to warn patients and doctors about the adverse effects, which it had described as "activation", years prior to the incident.There is less data on fluoxetine than on antidepressants as a whole. In 2004, the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications to obtain statistically significant results. Considered separately, fluoxetine use in children increased the odds of suicidality by 50%, and in adults decreased the odds of suicidality by approximately 30%. A study published in May 2009 found that fluoxetine was more likely to increase overall suicidal behavior. 14.7% of the patients (n = 44) on fluoxetine had suicidal events, compared to 6.3% in the psychotherapy group and 8.4% from the combined treatment group. Similarly, the analysis conducted by the UK MHRA found a 50% increase in suicide-related events, not reaching statistical significance, in the children and adolescents on fluoxetine as compared to the ones on placebo. According to the MHRA data, fluoxetine did not change the rate of self-harm in adults and statistically significantly decreased suicidal ideation by 50%. QT prolongation Fluoxetine can affect the electrical currents that heart muscle cells use to coordinate their contraction, specifically the potassium currents Ito and IKs that repolarise the cardiac action potential. Under certain circumstances, this can lead to prolongation of the QT interval, a measurement made on an electrocardiogram reflecting how long it takes for the heart to electrically recharge after each heartbeat. When fluoxetine is taken alongside other drugs that prolong the QT interval, or by those with a susceptibility to long QT syndrome, there is a small risk of potentially lethal abnormal heart rhythms such as torsades de pointes. A study completed in 2011 found that fluoxetine does not alter the QT interval and has no clinically meaningful effects on the cardiac action potential. Overdose In overdose, most frequent adverse effects include: Interactions Contraindications include prior treatment (within the past 5–6 weeks, depending on the dose) with MAOIs such as phenelzine and tranylcypromine, due to the potential for serotonin syndrome. Its use should also be avoided in those with known hypersensitivities to fluoxetine or any of the other ingredients in the formulation used. Its use in those concurrently receiving pimozide or thioridazine is also advised against.In case of short term administration of codeine for pain management, it is advised to monitor and adjust dosage. Codeine might not provide sufficient analgesia when Fluoxetine is co-administered. If opioid treatment is required, oxycodone use should be monitored since oxycodone is metabolized by the cytochrome P450 (CYP) enzyme system and fluoxetine and paroxetine are potent inhibitors of CYP2D6 enzymes. This means combinations of codeine or oxycodone with fluoxetine antidepressant may lead to reduced analgesia.In some cases, use of dextromethorphan-containing cold and cough medications with fluoxetine is advised against, due to fluoxetine increasing serotonin levels, as well as the fact that fluoxetine is a cytochrome P450 2D6 inhibitor, which causes dextromethorphan to not be metabolized at a normal rate, thus increasing the risk of serotonin syndrome and other potential side effects of dextromethorphan.Patients who are taking NSAIDs, antiplatelet drugs, anticoagulants, omega-3 fatty acids, vitamin E, and garlic supplements must be careful when taking fluoxetine or other SSRIs, as they can sometimes increase the blood-thinning effects of these medications.Fluoxetine and norfluoxetine inhibit many isozymes of the cytochrome P450 system that are involved in drug metabolism. Both are potent inhibitors of CYP2D6 (which is also the chief enzyme responsible for their metabolism) and CYP2C19, and mild to moderate inhibitors of CYP2B6 and CYP2C9. In vivo, fluoxetine and norfluoxetine do not significantly affect the activity of CYP1A2 and CYP3A4. They also inhibit the activity of P-glycoprotein, a type of membrane transport protein that plays an important role in drug transport and metabolism and hence P-glycoprotein substrates such as loperamide may have their central effects potentiated. This extensive effect on the bodys pathways for drug metabolism creates the potential for interactions with many commonly used drugs.Its use should also be avoided in those receiving other serotonergic drugs such as monoamine oxidase inhibitors, tricyclic antidepressants, methamphetamine, amphetamine, MDMA, triptans, buspirone, ginseng, dextromethorphan (DXM), linezolid, tramadol, serotonin–norepinephrine reuptake inhibitors, and other SSRIs due to the potential for serotonin syndrome to develop as a result.Fluoxetine may also increase the risk of opioid overdose in some instances, in part due to its inhibitory effect on cytochrome P-450. Similar to how fluoxetine can effect the metabolization of dextromethorphan, it may cause medications like oxycodone to not be metabolized at a normal rate, thus increasing the risk of serotonin syndrome as well as resulting in an increased concentration of oxycodone in the blood, which may lead to accidental overdose. A 2022 study which examined the health insurance claims of over 2 million Americans who began taking oxycodone while using SSRIs between 2000 and 2020, found that patients taking paroxetine or fluoxetine had a 23% higher risk of overdosing on oxycodone than those using other SSRIs.There is also the potential for interaction with highly protein-bound drugs due to the potential for fluoxetine to displace said drugs from the plasma or vice versa hence increasing serum concentrations of either fluoxetine or the offending agent. Pharmacology Pharmacodynamics Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and does not appreciably inhibit norepinephrine and dopamine reuptake at therapeutic doses. It does, however, delay the reuptake of serotonin, resulting in serotonin persisting longer when it is released. Large doses in rats have been shown to induce a significant increase in synaptic norepinephrine and dopamine. Thus, dopamine and norepinephrine may contribute to the antidepressant action of fluoxetine in humans at supratherapeutic doses (60–80 mg). This effect may be mediated by 5HT2C receptors, which are inhibited by higher concentrations of fluoxetine.Fluoxetine increases the concentration of circulating allopregnanolone, a potent GABAA receptor positive allosteric modulator, in the brain. Norfluoxetine, a primary active metabolite of fluoxetine, produces a similar effect on allopregnanolone levels in the brains of mice. Additionally, both fluoxetine and norfluoxetine are such modulators themselves, actions which may be clinically-relevant.In addition, fluoxetine has been found to act as an agonist of the σ1-receptor, with a potency greater than that of citalopram but less than that of fluvoxamine. However, the significance of this property is not fully clear. Fluoxetine also functions as a channel blocker of anoctamin 1, a calcium-activated chloride channel. A number of other ion channels, including nicotinic acetylcholine receptors and 5-HT3 receptors, are also known to be inhibited at similar concentrations.Fluoxetine has been shown to inhibit acid sphingomyelinase, a key regulator of ceramide levels which derives ceramide from sphingomyelin. Mechanism of action Fluoxetine elicits antidepressant effect by inhibiting serotonin reuptake in the synapse by binding to the reuptake pump on the neuronal membrane to increase serotonin availability and enhance neurotransmission. 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, which may contribute to a reduction in negative affective biases. Norfluoxetine and desmethylfluoxetine are metabolites of fluoxetine and also act as serotonin reuptake inhibitors, increasing the duration of action of the drug. Pharmacokinetics The bioavailability of fluoxetine is relatively high (72%), and peak plasma concentrations are reached in 6–8 hours. It is highly bound to plasma proteins, mostly albumin and α1-glycoprotein. Fluoxetine is metabolized in the liver by isoenzymes of the cytochrome P450 system, including CYP2D6. The role of CYP2D6 in the metabolism of fluoxetine may be clinically important, as there is great genetic variability in the function of this enzyme among people. CYP2D6 is responsible for converting fluoxetine to its only active metabolite, norfluoxetine. Both drugs are also potent inhibitors of CYP2D6.The extremely slow elimination of fluoxetine and its active metabolite norfluoxetine from the body distinguishes it from other antidepressants. With time, fluoxetine and norfluoxetine inhibit their own metabolism, so fluoxetine elimination half-life increases from 1 to 3 days, after a single dose, to 4 to 6 days, after long-term use. Similarly, the half-life of norfluoxetine is longer (16 days) after long-term use. Therefore, the concentration of the drug and its active metabolite in the blood continues to grow through the first few weeks of treatment, and their steady concentration in the blood is achieved only after four weeks. Moreover, the brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment. For major depressive disorder, while onset of antidepressant action may be felt as early as 1-2 weeks, the full benefit of the current dose a patient receives is not realized for at least a month following ingestion. For example, in one 6-week study, the median time to achieving consistent response was 29 days. Likewise, complete excretion of the drug may take several weeks. During the first week after treatment discontinuation, the brain concentration of fluoxetine decreases by only 50%, The blood level of norfluoxetine four weeks after treatment discontinuation is about 80% of the level registered by the end of the first treatment week, and, seven weeks after discontinuation, norfluoxetine is still detectable in the blood. Measurement in body fluids Fluoxetine and norfluoxetine may be quantitated in blood, plasma or serum to monitor therapy, confirm a diagnosis of poisoning in hospitalized person or assist in a medicolegal death investigation. Blood or plasma fluoxetine concentrations are usually in a range of 50–500 μg/L in persons taking the drug for its antidepressant effects, 900–3000 μg/L in survivors of acute overdosage and 1000–7000 μg/L in victims of fatal overdosage. Norfluoxetine concentrations are approximately equal to those of the parent drug during chronic therapy, but may be substantially less following acute overdosage, since it requires at least 1–2 weeks for the metabolite to achieve equilibrium. Usage In 2010, over 24.4 million prescriptions for generic fluoxetine were filled in the United States, making it the third-most prescribed antidepressant after sertraline and citalopram. In 2011, 6 million prescriptions for fluoxetine were filled in the United Kingdom. History The work which eventually led to the discovery of fluoxetine began at Eli Lilly and Company in 1970 as a collaboration between Bryan Molloy and Robert Rathbun. It was known at that time that the antihistamine diphenhydramine shows some antidepressant-like properties. 3-Phenoxy-3-phenylpropylamine, a compound structurally similar to diphenhydramine, was taken as a starting point, and Molloy synthesized a series of dozens of its derivatives. Hoping to find a derivative inhibiting only serotonin reuptake, an Eli Lilly scientist, David T. Wong, proposed to retest the series for the in vitro reuptake of serotonin, norepinephrine and dopamine. This test, carried out by Jong-Sir Horng in May 1972, showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series. Wong published the first article about fluoxetine in 1974. A year later, it was given the official chemical name fluoxetine and the Eli Lilly and Company gave it the trade name Prozac. In February 1977, Dista Products Company, a division of Eli Lilly & Company, filed an Investigational New Drug application to the U.S. Food and Drug Administration (FDA) for fluoxetine.Fluoxetine appeared on the Belgian market in 1986. In the U.S., the FDA gave its final approval in December 1987, and a month later Eli Lilly began marketing Prozac; annual sales in the U.S. reached $350 million within a year. Worldwide sales eventually reached a peak of $2.6 billion a year.Lilly tried several product line extension strategies, including extended release formulations and paying for clinical trials to test the efficacy and safety of fluoxetine in premenstrual dysphoric disorder and rebranding fluoxetine for that indication as "Sarafem" after it was approved by the FDA in 2000, following the recommendation of an advisory committee in 1999. The invention of using fluoxetine to treat PMDD was made by Richard Wurtman at MIT; the patent was licensed to his startup, Interneuron, which in turn sold it to Lilly.To defend its Prozac revenue from generic competition, Lilly also fought a five-year, multimillion-dollar battle in court with the generic company Barr Pharmaceuticals to protect its patents on fluoxetine, and lost the cases for its line-extension patents, other than those for Sarafem, opening fluoxetine to generic manufacturers starting in 2001. When Lillys patent expired in August 2001, generic drug competition decreased Lillys sales of fluoxetine by 70% within two months.In 2000 an investment bank had projected that annual sales of Sarafem could reach $250M/year. Sales of Sarafem reached about $85M/year in 2002, and in that year Lilly sold its assets connected with the drug for $295M to Galen Holdings, a small Irish pharmaceutical company specializing in dermatology and womens health that had a sales force tasked to gynecologists offices; analysts found the deal sensible since the annual sales of Sarafem made a material financial difference to Galen, but not to Lilly.Bringing Sarafem to market harmed Lillys reputation in some quarters. The diagnostic category of PMDD was controversial since it was first proposed in 1987, and Lillys role in retaining it in the appendix of the DSM-IV-TR, the discussions for which got under way in 1998, has been criticized. Lilly was criticized for inventing a disease in order to make money, and for not innovating but rather just seeking ways to continue making money from existing drugs. It was also criticized by the FDA and groups concerned with womens health for marketing Sarafem too aggressively when it was first launched; the campaign included a television commercial featuring a harried woman at the grocery store who asks herself if she has PMDD. Society and culture American aircraft pilots Beginning 5 April 2010, fluoxetine became one of four antidepressant drugs that the FAA permitted for pilots with authorization from an aviation medical examiner. The other permitted antidepressants are sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro). These four remain the only antidepressants permitted by FAA as of 2 December 2016.Sertraline, citalopram and escitalopram are the only antidepressants permitted for EASA medical certification, as of January 2019. Environmental effects Fluoxetine has been detected in aquatic ecosystems, especially in North America. There is a growing body of research addressing the effects of fluoxetine (among other SSRIs) exposure on non-target aquatic species.In 2003, one of the first studies addressed in detail the potential effects of fluoxetine on aquatic wildlife; this research concluded that exposure at environmental concentrations was of little risk to aquatic systems if a hazard quotient approach was applied to risk assessment. However, they also stated the need for further research addressing sub-lethal consequences of fluoxetine, specifically focusing on study species sensitivity, behavioural responses, and endpoints modulated by the serotonin system.Fluoxetine – similar to several other SSRIs – induces reproductive behavior in some shellfish at concentrations as low as 10-10 M, or 30 parts per trillion.: 21 Since 2003, a number of studies have reported fluoxetine-induced impacts on a number of behavioural and physiological endpoints, inducing antipredator behaviour, reproduction, and foraging at or below field-detected concentrations. However, a 2014 review on the ecotoxicology of fluoxetine concluded that, at that time, a consensus on the ability of environmentally realistic dosages to affect the behaviour of wildlife could not be reached. At environmentally realistic concentrations, fluoxetine alters insect emergence timing. Richmond et al., 2019 find that at low concentrations it accelerates emergence of Diptera, while at unusually high concentrations it has no discernable effect.Several common plants are known to absorb fluoxetine. Several crops have been tested, and Redshaw et al. 200
Fluoxetine	8 find that cauliflower absorbs large amounts into the stem and leaf but not the head or root. Wu et al. 2012 find that lettuce and spinach also absorb detectable amounts, while Carter et al. 2014 find that radish (Raphanus sativus), ryegrass (Lolium perenne) – and Wu et al. 2010 find that soybean (Glycine max) – absorb little. Wu tested all tissues of soybean and all showed only low concentrations. By contrast various Reinhold et al. 2010 find duckweeds have a high uptake of fluoxetine and show promise for bioremediation of contaminated water, especially Lemna minor and Landoltia punctata. Ecotoxicity for organisms involved in aquaculture is well documented.: 275–276 Fluoxetine affects both aquacultured invertebrates and vertebrates, and inhibits soil microbes including a large antibacterial effect. For applications of this see § Other uses. Politics During the 1990 campaign for Governor of Florida, it was disclosed that one of the candidates, Lawton Chiles, had depression and had resumed taking fluoxetine, leading his political opponents to question his fitness to serve as Governor. Other uses The antibacterial effect in described above (§ Environmental effects) could be applied against multiresistant biotypes in crop bacterial diseases and bacterial aquaculture diseases. In a glucocorticoid receptor-defective zebrafish mutant (Danio rerio) with reduced exploratory behavior, fluoxetine rescued the normal exploratory behavior. This demonstrates relationships between glucocorticoids, fluoxetine, and exploration in this fish.Fluoxetine has an anti-nematode effect. Choy et al., 1999 finds some of this effect is due to interference with certain transmembrane proteins. References Further reading Shorter E (2014). "The 25th anniversary of the launch of Prozac gives pause for thought: where did we go wrong?". The British Journal of Psychiatry. 204 (5): 331–2. doi:10.1192/bjp.bp.113.129916. PMID 24785765. Haberman C (21 September 2014). "Selling Prozac as the Life-Enhancing Cure for Mental Woes". The New York Times. External links "Fluoxetine". Drug Information Portal. U.S. National Library of Medicine. "Fluoxetine hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Polycarbophil calcium	Polycarbophil calcium (INN) is a drug used as a stool stabilizer. Chemically, it is a synthetic polymer of polyacrylic acid cross-linked with divinyl glycol, with calcium as a counter-ion. Clinical uses It is used as stool stabilizer to treat constipation, diarrhea and abdominal discomfort. Bulk laxatives absorb liquid in the intestines and swell to form a soft bulky stool. The bulky mass stimulates the intestinal muscles, speeding stool transit time through the colon. Results usually occur within 12 to 72 hours. Calcium polycarbophil will not work without increased fluid intake. Calcium polycarbophil has been marketed as an over-the-counter agent used for treating functional bowel disorder and as a bulk-producing agent. A study looked at the effects of calcium polycarbophil on general irritable bowel syndrome (IBS) symptoms. Fourteen patients with IBS-diarrhea and twelve with IBS-constipation were given calcium polycarbophil for eight weeks and their colon transit times were measured with radiopaque markers in the colon. The patients with diarrhea reported fewer bowel movements, more solid stools and reduced abdominal pain. Patients with constipation reported more frequent bowel movements, looser stools and less pain.The human stomach presents a mild acidic environment due to the presence of HCl. Polycarbophil absorbs about ten times its own weight of water under acidic conditions, but the swelling ratio markedly increases at above pH 4.0 and reaches 70 times the initial weight under pH-neutral conditions. The swelling of polycarbophil is not affected by non-ionic osmolarity, but by ionic strength, showing a decrease with increase of ionic strength. Monovalent metal ions such as sodium and potassium ions in gastrointestinal fluid do not reduce the equilibrium swelling of polycarbophil, but divalent ions such as calcium and magnesium ions do. However, calcium ions only slightly reduce the equilibrium swelling under sodium-rich conditions. Adverse effects Common side effects can include: Mild stomach painBloating GasSeek medical attention if: severe stomach cramps rectal bleeding no bowel movement within 3 days after using polycarbophil References == Further reading ==
Trastuzumab	Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. It may be used by itself or together with other chemotherapy medication. Trastuzumab is given by slow injection into a vein and injection just under the skin.Common side effects include fever, infection, cough, headache, trouble sleeping, and rash. Other severe side effects include heart failure, allergic reactions, and lung disease. Use during pregnancy may harm the baby. Trastuzumab works by binding to the HER2 receptor and slowing down cell replication.Trastuzumab was approved for medical use in the United States in September 1998, and in the European Union in August 2000. It is on the World Health Organizations List of Essential Medicines. A biosimilar was approved in the European Union in November 2017, and in the United States in December 2018. Medical uses The safety and efficacy of trastuzumab-containing combination therapies (with chemotherapy, hormone blockers, or lapatinib) for the treatment of metastatic breast cancer. The overall hazard ratios (HR) for overall survival and progression free survival were 0.82 and 0.61, respectively. It was difficult to accurately ascertain the true impact of trastuzumab on survival, as in three of the seven trials, over half of the patients in the control arm were allowed to cross-over and receive trastuzumab after their cancer began to progress. Thus, this analysis likely underestimates the true survival benefit associated with trastuzumab treatment in this population. In these trials, trastuzumab also increased the risk of heart problems, including heart failure and left ventricular ejection fraction decline.In early-stage HER2-positive breast cancer, trastuzumab-containing regimens improved overall survival (Hazard ratio (HR) = 0.66) and disease-free survival (HR = 0.60). Increased risk of heart failure (RR = 5.11) and decline in left ventricular ejection fraction (relative risk RR = 1.83) were seen in these trials as well. Two trials involving shorter term treatment with trastuzumab did not differ in efficacy from longer trials, but produced less cardiac toxicity.The original studies of trastuzumab showed that it improved overall survival in late-stage (metastatic) HER2-positive breast cancer from 20.3 to 25.1 months. In early-stage HER2-positive breast cancer, it reduces the risk of cancer returning after surgery. The absolute reduction in the risk of cancer returning within three years was 9.5%, and the absolute reduction in the risk of death within 3 years was reduced by 3%. However, it increases serious heart problems by an absolute risk of 2.1%, though the problems may resolve if treatment is stopped.Trastuzumab has had a "major impact in the treatment of HER2-positive metastatic breast cancer." The combination of trastuzumab with chemotherapy has been shown to increase both survival and response rate, in comparison to trastuzumab alone.It is possible to determine the "erbB2 status" of a tumor, which can be used to predict efficacy of treatment with trastuzumab. If it is determined that a tumor is overexpressing the erbB2 oncogene and the patient has no significant pre-existing heart disease, then a patient is eligible for treatment with trastuzumab. It is surprising that although trastuzumab has great affinity for HER2 and high doses can be administered (because of its low toxicity), 70% of HER2+ patients do not respond to treatment. In fact resistance to the treatment develops rapidly, in virtually all patients. A mechanism of resistance involves failure to downregulate p27 (Kip1) as well as suppressing p27 translocation to the nucleus in breast cancer, enabling cdk2 to induce cell proliferation.In May 2021, the FDA approved pembrolizumab in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of people with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. Duration of treatment The optimal duration of add-on trastuzumab treatment after surgery for early breast cancer is unknown. One year of treatment is generally accepted based on clinical trial evidence that demonstrated the superiority of one-year treatment over none. However, a small Finnish trial also showed similar improvement with nine weeks of treatment over no therapy. Because of the lack of direct head-to-head comparison in clinical trials, it is unknown whether a shorter duration of treatment may be just as effective (with fewer side effects) than the accepted practice of treatment for one year. Debate about treatment duration has become a relevant issue for many public health policy makers because administering trastuzumab for a year is very expensive. Consequently, some countries with a taxpayer-funded public health system, such as New Zealand, chose to fund limited adjuvant therapy. However, subsequently New Zealand has revised its policy and now funds trastuzumab treatment for up to 12 months. Adverse effects Some of the common side effects of trastuzumab are flu-like symptoms (such as fever, chills and mild pain), nausea and diarrhea. Cardiac toxicity One of the more serious complications of trastuzumab is its effect on the heart, although this is rare. In 2-7% of cases, trastuzumab is associated with cardiac dysfunction, which includes congestive heart failure. As a result, regular cardiac screening with either a MUGA scan or echocardiography is commonly undertaken during the trastuzumab treatment period. The decline in ejection fraction appears to be reversible.Trastuzumab downregulates neuregulin-1 (NRG-1), which is essential for the activation of cell survival pathways in cardiomyocytes and the maintenance of cardiac function. NRG-1 activates the MAPK pathway and the PI3K/AKT pathway as well as focal adhesion kinases (FAK). These are all significant for the function and structure of cardiomyocytes. Trastuzumab can therefore lead to cardiac dysfunction.Approximately 10% of people are unable to tolerate the drug because of pre-existing heart problems; physicians are balancing the risk of recurrent cancer against the higher risk of death due to cardiac disease in this population. The risk of cardiomyopathy is increased when trastuzumab is combined with anthracycline chemotherapy (which itself is associated with cardiac toxicity). Birth control Women having periods (or whose periods stopped due to chemotherapy) may need to use barrier contraception (such as condoms) while taking trastuzumab, and for at least six months afterwards. This is because of the possibility of harming a developing fetus. Mechanism of action The HER2 gene (also known as HER2/neu and ErbB2 gene) is amplified in 20–30% of early-stage breast cancers. Trastuzumab is a monoclonal antibody targeting HER2, inducing an immune-mediated response that causes internalization and recycling of HER2. It may also upregulate cell cycle inhibitors such as p21Waf1 and p27Kip1.The HER2 pathway promotes cell growth and division when it is functioning normally; however, when it is overexpressed, cell growth accelerates beyond its normal limits. In some types of cancer, the pathway is exploited to promote rapid cell growth and proliferation and hence tumor formation. The EGF pathway includes the receptors HER1 (EGFR), HER2, HER3, and HER4; the binding of ligands (e.g. EGF etc.) to HER receptors is required to activate the pathway. The pathway initiates the MAP kinase pathway as well as the PI3 kinase/AKT pathway, which in turn activates the NF-κB pathway. In cancer cells the HER2 protein can be expressed up to 100 times more than in normal cells (2 million versus 20,000 per cell). This overexpression leads to strong and constant proliferative signaling and hence tumor formation. Overexpression of HER2 also causes deactivation of checkpoints, allowing for even greater increases in proliferation.The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell (molecules called EGFs) to inside the cell, and turn genes on and off. The HER (human epidermal growth factor receptor) protein, binds to human epidermal growth factor, and stimulates cell proliferation. In some cancers, notably certain types of breast cancer, HER2 is over-expressed and causes cancer cells to reproduce uncontrollably.HER2 is localized at the cell surface, and carries signals from outside the cell to the inside. Signaling compounds called mitogens (specifically EGF in this case) arrive at the cell membrane, and bind to the extracellular domain of the HER family of receptors. Those bound proteins then link (dimerize), activating the receptor. HER2 sends a signal from its intracellular domain, activating several different biochemical pathways. These include the PI3K/Akt pathway and the MAPK pathway. Signals on these pathways promote cell proliferation and the growth of blood vessels to nourish the tumor (angiogenesis). ERBB2 is the preferred dimerization partner for the other family members and ERBB2 heterodimers signaling is stronger and longer acting compared to heterodimers between other ERBB members. It has been reported that Trastuzumab induces the formation of complementarity-determining regions (CDRs) leading to surface redistribution of ERBB2 and EGFR in CDRs and that the ERBB2-dependent MAPK phosphorylation and EGFR/ERBB1 expression are both required for CDR formation. CDR formation requires activation of both the protein regulator of actin polymerization N-WASP, mediated by ERK1/2, and of the actin-depolymerizing protein cofilin, mediated by EGFR/ERBB1. Furthermore, this latter event may be inhibited by the negative cell motility regulator p140Cap, as we found that p140Cap overexpression led to cofilin deactivation and inhibition of CDR formation. Normal cell division—mitosis—has checkpoints that keep cell division under control. Some of the proteins that control this cycle are called cdk2 (CDKs). Overexpression of HER2 sidesteps these checkpoints, causing cells to proliferate in an uncontrolled fashion. This is caused by phosphorylation by Akt.Trastuzumab binds to domain IV of the extracellular segment of the HER2/neu receptor. Monoclonal antibodies that bind to this region have been shown to reverse the phenotype of HER2/neu expressing tumor cells. Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferation. It has been suggested that trastuzumab does not alter HER-2 expression, but downregulates activation of AKT. In addition, trastuzumab suppresses angiogenesis both by induction of antiangiogenic factors and repression of proangiogenic factors. It is thought that a contribution to the unregulated growth observed in cancer could be due to proteolytic cleavage of HER2/neu that results in the release of the extracellular domain. One of the most relevant proteins that trastuzumab activates is the tumor suppressor p27 (kip1), also known as CDKN1B. Trastuzumab has been shown to inhibit HER2/neu ectodomain cleavage in breast cancer cells.Experiments in laboratory animals indicate that antibodies, including trastuzumab, when bound to a cell, induce immune cells to kill that cell, and that such antibody-dependent cell-mediated cytotoxicity is another important mechanism of action. Predicting response Trastuzumab inhibits the effects of overexpression of HER2. If the breast cancer does not overexpress HER2, trastuzumab will have no beneficial effect (and may cause harm). Doctors use laboratory tests to discover whether HER2 is overexpressed. In the routine clinical laboratory, the most commonly employed methods for this are immunohistochemistry (IHC) and either silver, chromogenic or fluorescent in situ hybridisation (SISH/CISH/FISH). HER2 amplification can be detected by virtual karyotyping of formalin-fixed paraffin embedded tumor. Virtual karyotyping has the added advantage of assessing copy number changes throughout the genome, in addition to detecting HER-2 amplification (but not overexpression). Numerous PCR-based methodologies have also been described in the literature. It is also possible to estimate HER2 copy number from microarray data.There are two FDA-approved commercial kits available for HER2 IHC; Dako HercepTest and Ventana Pathway. These are highly standardised, semi-quantitative assays which stratify expression levels into; 0 (<20,000 receptors per cell, no visible expression), 1+ (~100,000 receptors per cell, partial membrane staining, < 10% of cells overexpressing HER-2), 2+ (~500,000 receptors per cell, light to moderate complete membrane staining, > 10% of cells overexpressing HER-2), and 3+ (~2,000,000 receptors per cell, strong complete membrane staining, > 10% of cells overexpressing HER-2). The presence of cytoplasmic expression is disregarded. Treatment with trastuzumab is indicated in cases where HER2 expression has a score of 3+. However, IHC has been shown to have numerous limitations, both technical and interpretative, which have been found to impact on the reproducibility and accuracy of results, especially when compared with ISH methodologies. It is also true, however, that some reports have stated that IHC provides excellent correlation between gene copy number and protein expression.Fluorescent in situ hybridization (FISH) is viewed as being the "gold standard" technique in identifying patients who would benefit from trastuzumab, but it is expensive and requires fluorescence microscopy and an image capture system. The main expense involved with CISH is in the purchase of FDA-approved kits, and as it is not a fluorescent technique it does not require specialist microscopy and slides may be kept permanently. Comparative studies of CISH and FISH have shown that these two techniques show excellent correlation. The lack of a separate chromosome 17 probe on the same section is an issue with regards to acceptance of CISH. As of June 2011 Roche has obtained FDA approval for the INFORM HER2 Dual ISH DNA Probe cocktail developed by Ventana Medical Systems. The DDISH (Dual-chromagen/Dual-hapten In-situ hybridization) cocktail uses both HER2 and Chromosome 17 hybridization probes for chromagenic visualization on the same tissue section. The detection can be achieved by using a combination of ultraView SISH(silver in-situ hybridization) and ultraView Red ISH for deposition of distinct chromgenic precipitates at the site of DNP or DIG labeled probes.The recommended assays are a combination of IHC and FISH, whereby IHC scores of 0 and 1+ are negative (no trastuzumab treatment), scores of 3+ are positive (trastuzumab treatment), and score of 2+ (equivocal case) is referred to FISH for a definitive treatment decision. Industry best practices indicate the use of FDA-cleared Automated Tissue Image Systems by laboratories for automated processing of specimens, thereby reducing process variability, avoiding equivocal cases, and ensuring maximum efficacy of trastuzumab therapy. Resistance One of the challenges in the treatment of breast cancer patients by herceptin is our understanding towards herceptin resistance. In the last decade, several assays have been performed to understand the mechanism of Herceptin resistance with/without supplementary drugs. Recently, all this information has been collected and compiled in form of a database HerceptinR. This database HerceptinR is a collection of assays performed to test sensitivity or resistance of Herceptin Antibodies towards breast cancer cell lines. This database provides comprehensive information about experimental data perform to understanding factors behind herceptin resistance as well as assays performed for improving Herceptin sensitivity with the help of supplementary drugs. This is the first database developed to understand herceptin resistance that can be used for designing herceptin sensitive biomarkers. History The drug was first discovered by scientists including Dr. Axel Ullrich and Dr. H. Michael Shepard at Genentech, Inc. in South San Francisco, CA. Earlier discovery about the neu oncogene by Robert Weinbergs lab and the monoclonal antibody recognizing the oncogenic receptor by Mark Greenes lab also contributed to the establishment of HER2 targeted therapies. Dr. Dennis Slamon subsequently worked on trastuzumabs development. A book about Dr. Slamons work was made into a television film called Living Proof, that premiered in 2008. Genentech developed trastuzumab jointly with UCLA, beginning the first clinical trial with 15 women in 1992. By 1996, clinical trials had expanded to over 900 women, but due to pressure from advocates based on early success, Genentech worked with the FDA to begin a lottery system allowing 100 women each quarter access to the medication outside the trials. Herceptin was Fast-tracked by the FDA and gained approval in September 1998.Biocon Ltd and its partner Mylan obtained regulatory approval to sell a biosimilar in 2014, but Roche contested the legality of the approval; that litigation ended in 2016, and Biocon and Mylan each introduced their own branded biosimilars. Society and culture Economics Trastuzumab costs about US$70,000 for a full course of treatment, Trastuzumab brought in $327 million in revenue for Genentech in the fourth quarter of 2007.Australia has negotiated a lower price of A$50,000 per course of treatment.Since October 2006, trastuzumab has been made available for Australian women and men with early-stage breast cancer via the Pharmaceutical Benefits Scheme. This is estimated to cost the country over A$470 million for 4–5 years supply of the drug.Roche has agreed with Emcure in India to make an affordable version of this cancer drug available to the Indian market.Roche has changed the brand name of the drug and has re-introduced an affordable version of the same in the Indian market. The new drug named Herclon would cost approximately RS75,000 INR (US$1,200) in the Indian market.On September 16, 2014, Genentech notified hospitals in the United States that, as of October, trastuzumab could only be purchased through their selected specialty drugs distributors not through the usual general line wholesalers. By being forced to purchase through specialty pharmacies, hospitals lost rebates from the big wholesalers and the ability to negotiate cost-minus discounts with their wholesalers. Biosimilars By 2014, around 20 companies, particularly from emerging markets, were developing biosimilar versions of trastuzumab after Roche/Genentechs patents expired in 2014 in Europe, and in 2019 in the United States. In 2013, Roche/Genentech relinquished its patent right for the drug in India because of the difficult IP environment there.In January 2015, BIOCAD announced the first trastuzumab biosimilar approved by the Ministry of Health of the Russian Federation. Iran also approved its own version of the monoclonal antibody in January 2016, as AryoTrust, and announced its readiness to export the drug to other countries in the Middle-East and Central Asia when trade sanctions were lifted.In 2016, the investigational biosimilar MYL-1401O has shown comparable efficacy and safety to the Herceptin branded trastuzumab.Trastuzumab-dkst (Ogivri, Mylan GmbH) was approved in the United States in December 2017, to "treat patients with breast cancer or gastric or gastroesophageal junction adenocarcinoma whose tumors overexpress the HER-2 gene." Ogivri was approved for medical use in the European Union in December 2018.In November 2017, the European Commission approved Ontruzant, a biosimilar-trastuzumab from Samsung Bioepis Co., Ltd, for the treatment of early breast cancer, metastatic breast cancer and metastatic gastric cancer. Ontruzant is the first trastuzumab biosimilar to receive regulatory approval in Europe.Herzuma was approved for medical use in the European Union in February 2018. Herzuma, a trastuzumab biosimilar, was approved in the United States in December 2018. The approval was based on comparisons of extensive structural and functional product characterization, animal data, human pharmacokinetic, clinical immunogenicity, and other clinical data demonstrating that Herzuma is biosimilar to US Herceptin. Herzuma has been approved as a biosimilar, not as an interchangeable product.Kanjinti was approved for medical use in the European Union in May 2018.Trazimera was approved for medical use in the European Union in July 2018.Ogivri was approved for medical use in Canada in May 2019.Trazimera was approved for medical use in Canada in August 2019.Herzuma was approved for medical use in Canada in September 2019.Kanjinti was approved for medical use in Canada in February 2020.Zercepac was approved for medical use in the European Union in July 2020.Trastucip and Tuzucip were approved for medical use in Australia in July 2022. Related conjugates Apart from the biosimilars noted above, trastuzumab is also a component of some antibody-drug conjugates, such as trastuzumab emtansine. Another ADC, trastuzumab deruxtecan was approved for use in the United States in December 2019. References Further reading Bazell, Robert. Her-2: the making of Herceptin, a revolutionary treatment for breast cancer. Random House, 1998. 214 pages. ISBN 0-679-45702-X Boseley, Sarah (29 March 2006). "The selling of a wonder drug". The Guardian. Dent S, Verma S, Latreille J, Rayson D, Clemons M, Mackey J, Verma S, Lemieux J, Provencher L, Chia S, Wang B, Pritchard K (2009). "The role of her2-targeted therapies in women with her2-overexpressing metastatic breast cancer". Curr Oncol. 16 (4): 25–35. doi:10.3747/co.v16i4.469. PMC 2722050. PMID 19672422. Dean L (2015). "Trastuzumab (Herceptin) Therapy and ERBB2 (HER2) Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520362. Bookshelf ID: NBK310376. External links "Trastuzumab". Drug Information Portal. U.S. National Library of Medicine. "Trastuzumab". National Cancer Institute. 5 October 2006.
Clonidine	Clonidine, sold under the brand name Catapres among others, is an α2-adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal (alcohol, opioids, or nicotine), menopausal flushing, diarrhea, spasticity, and certain pain conditions. It is used by mouth, by injection, or as a skin patch. Onset of action is typically within an hour with the effects on blood pressure lasting for up to eight hours.Common side effect include dry mouth, dizziness, headaches, hypotension, and sleepiness. Severe side effects may include hallucinations, heart arrhythmias, and confusion. If rapidly stopped, withdrawal effects may occur. Use during pregnancy or breastfeeding is not recommended. Clonidine lowers blood pressure by stimulating α2 receptors in the brain, which results in relaxation of many arteries.Clonidine was patented in 1961 and came into medical use in 1966. It is available as a generic medication. In 2019, it was the 64th most commonly prescribed medication in the United States, with more than 11 million prescriptions. Medical uses Clonidine is used to treat high blood pressure, attention deficit hyperactivity disorder (ADHD), drug withdrawal (alcohol, opioids, or smoking), menopausal flushing, diarrhea, and certain pain conditions. It also sees some use off-label for episodic insomnia, restless-legs syndrome, and anxiety, among other uses. Resistant hypertension Clonidine may be effective for lowering blood pressure in people with resistant hypertension.Clonidine works by slowing the pulse rate and exerts a reduction of serum concentrations of renin, aldosterone, and catecholamines. Attention deficit hyperactivity disorder Clonidine may improve symptoms of attention deficit hyperactivity disorder in some people but causes many adverse effects and the beneficial effect is modest. In Australia, clonidine is an accepted but not approved use for ADHD by the TGA. Clonidine, along with methylphenidate, has been studied for treatment of ADHD. While not as effective as methylphenidate in treating ADHD, clonidine does offer some benefit; it can also be useful in combination with stimulant medications. Some studies show clonidine to be more sedating than guanfacine, which may be better at bedtime along with an arousing stimulant in the morning. Clonidine has been used to reduce sleep disturbances in ADHD, including to help offset stimulant-associated insomnia. Drug withdrawal Clonidine may be used to ease drug withdrawal symptoms associated with abruptly stopping the long-term use of opioids, alcohol, benzodiazepines and nicotine. It can alleviate opioid withdrawal symptoms by reducing the sympathetic nervous system response such as tachycardia and hypertension, hyperhidrosis (excessive sweating), hot and cold flashes, and akathisia. It may also be helpful in aiding smokers to quit. The sedation effect is also useful. However, its side effects can sometimes include insomnia, thus exacerbating an already common feature of most withdrawal syndromes. Clonidine may also reduce severity of neonatal abstinence syndrome in infants born to mothers that are using certain drugs, particularly opioids. In infants with neonatal withdrawal syndrome, clonidine may improve the neonatal intensive care unit Network Neurobehavioral Score.Clonidine has also been suggested as a treatment for rare instances of dexmedetomidine withdrawal. Spasticity Clonidine has some role in the treatment of spasticity, acting principally by inhibiting excessive sensory transmission below the level of injury. Its use, however, is mainly as a second or third line agent, due to side effects such as hypotension, bradycardia, and drowsiness. Other uses Clonidine also has several off-label uses, and has been prescribed to treat psychiatric disorders including stress, sleep disorders, hyperarousal caused by post-traumatic stress disorder, borderline personality disorder, and other anxiety disorders. Clonidine is also a mild sedative, and can be used as premedication before surgery or procedures. Its epidural use for pain during heart attack, and postoperative and intractable pain has also been studied extensively. Clonidine can be used in restless legs syndrome. It can also be used to treat facial flushing and redness associated with rosacea. It has also been successfully used topically in a clinical trial as a treatment for diabetic neuropathy. Clonidine can also be used for migraine headaches and hot flashes associated with menopause. Clonidine has also been used to treat refractory diarrhea associated with irritable bowel syndrome, fecal incontinence, diabetes, diarrhea associated with opioid withdrawal, intestinal failure, neuroendocrine tumors, and cholera. Clonidine can be used in the treatment of Tourette syndrome (specifically for tics). Clonidine has also had some success in clinical trials for helping to remove or ameliorate the symptoms of hallucinogen persisting perception disorder (HPPD).Injection of α2 receptor agonists into the knee joint space, including clonidine, may reduce the severity of knee pain after arthroscopic knee surgery.Light-activated derivatives of clonidine (adrenoswitches) have been developed for research purposes and shown to control pupillary reflex with light in blind mice by topical application. Clonidine suppression test The reduction in circulating norepinephrine by clonidine was used in the past as an investigatory test for phaeochromocytoma, which is a catecholamine-synthesizing tumor, usually found in the adrenal medulla. In a clonidine suppression test, plasma catecholamine levels are measured before and 3 hours after a 0.3 mg oral test dose has been given to the patient. A positive test occurs if there is no decrease in plasma levels. Pregnancy and breastfeeding Clonidine is classed by the FDA as pregnancy category C. It is classified by the TGA of Australia as pregnancy category B3, which means that it has shown some detrimental effects on fetal development in animal studies, although the relevance of this to human beings is unknown. Clonidine appears in high concentration in breast milk and nursing infants have approximately 2/3 of serum clonidine concentrations as the mother. Caution is warranted in women who are pregnant, planning to become pregnant, or are breastfeeding. Adverse effects The principal adverse effects of clonidine are sedation, dry mouth, and hypotension (low blood pressure).By frequencyVery common (>10% frequency): Common (1-10% frequency): Uncommon (0.1-1% frequency): Rare (<0.1% frequency): Withdrawal Because clonidine suppresses sympathetic outflow, resulting in lower blood pressure, sudden discontinuation can result in acute hypertension due to a rebound in sympathetic outflow. In extreme cases, this can result in a hypertensive crisis, which is a medical emergency.Clonidine therapy should generally be gradually tapered when discontinuing therapy to avoid rebound effects from occurring. Treatment of clonidine withdrawal hypertension depends on the severity of the condition. Reintroduction of clonidine for mild cases, alpha and beta blockers for more urgent situations. Beta blockers never should be used alone to treat clonidine withdrawal as alpha vasoconstriction would still continue. Pharmacology Mechanism of action Clonidine crosses the blood-brain barrier. High blood pressure Clonidine treats high blood pressure by stimulating α2 receptors in the brainstem, which decreases peripheral vascular resistance, lowering blood pressure. It has specificity towards the presynaptic α2 receptors in the vasomotor center in the brainstem. This binding has a sympatholytic effect, suppresses release of norepinephrine, ATP, renin, and neuropeptide Y which if released would increase vascular resistance.: 201–203 Clonidine also acts as an agonist at imidazoline-1 (I1) receptors in the brain, and it is hypothesized that this effect may contribute to reducing blood pressure by reducing signaling in the sympathetic nervous system; this effect acts upstream of the central α2 agonist effect of clonidine.: 201–203 Clonidine may also cause bradycardia, theoretically by increasing signaling through the vagus nerve. When given intravenously, clonidine can temporarily increase blood pressure by stimulating α1 receptors in smooth muscles in blood vessels. This hypertensive effect is not usual when clonidine is given by mouth or by the transdermal route.: 201–203 Plasma concentration of clonidine exceeding 2.0 ng/mL does not provide further blood pressure reduction. Attention deficit hyperactivity disorder In the setting of attention deficit hyperactivity disorder (ADHD), clonidines molecular mechanism of action occurs due to its agonism at the alpha-2A adrenergic receptor, the subtype of the adrenergic receptor that is most principally found in the brain. Within the brain, the alpha-2A adrenergic receptors are found within the prefrontal cortex (PFC), among other areas. The alpha-2A adrenergic receptors are found on the presynaptic cleft of a given neuron, and, when activated by an agonist, the effect on downstream neurons is inhibitory. The inhibition is accomplished by preventing the secretion of the neurotransmitter norepinephrine. Thus, clonidines agonism on alpha-2A adrenergic receptors in the PFC inhibits the action of downstream neurons by preventing the secretion of norepinephrine.This mechanism is similar to the brains physiological inhibition of PFC neurons by the locus ceruleus (LC), which secretes norepinephrine into the PFC. Although norepinephrine can also bind to target adrenergic receptors on the downstream neuron (otherwise inducing a stimulatory effect), norepinephrine also binds to alpha-2A adrenergic receptors (akin to clonidines mechanism of action), inhibiting the release of norepinephrine by that neuron and inducing an inhibitory effect. Because the PFC is required for working memory and attention, it is thought that clonidines inhibition of PFC neurons helps to eliminate irrelevant attention (and subsequent behaviors), improving the persons focus and correcting deficits in attention. Growth hormone test Clonidine stimulates release of HGH hormone from the hypothalamus, which in turn stimulates pituitary release of growth hormone. This effect has been used as part of a "growth hormone test," which can assist with diagnosing growth hormone deficiency in children. Pharmacokinetics After being ingested, clonidine is absorbed into the blood stream rapidly and nearly completely, with peak concentrations in human plasma occurring within 60–90 minutes for the "Immediate Release" (IR) version of the drug, which is shorter than the "Extended Release" (ER/XR) version. Clonidine is fairly lipid soluble with the logarithm of its partition coefficient (log P) equal to 1.6; to compare, the optimal log P to allow a drug that is active in the human central nervous system to penetrate the blood brain barrier is 2.0. Less than half of the absorbed portion of an orally administered dose will be metabolized by the liver into inactive metabolites, with roughly the other half being excreted unchanged by the kidneys. About one-fifth of an oral dose will not be absorbed, and is thus excreted in the feces. The half-life of clonidine varies widely, with estimates between 6 and 23 hours, and is greatly affected by and prolonged in the setting of poor kidney function. History Clonidine was introduced in 1966. It was first used as a hypertension treatment under the trade name of Catapres. Society and culture Brand names As of June 2017, clonidine was marketed under many brand names worldwide: Arkamin, Aruclonin, Atensina, Catapin, Catapres, Catapresan, Catapressan, Chianda, Chlofazoline, Chlophazolin, Clonid-Ophtal, Clonidin, Clonidina, Clonidinã, Clonidine, Clonidine hydrochloride, Clonidinhydrochlorid, Clonidini, Clonidinum, Clonigen, Clonistada, Clonnirit, Clophelinum, Dixarit, Duraclon, Edolglau, Haemiton, Hypodine, Hypolax, Iporel, Isoglaucon, Jenloga, Kapvay, Klofelino, Kochaniin, Lonid, Melzin, Menograine, Normopresan, Paracefan, Pinsanidine, Run Rui, and Winpress. It was marketed as a combination drug with chlortalidone as Arkamin-H, Bemplas, Catapres-DIU, and Clorpres, and in combination with bendroflumethiazide as Pertenso. See also Ajmalicine Serpentine References External links "Clonidine". Drug Information Portal. U.S. National Library of Medicine. Alpha-2 agonists in ADHD
Lidocaine	Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a local anesthetic of the amino amide type. It is also used to treat ventricular tachycardia. When used for local anaesthesia or in nerve blocks, lidocaine typically begins working within several minutes and lasts for half an hour to three hours. Lidocaine mixtures may also be applied directly to the skin or mucous membranes to numb the area. It is often used mixed with a small amount of adrenaline (epinephrine) to prolong its local effects and to decrease bleeding.If injected intravenously, it may cause cerebral effects such as confusion, changes in vision, numbness, tingling, and vomiting. It can cause low blood pressure and an irregular heart rate. There are concerns that injecting it into a joint can cause problems with the cartilage. It appears to be generally safe for use in pregnancy. A lower dose may be required in those with liver problems. It is generally safe to use in those allergic to tetracaine or benzocaine. Lidocaine is an antiarrhythmic medication of the class Ib type. This means it works by blocking sodium channels and thus decreasing the rate of contractions of the heart. When injected near nerves, the nerves cannot conduct signals to or from the brain.Lidocaine was discovered in 1946 and went on sale in 1948. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 219th most commonly prescribed medication in the United States, with more than 2 million prescriptions. Medical uses Local numbing agent The efficacy profile of lidocaine as a local anaesthetic is characterized by a rapid onset of action and intermediate duration of efficacy. Therefore, lidocaine is suitable for infiltration, block, and surface anaesthesia. Longer-acting substances such as bupivacaine are sometimes given preference for spinal and epidural anaesthesias; lidocaine, though, has the advantage of a rapid onset of action. Adrenaline vasoconstricts arteries, reducing bleeding and also delaying the resorption of lidocaine, almost doubling the duration of anaesthesia. Lidocaine is one of the most commonly used local anaesthetics in dentistry. It can be administered in multiple ways, most often as a nerve block or infiltration, depending on the type of treatment carried out and the area of the mouth worked on.For surface anaesthesia, several formulations can be used for endoscopies, before intubations, etc. Buffering the pH of lidocaine makes local numbing less painful. Lidocaine drops can be used on the eyes for short ophthalmic procedures. There is tentative evidence for topical lidocaine for neuropathic pain and skin graft donor site pain. As a local numbing agent, it is used for the treatment of premature ejaculation.An adhesive transdermal patch containing a 5% concentration of lidocaine in a hydrogel bandage, is approved by the US FDA for reducing nerve pain caused by shingles. The transdermal patch is also used for pain from other causes, such as compressed nerves and persistent nerve pain after some surgeries. Heart arrhythmia Lidocaine is also the most important class-1b antiarrhythmic drug; it is used intravenously for the treatment of ventricular arrhythmias (for acute myocardial infarction, digoxin poisoning, cardioversion, or cardiac catheterization) if amiodarone is not available or contraindicated. Lidocaine should be given for this indication after defibrillation, CPR, and vasopressors have been initiated. A routine preventive dose is no longer recommended after a myocardial infarction as the overall benefit is not convincing. Epilepsy A 2013 review on treatment for neonatal seizures recommended intravenous lidocaine as a second-line treatment, if phenobarbital fails to stop seizures. Other Intravenous lidocaine infusions are also used to treat chronic pain and acute surgical pain as an opiate sparing technique. The quality of evidence for this use is poor so it is difficult to compare it to placebo or an epidural.Inhaled lidocaine can be used as a cough suppressor acting peripherally to reduce the cough reflex. This application can be implemented as a safety and comfort measure for patients who have to be intubated, as it reduces the incidence of coughing and any tracheal damage it might cause when emerging from anaesthesia.Lidocaine, along with ethanol, ammonia, and acetic acid, may also help in treating jellyfish stings, both numbing the affected area and preventing further nematocyst discharge.For gastritis, drinking a viscous lidocaine formulation may help with the pain. Adverse effects Adverse drug reactions (ADRs) are rare when lidocaine is used as a local anesthetic and is administered correctly. Most ADRs associated with lidocaine for anesthesia relate to administration technique (resulting in systemic exposure) or pharmacological effects of anesthesia, and allergic reactions only rarely occur. Systemic exposure to excessive quantities of lidocaine mainly result in central nervous system (CNS) and cardiovascular effects – CNS effects usually occur at lower blood plasma concentrations and additional cardiovascular effects present at higher concentrations, though cardiovascular collapse may also occur with low concentrations. ADRs by system are: CNS excitation: nervousness, agitation, anxiety, apprehension, tingling around the mouth (circumoral paraesthesia), headache, hyperesthesia, tremor, dizziness, pupillary changes, psychosis, euphoria, hallucinations, and seizures CNS depression with increasingly heavier exposure: drowsiness, lethargy, slurred speech, hypoesthesia, confusion, disorientation, loss of consciousness, respiratory depression and apnoea. Cardiovascular: hypotension, bradycardia, arrhythmias, flushing, venous insufficiency, increased defibrillator threshold, edema, and/or cardiac arrest – some of which may be due to hypoxemia secondary to respiratory depression. Respiratory: bronchospasm, dyspnea, respiratory depression or arrest Gastrointestinal: metallic taste, nausea, vomiting Ears: tinnitus Eyes: local burning, conjunctival hyperemia, corneal epithelial changes/ulceration, diplopia, visual changes (opacification) Skin: itching, depigmentation, rash, urticaria, edema, angioedema, bruising, inflammation of the vein at the injection site, irritation of the skin when applied topically Blood: methemoglobinemia AllergyADRs associated with the use of intravenous lidocaine are similar to toxic effects from systemic exposure above. These are dose-related and more frequent at high infusion rates (≥3 mg/min). Common ADRs include: headache, dizziness, drowsiness, confusion, visual disturbances, tinnitus, tremor, and/or paraesthesia. Infrequent ADRs associated with the use of lidocaine include: hypotension, bradycardia, arrhythmias, cardiac arrest, muscle twitching, seizures, coma, and/or respiratory depression.It is generally safe to use lidocaine with vasoconstrictor such as adrenaline, including in regions such as the nose, ears, fingers, and toes. While concerns of tissue death if used in these areas have been raised, evidence does not support these concerns.The use of lidocaine for spinal anesthesia may lead to an increased risk of transient neurological symptoms, a painful condition that is sometimes experienced immediately after surgery. There is some weak evidence to suggest that the use of alternative anesthetic medications such as prilocaine, procaine, bupivacaine, ropivacaine, or levobupivacaine may decrease the risk of a person developing transient neurological symptoms. Low quality evidence suggests that 2‐chloroprocaine and mepivacaine when used for spinal anesthetic have a similar risk of the person developing transient neurological symptoms as lidocaine. Interactions Any drugs that are also ligands of CYP3A4 and CYP1A2 can potentially increase serum levels and potential for toxicity or decrease serum levels and the efficacy, depending on whether they induce or inhibit the enzymes, respectively. Drugs that may increase the chance of methemoglobinemia should also be considered carefully. Dronedarone and liposomal morphine are both absolutely a contraindication, as they may increase the serum levels, but hundreds of other drugs require monitoring for interaction. Contraindications Absolute contraindications for the use of lidocaine include: Heart block, second or third degree (without pacemaker) Severe sinoatrial block (without pacemaker) Serious adverse drug reaction to lidocaine or amide local anesthetics Hypersensitivity to corn and corn-related products (corn-derived dextrose is used in the mixed injections) Concurrent treatment with quinidine, flecainide, disopyramide, procainamide (class I antiarrhythmic agents) Prior use of amiodarone hydrochloride Adams-Stokes syndrome Wolff-Parkinson-White syndrome Lidocaine viscous is not recommended by the FDA to treat teething pain in children and infants.Exercise caution in patients with any of these: Hypotension not due to arrhythmia Bradycardia Accelerated idioventricular rhythm Elderly Ehlers–Danlos syndromes; efficiency of local anesthetics can be reduced Pseudocholinesterase deficiency Intra-articular infusion (this is not an approved indication and can cause chondrolysis) Porphyria, especially acute intermittent porphyria; lidocaine has been classified as porphyrogenic because of the hepatic enzymes it induces, although clinical evidence suggests it is not. Bupivacaine is a safe alternative in this case. Impaired liver function – people with lowered hepatic function may have an adverse reaction with repeated administration of lidocaine because the drug is metabolized by the liver. Adverse reactions may include neurological symptoms (e.g. dizziness, nausea, muscle twitches, vomiting, or seizures). Overdosage Overdoses of lidocaine may result from excessive administration by topical or parenteral routes, accidental oral ingestion of topical preparations by children (who are more susceptible to overdose), accidental intravenous (rather than subcutaneous, intrathecal, or paracervical) injection, or from prolonged use of subcutaneous infiltration anesthesia during cosmetic surgery. Such overdoses have often led to severe toxicity or death in both children and adults. Lidocaine and its two major metabolites may be quantified in blood, plasma, or serum to confirm the diagnosis in potential poisoning victims or to assist forensic investigation in a case of fatal overdose. Lidocaine is often given intravenously as an antiarrhythmic agent in critical cardiac-care situations. Treatment with intravenous lipid emulsions (used for parenteral feeding) to reverse the effects of local anaesthetic toxicity is becoming more common. Postarthroscopic glenohumeral chondrolysis Lidocaine in large amounts may be toxic to cartilage and intra-articular infusions can lead to postarthroscopic glenohumeral chondrolysis. Pharmacology Mechanism of action Lidocaine alters signal conduction in neurons by prolonging the inactivation of the fast voltage-gated Na+ channels in the neuronal cell membrane responsible for action potential propagation. With sufficient blockage, the voltage-gated sodium channels will not open and an action potential will not be generated. Careful titration allows for a high degree of selectivity in the blockage of sensory neurons, whereas higher concentrations also affect other types of neurons. The same principle applies for this drugs actions in the heart. Blocking sodium channels in the conduction system, as well as the muscle cells of the heart, raises the depolarization threshold, making the heart less likely to initiate or conduct early action potentials that may cause an arrhythmia. Pharmacokinetics When used as an injectable it typically begins working within four minutes and lasts for half an hour to three hours. Lidocaine is about 95% metabolized (dealkylated) in the liver mainly by CYP3A4 to the pharmacologically active metabolites monoethylglycinexylidide (MEGX) and then subsequently to the inactive glycine xylidide. MEGX has a longer half-life than lidocaine, but also is a less potent sodium channel blocker. The volume of distribution is 1.1 L/kg to 2.1 L/kg, but congestive heart failure can decrease it. About 60% to 80% circulates bound to the protein alpha1 acid glycoprotein. The oral bioavailability is 35% and the topical bioavailability is 3%. The elimination half-life of lidocaine is biphasic and around 90 min to 120 min in most patients. This may be prolonged in patients with hepatic impairment (average 343 min) or congestive heart failure (average 136 min). Lidocaine is excreted in the urine (90% as metabolites and 10% as unchanged drug). History Lidocaine, the first amino amide–type local anesthetic, was first synthesized under the name xylocaine by Swedish chemist Nils Löfgren in 1943. His colleague Bengt Lundqvist performed the first injection anesthesia experiments on himself. It was first marketed in 1949. Society and culture Dosage forms Lidocaine, usually in the form of its hydrochloride salt, is available in various forms including many topical formulations and solutions for injection or infusion. It is also available as a transdermal patch, which is applied directly to the skin. Names Lidocaine is the International Nonproprietary Name (INN), British Approved Name (BAN), and Australian Approved Name (AAN), while lignocaine is the former BAN and AAN. Both the old and new names will be displayed on the product label in Australia until at least 2023.Xylocaine is a brand name. Recreational use As of 2021, lidocaine is not listed by the World Anti-Doping Agency as a substance whose use is banned in sport. It is used as an adjuvant, adulterant, and diluent to street drugs such as cocaine and heroin. It is one of the three common ingredients in site enhancement oil used by bodybuilders. Adulterant in cocaine Lidocaine is often added to cocaine as a diluent. Cocaine and lidocaine both numb the gums when applied. This gives the user the impression of high-quality cocaine, when in actuality the user is receiving a diluted product. Compendial status Japanese Pharmacopoeia 15 United States Pharmacopeia 31 Veterinary use It is a component of the veterinary drug Tributame along with embutramide and chloroquine used to carry out euthanasia on horses and dogs. See also Dimethocaine (has some DRI activity) Lidocaine/prilocaine Procaine Mexiletine References External links "Lidocaine". Drug Information Portal. U.S. National Library of Medicine. "Lidocaine Transdermal Patch". MedlinePlus. US patent 2441498, Nils Magnus Loefgren & Bengt Josef Lundqvist, "Alkyl glycinanilides", published 1948-05-11, issued 1948-05-11, assigned to ASTRA APOTEKARNES KEM FAB
Glasdegib	Glasdegib, sold under the brand name Daurismo, is a medication for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults older than 75 years or those who have comorbidities that preclude use of intensive induction chemotherapy. It is taken by mouth and is used in combination with low-dose cytarabine.The recommended dose of glasdegib is 100 mg orally once daily on days 1 to 28 in combination with cytarabine 20 mg subcutaneously twice daily on days 1 to 10 of each 28-day cycle in the absence of unacceptable toxicity or loss of disease control.The most common adverse reactions are anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash.It is a small molecule inhibitor of sonic hedgehog, which is a protein overexpressed in many types of cancer. It inhibits the sonic hedgehog receptor smoothened (SMO), as do most drugs in its class. History Glasdegib was approved for medical use in the United States in December 2018.FDA approval was based on a multicenter, open-label, randomized study (BRIGHT AML 1003, NCT01546038) that included 115 subjects with newly-diagnosed AML who met at least one of the following criteria: a) age 75 years or older, b) severe cardiac disease, c) baseline Eastern Cooperative Oncology Group performance status of 2, or d) baseline serum creatinine >1.3 mg/dL. Subjects were randomized 2:1 to receive glasdegib, 100 mg daily, with LDAC 20 mg subcutaneously twice daily on days 1 to 10 of a 28-day cycle (N=77) or LDAC alone (N=38) in 28-day cycles until disease progression or unacceptable toxicity. The trial was conducted in United States, Canada and Europe.Efficacy was established based on an improvement in overall survival (date of randomization to death from any cause). With a median follow-up of 20 months, median survival was 8.3 months (95% CI: 4.4, 12.2) for the glasdegib + LDAC arm and 4.3 months (95% CI: 1.9, 5.7) for the LDAC alone arm and HR of 0.46 (95% CI: 0.30, 0.71; p=0.0002).Glasdegib was granted priority review and orphan drug designation by the U.S. Food and Drug Administration (FDA). It was granted orphan drug designation by the European Medicines Agency (EMA) in October 2017.Glasdegib was approved for medical use in the European Union in June 2020. References External links "Glasdegib". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT01546038 for "A Study To Evaluate PF-04449913 With Chemotherapy In Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome" at ClinicalTrials.gov
Pexidartinib	Pexidartinib, sold under the brand name Turalio, is a kinase inhibitor drug for the treatment of adults with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Pexidartinib blocks the activity of the colony-stimulating factor-1 receptor (CSF-1R). Common side effects are increased lactate dehydrogenase (proteins that helps produce energy in the body), increased aspartate aminotransferase (enzymes that are mostly in the liver but also in muscles), loss of hair color, increased alanine aminotransferase (enzymes that are primarily in the liver and kidney) and increased cholesterol. Additional side effects include neutropenia (low level of white blood cells that help the immune system defend against disease and infection), increased alkaline phosphatase (enzymes that are mostly in the cells of bone and the liver), decreased lymphocytes (white blood cells that help the immune system defend against disease and infection), eye edema (swelling around the eyes), decreased hemoglobin (protein in red blood cells that carry oxygen), rash, dysgeusia (altered sense of taste) and decreased phosphate (electrolytes that help with energy). The US prescribing information for pexidartinib includes a boxed warning about the risk of serious and potentially fatal liver injury.In August 2019, it was approved by U.S. FDA for treatment of giant-cell tumor of the tendon sheath (GC-TS). Pexidartinib is available in the US only through the Turalio Risk Evaluation and Mitigation Strategy (REMS) Program. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. History The approval of pexidartinib was based on the results of a multi-center international clinical trial of 120 subjects, 59 of whom received placebo. The primary efficacy endpoint was the overall response rate (ORR) analyzed after 25 weeks of treatment. The clinical trial demonstrated a statistically significant improvement in ORR in subjects who received pexidartinib, with an ORR of 38%, compared to no responses in subjects who received placebo. The complete response rate was 15% and the partial response rate was 23%. A total of 22 out of 23 responders who had been followed for a minimum of six months following the initial response maintained their response for six or more months, and a total of 13 out of 13 responders who had been followed for a minimum of 12 months following the initial response maintained their response for 12 or more months.The U.S. Food and Drug Administration (FDA) granted the application for pexidartinib breakthrough therapy designation, orphan drug designation, and priority review designation. The FDA granted the approval of Turalio to Daiichi Sankyo. References Further reading "Pexidartinib". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases. October 2019. PMID 31869194. NBK551730. Lamb YN (November 2019). "Pexidartinib: First Approval". Drugs. 79 (16): 1805–1812. doi:10.1007/s40265-019-01210-0. PMC 7044138. PMID 31602563. Roskoski R (February 2020). "Properties of FDA-approved small molecule protein kinase inhibitors: A 2020 update". Pharmacol. Res. 152: 104609. doi:10.1016/j.phrs.2019.104609. PMID 31862477. S2CID 209435035. External links "Pexidartinib". Drug Information Portal. U.S. National Library of Medicine.
Insulin glargine/lixisenatide	Insulin glargine/lixisenatide, sold under the brand name Soliqua 100/33 among others, is a fixed-dose combination medication that combines insulin glargine and lixisenatide and is used to treat diabetes. The most common side effects include hypoglycemia (low blood glucose), diarrhea, vomiting and nausea (feeling sick).Insulin glargine/lixisenatide was approved for medical use in the United States in November 2016, and in the European Union in January 2017. Medical uses Insulin glargine/lixisenatide is approved as a prescription for adults with type 2 diabetes mellitus poorly controlled by lixisenatide or basal insulin alone. According to the American Diabetes Association, combination treatment of a GLP-1 receptor agonist with basal insulin should occur after HbA1C levels remain above target (7% for most type 2 people with diabetes) following use of basal insulin.The use of insulin glargine/lixisenatide and lixisenatide-containing products is not recommended for use while pregnant. There is insufficient data in humans to form a pregnancy risk category for lixisenatide. Animal pregnancy studies have shown potential risks to the prenate, but it is unclear if these risks are related to the drug. It is unknown if insulin glargine and lixisenatide are present in human milk or the effects these drugs would have on breastfed infants. Potential adverse effects to the mother and child as well as management of diabetes and glucose control should be considered prior to use of Soliqua during breastfeeding. Adverse effects Prior to the approval of insulin glargine/lixisenatide, two studies were conducted to evaluate the safety of the formulation. Adverse reactions for at least 5% of people taking it were hypoglycemia, nausea, nasopharyngitis, diarrhea, upper respiratory tract infections, and headache. In Study A (N=469), symptoms of hypoglycemia were recorded in 25.6% of people with zero cases of severe symptomatic hypoglycemia. Study B (N=365) had a 40% incidence of hypoglycemic events with 1.1% incidence of severe hypoglycemia requiring assistance. Interactions Lixisenatide and other GLP-1 receptor agonist slow emptying of stomach contents, which may affect the absorption of orally administered medications. For effective use, oral contraceptives should be taken 1 hour before or 11 hours after taking lixisenatide-containing products. Acetaminophen and antibiotics are among other drugs that are affected by this action of lixisenatide. History Lixisenatide is a GLP-1 receptor agonist that was created by Zealand Pharma A/S of Denmark; in 2003 Zealand licensed it to Sanofi which developed the drug. Lixisenatide was approved by the European Commission on February 1, 2013. Sanofi submitted an NDA in the US, which was accepted for review by the US FDA in February 2013 but after discussions with the FDA about the cardiovascular safety data included in the package (starting in 2008, the FDA had required stronger CV safety data for new anti-diabetes drugs, following the controversy around the risks of Avandia) Sanofi decided to withdraw the NDA and wait for the results of a Phase III study that was scheduled to be completed in 2015. Sanofi resubmitted the application which the FDA accepted in September 2015, by which time Sanofi had lost the lead in the field of anti-diabetic drugs to Novo Nordisk. Lixisenatide received FDA approval on July 28, 2016.In 2010, Sanofi extended a license agreement it had with Zealand for lixisenatide to allow Sanofi to combine it with insulin glargine, which was Sanofis best selling drug at the time, with sales of around €3 billion in 2009. Sanofi planned to start the Phase III trial that year. Sanofi submitted the new drug application in December 2015 for the combination and spent a US$245M priority voucher to gain a faster review, to try to outrace Novo Nordisk’s Xultophy, a similar combination drug of Novos insulin Tresiba and Novos GLP-1 agonist Victoza. Sanofis application was considered by the same Endocrinologic and Metabolic Drugs Advisory FDA Committee that was considering lixisenatide as a single agent. In May 2016 by a vote of 12–2, with several members of the committee expressing reservations about Sanofis plans to offer two pens with different ratios of insulin glargine and lixisenatide - one for people who had never taken insulin before and one for people who had; there was also concern about how to handle dosing when switching people from a single drug regimen to the combination drug. In August 2016 the FDA told Sanofi that it was delaying a final decision for three months, and asked Sanofi for more data on how people used the delivery devices. In November 2016, the FDA approved Sanofis Soliqua formulation (insulin glargine 100 units/mL and lixisenatide 33 mcg/mL). Soliqua became available in American pharmacies in January 2017. Society and culture Cost Following the US approval of Soliqua, Sanofi made a US$25 million milestone payment to Zealand. Zealand may receive additional payments up to US$110 million along with receiving royalties on global sales. Royalties paid to Zealand for Soliqua are based on a fixed low double-digit percentage of net sales.In January 2017, Sanofi announced that the wholesale acquisition cost (WAC) of a 3 ml pen of Soliqua is US$127. At the average dose used in clinical trials, this amounts to US$19.90 per day.According to Sanofis Half-Year Financial Report, the net sales of Soliqua reached €9 million in the first six months of availability in the United States. Brands Insulin glargine/lixisenatide was called HOE901/AVE0010 during development and as of October 2017, had been marketed under the brand names iGlarLixi, Lantus/Lyxumia, LixiLan, and Soliqua. References External links "Insulin glargine mixture with lixisenatide". Drug Information Portal. U.S. National Library of Medicine.
Insulin glargine	Insulin glargine, sold under the brand name Lantus among others, is a long-acting modified form of medical insulin, used in the management of type I and type II diabetes. It is typically the recommended long acting insulin in the United Kingdom. It is used once a day as an injection just under the skin. Effects generally begin an hour after use.Common side effects include low blood sugar, problems at the site of injection, itchiness, and weight gain. Other serious side effects include low blood potassium. NPH insulin rather than insulin glargine is generally preferred in pregnancy. After injection microcrystals slowly release insulin for about 24 hours. This insulin causes body tissues to absorb glucose from the blood and decreases glucose production by the liver.Insulin glargine was approved for medical use in the United States in 2000. It is on the World Health Organizations List of Essential Medicines. In 2020, it was the 32nd most commonly prescribed medication in the United States with more than 17 million prescriptions. Medical uses The long-acting insulin class, which includes insulin glargine, do not appear much better than neutral protamine Hagedorn (NPH) insulin, but do have a greater cost, making them, as of 2010, not cost effective for the treatment of type 2 diabetes. In a previous review it was unclear if there is a difference in hypoglycemia, as there was not enough data to determine any differences with respect to long term outcomes, however a more recent Cochrane systematic review did not find clinically significant difference when comparing insulin glargine to NHP insulin, insulin detemir or insulin degludec in the management of type I Diabetes in neither adults or children in periods of 6 months or longer. It is not typically the recommended long acting insulin in the United Kingdom. Mixing with other insulins Unlike some other longer-acting insulins, glargine must not be diluted or mixed with other insulin or solution in the same syringe. However, this restriction has been questioned. Adverse effects Common side effects include low blood sugar, problems at the site of injection, itchiness, and weight gain. Serious side effects include low blood potassium.As of 2012, tentative evidence shows no association between insulin glargine and cancer. Previous studies had raised concerns.When comparing insulin glargine to NPH insulin, insulin detemir or insulin degludec, no significant adverse effects were found in the management of type I Diabetes in neither adults or children in periods of 6 months or longer. Pharmacology Mechanism of action Insulin glargine differs from human insulin by replacing asparagine with glycine in position 21 of the A-chain and by carboxy-terminal extension of B-chain by 2 arginine residues. The arginine amino acids shift the isoelectric point from a pH of 5.4 to 6.7, making the molecule more soluble at an acidic pH and less soluble at physiological pH. The isoelectric shift also allows for the subcutaneous injection of a clear solution. The glycine substitution prevents deamidation of the acid-sensitive asparagine at acidic pH. In the neutral subcutaneous space, higher-order aggregates form, resulting in a slow, peakless dissolution and absorption of insulin from the site of injection. It can achieve a peakless level for at least 24 hours. Acceptance and repartition in the body Insulin glargine is formulated at an acidic pH 4, where it is completely water-soluble. After subcutaneous injection of the acidic solute (which can cause discomfort and a stinging sensation), when a physiologic pH (approximately 7.4) is achieved the increase in pH causes the insulin to come out of solution resulting in the formation of higher order aggregates of insulin hexamers. The higher order aggregation slows the dissociation of the hexamers into insulin monomers, the functional and physiologically active unit of insulin. This gradual process ensures that small amounts of insulin glargine are released into the body continuously, giving an almost peakless profile. History On 9 June 2000, the European Commission formally approved the launching of Lantus by Sanofi-Aventis Germany Ltd. in the entire European Union. The admission was prolonged on 9 June 2005.A three-fold more concentrated formulation, brand name "Toujeo", was introduced after FDA approval in 2015. Society and culture Biosimilars Abasaglar was approved for medical use in the European Union in September 2014.Lusduna was approved for medical use in the European Union in January 2017.In March 2018, insulin glargine (Semglee) was approved for medical use in the European Union.In July 2021, insulin glargine-yfgn (Semglee) was approved for medical use in the United States as the first interchangeable biosimilar of Lantus. Patent expiry Patent protection for insulin glargine expired in most countries in 2015 and in the U.S.A. is expected to expire on 2027-07-05. Insulin glargine from competitor Eli Lilly became available in most countries during 2015, under the brand names Basaglar (as a follow-on in the US) and Abasaglar (as a biosimilar in the EU). References External links "Insulin glargine". Drug Information Portal. U.S. National Library of Medicine.
Tenofovir alafenamide	Tenofovir alafenamide, sold under the brand name Vemlidy, is a hepatitis B virus (HBV) nucleotide reverse transcriptase inhibitor medication for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease. It is taken by mouth.Tenofovir alafenamide is a prodrug of tenofovir. It was developed by Gilead Sciences based on the protide technology of Chris McGuigan for use in the treatment of HIV/AIDS and chronic hepatitis B, and is applied in the form of tenofovir alafenamide fumarate (TAF). Closely related to the commonly used reverse-transcriptase inhibitor tenofovir disoproxil fumarate (TDF), TAF has greater antiviral activity and better distribution into lymphoid tissues than that agent. Vemlidy was approved by the U.S. Food and Drug Administration (FDA) in November 2016. Fixed-dose combinations containing tenofovir alafenamide Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya) — approved both in the United States and in the European Union in November 2015 (compare elvitegravir/cobicistat/emtricitabine/tenofovir; (Stribild)) Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) — approved in the United States in March 2016, and in the European Union in June 2016 (compare Emtricitabine/rilpivirine/tenofovir; (Complera)) Emtricitabine/tenofovir alafenamide (Descovy) — approved in the United States in April 2016 (compare emtricitabine/tenofovir; (Truvada)). In October 2019, Descovy was approved in the United States for HIV-1 pre-exposure prophylaxis (PrEP). Bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy) — approved in the United States in February 2018. Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (Symtuza) — approved in the European Union in September 2017, in the United States in July 2018, and in Australia in November 2019. Dolutegravir/emtricitabine/tenofovir alafenamide. Dolutegravir/lamivudine/tenofovir alafenamide. Research Gilead announced a Phase III clinical trial evaluating a single-tablet regimen combining tenofovir alafenamide with cobicistat, emtricitabine and elvitegravir and developed a coformulation of the drug with cobicistat, emtricitabine and the protease inhibitor darunavir. In a 48-week study comparing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil (Stribild) to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya), the results showed the newer drugs effects to be non-inferior to the established agent, but at much lower dosages and with lower incidence of adverse side effects such as impaired kidney function. The FDA approved the TAF-based treatment regimen for treatment of HIV-1 in November 2015. Genvoya is the first TAF-based regimen to receive approval. References External links "Tenofovir alafenamide". Drug Information Portal. U.S. National Library of Medicine. "Tenofovir alafenamide fumarate". Drug Information Portal. U.S. National Library of Medicine.
Mafenide	Mafenide (INN; usually as mafenide acetate, trade name Sulfamylon) is a sulfonamide-type medication used as an antibiotic. It was approved by the FDA in 1948. Uses Mafenide is used to treat severe burns. It is used topically as an adjunctive therapy for second- and third-degree burns. It is bacteriostatic against many gram-positive and gram-negative organisms, including Pseudomonas aeruginosa. Some sources state that mafenide is more appropriate for non-facial burns, while chloramphenicol/prednisolone or bacitracin are more appropriate for facial burns. Mechanism of action Mafenide works by reducing the bacterial population present in the avascular tissues of burns and permits spontaneous healing of deep partial-thickness burns. Adverse reactions Adverse reactions can include superinfection, pain or burning upon application, rash, pruritus, tachypnea, or hyperventilation. Mafenide is metabolized to a carbonic anhydrase inhibitor, which could potentially result in metabolic acidosis. Drug interactions There are no significant interactions. Contraindications Mafenide is contraindicated in those with sulfonamide hypersensitivity or renal impairment. Dosage For use as adjunctive therapy for second- and third-degree burns to prevent infection, adults and children should apply topically to a thickness of approximately 1.6 mm to cleaned and debrided wound once or twice per day with a sterile gloved hand. The burned area should be covered with cream at all times. References External links Mafenide information on RxList
Warfarin	Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent stroke in people who have atrial fibrillation, valvular heart disease, or artificial heart valves. Less commonly, it is used following ST-segment elevation myocardial infarction and orthopedic surgery. It is generally taken by mouth, but may also be used intravenously.The common side effect is bleeding. Less common side effects may include areas of tissue damage and purple toes syndrome. Use is not recommended during pregnancy. The effects of warfarin typically should be monitored by checking prothrombin time (INR) every one to four weeks. Many other medications and dietary factors can interact with warfarin, either increasing or decreasing its effectiveness. The effects of warfarin may be reversed with phytomenadione (vitamin K1), fresh frozen plasma, or prothrombin complex concentrate.Warfarin decreases blood clotting by blocking an enzyme called vitamin K epoxide reductase that reactivates vitamin K1. Without sufficient active vitamin K1, clotting factors II, VII, IX, and X have decreased clotting ability. The anticlotting protein C and protein S are also inhibited, but to a lesser degree. A few days are required for full effect to occur, and these effects can last for up to five days. Additionally, because the mechanism involves enzymes such as VKORC1, patients on warfarin with polymorphisms of the enzymes may require adjustments in therapy to account if the genetic variant that they have is more readily inhibited by warfarin, thus requiring lower doses.Warfarin first came into large-scale commercial use in 1948 as a rat poison. Warfarin was formally approved for human use by the U.S. Food and Drug Administration to treat blood clots in 1954. In 1955, warfarins reputation as a safe and acceptable treatment was bolstered when President Dwight D. Eisenhower received warfarin following a massive and highly publicized heart attack. Eisenhowers illness kickstarted a transformation in medicine where coronary artery disease, arterial plaques, and ischemic strokes were treated and prevented by using anticoagulants such as warfarin. It is on the World Health Organizations List of Essential Medicines. Warfarin is available as a generic medication. In 2020, it was the 58th most commonly prescribed medication in the United States, with more than 11 million prescriptions. Medical uses Warfarin is used to decrease the tendency for thrombosis, or as secondary prophylaxis (prevention of further episodes) in those individuals who have already formed a blood clot (thrombus). Warfarin treatment can help prevent formation of future blood clots and help reduce the risk of embolism (migration of a thrombus to a spot where it blocks blood supply to a vital organ).Warfarin is best suited for anticoagulation (clot formation inhibition) in areas of slowly running blood (such as in veins and the pooled blood behind artificial and natural valves), and in blood pooled in dysfunctional cardiac atria. Thus, common clinical indications for warfarin use are atrial fibrillation, the presence of artificial heart valves, deep venous thrombosis, and pulmonary embolism (where the embolized clots first form in veins). Warfarin is also used in antiphospholipid syndrome. It has been used occasionally after heart attacks (myocardial infarctions), but is far less effective at preventing new thromboses in coronary arteries. Prevention of clotting in arteries is usually undertaken with antiplatelet drugs, which act by a different mechanism from warfarin (which normally has no effect on platelet function). It can be used to treat people following ischemic strokes due to atrial fibrillation, though direct oral anticoagulants (DOACs) may offer greater benefits. Dosing Dosing of warfarin is complicated because it is known to interact with many commonly used medications and certain foods. These interactions may enhance or reduce warfarins anticoagulation effect. To optimize the therapeutic effect without risking dangerous side effects such as bleeding, close monitoring of the degree of anticoagulation is required by a blood test measuring an INR. During the initial stage of treatment, INR is checked daily; intervals between tests can be lengthened if the patient manages stable therapeutic INR levels on an unchanged warfarin dose. Newer point-of-care testing is available and has increased the ease of INR testing in the outpatient setting. Instead of a blood draw, the point-of-care test involves a simple finger prick. Maintenance dose Recommendations by many national bodies, including the American College of Chest Physicians, have been distilled to help manage dose adjustments.The maintenance dose of warfarin can fluctuate significantly depending on the amount of vitamin K1 in the diet. Keeping vitamin K1 intake at a stable level can prevent these fluctuations. Leafy green vegetables tend to contain higher amounts of vitamin K1. Green parts of members of the family Apiaceae, such as parsley, cilantro, and dill are extremely rich sources of vitamin K; cruciferous vegetables such as cabbage and broccoli, as well as the darker varieties of lettuces and other leafy greens, are also relatively high in vitamin K1. Green vegetables such as peas and green beans do not have such high amounts of vitamin K1 as leafy greens. Certain vegetable oils have high amounts of vitamin K1. Foods low in vitamin K1 include roots, bulbs, tubers, and most fruits and fruit juices. Cereals, grains, and other milled products are also low in vitamin K1. Self-testing Anticoagulation with warfarin can also be monitored by patients at home. International guidelines on home testing were published in 2005. The guidelines stated: The consensus agrees that patient self-testing and patient self-management are effective methods of monitoring oral anticoagulation therapy, providing outcomes at least as good as, and possibly better than, those achieved with an anticoagulation clinic. All patients must be appropriately selected and trained. Currently available self-testing/self-management devices give INR results that are comparable with those obtained in laboratory testing. A 2006 systematic review and meta-analysis of 14 randomized trials showed home testing led to a reduced incidence of complications (thrombosis and major bleeding), and improved the time in the therapeutic range. Alternative anticoagulants In some countries, other coumarins are used instead of warfarin, such as acenocoumarol and phenprocoumon. These have a shorter (acenocoumarol) or longer (phenprocoumon) half-life, and are not completely interchangeable with warfarin. Several types of anticoagulant drugs offering the efficacy of warfarin without a need for monitoring, such as dabigatran, apixaban, edoxaban, and rivaroxaban, have been approved in a number of countries for classical warfarin uses. Complementing these drugs are reversal agents available for dabigatran (idarucizumab), and for apixaban, and rivaroxaban (andexanet alfa). Andexanet alfa is suggested for edoxaban, but use of it is considered off label due to limited evidence. A reversal agent for dabigatran, apixaban, edoxaban, and rivaroxaban is in development (ciraparantag). Contraindications All anticoagulants are generally contraindicated in situations in which the reduction in clotting that they cause might lead to serious and potentially life-threatening bleeds. This includes people with active bleeding conditions (such as gastrointestinal ulcers), or disease states with increased risk of bleeding (e.g., low platelets, severe liver disease, uncontrolled hypertension). For patients undergoing surgery, treatment with anticoagulants is generally suspended. Similarly, spinal and lumbar puncture (e.g., spinal injections, epidurals, etc.) carry increased risk, so treatment is suspended prior to these procedures.Warfarin should not be given to people with heparin-induced thrombocytopenia until platelet count has improved or normalised. Warfarin is usually best avoided in people with protein C or protein S deficiency, as these thrombophilic conditions increase the risk of skin necrosis, which is a rare but serious side effect associated with warfarin. Pregnancy Warfarin is contraindicated in pregnancy, as it passes through the placental barrier and may cause bleeding in the fetus; warfarin use during pregnancy is commonly associated with spontaneous abortion, stillbirth, neonatal death, and preterm birth. Coumarins (such as warfarin) are also teratogens, that is, they cause birth defects; the incidence of birth defects in infants exposed to warfarin in utero appears to be around 5%, although higher figures (up to 30%) have been reported in some studies. Depending on when exposure occurs during pregnancy, two distinct combinations of congenital abnormalities can arise. First trimester of pregnancy Usually, warfarin is avoided in the first trimester, and a low-molecular-weight heparin such as enoxaparin is substituted. With heparin, risks of maternal haemorrhage and other complications are still increased, but heparins do not cross the placental barrier, so do not cause birth defects. Various solutions exist for the time around delivery. When warfarin (or another 4-hydroxycoumarin derivative) is given during the first trimester—particularly between the sixth and ninth weeks of pregnancy—a constellation of birth defects known variously as fetal warfarin syndrome (FWS), warfarin embryopathy, or coumarin embryopathy can occur. FWS is characterized mainly by skeletal abnormalities, which include nasal hypoplasia, a depressed or narrowed nasal bridge, scoliosis, and calcifications in the vertebral column, femur, and heel bone, which show a peculiar stippled appearance on X-rays. Limb abnormalities, such as brachydactyly (unusually short fingers and toes) or underdeveloped extremities, can also occur. Common nonskeletal features of FWS include low birth weight and developmental disabilities. Second trimester and later Warfarin administration in the second and third trimesters is much less commonly associated with birth defects, and when they do occur, are considerably different from FWS. The most common congenital abnormalities associated with warfarin use in late pregnancy are central nervous system disorders, including spasticity and seizures, and eye defects. Because of such later pregnancy birth defects, anticoagulation with warfarin poses a problem in pregnant women requiring warfarin for vital indications, such as stroke prevention in those with artificial heart valves. According to the American College of Chest Physicians, warfarin may be used in lactating women who wish to breastfeed their infants. Available data does not suggest that warfarin crosses into the breast milk. Similarly, INR levels should be checked to avoid adverse effects. Adverse effects Bleeding The only common side effect of warfarin is hemorrhage. The risk of severe bleeding is small but definite (a typical yearly rate of 1–3% has been reported), and any benefit needs to outweigh this risk when warfarin is considered. All types of bleeding occur more commonly, but the most severe ones are those involving the brain (intracerebral hemorrhage/hemorrhagic stroke) and the spinal cord. Risk of bleeding is increased if the INR is out of range (due to accidental or deliberate overdose or due to interactions). This risk increases greatly once the INR exceeds 4.5.Several risk scores exist to predict bleeding in people using warfarin and similar anticoagulants. A commonly used score (HAS-BLED) includes known predictors of warfarin-related bleeding: uncontrolled high blood pressure (H), abnormal kidney function (A), previous stroke (S), known previous bleeding condition (B), previous labile INR when on anticoagulation (L), elderly as defined by age over 65 (E), and drugs associated with bleeding (e.g., aspirin) or alcohol misuse (D). While their use is recommended in clinical practice guidelines, they are only moderately effective in predicting bleeding risk and do not perform well in predicting hemorrhagic stroke. Bleeding risk may be increased in people on hemodialysis. Another score used to assess bleeding risk on anticoagulation, specifically Warfarin or Coumadin, is the ATRIA score, which uses a weighted additive scale of clinical findings to determine bleeding risk stratification. The risks of bleeding are increased further when warfarin is combined with antiplatelet drugs such as clopidogrel, aspirin, or nonsteroidal anti-inflammatory drugs. Warfarin necrosis A rare but serious complication resulting from treatment with warfarin is warfarin necrosis, which occurs more frequently shortly after commencing treatment in patients with a deficiency of protein C, an innate anticoagulant that, like the procoagulant factors whose synthesis warfarin inhibits, requires vitamin K-dependent carboxylation for its activity. Since warfarin initially decreases protein C levels faster than the coagulation factors, it can paradoxically increase the bloods tendency to coagulate when treatment is first begun (many patients when starting on warfarin are given heparin in parallel to combat this), leading to massive thrombosis with skin necrosis and gangrene of limbs. Its natural counterpart, purpura fulminans, occurs in children who are homozygous for certain protein C mutations. Osteoporosis After initial reports that warfarin could reduce bone mineral density, several studies demonstrated a link between warfarin use and osteoporosis-related fracture. A 1999 study in 572 women taking warfarin for deep venous thrombosis, risk of vertebral fracture and rib fracture was increased; other fracture types did not occur more commonly. A 2002 study looking at a randomly selected selection of 1,523 patients with osteoporotic fracture found no increased exposure to anticoagulants compared to controls, and neither did stratification of the duration of anticoagulation reveal a trend towards fracture.A 2006 retrospective study of 14,564 Medicare recipients showed that warfarin use for more than one year was linked with a 60% increased risk of osteoporosis-related fracture in men, but no association in women was seen. The mechanism was thought to be a combination of reduced intake of vitamin K (a vitamin necessary for bone health) and inhibition by warfarin of vitamin K-mediated carboxylation of certain bone proteins, rendering them nonfunctional. Purple toe syndrome Another rare complication that may occur early during warfarin treatment (usually within 3 to 8 weeks of commencement) is purple toe syndrome. This condition is thought to result from small deposits of cholesterol breaking loose and causing embolisms in blood vessels in the skin of the feet, which causes a blueish-purple colour and may be painful.It is typically thought to affect the big toe, but it affects other parts of the feet, as well, including the bottom of the foot (plantar surface). The occurrence of purple toe syndrome may require discontinuation of warfarin. Calcification Several studies have also implicated warfarin use in valvular and vascular calcification. No specific treatment is available, but some modalities are under investigation. Overdose The major side effect of warfarin use is bleeding. Risk of bleeding is increased if the INR is out of range (due to accidental or deliberate overdose or due to interactions). Many drug interactions can increase the effect of warfarin, also causing an overdose.In patients with supratherapeutic INR but INR less than 10 and no bleeding, it is enough to lower the dose or omit a dose, monitor the INR and resume warfarin at an adjusted lower dose when the target INR is reached. For people who need rapid reversal of warfarin – such as due to serious bleeding – or who need emergency surgery, the effects of warfarin can be reversed with vitamin K, prothrombin complex concentrate (PCC), or fresh frozen plasma (FFP) Generally, four-factor PCC can be given more quickly than FFP, the amount needed is a smaller volume of fluid than FFP, and does not require ABO blood typing. Administration of PCCs results in rapid hemostasis, similar to that of FFP, namely, with comparable rates of thromboembolic events, but with reduced rates of volume overload. Blood products should not be routinely used to reverse warfarin overdose, when vitamin K could work alone. While PCC has been found in lab tests to be better than FFP, when rapid reversal is needed, as of 2018, whether a difference in outcomes such as death or disability exists is unclear.When warfarin is being given and INR is in therapeutic range, simple discontinuation of the drug for five days is usually enough to reverse the effect and cause INR to drop below 1.5. Interactions Warfarin interacts with many commonly used drugs, and the metabolism of warfarin varies greatly between patients. Some foods have also been reported to interact with warfarin. Apart from the metabolic interactions, highly protein bound drugs can displace warfarin from serum albumin and cause an increase in the INR. This makes finding the correct dosage difficult, and accentuates the need of monitoring; when initiating a medication that is known to interact with warfarin (e.g., simvastatin), INR checks are increased or dosages adjusted until a new ideal dosage is found. When taken with nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin increases the risk for gastrointestinal bleeding. This increased risk is due to the antiplatelet effect of NSAIDs and possible damage to the gastrointestinal mucosa.Many commonly used antibiotics, such as metronidazole or the macrolides, greatly increase the effect of warfarin by reducing the metabolism of warfarin in the body. Other broad-spectrum antibiotics can reduce the amount of the normal bacterial flora in the bowel, which make significant quantities of vitamin K1, thus potentiating the effect of warfarin. In addition, food that contains large quantities of vitamin K1 will reduce the warfarin effect. Thyroid activity also appears to influence warfarin dosing requirements; hypothyroidism (decreased thyroid function) makes people less responsive to warfarin treatment, while hyperthyroidism (overactive thyroid) boosts the anticoagulant effect. Several mechanisms have been proposed for this effect, including changes in the rate of breakdown of clotting factors and changes in the metabolism of warfarin.Excessive use of alcohol is also known to affect the metabolism of warfarin and can elevate the INR, and thus increase the risk of bleeding. The U.S. Food and Drug Administration (FDA) product insert on warfarin states that alcohol should be avoided. The Cleveland Clinic suggests that when taking warfarin one should not drink more than "one beer, 6 oz of wine, or one shot of alcohol per day".Warfarin also interacts with many herbs and spices, some used in food (such as ginger and garlic) and others used purely for medicinal purposes (such as ginseng and Ginkgo biloba). All may increase bleeding and bruising in people taking warfarin; similar effects have been reported with borage (starflower) oil. St. Johns wort, sometimes recommended to help with mild to moderate depression, reduces the effectiveness of a given dose of warfarin; it induces the enzymes that break down warfarin in the body, causing a reduced anticoagulant effect.Between 2003 and 2004, the UK Committee on Safety of Medicines received several reports of increased INR and risk of haemorrhage in people taking warfarin and cranberry juice. Data establishing a causal relationship are still lacking, and a 2006 review found no cases of this interaction reported to the USFDA; nevertheless, several authors have recommended that both doctors and patients be made aware of its possibility. The mechanism behind the interaction is still unclear. Chemistry X-ray crystallographic studies of warfarin show that it exists in tautomeric form, as the cyclic hemiketal, which is formed from the 4-hydroxycoumarin and the ketone in the 3-position substituent. However, the existence of many 4-hydroxycoumadin anticoagulants (for example phenprocoumon) that possess no ketone group in the 3-substituent to form such a structure, suggests that the hemiketal must tautomerise to the 4-hydroxy form in order for warfarin to be active. Stereochemistry Warfarin contains a stereocenter and consists of two enantiomers. This is a racemate, i.e., a 1: 1 mixture of ( R ) – and the ( S ) – form: Pharmacology Pharmacokinetics Warfarin consists of a racemic mixture of two active enantiomers—R- and S- forms—each of which is cleared by different pathways. S-warfarin is two to five times more potent than the R-isomer in producing an anticoagulant response. Both the enantiomers of warfarin undergo CYP-mediated metabolism by many different CYPs to form 3,4,6,7,8 and 10-hydroxy warfarin metabolites, major being 7-OH warfarin formed from S-warfarin by CYP2C9 and 10-OH warfarin from R-warfarin by CYP3A4.Warfarin is slower-acting than the common anticoagulant heparin, though it has a number of advantages. Heparin must be given by injection, whereas warfarin is available orally. Warfarin has a long half-life and need only be given once a day. Heparin can also cause a prothrombotic condition, heparin-induced thrombocytopenia (an antibody-mediated decrease in platelet levels), which increases the risk for thrombosis. It takes several days for warfarin to reach the therapeutic effect, since the circulating coagulation factors are not affected by the drug (thrombin has a half-life time of days). Warfarins long half-life means that it remains effective for several days after it is stopped. Furthermore, if given initially without additional anticoagulant cover, it can increase thrombosis risk (see below). Mechanism of action While warfarin is one of several drugs popularly referred to as a "blood thinner", this is a misnomer, since it does not affect the viscosity of blood.Warfarin inhibits the vitamin K-dependent synthesis of biologically active forms of the clotting factors II, VII, IX and X, as well as the regulatory factors protein C, protein S, and protein Z. Other proteins not involved in blood clotting, such as osteocalcin, or matrix Gla protein, may also be affected. The precursors of these factors require gamma carboxylation of their glutamic acid residues to allow the coagulation factors to bind to phospholipid surfaces inside blood vessels, on the vascular endothelium. The enzyme that carries out the carboxylation of glutamic acid is gamma-glutamyl carboxylase. The carboxylation reaction proceeds only if the carboxylase enzyme is able to convert a reduced form of vitamin K (vitamin K hydroquinone) to vitamin K epoxide at the same time. The vitamin K epoxide is, in turn, recycled back to vitamin K and vitamin K hydroquinone by another enzyme, the vitamin K epoxide reductase (VKOR). Warfarin inhibits VKOR (specifically the VKORC1 subunit), thereby diminishing available vitamin K and vitamin K hydroquinone in the tissues, which decreases the carboxylation activity of the glutamyl carboxylase. When this occurs, the coagulation factors are no longer carboxylated at certain glutamic acid residues, and are incapable of binding to the endothelial surface of blood vessels, and are thus biologically inactive. As the bodys stores of previously produced active factors degrade (over several days) and are replaced by inactive factors, the anticoagulation effect becomes apparent. The coagulation factors are produced, but have decreased functionality due to undercarboxylation; they are collectively referred to as PIVKAs (proteins induced [by] vitamin K absence), and individual coagulation factors as PIVKA-number (e.g., PIVKA-II). When warfarin is newly started, it may promote clot formation temporarily, because the level of proteins C and S are also dependent on vitamin K activity. Warfarin causes decline in protein C levels in first 36 hours. In addition, reduced levels of protein S lead to a reduction in activity of protein C (for which it is the co-factor), so reduces degradation of factor Va and factor VIIIa. Although loading doses of warfarin over 5 mg also produce a precipitous decline in factor VII, resulting in an initial prolongation of the INR, full antithrombotic effect does not take place until significant reduction in factor II occurs days later. The haemostasis system becomes temporarily biased towards thrombus formation, leading to a prothrombotic state. Thus, when warfarin is loaded rapidly at greater than 5 mg per day, to co-administering heparin, an anticoagulant that acts upon antithrombin and helps reduce the risk of thrombosis, is beneficial, with warfarin therapy for four to five days, to have the benefit of anticoagulation from heparin until the full effect of warfarin has been achieved. Pharmacogenomics Warfarin activity is determined partially by genetic factors. Polymorphisms in two genes (VKORC1 and CYP2C9) play a particularly large role in response to warfarin. VKORC1 polymorphisms explain 30% of the dose variation between patients: particular mutations make VKORC1 less susceptible to suppression by warfarin. There are two main haplotypes that explain 25% of variation: low-dose haplotype group (A) and a high-dose haplotype group (B). VKORC1 polymorphisms explain why African Americans are on average relatively resistant to warfarin (higher proportion of group B haplotypes), while Asian Americans are generally more sensitive (higher proportion of group A haplotypes). Group A VKORC1 polymorphisms lead to a more rapid achievement of a therapeutic INR, but also a shorter time to reach an INR over 4, which is associated with bleeding.CYP2C9 polymorphisms explain 10% of the dose variation between patients, mainly among Caucasian patients as these variants are rare in African American and most Asian populations. These CYP2C9 polymorphisms do not influence time to effective INR as opposed toVKORC1, but does shorten the time to INR >4.Despite the promise of pharmacogenomic testing in warfarin dosing, its use in clinical practice is controversial. In August 2009, the Centers for Medicare and Medicaid Services concluded, "the available evidence does not demonstrate that pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness improves health outcomes in Medicare beneficiaries." A 2014 meta-analysis showed that using genotype-based dosing did not confer benefit in terms of time within therapeutic range, excessive anticoagulation (as defined by INR greater than 4), or a reduction in either major bleeding or thromboembolic events. History In the early 1920s, an outbreak occurred of a previously unrecognized cattle disease in the northern United States and Canada. Cattle were haemorrhaging after minor procedures, and on some occasions spontaneously. For example, 21 of 22 cows died after dehorning, and 12 of 25 bulls died after castration. All of these animals had bled to death.In 1921, Frank Schofield, a Canadian veterinary pathologist, determined that the cattle were ingesting moldy silage made from sweet clover, and that
Warfarin	this was functioning as a potent anticoagulant. Only spoiled hay made from sweet clover (grown in northern states of the US and in Canada since the turn of the century) produced the disease. Schofield separated good clover stalks and damaged clover stalks from the same hay mow, and fed each to a different rabbit. The rabbit that had ingested the good stalks remained well, but the rabbit that had ingested the damaged stalks died from a haemorrhagic illness. A duplicate experiment with a different sample of clover hay produced the same result. In 1929, North Dakota veterinarian Lee M. Roderick demonstrated that the condition was due to a lack of functioning prothrombin.The identity of the anticoagulant substance in spoiled sweet clover remained a mystery until 1940. In 1933, Karl Paul Link and his laboratory of chemists working at the University of Wisconsin set out to isolate and characterize the haemorrhagic agent from the spoiled hay. Five years were needed before Links student, Harold A. Campbell, recovered 6 mg of crystalline anticoagulant. Next, Links student, Mark A. Stahmann, took over the project and initiated a large-scale extraction, isolating 1.8 g of recrystallized anticoagulant in about 4 months. This was enough material for Stahmann and Charles F. Huebner to check their results against Campbells, and to thoroughly characterize the compound. Through degradation experiments, they established that the anticoagulant was 3,3-methylenebis-(4-hydroxycoumarin), which they later named dicoumarol. They confirmed their results by synthesizing dicoumarol and proving in 1940 that it was identical to the naturally occurring agent.Dicoumarol was a product of the plant molecule coumarin (not to be confused with Coumadin, a later tradename for warfarin). Coumarin is now known to be present in many plants, and produces the notably sweet smell of freshly cut grass or hay and plants suc as sweet grass; in fact, the plants high content of coumarin is responsible for the original common name of "sweet clover", which is named for its sweet smell, not its bitter taste. They are present notably in woodruff (Galium odoratum, Rubiaceae), and at lower levels in licorice, lavender, and various other species. The name coumarin comes from the French pronunciation of coumarou, the Indian name for the tree of the tonka bean, which notably contains a high concentration of coumarin. However, coumarins themselves do not influence clotting or warfarin-like action, but must first be metabolized by various fungi into compounds such as 4-hydroxycoumarin, then further (in the presence of naturally occurring formaldehyde) into dicoumarol, to have any anticoagulant properties. Over the next few years, numerous similar chemicals (specifically 4-hydroxycoumarins with a large aromatic substituent at the 3 position) were found to have the same anticoagulant properties. The first drug in the class to be widely commercialized was dicoumarol itself, patented in 1941 and later used as a pharmaceutical. Karl Link continued working on developing more potent coumarin-based anticoagulants for use as rodent poisons, resulting in warfarin in 1948. The name "warfarin" stems from the acronym WARF, for Wisconsin Alumni Research Foundation + the ending "-arin" indicating its link with coumarin. Warfarin was first registered for use as a rodenticide in the US in 1948, and was immediately popular. Although warfarin was developed by Link, the Wisconsin Alumni Research Foundation financially supported the research and was assigned the patent.After an incident in 1951, in which an army inductee attempted suicide with multiple doses of warfarin in rodenticide, but recovered fully after presenting to a naval hospital and being treated with vitamin K (by then known as a specific antidote), studies began in the use of warfarin as a therapeutic anticoagulant. It was found to be generally superior to dicoumarol, and in 1954, was approved for medical use in humans. An early recipient of warfarin was US President Dwight Eisenhower, who was prescribed the drug after having a heart attack in 1955.The exact mechanism of action remained unknown until it was demonstrated, in 1978, that warfarin inhibits the enzyme vitamin K epoxide reductase, and hence interferes with vitamin K metabolism.Lavrenty Beria and I. V. Khrustalyov are thought to have conspired to use warfarin to poison Soviet leader Joseph Stalin. Warfarin is tasteless and colourless, and produces symptoms similar to those that Stalin exhibited. Pest control Rodents Coumarins (4-hydroxycoumarin derivatives) are used as rodenticides for controlling rats and mice in residential, industrial, and agricultural areas. Warfarin is both odorless and tasteless, and is effective when mixed with food bait, because the rodents will return to the bait and continue to feed over a period of days until a lethal dose is accumulated (considered to be 1 mg/kg/day over about six days). It may also be mixed with talc and used as a tracking powder, which accumulates on the animals skin and fur, and is subsequently consumed during grooming. The LD50 for warfarin is 50–100 mg/kg for a single dose, after 5–7 days. LD50 1 mg/kg for repeated daily doses for 5 days, after 5–8 days. The IDLH value is 100 mg/m3 (warfarin; various species).The use of warfarin itself as a rat poison is now declining, because many rat populations have developed resistance to it, and poisons of considerably greater potency are now available. Resistance is due to an autosomal dominant on chromosome 1 in Norway rats. This has arisen independently and become fixed several times around the world. Other 4-hydroxycoumarins used as rodenticides include coumatetralyl and brodifacoum, which is sometimes referred to as "super-warfarin", because it is more potent, longer-acting, and effective even in rat and mouse populations that are resistant to warfarin. Unlike warfarin, which is readily excreted, newer anticoagulant poisons also accumulate in the liver and kidneys after ingestion. However, such rodenticides may also accumulate in birds of prey and other animals that eat the poisoned rodents or baits. Vampire bats Warfarin is used to cull vampire bat populations in areas where human–wildlife conflict is a concern. Vampire bats are captured with mist nets and coated with a combination of petroleum jelly and warfarin. The bat returns to its roost and other members of the roost become poisoned as well by ingesting the warfarin after reciprocal grooming. Suspected vampire bat roosts may also be coated in the warfarin solution, though this kills other bat species and remains in the environment for years. The efficacy of killing vampire bats to reduce rabies transmission is questionable; a study in Peru showed that culling programs did not lead to lower transmission rates of rabies to livestock and humans. Occupational safety People can be exposed to warfarin in the workplace by breathing it in, swallowing it, skin absorption, and eye contact. The Occupational Safety and Health Administration has set the legal limit (permissible exposure limit) for warfarin exposure in the workplace as 0.1 mg/m3 over an 8-hour workday. The National Institute for Occupational Safety and Health has set a recommended exposure limit of 0.1 mg/m3 over an 8-hour workday. At levels of 100 mg/m3, warfarin is immediately dangerous to life and health.It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities. Names Warfarin is a derivative of dicoumarol, an anticoagulant originally discovered in spoiled sweet clover. Dicoumarol, in turn, is from coumarin, a sweet-smelling but coagulation-inactive chemical found in "sweet" clover and tonka beans (also known as cumaru from which coumarins name derives). The drug is marketed under many brand and generic names, including Aldocumar, Anasmol, Anticoag, Befarin, Cavamed, Cicoxil, Circuvit, Cofarin, Coumadin, Coumadine, Cumar, Farin, Foley, Haemofarin, Jantoven, Kovar, Lawarin, Maforan, Marevan, Marfarin, Marivanil, Martefarin, Morfarin, Orfarin, Panwarfin, Scheme, Simarc, Varfarin, Varfarins, Varfine, Waran, Warcok, Warf, Warfareks, Warfarin, Warfarina, Warfarine, Warfarinum, Warfen, Warfin, Warik, Warin, Warlin, and Zyfarin. Research Long-term use of VKOR inhibitors as anticoagulation therapy was associated with lower cancer incidence. References Further reading Dean L (2012). "Warfarin Therapy and VKORC1 and CYP Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520347. Bookshelf ID: NBK84174. External links "Warfarin". Drug Information Portal. U.S. National Library of Medicine. Historical information on warfarin from the Wisconsin Alumni Research Foundation CDC – NIOSH Pocket Guide to Chemical Hazards Warfarin in the Pesticide Properties DataBase (PPDB)
Sulfacetamide/sulfur	The drug combination sulfacetamide/sulfur is a topical acne medication manufactured by Medicis under the trade name Plexion and also available under other trade names such as Clenia, Prascion, and Avar. It combines sodium sulfacetamide, a sulfonamide antibiotic, and sulfur, a keratolytic agent. It is available in four formulations: as a cleansing cloth, cleanser, topical suspension, and as a facial mask. The sulfacetamide inhibits the growth of the bacterium Cutibacterium acnes that is associated with acne, while sulfur facilitates the removal of dead skin cells to prevent clogged pores. == References ==
Hydrocodone/aspirin	Hydrocodone/aspirin (INNs) is an oral combination drug formulation of the opioid analgesic hydrocodone and the nonsteroidal anti-inflammatory drug (NSAID) aspirin that is used in the treatment of chronic and acute pain. It is sold under brand names including Alor 5/500, Azdone, Damason-P, Lortab ASA, and Panasal 5/500. Adverse effects See also Hydrocodone/paracetamol Hydrocodone/ibuprofen Oxycodone/aspirin == References ==
Larotrectinib	Larotrectinib, sold under the brand name Vitrakvi, is a medication for the treatment of cancer. It is an inhibitor of tropomyosin kinase receptors TrkA, TrkB, and TrkC. It was discovered by Array BioPharma and licensed to Loxo Oncology in 2013. Larotrectinib was initially awarded orphan drug status in 2015, for soft tissue sarcoma, and breakthrough therapy designation in 2016 for the treatment of metastatic solid tumors with NTRK fusion. Some clinical trial results were announced in 2017. On 26 November 2018, Larotrectinib was approved by the FDA.Larotrectinib was the first drug to be specifically developed and approved to treat any cancer containing certain mutations, as opposed to cancers of specific tissues (i.e., the approval is "tissue agnostic"). Several earlier drugs, including pembrolizumab, were eventually approved by the FDA for treatment of specific mutations independent of the type of cancer, but those drugs had been initially developed for specific cancer types. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.Phase II clinical trials evaluating the drug for efficacy and safety in treating several types of solid tumors are ongoing.Larotrectinib was approved for medical use in the European Union in September 2019. It was approved for medical use in Australia in August 2020. References External links "Larotrectinib". Drug Information Portal. U.S. National Library of Medicine. "Larotrectinib sulfate". National Cancer Institute. "Larotrectinib sulfate". NCI Dictionary of Cancer Terms. National Cancer Institute.
Ergocalciferol	Ergocalciferol, also known as vitamin D2 and nonspecifically calciferol, is a type of vitamin D found in food and used as a dietary supplement. As a supplement it is used to prevent and treat vitamin D deficiency. This includes vitamin D deficiency due to poor absorption by the intestines or liver disease. It may also be used for low blood calcium due to hypoparathyroidism. It is used by mouth or injection into a muscle.Excessive doses can result in increased urine production, high blood pressure, kidney stones, kidney failure, weakness, and constipation. If high doses are taken for a long period of time, tissue calcification may occur. Normal doses are safe in pregnancy. It works by increasing the amount of calcium absorbed by the intestines and kidneys. Food in which it is found include some mushrooms.Ergocalciferol was first described in 1936. Ergocalciferol is available as a generic medication and over the counter. In 2020, it was the 46th most commonly prescribed medication in the United States, with more than 14 million prescriptions. Certain foods such as breakfast cereal and margarine have ergocalciferol added to them in some countries. It is on the World Health Organizations List of Essential Medicines. Use Ergocalciferol may be used as a vitamin D supplement, whereas cholecalciferol (vitamin D3) is produced naturally by the skin when exposed to ultraviolet light. Ergocalciferol (D2) and cholecalciferol (D3) are considered to be equivalent for vitamin D production, as both forms appear to have similar efficacy in ameliorating rickets and reducing the incidence of falls in elderly patients. Conflicting reports exist, however, concerning the relative effectiveness, with some studies suggesting that ergocalciferol has less efficacy based on limitations in absorption, binding, and inactivation. A meta-analysis concluded that evidence usually favors cholecalciferol in raising vitamin D levels in blood, although it stated more research is needed. Mechanism Ergocalciferol is a secosteroid formed by a photochemical bond breaking of a steroid, specifically, by the action of ultraviolet light (UV-B or UV-C) on ergosterol, a form of provitamin D2.Like cholecalciferol, ergocalciferol is inactive by itself. It requires two hydroxylations to become active: the first in the liver by CYP2R1 to form 25-hydroxyergocalciferol (ercalcidiol or 25-OH D2), and the second in the kidney by CYP27B1, to form the active 1,25-dihydroxyergocalciferol (ercalcitriol or 1,25-(OH)2D2), which activates the vitamin D receptor. Unlike cholecalciferol, 25-hydroxylation is not performed by CYP27A1 for ergocalciferol.Ergocalciferol and metabolites have lower affinity to the vitamin D-binding protein compared to the D3 counterparts. The binding affinity of ercalcitriol to the vitamin D receptor is similar to that of calcitriol. Ergocalciferol itself and metabolites can be deactivated by 24-hydroxylation. Sources Fungus, from USDA nutrient database (per 100g), D2 + D3: Mushrooms, Agaricus bisporus: raw portobello: 0.3 μg (10 IU); exposed to ultraviolet light: 11.2 µg (446 IU) raw crimini: 0.1 μg (3 IU); exposed to ultraviolet light: 31.9 µg (1276 IU) Mushrooms, shiitake: raw: Vitamin D (D2 + D3): 0.4 μg (18 IU) dried: Vitamin D (D2 + D3): 3.9 μg (154 IU)Lichen Cladina arbuscula specimens grown under different natural conditions contain provitamin D2 and vitamin D2, ranges 89-146 and 0.22-0.55 μg/g dry matter respectively. They also contain vitamin D3 (range 0.67 to 2.04 μg/g) although provitamin D3 could not be detected. Vitamin D levels correlate positively with UV irradiation.Plantae Alfalfa (Medicago sativa subsp. sativa), shoot: 4.8 μg (192 IU) vitamin D2, 0.1 μg (4 IU) vitamin D3 Biosynthesis The vitamin D2 content in mushrooms and C. arbuscula increase with exposure to ultraviolet light. Ergosterol (provitamin D2) found in these fungi is converted to previtamin D2 on UV exposure, which then turns into vitamin D2. As cultured mushrooms are generally grown in darkness, less vitamin D2 is found compared to those grown in the wild or dried in the sun.When fresh mushrooms or dried powders are purposely exposed to ultraviolet light, vitamin D2 levels can be concentrated to much higher levels. The irradiation procedure does not cause significant discoloration, or whitening, of mushrooms. Claims have been made that a normal serving (approx. 2 oz or 60 grams) of fresh mushrooms treated with ultraviolet light have increased vitamin D content to levels up to 80 micrograms or 3200 IU if exposed to just five minutes of UV light after being harvested.Button mushrooms with enhanced vitamin D2 content produced this way functions similarly to a vitamin D2 supplement; both effectively improves vitamin D status. Vitamin D2 from UV-irradiated yeast baked into bread or mushrooms is bioavailable and increases blood levels of 25(OH)D. Names Viosterol, the name given to early preparations of irradiated ergosterol, is essentially synonymous with ergocalciferol. However, currently, Viosterol is also the brand name for cholecalciferol (vitamin D3) in some countries.Ergocalciferol is manufactured and marketed under various names, including Deltalin (Eli Lilly and Company), Drisdol (Sanofi-Synthelabo) and Calcidol (Patrin Pharma). References External links "Ergocalciferol". Drug Information Portal. U.S. National Library of Medicine. NIST Chemistry WebBook page for ergocalciferol
Azilsartan	Azilsartan is an angiotensin II receptor antagonist used in the treatment of hypertension, developed by Takeda. It is marketed in tablet form under the brand name Edarbi as the prodrug azilsartan medoxomil.The most common adverse reaction in adults is diarrhea.It is also sold as a combination drug with chlortalidone under the brand name Edarbyclor. Structure activity relationship Like other ARBs, the Azilsartan group has an extended diphenyl group within the structure. An interesting aspect of the molecule is that unlike other ARBs which have a tetrazole attached to the molecule, Azilsartan has an oxadiazole, which has an acidic proton at the nitrogen. The tetraziole represents a non-classical bio-isostere. The carboxylate seen in the molecule is the active moiety after the molecule has been metabolized. Azilsartan is a pro-drug. Medical uses Azilsartan is used for the treatment of hypertension in adults. One of the benefits of the medication is that Azilsartan does not need dose adjustments for patients with renal or hepatic dysfunction. Contraindications Azilsartan must not be used with aliskiren, a renin inhibitor, in patients with diabetes as this increases the risk of serious adverse effects. Like other antihypertensive drugs acting on the renin–angiotensin system, it is contraindicated during the second and third trimesters of pregnancy. It should not be used during pregnancy in the United States. Interactions No relevant drug interactions have been found in studies. Based on experiences with other drugs acting on the renin–angiotensin system, it is theorized that azilsartan could increase the toxicity of lithium and of other drugs increasing potassium levels, such as potassium sparing diuretics. Pharmacology Mechanism of action Azilsartan medoxomil lowers blood pressure by blocking the action of angiotensin II at the AT1 receptor, a hormone that contracts blood vessels and reduces water excretion through the kidneys. Pharmacokinetics Azilsartan medoxomil is quickly absorbed from the gut, independently of food intake. Maximal blood plasma concentrations are reached after one to three hours. The liver enzyme CYP2C9 is involved in the formation of the two main metabolites, which are pharmacologically inactive; they are the O-deethylation and decarboxylation products of azilsartan. Elimination half life is about 11 hours. 55% are excreted via the feces, and 42% via the urine, of which 15% are present as azilsartan and the rest in form of the metabolites. Chemistry The drug formulation contains the potassium salt of azilsartan medoxomil (codenamed TAK-491), an ester of azilsartans carboxyl group with the alcohol (5-methyl-2-oxo-1,3-dioxol-4-yl)methanol. This ester is more lipophilic than azilsartan itself. History In February 2011, the U.S. Food and Drug Administration (FDA) approved azilsartan medoxomil for the treatment of high blood pressure in adults. In July 2011, azilsartan medoxomil was approved in the European Union for the treatment of essential hypertension. In March 2012, Health Canada approved the drug for mild to moderate essential hypertension.In December 2014, Valeant Canada acquired the marketing rights to Edarbi and Edarbyclor from Takeda Pharmaceutical. References External links "Azilsartan". Drug Information Portal. U.S. National Library of Medicine. "Azilsartan medoxomil". Drug Information Portal. U.S. National Library of Medicine.
Pyridostigmine	Pyridostigmine is a medication used to treat myasthenia gravis and underactive bladder. It is also used together with atropine to end the effects of neuromuscular blocking medication of the non-depolarizing type. It is typically given by mouth but can also be used by injection. The effects generally begin within 45 minutes and last up to 6 hours.Common side effects include nausea, diarrhea, frequent urination, and abdominal pain. More severe side effects include low blood pressure, weakness, and allergic reactions. It is unclear if use in pregnancy is safe for the fetus. Pyridostigmine is an acetylcholinesterase inhibitor in the cholinergic family of medications. It works by blocking the action of acetylcholinesterase and therefore increases the levels of acetylcholine.Pyridostigmine was patented in 1945 and came into medical use in 1955. It is on the World Health Organizations List of Essential Medicines. Pyridostigmine is available as a generic medication. Medical uses Pyridostigmine is used to treat muscle weakness in people with myasthenia gravis or forms of congenital myasthenic syndrome and to combat the effects of curariform drug toxicity. Pyridostigmine bromide has been FDA approved for military use during combat situations as an agent to be given prior to exposure to the nerve agent Soman in order to increase survival. Used in particular during the first Gulf War, pyridostigmine bromide has been implicated as a causal factor in Gulf War syndrome.With pyridostigmine classified as a type of parasympathomimetic, it can be used to treat underactive bladder.Pyridostigmine sometimes is used to treat orthostatic hypotension. It may also be of benefit in chronic axonal polyneuropathy.It is also being prescribed off-label for postural tachycardia syndrome as well as complications resulting from Ehlers–Danlos syndrome. Contraindications Pyridostigmine bromide is contraindicated in cases of mechanical intestinal or urinary obstruction and should be used with caution in patients with bronchial asthma. Side effects Common side effects include: Sweating Diarrhea Nausea Vomiting Abdominal cramps Increased salivation Tearing Increased bronchial secretions Constricted pupils Facial flushing due to vasodilation Erectile dysfunctionAdditional side effects include: Muscle twitching Muscle cramps and weakness Mechanism of action Pyridostigmine inhibits acetylcholinesterase in the synaptic cleft, thus slowing down the hydrolysis of acetylcholine. It is a quaternary carbamate inhibitor of cholinesterase that does not cross the blood–brain barrier which carbamylates about 30% of peripheral cholinesterase enzyme. The carbamylated enzyme eventually regenerates by natural hydrolysis and excess acetylcholine (ACh) levels revert to normal. The ACh diffuses across the synaptic cleft and binds to receptors on the post synaptic membrane, causing an influx of sodium (Na+,) resulting in depolarization. If large enough, this depolarization results in an action potential. To prevent constant stimulation once the ACh is released, an enzyme called acetylcholinesterase is present in the endplate membrane close to the receptors on the post synaptic membrane, and quickly hydrolyses ACh. Names Pyridostigmine bromide is available under the trade names Mestinon (Valeant Pharmaceuticals), Regonol and Gravitor (SUN Pharma). References External links "Pyridostigmine". Drug Information Portal. U.S. National Library of Medicine.
Ganaxolone	Ganaxolone, sold under the brand name Ztalmy, is a medication used to treat seizures in people with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD).Ganaxolone was approved for medical use in the United States in March 2022. Pharmacology Mechanism of action The exact mechanism of action for ganaxolone is unknown; however, results from animal studies suggest that it acts by blocking seizure propagation and elevating seizure thresholds.Ganaxolone is thought to modulate both synaptic and extrasynaptic GABAA receptors to normalize over-excited neurons. Ganaxolones activation of the extrasynaptic receptor is an additional mechanism that provides stabilizing effects that potentially differentiates it from other drugs that increase GABA signaling.Ganaxolone binds to allosteric sites of the GABAA receptor to modulate and open the chloride ion channel, resulting in a hyperpolarization of the neuron. This causes an inhibitory effect on neurotransmission, reducing the chance of a successful action potential (depolarization) from occurring.It is unknown if ganaxolone possesses significant hormonal activity in vivo, with a 2020 study finding evidence of in vitro binding to the membrane progesterone receptor. Chemistry Ganaxolone is a analog of the neuroactive steroid allopregnanolone which possesses no known hormonal activity and, instead, is thought to primarily function by binding to GABAa receptors as a positive allosteric modulator.Other pregnane neurosteroids include alfadolone, alfaxolone, allopregnanolone (brexanolone), hydroxydione, minaxolone, pregnanolone (eltanolone), and renanolone, among others. Research Ganaxolone is being investigated for potential medical use in the treatment of epilepsy. It is well tolerated in human trials, with the most commonly reported side effects being somnolence (sleepiness), dizziness, and fatigue. Trials in adults with focal onset seizures and in children with infantile spasms have recently been completed. There are ongoing studies in patients with focal onset seizures, PCDH19 pediatric epilepsy, and behaviors in Fragile X syndrome.Ganaxolone has been shown to protect against seizures in animal models, and to act a positive allosteric modulator of the GABAA receptor. Clinical trials The most common adverse events reported across clinical trials have been somnolence (sleepiness), dizziness, and fatigue. In 2015, the MIND Institute at the University of California, Davis, announced that it was conducting, in collaboration with Marinus Pharmaceuticals, a randomized, placebo-controlled, Phase 2 clinical trial evaluating the effect of ganaxolone on behaviors associated with Fragile X syndrome in children and adolescents. References External links "Ganaxolone". Drug Information Portal. U.S. National Library of Medicine.
Apomorphine	Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non-selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antagonist of 5-HT2 and α-adrenergic receptors with high affinity. The compound is historically a morphine decomposition product made by boiling morphine with concentrated acid, hence the -morphine suffix. Contrary to its name, apomorphine does not actually contain morphine or its skeleton, nor does it bind to opioid receptors. The apo- prefix relates to it being a morphine derivative ("[comes] from morphine"). Historically, apomorphine has been tried for a variety of uses, including as a way to relieve anxiety and craving in alcoholics, an emetic (to induce vomiting), for treating stereotypies (repeated behaviour) in farmyard animals, and more recently in treating erectile dysfunction. Currently, apomorphine is used in the treatment of Parkinsons disease. It is a potent emetic and should not be administered without an antiemetic such as domperidone. The emetic properties of apomorphine are exploited in veterinary medicine to induce therapeutic emesis in canines that have recently ingested toxic or foreign substances. Apomorphine was also used as a private treatment of heroin addiction, a purpose for which it was championed by the author William S. Burroughs. Burroughs and others claimed that it was a "metabolic regulator" with a restorative dimension to a damaged or dysfunctional dopaminergic system. Despite anecdotal evidence that this offers a plausible route to an abstinence-based mode, no clinical trials have ever tested this hypothesis. A recent study indicates that apomorphine might be a suitable marker for assessing central dopamine system alterations associated with chronic heroin consumption. There is, however, no clinical evidence that apomorphine is an effective and safe treatment regimen for opiate addiction. Medical uses Apomorphine is used in advanced Parkinsons disease intermittent hypomobility ("off" episodes), where a decreased response to an anti-Parkinson drug such as L-DOPA causes muscle stiffness and loss of muscle control. While apomorphine can be used in combination with L-DOPA, the intention is usually to reduce the L-DOPA dosing, as by this stage the patient often has many of dyskinesias caused by L-DOPA and hypermobility periods. When an episode sets in, the apomorphine is injected subcutaneously or applied sublingually, and signs subside. It is used an average of three times a day. Some people use portable mini-pumps that continuously infuse them with apomorphine, allowing them to stay in the "on" state and using apomorphine as an effective monotherapy. Contraindications The main and absolute contraindication to using apomorphine is the concurrent use of adrenergic receptor antagonists; combined, they cause a severe drop in blood pressure and fainting. Alcohol causes an increased frequency of orthostatic hypotension (a sudden drop in blood pressure when getting up), and can also increase the chances of pneumonia and heart attacks. Dopamine antagonists, by their nature of competing for sites at dopamine receptors, reduce the effectiveness of the agonistic apomorphine.IV administration of apomorphine is highly discouraged, as it can crystallize in the veins and create a blood clot (thrombus) and block a pulmonary artery (pulmonary embolism). Side effects Nausea and vomiting are common side effects when first beginning therapy with apomorphine; antiemetics such as trimethobenzamide or domperidone, dopamine antagonists, are often used while first starting apomorphine. Around 50% of people grow tolerant enough to apomorphines emetic effects that they can discontinue the antiemetic.Other side effects include orthostatic hypotension and resultant fainting, sleepiness, dizziness, runny nose, sweating, paleness, and flushing. More serious side effects include dyskinesias (especially when taking L-DOPA), fluid accumulation in the limbs (edema), suddenly falling asleep, confusion and hallucinations, increased heart rate and heart palpitations, and persistent erections (priapism). The priapism is caused by apomorphine increasing arterial blood supply to the penis. This side effect has been exploited in studies attempting to treat erectile dysfunction. Pharmacology Mechanism of action Apomorphines R-enantiomer is an agonist of both D1 and D2 dopamine receptors, with higher activity at D2. The members of the D2 subfamily, consisting of D2, D3, and D4 receptors, are inhibitory G protein–coupled receptors. The D4 receptor in particular is an important target in the signaling pathway, and is connected to several neurological disorders. Shortage or excess of dopamine can prevent proper function and signaling of these receptors leading to disease states.Apomorphine improves motor function by activating dopamine receptors in the nigrostriatal pathway, the limbic system, the hypothalamus, and the pituitary gland. It also increases blood flow to the supplementary motor area and to the dorsolateral prefrontal cortex (stimulation of which has been found to reduce the tardive dyskinesia effects of L-DOPA). Parkinsons has also been found to have excess iron at the sites of neurodegeneration; both the (R)- and (S)-enantiomers of apomorphine are potent iron chelators and radical scavengers.Apomorphine also decreases the breakdown of dopamine in the brain (though it inhibits its synthesis as well). It is an upregulator of certain neural growth factors, in particular NGF but not BDNF, epigenetic downregulation of which has been associated with addictive behaviour in rats.Apomorphine causes vomiting by acting on dopamine receptors in the chemoreceptor trigger zone of the medulla; this activates the nearby vomiting center. Pharmacokinetics While apomorphine has lower bioavailability when taken orally, due to not being absorbed well in the GI tract and undergoing heavy first-pass metabolism, it has a bioavailability of 100% when given subcutaneously. It reaches peak plasma concentration in 10–60 minutes. Ten to twenty minutes after that, it reaches its peak concentration in the cerebrospinal fluid. Its lipophilic structure allows it to cross the blood–brain barrier.Apomorphine possesses affinity for the following receptors (note that a higher Ki indicates a lower affinity): It has a Ki of over 10,000 nM (and thus negligible affinity) for β-adrenergic, H1, and mACh.Apomorphine has a high clearance rate (3–5 L/kg/hr) and is mainly metabolized and excreted by the liver. It is likely that while the cytochrome P450 system plays a minor role, most of apomorphines metabolism happens via auto-oxidation, O-glucuronidation, O-methylation, N-demethylation, and sulfation. Only 3–4% of the apomorphine is excreted unchanged and into the urine. The half-life is 30–60 minutes, and the effects of the injection last for up to 90 minutes.Toxicity depends on the route of administration; the LD50s in mice were 300 mg/kg for the oral route, 160 mg/kg for intraperitoneal, and 56 mg/kg intravenous. Chemistry Properties Apomorphine has a catechol structure similar to that of dopamine. Synthesis Several techniques exist for the creation of apomorphine from morphine. In the past, morphine had been combined with hydrochloric acid at high temperatures (around 150 °C) to achieve a low yield of apomorphine, ranging anywhere from 0.6% to 46%. More recent techniques create the apomorphine in a similar fashion, by heating it in the presence of any acid that will promote the essential dehydration rearrangement of morphine-type alkaloids, such as phosphoric acid. The method then deviates by including a water scavenger, which is essential to remove the water produced by the reaction that can react with the product and lead to decreased yield. The scavenger can be any reagent that will irreversibly react with water such as phthalic anhydride or titanium chloride. The temperature required for the reaction varies based upon choice of acid and water scavenger. The yield of this reaction is much higher: at least 55%. History The pharmacological effects of the naturally-occurring analog aporphine in the blue lotus (Nymphaea caerulea) were known to the ancient Egyptians and Mayans, with the plant featuring in tomb frescoes and associated with entheogenic rites. It is also observed in Egyptian erotic cartoons, suggesting that they were aware of its erectogenic properties. The modern medical history of apomorphine begins with its synthesis by Arppe in 1845 from morphine and sulfuric acid, although it was named sulphomorphide at first. Matthiesen and Wright (1869) used hydrochloric acid instead of sulfuric acid in the process, naming the resulting compound apomorphine. Initial interest in the compound was as an emetic, tested and confirmed safe by London doctor Samuel Gee, and for the treatment of stereotypies in farmyard animals. Key to the use of apomorphine as a behavioural modifier was the research of Erich Harnack, whose experiments in rabbits (which do not vomit) demonstrated that apomorphine had powerful effects on the activity of rabbits, inducing licking, gnawing and in very high doses convulsions and death. Treatment of alcoholism Apomorphine was one of the earliest used pharmacotherapies for alcoholism. The Keeley Cure (1870s to 1900) contained apomorphine, among other ingredients, but the first medical reports of its use for more than pure emesis come from James Tompkins and Charles Douglas. Tompkins reported, after injection of 6.5 mg ("one tenth of a grain"):In four minutes free emesis followed, rigidity gave way to relaxation, excitement to somnolence, and without further medication the patient, who before had been wild and delirious, went off into a quiet sleep.Douglas saw two purposes for apomorphine:[it can be used to treat] a paroxysm of dipsomania [an episode of intense alcoholic craving]... in minute doses it is much more rapidly efficient in stilling the dipsomaniac craving than strychnine or atropine… Four or even 3m [minim – roughly 60 microlitres] of the solution usually checks for some hours the incessant demands of the patient… when he awakes from the apomorphine sleep he may still be demanding alcohol, though he is never then so insistent as before. Accordingly it may be necessary to repeat the dose, and even to continue to give it twice or three times a day. Such repeated doses, however, do not require to be so large: 4 or even 3m is usually sufficient.This use of small, continuous doses (1/30th of a grain, or 2.16 mg by Douglas) of apomorphine to reduce alcoholic craving comes some time before Pavlovs discovery and publication of the idea of the "conditioned reflex" in 1903. This method was not limited to Douglas; the Irish doctor Francis Hare, who worked in a sanatorium outside London from 1905 onward, also used low-dose apomorphine as a treatment, describing it as "the most useful single drug in the therapeutics of inebriety". He wrote:In (the) sanatorium it is used in three different sets of circumstances: (1) in maniacal or hysterical drunkenness: (2) during the paroxysm of dipsomania, in order to still the craving for alcohol; and (3) in essential insomnia of a special variety... [after giving apomorphine] the patients mental condition is entirely altered. He may be sober: he is free from the time being from any craving from alcohol. The craving may return, however, and then it is necessary to repeat the injection, it may be several times at intervals of a few hours. These succeeding injections should be quite small, 3 to 6 min. being sufficient. Doses of this size are rarely emetic. There is little facial pallor, a sensation as of the commencement of sea-sickness, perhaps a slight malaise with a sudden subsidence of the craving for alcohol, followed by a light and short doze.He also noted there appeared to be a significant prejudice against the use of apomorphine, both from the associations of its name and doctors being reluctant to give hypodermic injections to alcoholics. In the US, the Harrison Narcotics Tax Act made working with any morphine derivatives extremely hard, despite apomorphine itself not being an opiate. In the 1950s the neurotransmitter dopamine was discovered in the brain by Katharine Montagu, and characterised as a neurotransmitter a year later by Arvid Carlsson, for which he would be awarded the Nobel Prize. A. N. Ernst then discovered in 1965 that apomorphine was a powerful stimulant of dopamine receptors. This, along with the use of sublingual apomorphine tablets, led to a renewed interest in the use of apomorphine as a treatment for alcoholism. A series of studies of non-emetic apomorphine in the treatment of alcoholism were published, with mostly positive results. However, there was little clinical consequence. Parkinsons disease The use of apomorphine to treat "the shakes" was first suggested by Weil in France in 1884, although seemingly not pursued until 1951. Its clinical use was first reported in 1970 by Cotzias et al., although its emetic properties and short half-life made oral use impractical. A later study found that combining the drug with the antiemetic domperidone improved results significantly. The commercialization of apomorphine for Parkinsons disease followed its successful use in patients with refractory motor fluctuations using intermittent rescue injections and continuous infusions. Aversion therapy Aversion therapy in alcoholism had its roots in Russia in the early 1930s, with early papers by Pavlov, Galant and Sluchevsky and Friken, and would remain a strain in the Soviet treatment of alcoholism well into the 1980s. In the US a particularly notable devotee was Dr Voegtlin, who attempted aversion therapy using apomorphine in the mid to late 1930s. However, he found apomorphine less able to induce negative feelings in his subjects than the stronger and more unpleasant emetic emetine. In the UK, however, the publication of J Y Dents (who later went on to treat Burroughs) 1934 paper "Apomorphine in the treatment of Anxiety States" laid out the main method by which apomorphine would be used to treat alcoholism in Britain. His method in that paper is clearly influenced by the then-novel idea of aversion:He is given his favourite drink, and his favourite brand of that drink... He takes it stronger than is usual to him... The small dose of apomorphine, one-twentieth of a grain [3.24mg], is now given subcutaneously into his thigh, and he is told that he will be sick in a quarter of an hour. A glass of whisky and water and a bottle of whisky are left by his bedside. At six oclock (four hours later) he is again visited and the same treatment is again administered... The nurse is told in confidence that if he does not drink, one-fortieth [1.62 mg] of a grain of apomorphine should be injected during the night at nine oclock, one oclock, and five oclock, but that if he drinks the injection should be given soon after the drink and may be increased to two hourly intervals. In the morning at about ten he is again given one or two glasses of whisky and water... and again one-twentieth of a grain [3.24 mg] of apomorphine is injected... The next day he is allowed to eat what he likes, he may drink as much tea as he likes... He will be strong enough to get up and two days later he leaves the home.However, even in 1934 he was suspicious of the idea that the treatment was pure conditioned reflex – "though vomiting is one of the ways that apomorphine relives the patient, I do not believe it to be its main therapeutic effect." – and by 1948 he wrote:It is now twenty-five years since I began treating cases of anxiety and alcoholism with apomorphine, and I read my first paper before this Society fourteen years ago. Up till then I had thought, and, unfortunately, I said in my paper, that the virtue of the treatment lay in the conditioned reflex of aversion produced in the patient. This statement is not even a half truth… I have been forced to the conclusion that apomorphine has some further action than the production of a vomit.This led to his development of lower-dose and non-aversive methods, which would inspire a positive trial of his method in Switzerland by Dr Harry Feldmann and later scientific testing in the 1970s, some time after his death. However, the use of apomorphine in aversion therapy had escaped alcoholism, with its use to treat homosexuality leading to the death of a British Army Captain Billy Clegg Hill in 1962, helping to cement its reputation as a dangerous drug used primarily in archaic behavioural therapies. Opioid addiction In his Deposition: Testimony Concerning a Sickness in the introduction to later editions of Naked Lunch (first published in 1959), William S. Burroughs wrote that apomorphine treatment was the only effective cure to opioid addiction he has encountered: The apomorphine cure is qualitatively different from other methods of cure. I have tried them all. Short reduction, slow reduction, cortisone, antihistamines, tranquilizers, sleeping cures, tolserol, reserpine. None of these cures lasted beyond the first opportunity to relapse. I can say that I was never metabolically cured until I took the apomorphine cure... The doctor, John Yerbury Dent, explained to me that apomorphine acts on the back brain to regulate the metabolism and normalize the blood stream in such a way that the enzyme stream of addiction is destroyed over a period of four to five days. Once the back brain is regulated apomorphine can be discontinued and only used in case of relapse. He goes on to lament the fact that as of his writing, little to no research has been done on apomorphine or variations of the drug to study its effects on curing addiction, and perhaps the possibility of retaining the positive effects while removing the side effect of vomiting. Despite his claims throughout his life, Burroughs never really cured his addiction and was back to using opiates within years of his apomorphine "cure". However, he insisted on apomorphines effectiveness in several works and interviews. Society and culture Apomorphine has a vital part in Agatha Christies detective story Sad Cypress. The 1965 Tuli Kupferberg song "Hallucination Horrors" recommends apomorphine at the end of each verse as a cure for hallucinations brought on by a humorous variety of intoxicants; the song was recorded by The Fugs and appears on the album Virgin Fugs. Research There is renewed interest in the use of apomorphine to treat addiction, in both smoking cessation and alcoholism. As the drug is known to be reasonably safe for use in humans, it is a viable target for repurposing. Apomorphine has been researched as a possible treatment for erectile dysfunction and female hypoactive sexual desire disorder, though its efficacy has been limited. Nonetheless, it was under development as a treatment for erectile dysfunction by TAP Pharmaceuticals under the brand name Uprima. In 2000, TAP withdrew its new drug application after an FDA review panel raised questions about the drugs safety, due to many clinical trial subjects fainting after taking the drug. Alzheimers disease Apomorphine is reported to be an inhibitor of amyloid beta protein fiber formation, whose presence is a hallmark of Alzheimers disease, and a potential therapeutic under the amyloid hypothesis. Alternative administration routes Two routes of administration are currently clinically utilized: subcutaneous (either as intermittent injections or continuous infusion) and sublingual. Other non-invasive administration routes were investigated as a substitute for parenteral administration, reaching different preclinical and clinical stages. These include: peroral, nasal, pulmonary, transdermal, rectal, and buccal, as well as iontophoresis methods. Veterinary use Apomorphine is used to inducing vomiting in dogs after ingestion of various toxins or foreign bodies. It can be given subcutaneously, intramuscularly, intravenously, or, when a tablet is crushed, in the conjunctiva of the eye. The oral route is ineffective, as apomorphine cannot cross the blood–brain barrier fast enough, and blood levels dont reach a high enough concentration to stimulate the chemoreceptor trigger zone. It can remove around 40–60% of the contents in the stomach.One of the reasons apomorphine is a preferred drug is its reversibility: in cases of prolonged vomiting, the apomorphine can be reversed with dopamine antagonists like the phenothiazines (for example, acepromazine). Giving apomorphine after giving acepromazine, however, will no longer stimulate vomiting, because apomorphines target receptors are already occupied. An animal who undergoes severe respiratory depression due to apomorphine can be treated with naloxone.Apomorphine does not work in cats, who have too few dopamine receptors. See also Apomorphine (data page) Propylnorapomorphine References External links "Apomorphine". Drug Information Portal. U.S. National Library of Medicine.
Somapacitan	Somapacitan, sold under the brand name Sogroya, is a growth hormone medication. Somapacitan is a human growth hormone analog. Somapacitan-beco is produced in Escherichia coli by recombinant DNA technology.The most common side effects include: back pain, joint paint, indigestion, a sleep disorder, dizziness, tonsillitis, swelling in the arms or lower legs, vomiting, adrenal insufficiency, hypertension, increase in blood creatine phosphokinase (a type of enzyme), weight increase, and anemia.It was approved for medical use in the United States in August 2020, and in the European Union in March 2021.Somapacitan is the first human growth hormone (hGH) therapy that adults only take once a week by injection under the skin; other FDA-approved hGH formulations for adults with growth hormone deficiency must be administered daily. It contains a small non-covalent moiety that reversibly binds to serum albumin which slows down elimination. Medical uses Somapacitan is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency (GHD).GHD is a condition when the body doesnt produce enough growth hormone on its own. Growth hormone regulates many functions in the body including accumulation of fat in the trunk or central area of the body that can be associated with serious medical issues. Contraindications Somapacitan should not be used in people with active malignancy, any stage of diabetic eye disease in which high blood sugar levels cause damage to blood vessels in the retina, acute critical illness, or those with acute respiratory failure, because of the increased risk of mortality with use of pharmacologic doses of somapacitan in critically ill individuals without growth hormone deficiency. History Somapacitan was evaluated in a randomized, double-blind, placebo-controlled trial (NCT02229851) in 300 participants with growth hormone deficiency who had never received growth hormone treatment or had stopped treatment with other growth hormone formulations at least three months before the study. Participants were randomly assigned to receive injections of weekly somapacitan, weekly placebo (inactive treatment), or daily somatropin, an FDA-approved growth hormone. The effectiveness of somapacitan was determined by the percentage change of truncal fat, the fat that is accumulated in the trunk or central area of the body that is regulated by growth hormone and can be associated with serious medical issues. The trial was conducted at 92 sites in 16 countries: the United States, Australia, Germany, India, Japan, Latvia, Lithuania, Malaysia, Poland, Romania, Russian Fed, South Africa, Sweden, Turkey, Ukraine and the United Kingdom.Adult participants were assigned at random to weekly Sogroya or placebo injections for 34 weeks. Neither the participants nor the investigators knew which treatment was given until the end of the trial. One additional group of participants with GHD received daily injections of somatotropin (an approved treatment for GHD). At the end of the 34-week treatment period, truncal fat decreased by 1.06%, on average, among participants taking weekly somapacitan while it increased among participants taking the placebo by 0.47%. In the daily somatropin group, truncal fat decreased by 2.23%. Participants in the weekly somapacitan and daily somatropin groups had similar improvements in other clinical endpoints. Society and culture Legal status Somapacitan was approved for medical use in the United States in August 2020. The U.S. Food and Drug Administration (FDA) granted the approval of Sogroya to Novo Nordisk, Inc.On 28 January 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Sogroya, intended for the treatment of growth hormone deficiency in adults. The applicant for this medicinal product is Novo Nordisk A/S. Somapacitan was approved for medical use in the European Union in March 2021. See also Growth hormone therapy References External links "Somapacitan". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT02229851 for "Trial to Compare the Efficacy and Safety of NNC0195-0092 (Somapacitan) With Placebo and Norditropin FlexPro (Somatropin) in Adults With Growth Hormone Deficiency. (REAL 1)" at ClinicalTrials.gov
Meropenem/vaborbactam	Meropenem/vaborbactam, sold under the brand name Vabomere among others, is a combination medication used to treat complicated urinary tract infections, complicated abdominal infections, and hospital-acquired pneumonia. It contains meropenem, a β-lactam antibiotic, and vaborbactam, a β-lactamase inhibitor. It is given by injection into a vein.Common side effects include headache, inflammation at the site of injection, nausea, diarrhea, liver inflammation, and low blood potassium. Severe side effects may include anaphylaxis, seizures, and Clostridium difficile-associated diarrhea. It is unclear if use during pregnancy is safe. Meropenem works by blocking the construction of the bacterial cell wall while vaborbactam blocks the breakdown of meropenem by some β-lactamases.The combination was approved for medical use in the United States in 2017 and Europe in 2018. It is on the World Health Organizations List of Essential Medicines. Medical uses It is used to treat complicated urinary tract infections, complicated abdominal infections, and hospital-acquired pneumonia.In a study of 545 adults with complicated urinary tract infections, 98 percent of adults treated with Vabomere compared with about 94 percent of adults treated with piperacillin/tazobactam were cured defined as improvement in symptoms and a negative urine culture. About seven days after completing treatment, roughly 77 percent of adults treated with Vabomere compared with about 73 percent of those treated with piperacillin/tazobactam had resolved symptoms and a negative urine culture. Children Successful bacteremia clearance in a child has been reported using a meropenem-vaborbactam dose of 40 mg/kg every 6 hours given over 3 hours. It attained 100% of meropenem serum concentrations above the minimum inhibitory concentration for at least 40% of the dosing interval. Side effects The most common adverse reactions were headache, infusion site reactions and diarrhea. Serious risks include allergic reactions and seizures and Meropenem/vaborbactam should not be used in people with severe allergic reactions to penicillins. History Rempex Pharmaceuticals developed the drug. It was designated as a "qualified infectious disease product" under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act and therefore received priority review. In August 2017, the US Food and Drug Administration approved it to treat complicated urinary tract infections and pyelonephritis. References External links "Meropenem mixture with vaborbactam". Drug Information Portal. U.S. National Library of Medicine.
Flurazepam	Flurazepam (marketed under the brand names Dalmane and Dalmadorm) is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It produces a metabolite with a long half-life, which may stay in the bloodstream for days. Flurazepam was patented in 1968 and came into medical use the same year. Flurazepam, developed by Roche Pharmaceuticals was one of the first benzo hypnotics (sleeping pills) to be marketed. Medical uses Flurazepam is officially indicated for mild to moderate insomnia and as such it is used for short-term treatment of patients with mild to moderate insomnia such as difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Flurazepam is a long-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep, though benzodiazepines with intermediate half-lives such as loprazolam, lormetazepam, and temazepam are also indicated for patients with difficulty maintaining sleep. Flurazepam was temporarily unavailable in the United States when its sole producer, Mylan Pharmaceuticals, discontinued making it in January 2019. In October 2019, the FDA informed pharmacies that they could expect to be resupplied by manufacturers in early to mid December 2019. As of this date, Flurazepam is now again available in the United States. Side effects The most common adverse effects are dizziness, drowsiness, light-headedness, and ataxia. Flurazepam has abuse potential and should never be used with alcoholic beverages or any other substance that can cause drowsiness. Addictive and possibly fatal results may occur. Flurazepam users should only take this drug strictly as prescribed, and should only be taken directly before the user plans on sleeping a full night. Next day drowsiness is common and may increase during the initial phase of treatment as accumulation occurs until steady-state plasma levels are attained. A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking hypnotic drugs compared to those taking a placebo.In September 2020, the U.S. Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class. Tolerance, dependence and withdrawal A review paper found that long-term use of flurazepam is associated with drug tolerance, drug dependence, rebound insomnia and central nervous system (CNS) related adverse effects. Flurazepam is best used for a short time period and at the lowest possible dose to avoid complications associated with long-term use. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality. Flurazepam and other benzodiazepines such as fosazepam, and nitrazepam lost some of their effect after seven days administration in psychogeriatric patients. Flurazepam shares cross tolerance with barbiturates and barbiturates can easily be substituted by flurazepam in those who are habituated to barbiturate sedative hypnotics.After discontinuation of flurazepam a rebound effect or benzodiazepine withdrawal syndrome may occur about four days after discontinuation of medication. Contraindications and special caution Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders. Elderly Flurazepam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments. An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines including flurazepam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy in elderly persons. Tolerability in elderly patients, however, is improved marginally in that benzodiazepines have moderately higher risks of falls, memory problems, and disinhibition ("paradoxical agitation") when compared to non-benzodiazepine sedatives. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Chronic use of sedative-hypnotic drugs for the management of insomnia does not have an evidence base and has been discouraged due to concerns including potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of sedative hypnotics has been determined to be no better than placebo after 3 months of therapy and worse than placebo after 6 months of therapy. Pharmacology Flurazepam is a "classical" benzodiazepine; some other classical benzodiazepines include diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, bromazepam, and clorazepate. Flurazepam generates an active metabolite, N-desalkylflurazepam, with a very long elimination half-life. Flurazepam could be therefore unsuitable as a sleeping medication for some individuals due to next-day sedation; however, this same effect may also provide next-day anxiety relief. Residual hangover effects after nighttime administration of flurazepam, such as sleepiness, impaired psychomotor and cognitive functions, may persist into the next day, which may impair the ability of users to drive safely and increase risks of falls and hip fractures.Flurazepam is lipophilic, is metabolized hepatically via oxidative pathways. The main pharmacological effect of flurazepam is to increase the effect of GABA at the GABAA receptor via binding to the benzodiazepine site on the GABAA receptor causing an increase influx of chloride ions into the GABAA neuron.Flurazepam is contraindicated in pregnancy. It is recommended to withdraw flurazepam during breast feeding, as flurazepam is excreted in breast milk. Society and culture Drug misuse Flurazepam is a drug with potential for misuse. Two types of drug misuse can occur, either recreational misuse where the drug is taken to achieve a high, or when the drug is continued long term against medical advice. Legal status Flurazepam is a Schedule IV drug under the Convention on Psychotropic Substances. See also Long-term effects of benzodiazepines References External links Rx-List – Flurazepam Inchem – Flurazepam
Polystyrene sulfonate	Polystyrene sulfonates are a group of medications used to treat high blood potassium. Effects generally take hours to days. They are also used to remove potassium, calcium, and sodium from solutions in technical applications. Common side effects include loss of appetite, gastrointestinal upset, constipation, and low blood calcium. These polymers are derived from polystyrene by the addition of sulfonate functional groups. Sodium polystyrene sulfonate was approved for medical use in the United States in 1958.A polystyrene sulfonate was developed in the 2000s to treat Clostridium difficile associated diarrhea under the name Tolevamer, but it was never marketed. Medical uses Polystyrene sulfonate is usually supplied in either the sodium or calcium form. It is used as a potassium binder in acute and chronic kidney disease for people with hyperkalemia (abnormal high blood serum potassium levels). However, it is unclear if it is beneficial and there is concern about possible side effects when it is combined with sorbitol.Polystyrene sulfonates are given by mouth with a meal or rectally by retention enema. Side effects Intestinal disturbances are common, including loss of appetite, nausea, vomiting, and constipation. In rare cases, it has been associated with colonic necrosis. Changes in electrolyte blood levels such as hypomagnesemia, hypocalcemia, and hypokalemia may occur. Polystyrene sulfonates should not be used in people with obstructive bowel disease and in newborns with reduced gut motility. Intestinal injury A total of 58 cases of intestinal injury including necrosis of the colon have been reported with polystyrene sulfonate as of 2013. Well more cases have been reported when used in combination with sorbitol and other cases have occurred when used alone. Interactions Polystyrene sulfonates can bind to various drugs within the digestive tract and thus lower their absorption and effectiveness. Common examples include lithium, thyroxine, and digitalis. In September 2017, the FDA recommended separating the dosing of polystyrene sulfonate from any other oral medications by at least three hours to avoid any potential interactions. Mechanism of action Hyperkalemia Polystyrene sulfonates release sodium or calcium ions in the stomach in exchange for hydrogen ions. When the resin reaches the large intestine the hydrogen ions are exchanged for free potassium ions; the resin is then eliminated in the feces. The net effect is lowering the amount of potassium available for absorption into the blood and increasing the amount that is excreted via the feces. The effect is a reduction of potassium levels in the body, at a capacity of 1 mEq of potassium exchanged per 1 g of resin. Production and chemical structure Polystyrene sulfonic acid, the acid whose salts are the polystyrene sulfonates, has the idealized formula (CH2CHC6H4SO3H)n. The material is prepared by sulfonation of polystyrene: (CH2CHC6H5)n + n SO3 → (CH2CHC6H4SO3H)nSeveral methods exist for this conversion, which can lead to varying degree of sulfonation. Usually the polystyrene is crosslinked, which keeps the polymer from dissolving. Since the sulfonic acid group (SO3H) is strongly acidic, this polymer neutralizes bases. In this way, various salts of the polymer can be prepared, leading to sodium, calcium, and other salts: (CH2CHC6H4SO3H)n + n NaOH → (CH2CHC6H4SO3Na)n + n H2OThese ion-containing polymers are called ionomers. Alternative sulfonation methods Double substitutions of the phenyl rings are known to occur, even with conversions well below 100%. Crosslinking reactions are also found, where condensation of two sulfonic acid groups yields a sulfonyl crosslink. On the other hand, the use of milder conditions such as acetyl sulfate leads to incomplete sulfonation. Recently, the atom transfer radical polymerization (ATRP) of protected styrene sulfonates has been reported, leading to well defined linear polymers, as well as more complicated molecular architectures. Chemical uses Polystyrene sulfonates are useful because of their ion exchange properties. Linear ionic polymers are generally water-soluble, whereas cross-linked materials (called resins) do not dissolve in water. These polymers are classified as polysalts and ionomers. Water softening Water softening is achieved by percolating hard water through a bed of the sodium form of cross-linked polystyrene sulfonate. The hard ions such as calcium (Ca2+) and magnesium (Mg2+) adhere to the sulfonate groups, displacing sodium ions. The resulting solution of sodium ions is softened. Other uses Sodium polystyrene sulfonate is used as a superplastifier in cement, as a dye improving agent for cotton, and as proton exchange membranes in fuel cell applications. In its acid form, the resin is used as a solid acid catalyst in organic synthesis. == References ==
Artane	Artane may refer to: Artane, Dublin, a suburb of Dublin, Ireland Artane Industrial school, a former industrial school Trihexyphenidyl, a drug used to treat Parkinsons disease with a brand-name Artane Artanë, a town and municipality in Kosovo See also Artana (disambiguation)
Diflunisal	Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It was developed by Merck Sharp & Dohme in 1971, as MK647, after showing promise in a research project studying more potent chemical analogs of aspirin. It was first sold under the brand name Dolobid, marketed by Merck & Co., but generic versions are now widely available. It is classed as a nonsteroidal anti-inflammatory drug (NSAID) and is available in 250 mg and 500 mg tablets. Mechanism of action Like all NSAIDs, diflunisal acts by inhibiting the production of prostaglandins, hormones which are involved in inflammation and pain. Diflunisal also has an antipyretic effect, but this is not a recommended use of the drug.It has been found to inhibit p300 and CREB-binding protein (CBP), which are epigenetic regulators that control the levels of proteins that cause inflammation or are involved in cell growth.It has been reported that diflunisal has some antibacterial activity in vitro against Francisella tularensis live vaccine strain (LVS). Duration of effect Though diflunisal has an onset time of 1 hour, and maximum analgesia at 2 to 3 hours, the plasma levels of diflunisal will not be steady until repeated doses are taken. The long plasma half-life is a distinctive feature of diflunisal in comparison to similar drugs. To increase the rate at which the diflunisal plasma levels become steady, a loading dose is usually used. It is primarily used to treat symptoms of arthritis, and for acute pain following oral surgery, especially removal of wisdom teeth.Effectiveness of diflunisal is similar to other NSAIDs, but the duration of action is twelve hours or more. This means fewer doses per day are required for chronic administration. In acute use, it is popular in dentistry when a single dose after oral surgery can maintain analgesia until the patient is asleep that night. Medical uses Pain, mild to moderate Osteoarthritis Rheumatoid arthritis Injury to tendons Inflammation ATTR amyloidosis Amyloidosis Both diflunisal and several of its analogues have been shown to be inhibitors of transthyretin-related hereditary amyloidosis, a disease which currently has few treatment options. Phase I trials have shown the drug to be well tolerated, with a small Phase II trial (double-blind, placebo-controlled, 130 patients for 2 years) in 2013 showing a reduced rate of disease progression and preserved quality of life. However a significantly larger Phase III trial would be needed to prove the drugs effectiveness for treating this condition. Side 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. Gastrointestinal The inhibition of prostaglandins has the effect of decreasing the protection given to the stomach from its own acid. Like all NSAIDS, this leads to an increased risk of stomach ulcers, and their complications, with long-term use. Elderly users of diflunisal are at greater risk for serious GI events. Increased risk of GI events including bleeding, ulceration, and stomach or intestine perforation. Abdominal pain or cramps Constipation Gas Diarrhea Nausea and vomiting Dyspepsia Cardiovascular Irregular heart beat Possible increased risk of serious and potentially fatal cardiovascular thrombotic events, MI, and stroke Risks may increase with duration of use and for cardiovascular disease history Ear, nose, throat, and eye Ringing in the ears Yellowing of eyes Central nervous system Drowsiness Dizziness Headache Insomnia Fatigue Somnolence Nervousness Skin Swelling of the feet, ankles, lower legs, and hands Yellowing of skin Rash Ecchymosis Contraindications Hypersensitivity to aspirin/NSAID-induced asthma or urticaria Aspirin triad 3rd trimester pregnancy Coronary artery bypass surgery (peri-op pain) Cautions Overdose Deaths that have occurred from diflunisal usually involved mixed drugs and or extremely high dosage. The oral LD50 is 500 mg/kg. Symptoms of overdose include coma, tachycardia, stupor, and vomiting. The lowest dose without the presence of other medicines which caused death was 15 grams. Mixed with other medicines, a death at 7.5 grams has also occurred. Diflunisal usually comes in 250 or 500 mg, making it relatively hard to overdose by accident. References External links Diflunisal: MedlinePlus Drug Information Dolobid Prescribing Information (manufacturers website) Dolobid Medication Guide (manufacturers website) "Single dose oral diflunisal for acute postoperative pain in adults"
Hyoscyamine	Hyoscyamine (also known as daturine or duboisine) is a naturally occurring tropane alkaloid and plant toxin. It is a secondary metabolite found in certain plants of the family Solanaceae, including henbane, mandrake, angels trumpets, jimsonweed, tomato, the sorcerers tree, and deadly nightshade. It is the levorotary isomer of atropine (third of the three major nightshade alkaloids) and thus sometimes known as levo-atropine.Brand names for hyoscyamine include Symax, HyoMax, Anaspaz, Egazil, Buwecon, Cystospaz, Levsin, Levbid, Levsinex, Donnamar, NuLev, Spacol T/S, and Neoquess. Uses Hyoscyamine is used to provide symptomatic relief of spasms caused by various lower abdominal and bladder disorders including peptic ulcers, irritable bowel syndrome, diverticulitis, pancreatitis, colic, and interstitial cystitis. It has also been used to relieve some heart problems, control some of the symptoms of Parkinsons disease, as well as for control of abnormal respiratory symptoms and "hyper-mucus secretions" in patients with lung disease.It is also useful in pain control for neuropathic pain, chronic pain and palliative care – "comfort care" – for those with intractable pain from treatment resistant, untreatable, and incurable diseases. When combined with opioids it increases the level of analgesia (pain relief) obtained. Several mechanisms are thought to contribute to this effect. The closely related drugs atropine and hyoscine and other members of the anticholinergic drug group like cyclobenzaprine, trihexyphenidyl, and orphenadrine are also used for this purpose. When hyoscyamine is used along with opioids or other anti-peristaltic agents, measures to prevent constipation are especially important given the risk of paralytic ileus. Adverse effects Side effects include dry mouth and throat, increased appetite leading to weight gain, eye pain, blurred vision, restlessness, dizziness, arrhythmia, flushing, and faintness. An overdose will cause headache, nausea, vomiting, and central nervous system symptoms including disorientation, hallucinations, euphoria, sexual arousal, short-term memory loss, and possible coma in extreme cases. The euphoric and sexual effects are stronger than those of atropine but weaker than those of Hyoscine, as well as dicycloverine, orphenadrine, cyclobenzaprine, trihexyphenidyl, and ethanolamine antihistamines like phenyltoloxamine. Pharmacology Hyoscyamine is an antimuscarinic; i.e., an antagonist of muscarinic acetylcholine receptors. It blocks the action of acetylcholine at parasympathetic sites in sweat glands, salivary glands, stomach secretions, heart muscle, sinoatrial node, smooth muscle in the gastrointestinal tract, and the central nervous system. It increases cardiac output and heart rate, lowers blood pressure and dries secretions. It may antagonize serotonin. At comparable doses, hyoscyamine has 98 per cent of the anticholinergic power of atropine. The other major belladonna-derived drug hyoscine (known in the United States as Scopolamine) has 92 per cent of the antimuscarinic potency of atropine. Biosynthesis in plants Hyoscyamine can be extracted from plants of the family Solanaceae, notably Datura stramonium. As hyoscyamine is a direct precursor in the plant biosynthesis of hyoscine, it is produced via the same metabolic pathway.The biosynthesis of hyoscine begins with the decarboxylation of L-ornithine to putrescine by ornithine decarboxylase (EC 4.1.1.17). Putrescine is methylated to N-methylputrescine by putrescine N-methyltransferase (EC 2.1.1.53).A putrescine oxidase (EC 1.4.3.10) that specifically recognizes methylated putrescine catalyzes the deamination of this compound to 4-methylaminobutanal which then undergoes a spontaneous ring formation to N-methylpyrrolium cation. In the next step, the pyrrolium cation condenses with acetoacetic acid yielding hygrine. No enzymatic activity could be demonstrated that catalyzes this reaction. Hygrine further rearranges to tropinone.Subsequently, tropinone reductase I (EC 1.1.1.206) converts tropinone to tropine which condenses with phenylalanine-derived phenyllactate to littorine. A cytochrome P450 classified as Cyp80F1 oxidizes and rearranges littorine to hyoscyamine aldehyde. Bush medicine basis A bush medicine developed by Aboriginal peoples of the eastern states of Australia from the soft corkwood tree, or Duboisia myoporoides, was used by the Allies in World War II to stop soldiers getting seasick when they sailed across the English Channel during the Invasion of Normandy. Later, it was found that the same substance could be used in the production of scopolamine and hyoscyamine, which are used in eye surgery, and a multi-million dollar industry was built in Queensland based on this substance. == References ==
Isoniazid/rifampicin	Isoniazid/rifampicin, also known as isoniazid/rifampin, is a medication used to treat tuberculosis. It is a fixed dose combination of isoniazid and rifampicin (rifampin). It is used together with other antituberculosis medication. It is taken by mouth.It is on the World Health Organizations List of Essential Medicines. Adverse effects and safety Side effects are those of the underlying medications. Common side effects include poor coordination, poor appetite, nausea, numbness, and feeling tired. More severe side effects include liver problems. Use is generally not recommended in children. It is unclear if use is safe in pregnancy. == References ==
Amoxapine	Amoxapine, sold under the brand name Asendin among others, is a tricyclic antidepressant (TCAs). It is the N-demethylated metabolite of loxapine. Amoxapine first received marketing approval in the United States in 1992 (approximately 30 to 40 years after most of the other TCAs were introduced in the United States). Medical uses Amoxapine is used in the treatment of major depressive disorder. Compared to other antidepressants it is believed to have a faster onset of action, with therapeutic effects seen within four to seven days. In excess of 80% of patients that do respond to amoxapine are reported to respond within two weeks of the beginning of treatment. It also has properties similar to those of the atypical antipsychotics, and may behave as one and may be used in the treatment of schizophrenia off-label. Despite its apparent lack of extrapyramidal side effects in patients with schizophrenia it has been found to exacerbate motor symptoms in patients with Parkinsons disease and psychosis. Contraindications As with all FDA-approved antidepressants it carries a black-box warning about the potential of an increase in suicidal thoughts or behaviour in children, adolescents and young adults under the age of 25. Its use is also advised against in individuals with known hypersensitivities to either amoxapine or other ingredients in its oral formulations. Its use is also recommended against in the following disease states: Severe cardiovascular disorders (potential of cardiotoxic adverse effects such as QT interval prolongation) Uncorrected narrow angle glaucoma Acute recovery post-myocardial infarctionIts use is also advised against in individuals concurrently on monoamine oxidase inhibitors or if they have been on one in the past 14 days and in individuals on drugs that are known to prolong the QT interval (e.g. ondansetron, citalopram, pimozide, sertindole, ziprasidone, haloperidol, chlorpromazine, thioridazine, etc.). Lactation Its use in breastfeeding mothers not recommended as it is excreted in breast milk and the concentration found in breast milk is approximately a quarter that of the maternal serum level. Side effects Adverse effects by incidence:Note: Serious (that is, those that can either result in permanent injury or are irreversible or are potentially life-threatening) are written in bold text. Very common (>10% incidence) adverse effects include: Constipation Dry mouth SedationCommon (1–10% incidence) adverse effects include: Oedema. An abnormal accumulation of fluids in the tissues of the body leading to swelling. Prolactin levels increased. Prolactin is a hormone that regulates the generation of breast milk. Prolactin elevation is not as significant as with risperidone or haloperidol.Uncommon/Rare (<1% incidence) adverse effects include: Vasculitis a disorder where blood vessels are destroyed by inflammation. Can be life-threatening if it affects the right blood vessels. Galactorrhoea (lactation that is not associated with pregnancy or breast feeding) Delayed micturition (that is, delays in urination from when a conscious effort to urinate is made) Hyperthermia (elevation of body temperature; its seriousness depends on the extent of the hyperthermia) Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) this is basically when the bodys level of the hormone, antidiuretic hormone, which regulates the conservation of water and the restriction of blood vessels, is elevated. This is potentially fatal as it can cause electrolyte abnormalities including hyponatraemia (low blood sodium), hypokalaemia (low blood potassium) and hypocalcaemia (low blood calcium) which can be life-threatening. Agranulocytosis a drop in white blood cell counts. The white blood cells are the cells of the immune system that fight off foreign invaders. Hence agranulocytosis leaves an individual open to life-threatening infections. Leukopaenia the same as agranulocytosis but less severe. Neuroleptic malignant syndrome (a potentially fatal reaction to antidopaminergic agents, most often antipsychotics. It is characterised by hyperthermia, diarrhoea, tachycardia, mental status changes [e.g. confusion], rigidity, extrapyramidal side effects) Tardive dyskinesia a most often irreversible neurologic reaction to antidopaminergic treatment, characterised by involuntary movements of facial muscles, tongue, lips, and other muscles. It develops most often only after prolonged (months, years or even decades) exposure to antidopaminergics. Extrapyramidal side effects. Motor symptoms such as tremor, parkinsonism, involuntary movements, reduced ability to move ones voluntary muscles, etc.Unknown incidence or relationship to drug treatment adverse effects include: Thrombocytopenia a significant drop in platelet count that leaves one open to life-threatening bleeds. Eosinophilia an elevated level of the eosinophils of the body. Eosinophils are the type of immune cell thats job is to fight off parasitic invaders. Jaundice yellowing of the skin, eyes and mucous membranes due to an impaired ability of the body to clear the by product of haem breakdown, bilirubin, most often the result of liver damage as it is the livers responsibility to clear bilirubin.It tends to produce less anticholinergic effects, sedation and weight gain than some of the earlier TCAs (e.g. amitriptyline, clomipramine, doxepin, imipramine, trimipramine). It may also be less cardiotoxic than its predecessors. Overdose It is considered particularly toxic in overdose, with a high rate of renal failure (which usually takes 2–5 days), rhabdomyolysis, coma, seizures and even status epilepticus. Some believe it to be less cardiotoxic than other TCAs in overdose, although reports of cardiotoxic overdoses have been made. Pharmacology Pharmacodynamics Amoxapine possesses a wide array of pharmacological effects. It is a moderate and strong reuptake inhibitor of serotonin and norepinephrine, respectively, and binds to the 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, D2, α1-adrenergic, D3, D4, and H1 receptors with varying but significant affinity, where it acts as an antagonist (or inverse agonist depending on the receptor in question) at all sites. It has weak but negligible affinity for the dopamine transporter and the 5-HT1A, 5-HT1B, D1, α2-adrenergic, H4, mACh, and GABAA receptors, and no affinity for the β-adrenergic receptors or the allosteric benzodiazepine site on the GABAA receptor. Amoxapine is also a weak GlyT2 blocker, as well as a weak (Ki = 2.5 μM, EC50 = 0.98 μM) δ-opioid receptor partial agonist.7-Hydroxyamoxapine, a major active metabolite of amoxapine, is a more potent dopamine receptor antagonist and contributes to its neuroleptic efficacy, whereas 8-hydroxyamoxapine is a norepinephrine reuptake inhibitor but a stronger serotonin reuptake inhibitor and helps to balance amoxapines ratio of serotonin to norepinephrine transporter blockade. Pharmacokinetics Amoxapine is metabolised into two main active metabolites: 7-hydroxyamoxapine and 8-hydroxyamoxapine. Where: - t1/2 is the elimination half life of the compound. - tmax is the time to peak plasma levels after oral administration of amoxapine. - CSS is the steady state plasma concentration. - protein binding is the extent of plasma protein binding. - Vd is the volume of distribution of the compound. Society and culture Brand names Brand names for amoxapine include (where † denotes discontinued brands): Adisen (KR) Amolife (IN) Amoxan (JP) Asendin† (previously marketed in CA, NZ, US) Asendis† (previously marketed in IE, UK) Défanyl (FR) Demolox (DK†, IN, ES†) Oxamine (IN) Oxcap (IN) See also Loxapine == References ==
Nortriptyline	Nortriptyline, sold under the brand name Pamelor, among others, is a medication used to treat depression. This medicine is used for: neuropathic pain, attention deficit hyperactivity disorder (ADHD), smoking cessation and anxiety. As with many antidepressants, its use for young people with depression and other psychiatric disorders may be limited due to increased suicidality in the 18-24 population initiating treatment. Nortriptyline is a less preferred treatment for ADHD and stopping smoking. It is taken by mouth.Common side effects include dry mouth, constipation, blurry vision, sleepiness, low blood pressure with standing, and weakness. Serious side effects may include seizures, an increased risk of suicide in those less than 25 years of age, urinary retention, glaucoma, mania, and a number of heart issues. Nortriptyline may cause problems if taken during pregnancy. Use during breastfeeding appears to be relatively safe. It is a tricyclic antidepressant (TCA) and is believed to work by altering levels of serotonin and norepinephrine.Nortriptyline was approved for medical use in the United States in 1964. It is available as a generic medication. In 2019, it was the 153rd most commonly prescribed medication in the United States, with more than 4 million prescriptions. Medical uses Nortriptyline is used to treat depression. This medication is in capsule or liquid and is taken by the mouth one to four times a day, with or without food. Usually people are started on a low dose and it is gradually increased. A level between 50 and 150 ng/mL of nortriptyline in the blood generally corresponds with an antidepressant effect.In the United Kingdom, it may also be used for treating nocturnal enuresis, with courses of treatment lasting no more than three months. It is also used off-label for the treatment of panic disorder, irritable bowel syndrome, migraine prophylaxis and chronic pain or neuralgia modification, particularly temporomandibular joint disorder. Neuropathic pain Although not approved by the FDA for neuropathic pain, many randomized controlled trials have demonstrated the effectiveness of TCAs for the treatment of this condition in both depressed and non-depressed individuals. In 2010, an evidence-based guideline sponsored by the International Association for the Study of Pain recommended nortriptyline as a first-line medication for neuropathic pain. However, in a 2015 Cochrane systematic review the authors did not recommend nortriptyline as a first-line agent for neuropathic pain. Irritable Bowel Syndrome Nortriptyline has also been used as an off-label treatment for Irritable Bowel Syndrome, or IBS. Contraindications Nortriptyline should not be used in the acute recovery phase after myocardial infarction (viz, heart attack). Use of tricyclic antidepressants along with a monoamine oxidase (MAO) inhibitor, linezolid, and IV methylene blue are contraindicated as it can cause an increased risk of developing serotonin syndrome.Closer monitoring is required for those with a history of cardiovascular disease, stroke, glaucoma, or seizures, as well as in persons with hyperthyroidism or receiving thyroid hormones. Side effects The most common side effects include dry mouth, sedation, constipation, increased appetite, blurred vision and tinnitus. An occasional side effect is a rapid or irregular heartbeat. Alcohol may exacerbate some of its side effects. Overdose The symptoms and the treatment of an overdose are generally the same as for the other TCAs, including anticholinergic effects, serotonin syndrome and adverse cardiac effects. TCAs, particularly nortriptyline, have a relatively narrow therapeutic index, which increase the chance of an overdose (both accidental and intentional). Symptoms of overdose include: irregular heartbeat, seizures, coma, confusion, hallucination, widened pupils, drowsiness, agitation, fever, low body temperature, stiff muscles and vomiting. Interactions Excessive consumption of alcohol in combination with nortriptyline therapy may have a potentiating effect, which may lead to the danger of increased suicidal attempts or overdosage, especially in patients with histories of emotional disturbances or suicidal ideation. It may interact with the following drugs: heart rhythm medications such as flecainide (Tambocor), propafenone (Rhythmol), or quinidine (Cardioquin, Quinidex, Quinaglute) cimetidine guanethidine reserpine Pharmacology Nortriptyline is a strong norepinephrine reuptake inhibitor and a moderate serotonin reuptake inhibitor. Its pharmacologic profile is as the table shows with (inhibition or antagonism of all sites). Pharmacodynamics Nortriptyline is an active metabolite of amitriptyline by demethylation in the liver. Chemically, it is a secondary amine dibenzocycloheptene and pharmacologically it is classed as a first-generation antidepressant.Nortriptyline may also have a sleep-improving effect due to antagonism of the H1 and 5-HT2A receptors. In the short term, however, nortriptyline may disturb sleep due to its activating effect. In one study, nortriptyline had the highest affinity for the dopamine transporter among the TCAs (KD = 1,140 nM) besides amineptine (a norepinephrine–dopamine reuptake inhibitor), although its affinity for this transporter was still 261- and 63-fold lower than for the norepinephrine and serotonin transporters (KD = 4.37 and 18 nM, respectively). Pharmacokinetics Pharmacogenetics Nortriptyline is metabolized in the liver by the hepatic enzyme CYP2D6, and genetic variations within the gene coding for this enzyme can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of nortriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drugs efficacy.Individuals can be categorized into different types of CYP2D6 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most individuals (about 77–92%) are extensive metabolizers, and have "normal" metabolism of nortriptyline. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers use nortriptyline much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure.The Clinical Pharmacogenetics Implementation Consortium recommends avoiding nortriptyline in persons who are CYP2D6 ultrarapid or poor metabolizers, due to the risk of a lack of efficacy and side effects, respectively. A reduction in starting dose is recommended for patients who are CYP2D6 intermediate metabolizers. If use of nortriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments. The Dutch Pharmacogenetics Working Group recommends reducing the dose of nortriptyline in CYP2D6 poor or intermediate metabolizers, and selecting an alternative drug or increasing the dose in ultrarapid metabolizers. Chemistry Nortriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzocycloheptadiene TCAs include amitriptyline (N-methylnortriptyline), protriptyline, and butriptyline. Nortriptyline is a secondary amine TCA, with its N-methylated parent amitriptyline being a tertiary amine. Other secondary amine TCAs include desipramine and protriptyline. The chemical name of nortriptyline is 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine and its free base form has a chemical formula of C19H21N1 with a molecular weight of 263.384 g/mol. The drug is used commercially mostly as the hydrochloride salt; the free base form is used rarely. The CAS Registry Number of the free base is 72-69-5 and of the hydrochloride is 894-71-3. History Nortriptyline was developed by Geigy. It first appeared in the literature in 1962 and was patented the same year. The drug was first introduced for the treatment of depression in 1963. Society and culture Generic names Nortriptyline is the English and French generic name of the drug and its INN, BAN, and DCF, while nortriptyline hydrochloride is its USAN, USP, BANM, and JAN. Its generic name in Spanish and Italian and its DCIT are nortriptilina, in German is nortriptylin, and in Latin is nortriptylinum. Brand names Brand names of nortriptyline include Allegron, Aventyl, Noritren, Norpress, Nortrilen, Norventyl, Norzepine, Pamelor, and Sensoval, among many others. References External links "Nortriptyline". Drug Information Portal. U.S. National Library of Medicine.
Triheptanoin	Triheptanoin, sold under the brand name Dojolvi, is a medication for the treatment of children and adults with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD).The most common adverse reactions include abdominal pain, diarrhea, vomiting, and nausea.Triheptanoin was approved for medical use in the United States in June 2020.Triheptanoin is a triglyceride that is composed of three seven-carbon (C7:0) fatty acids. These odd-carbon fatty acids are able to provide anaplerotic substrates for the TCA cycle. Triheptanoin is used clinically in humans to treat inherited metabolic diseases, such as pyruvate carboxylase deficiency and carnitine palmitoyltransferase II deficiency. It also appears to increase the efficacy of the ketogenic diet as a treatment for epilepsy. Since triheptanoin is composed of odd-carbon fatty acids, it can produce ketone bodies with five carbon atoms, as opposed to even-carbon fatty acids which are metabolized to ketone bodies with four carbon atoms. The five-carbon ketones produced from triheptanoin are beta-ketopentanoate and beta-hydroxypentanoate. Each of these ketone bodies easily crosses the blood–brain barrier and enters the brain. Medical uses Dojolvi is indicated as a source of calories and fatty acids for the treatment of children and adults with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD). History Triheptanoin was designated an orphan drug by the U.S. Food and Drug Administration (FDA) in 2006, 2008, 2014, and 2015. Triheptanoin was also designated an orphan drug by the European Medicines Agency (EMA).Triheptanoin was approved for medical use in the United States in June 2020.The FDA approved triheptanoin based on evidence from three clinical trials (Trial 1/NCT018863, Trial 2/NCT022141 and Trial 3/NCT01379625). The trials enrolled children and adults with LC-FAOD. Trials 1 and 2 were conducted at 11 sites in the United States and the United Kingdom, and Trial 3 was conducted at two sites in the United States.Trial 1 and Trial 2 were used to evaluate the side effects of triheptanoin. Both trials enrolled children and adults diagnosed with LC-FAOD. In Trial 1, participants received triheptanoin for 78 weeks. Trial 2 enrolled participants from other trials who were already treated with triheptanoin (including those from Trial 1) as well as participants who were never treated with triheptanoin before. Trial 2 is still ongoing and is planned to last up to five years.The benefit of triheptanoin was evaluated in Trial 3 which enrolled children and adults with LC-FAOD. Half of the participants received triheptanoin and half received trioctanoin for four months. Neither the participants nor the investigators knew which treatment was given until the end of the trial. The benefit of triheptanoin in comparison to trioctanoin was assessed by measuring the changes in heart and muscle function. Names Triheptanoin is the international nonproprietary name. References Further reading de Almeida Rabello Oliveira M, da Rocha Ataíde T, de Oliveira SL, de Melo Lucena AL, de Lira CE, Soares AA, et al. (March 2008). "Effects of short-term and long-term treatment with medium- and long-chain triglycerides ketogenic diet on cortical spreading depression in young rats". Neurosci. Lett. 434 (1): 66–70. doi:10.1016/j.neulet.2008.01.032. PMID 18281154. S2CID 7754768. Mochel F, DeLonlay P, Touati G, Brunengraber H, Kinman RP, Rabier D, et al. (April 2005). "Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy". Mol. Genet. Metab. 84 (4): 305–12. doi:10.1016/j.ymgme.2004.09.007. PMID 15781190. Borges K, Sonnewald U (July 2012). "Triheptanoin--a medium chain triglyceride with odd chain fatty acids: a new anaplerotic anticonvulsant treatment?". Epilepsy Res. 100 (3): 239–44. doi:10.1016/j.eplepsyres.2011.05.023. PMC 3422680. PMID 21855298. External links "Triheptanoin". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT01379625 for "Study of Triheptanoin for Treatment of Long-Chain Fatty Acid Oxidation Disorder (Triheptanoin)" at ClinicalTrials.gov
Nifurtimox	Nifurtimox, sold under the brand name Lampit, is a medication used to treat Chagas disease and sleeping sickness. For sleeping sickness it is used together with eflornithine in nifurtimox-eflornithine combination treatment. In Chagas disease it is a second-line option to benznidazole. It is given by mouth.Common side effects include abdominal pain, headache, nausea, and weight loss. There are concerns from animal studies that it may increase the risk of cancer but these concerns have not been found in human trials. Nifurtimox is not recommended in pregnancy or in those with significant kidney or liver problems. It is a type of nitrofuran.Nifurtimox came into medication use in 1965. It is on the World Health Organizations List of Essential Medicines. It is not available commercially in Canada. It was approved for medical use in the United States in August 2020. In regions of the world where the disease is common nifurtimox is provided for free by the World Health Organization (WHO). Medical uses Nifurtimox has been used to treat Chagas disease, when it is given for 30 to 60 days. However, long-term use of nifurtimox does increase chances of adverse events like gastrointestinal and neurological side effects. Due to the low tolerance and completion rate of nifurtimox, benznidazole is now being more considered for those who have Chagas disease and require long-term treatment.In the United States nifurtimox is indicated in children and adolescents (birth to less than 18 years of age and weighing at least 2.5 kilograms (5.5 lb) for the treatment of Chagas disease (American Trypanosomiasis), caused by Trypanosoma cruzi.Nifurtimox has also been used to treat African trypanosomiasis (sleeping sickness), and is active in the second stage of the disease (central nervous system involvement). When nifurtimox is given on its own, about half of all patients will relapse, but the combination of melarsoprol with nifurtimox appears to be efficacious. Trials are awaited comparing melarsoprol/nifurtimox against melarsoprol alone for African sleeping sickness.Combination therapy with eflornithine and nifurtimox is safer and easier than treatment with eflornithine alone, and appears to be equally or more effective. It has been recommended as first-line treatment for second-stage African trypanosomiasis. Pregnancy and breastfeeding Use of nifurtimox should be avoided in pregnant women due to limited use. There is limited data shown that nifurtimox doses up to 15 mg/kg daily can cause adverse effects in breastfed infants. Other authors do not consider breastfeeding a contraindication during nifurtimox use. Side effects Side effects occur following chronic administration, particularly in elderly people. Major toxicities include immediate hypersensitivity such as anaphylaxis and delayed hypersensitivity reaction involving icterus and dermatitis. Central nervous system disturbances and peripheral neuropathy may also occur.Most common side effects anorexia weight loss nausea vomiting headache dizziness amnesiaLess common effects rash depression anxiety confusion fever sore throat chills seizures impotence tremors muscle weakness numbness of hands or feet Contraindications Nifurtimox is contraindicated in people with severe liver or kidney disease, as well as people with a background of neurological or psychiatric disorders. Mechanism of action Nifurtimox forms a nitro-anion radical metabolite that reacts with nucleic acids of the parasite causing significant breakdown of DNA. Its mechanism is similar to that proposed for the antibacterial action of metronidazole. Nifurtimox undergoes reduction and creates oxygen radicals such as superoxide. These radicals are toxic to T. cruzi. Mammalian cells are protected by presence of catalase, glutathione, peroxidases, and superoxide dismutase. Accumulation of hydrogen peroxide to cytotoxic levels results in parasite death. Society and culture Legal status Nifurtimox is only licensed for use in Argentina, the United States, and Germany. It was approved for medical use in the United States in August 2020. Names Research Nifurtimox is in a phase-II clinical trial for the treatment of pediatric neuroblastoma and medulloblastoma. References External links "Nifurtimox". Drug Information Portal. U.S. National Library of Medicine.
Amitriptyline/perphenazine	Amitriptyline/perphenazine (Duo-Vil, Etrafon, Triavil, Triptafen) is a formulation that contains the tricyclic antidepressant amitriptyline and the medium-potency typical (first-generation) antipsychotic, perphenazine. In the United States amitriptyline/perphenazine is marketed by Mylan Pharmaceuticals Inc. and Remedy Repack Inc. Medical uses In the United States amitriptyline/perphenazine is indicated for the treatment of patients with: Moderate-severe anxiety and/or agitation and depression Depression and anxiety in association with chronic physical disease Schizophrenia with prominent depressive symptoms Adverse effects Common (>1% incidence) adverse effects include Sedation Hypertension — high blood pressure. Neurological impairments (such as extrapyramidal side effects which include dystonia, akathisia, parkinsonism, muscle rigidity, etc.) Anticholinergic side effects such as:- Blurred vision - Constipation - Dry mouth - Nasal congestionIncreased appetite Weight gain Nausea Dizziness Headache VomitingUnknown frequency adverse effects include Diarrhoea Alopecia — hair loss Photophobia Pigmentation Eczema up to exfoliative dermatitis Urticaria Erythema Itching Photosensitivity (increased sensitivity of affected skin to sunlight) Hypersalivation — excessive salivation. Hyperprolactinaemia — elevated blood prolactin levels. This may present with the following symptoms:- Galactorrhea — the release of milk that is not associated with pregnancy or breastfeeding - Gynaecomastia — the development of breast tissue in males - Disturbances in menstrual cycle - Sexual dysfunctionPigmentation of the cornea and lens Hyperglycaemia — elevated blood glucose (sugar) levels. Hypoglycaemia — low blood glucose (sugar) levels. Disturbed concentration Excitement Anxiety Insomnia Restlessness Nightmares Weakness Fatigue Diaphoresis — excessive/abnormal sweating.Uncommon/Rare adverse effects include Tardive dyskinesia, an often irreversible adverse effect that usually results from chronic use antipsychotic medications, especially the high-potency first-generation antipsychotics. It is characterised by slow (hence tardive), involuntary, repetitive, purposeless muscle movements. Neuroleptic malignant syndrome, a potentially fatal complication of antipsychotic drug use. It is characterised by the following symptoms:- Muscle rigidity - Tremors - Mental status change (e.g. hallucinations, agitation, stupor, confusion, etc.) - Hyperthermia — elevated body temperature - Autonomic instability (e.g. tachycardia, high blood pressure, diaphoresis, diarrhoea, etc.)Urinary retention — the inability to pass urine despite having urine to pass. Blood dyscrasias e.g. agranulocytosis (a potentially fatal drop in white blood cell count), leukopaenia (a drop in white blood cell counts but not to as extreme an extent as agranulocytosis), neutropaenia (a drop in neutrophil [the cells of the immune system that specifically destroy bacteria] count), thrombocytopaenia (a dangerous drop in platelet [a cell found in the blood that plays a crucial role in the blood clotting process] counts), purpura (the appearance of red or purple discolourations of the skin that do not blanch when pressure is applied), eosinophilia (raised eosinophil [the cells of the immune system that specifically fights off parasites] count) Hepatitis — inflammation of the liver Jaundice Pigmentary retinopathy Anaphylactoid reactions Oedema — the abnormal buildup of fluids in the tissues Asthma Coma Seizures Confusional states Disorientation Incoordination Ataxia Tremors Peripheral neuropathy — nerve damage Numbness, tingling and paresthesias of the extremities Dysarthria Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Tinnitus — falsely hearing ringing in the ears. Alteration in EEG patterns Paralytic ileus — cessation of the peristaltic waves that propel partially digested food through the digestive tract. Hyperpyrexia (elevated body temperature) Disturbance of accommodation Increased intraocular pressure Mydriasis Pharmacology Binding affinities (Ki[nM]; for human cloned receptors when available) See also Flupentixol/melitracen Olanzapine/fluoxetine Tranylcypromine/trifluoperazine == References ==
Procaine benzylpenicillin	Procaine benzylpenicillin also known as penicillin G procaine, is an antibiotic useful for the treatment of a number of bacterial infections. Specifically it is used for syphilis, anthrax, mouth infections, pneumonia, diphtheria, cellulitis, and animal bites. It is given by injection into a muscle.Side effects include pain at the site of injection, blood clotting problems, seizures, and allergic reactions including anaphylaxis. When used to treat syphilis a reaction known as Jarisch-Herxheimer may occur. It is not recommended in those with a history of penicillin allergy or procaine allergy. Use during pregnancy and breastfeeding is relatively safe. Procaine benzylpenicillin is in the penicillin and beta lactam family of medications. It works via benzylpenicillin and results in bacterial death. Procaine makes the combination long acting.Procaine benzylpenicillin was introduced for medical use in 1948. It is on the World Health Organizations List of Essential Medicines. Medical uses Specific indications for procaine penicillin include: Syphilis In the United States, Bicillin C-R (an injectable suspension which 1.2 million units of benzathine penicillin and 1.2 million units of procaine penicillin per 4 ml) is not recommended for treating syphilis, since it contains only half the recommended dose of benzathine penicillin. Medication errors have been made due to the confusion between Bicillin L-A & Bicillin C-R. As a result, changes in product packaging have been made; specifically, the statement "Not for the Treatment of Syphilis" has been added in red text to both the Bicillin CR and Billin CR 900/300 syringe labels. Respiratory tract infections where compliance with oral treatment is unlikely Alongside Pen V and Erythromycin, Bicillin C-R is used to treat strep throat, given as one IM injection Cellulitis, erysipelas Procaine penicillin is also used as an adjunct in the treatment of anthrax. Adverse effects At high doses procaine penicillin can cause seizures and CNS abnormalities due to procaine present in it. Mechanism It is a form of penicillin which is a combination of benzylpenicillin and the local anaesthetic agent procaine. Following deep intramuscular injection, it is slowly absorbed into the circulation and hydrolysed to benzylpenicillin — thus it is used where prolonged low concentrations of benzylpenicillin are required. Compendial status British Pharmacopoeia See also Benzathine benzylpenicillin/procaine benzylpenicillin References External links "Penicillin G Procaine". Drug Information Portal. U.S. National Library of Medicine.
Hydrochlorothiazide	Hydrochlorothiazide is a diuretic medication often used to treat high blood pressure and swelling due to fluid build up. Other uses include treating diabetes insipidus and renal tubular acidosis and to decrease the risk of kidney stones in those with a high calcium level in the urine. Hydrochlorothiazide is less effective than chlortalidone for prevention of heart attack or stroke. Hydrochlorothiazide is taken by mouth and may be combined with other blood pressure medications as a single pill to increase effectiveness.Potential side effects include poor kidney function; electrolyte imbalances, including low blood potassium, and, less commonly, low blood sodium, gout, high blood sugar, and feeling lightheaded with standing. While allergies to hydrochlorothiazide are reported to occur more often in those with allergies to sulfa drugs, this association is not well supported. It may be used during pregnancy, but it is not a first-line medication in this group.It is in the thiazide medication class and acts by decreasing the kidneys ability to retain water. This initially reduces blood volume, decreasing blood return to the heart and thus cardiac output. It is believed to lower peripheral vascular resistance in the long run.Two companies, Merck and Ciba, state they discovered the medication which became commercially available in 1959. It is on the World Health Organizations List of Essential Medicines. It is available as a generic drug and is relatively affordable. In 2020, it was the eleventh most commonly prescribed medication in the United States, with more than 41 million prescriptions. Medical uses Hydrochlorothiazide is used for the treatment of hypertension, congestive heart failure, symptomatic edema, diabetes insipidus, renal tubular acidosis. It is also used for the prevention of kidney stones in those who have high levels of calcium in their urine.Multiple studies suggest hydrochlorothiazide could be used as initial monotherapy in people with primary hypertension; however, the decision should be weighed against the consequence of long-term adverse metabolic abnormalities. A review of randomised trials showed varying efficacy in cardiovascular outcomes on age, ethnicity and existing cardiovascular risks. A systematic, multinational, large-scale analysis by Suchard et al. supported equivalence between drug classes for initiating monotherapy in hypertension, however thiazide or thiazide-like diuretics showed better primary effectiveness and safety profiles than angiotensin-converting enzyme inhibitors and non-dihydropyridine calcium channel blockers.Hydrochlorothiazide is less potent but not necessarily less effective than chlorthalidone in reducing blood pressure. More robust studies are required to confirm which drug is superior in reducing cardiovascular events. Side effect profile for both drugs appear similar and are dose dependant.Hydrochlorothiazide is also sometimes used to prevent osteopenia and for treatment of hypoparathyroidism, hypercalciuria, Dents disease, and Ménières disease. For diabetes insipidus, the effect of thiazide diuretics is presumably mediated by a hypovolemia-induced increase in proximal sodium and water reabsorption, thereby diminishing water delivery to the ADH-sensitive sites in the collecting tubules and increasing the urine osmolality.A low level of evidence, predominantly from observational studies, suggests that thiazide diuretics have a modest beneficial effect on bone mineral density and are associated with a decreased fracture risk when compared with people not taking thiazides. Thiazides decrease mineral bone loss by promoting calcium retention in the kidney, and by directly stimulating osteoblast differentiation and bone mineral formation.The combination of fixed-dose preparation such as losartan/hydrochlorothiazide has added advantages of a more potent antihypertensive effect with additional antihypertensive efficacy at the dose of 100 mg/25 mg when compared to monotherapy. Adverse effects Hypokalemia, or low blood levels of potassium are an occasional side effect. It can be usually prevented by potassium supplements or by combining hydrochlorothiazide with a potassium-sparing diuretic Other disturbances in the levels of serum electrolytes, including hypomagnesemia (low magnesium), hyponatremia (low sodium), and hypercalcemia (high calcium) Hyperuricemia (high levels of uric acid in the blood). All thiazide diuretics including hydrochlorothiazide can inhibit excretion of uric acid by the kidneys, thereby increasing serum concentrations of uric acid.This may increase the incidence of gout in doses of ≥ 25 mg per day and in more susceptible patients such as male gender of <60 years old. Hyperglycemia, high blood sugar Hyperlipidemia, high cholesterol and triglycerides Headache Nausea/vomiting Photosensitivity Weight gain PancreatitisPackage inserts contain vague and inconsistent data surrounding the use of thiazide diuretics in patients with allergies to sulfa drugs, with little evidence to support these statements. A retrospective cohort study conducted by Strom et al. concluded that there is an increased risk of an allergic reaction occurring in patients with a predisposition to allergic reactions in general rather than cross reactivity from structural components of the sulfonamide-based drug. Prescribers should examine the evidence carefully and assess each patient individually, paying particular attention to their prior history of sulfonamide hypersensitivity rather than relying on drug monograph information.There is an increased risk of non-melanoma skin cancer. In August 2020, the Australian Therapeutic Goods Administration required the Product Information (PI) and Consumer Medicine Information (CMI) for medicines containing hydrochlorothiazide to be updated to include details about an increased risk of non-melanoma skin cancer. In August 2020, the U.S. Food and Drug Administration (FDA) updated the drug label about an increased risk of non-melanoma skin cancer (basal cell skin cancer or squamous cell skin cancer). Mechanism of action Hydrochlorothiazide belongs to the thiazide class of diuretics. It reduces blood volume by acting on the kidneys to reduce sodium (Na+) reabsorption in the distal convoluted tubule. The major site of action in the nephron appears on an electroneutral NaCl co-transporter by competing for the chloride site on the transporter. By impairing Na+ transport in the distal convoluted tubule, hydrochlorothiazide induces a natriuresis and concomitant water loss. Thiazides increase the reabsorption of calcium in this segment in a manner unrelated to sodium transport. Additionally, by other mechanisms, hydrochlorothiazide is believed to lower peripheral vascular resistance. Dosage In a double-blind, randomized study, the effects of 25 mg/day vs. 50 mg/day of hydrochlorothiazide were evaluated in geriatric patients (n = 51) with isolated systolic hypertension. Both dosages were associated with similar reductions in blood pressure; however, the higher dose (50 mg/day) caused a greater decline in serum potassium concentration. Society and culture Brand names Hydrochlorothiazide is available as a generic drug under a large number of brand names, including Apo-Hydro, Aquazide, BPZide, Dichlotride, Esidrex, Hydrochlorot, Hydrodiuril, HydroSaluric, Hypothiazid, Microzide, Oretic and many others.To reduce pill burden and in order to reduce side effects, hydrochlorothiazide is often used in fixed-dose combinations with many other classes of antihypertensive drugs such as: ACE inhibitors — e.g. Prinzide or Zestoretic (with lisinopril), Co-Renitec (with enalapril), Capozide (with captopril), Accuretic (with quinapril), Monopril HCT (with fosinopril), Lotensin HCT (with benazepril), etc. Angiotensin receptor blockers — e.g. Hyzaar (with losartan), Co-Diovan or Diovan HCT (with valsartan), Teveten Plus (with eprosartan), Avalide or CoAprovel (with irbesartan), Atacand HCT or Atacand Plus (with candesartan), etc. Beta blockers — e.g. Ziac or Lodoz (with bisoprolol), Nebilet Plus or Nebilet HCT (with nebivolol), Dutoprol or Lopressor HCT (with metoprolol), etc. Direct renin inhibitors — e.g. Co-Rasilez or Tekturna HCT (with aliskiren) Potassium sparing diuretics: Dyazide and Maxzide triamterene Sport Use of hydrochlorothiazide is prohibited by the World Anti-Doping Agency for its ability to mask the use of performance-enhancing drugs. References External links "Hydrochlorothiazide". Drug Information Portal. U.S. National Library of Medicine.
Ellipsis	The ellipsis ... (, also known informally as dot dot dot) is a series of dots that indicates an intentional omission of a word, sentence, or whole section from a text without altering its original meaning. The plural is ellipses. The term originates from the Ancient Greek: ἔλλειψις, élleipsis meaning leave out.Opinions differ as to how to render ellipses in printed material. According to The Chicago Manual of Style, it should consist of three periods, each separated from its neighbor by a non-breaking space: . . .. According to the AP Stylebook, the periods should be rendered with no space between them: .... A third option is to use the Unicode character U+2026 … HORIZONTAL ELLIPSIS. Background The ellipsis is also called a suspension point, points of ellipsis, periods of ellipsis, or (colloquially) "dot-dot-dot". Depending on their context and placement in a sentence, ellipses can indicate an unfinished thought, a leading statement, a slight pause, an echoing voice, or a nervous or awkward silence. Aposiopesis is the use of an ellipsis to trail off into silence—for example: "But I thought he was..." When placed at the end of a sentence, an ellipsis may be used to suggest melancholy or longing.The most common forms of an ellipsis include a row of three periods or full points ... or a precomposed triple-dot glyph, the horizontal ellipsis …. Style guides often have their own rules governing the use of ellipses. For example, The Chicago Manual of Style (Chicago style) recommends that an ellipsis be formed by typing three periods, each with a space on both sides . . . , while the Associated Press Stylebook (AP style) puts the dots together, but retains a space before and after the group, thus: ... . Whether an ellipsis at the end of a sentence needs a fourth dot to finish the sentence is a matter of debate; Chicago advises it, as does the Publication Manual of the American Psychological Association (APA style), while some other style guides do not; the Merriam-Webster Dictionary and related works treat this style as optional, saying that it "may" be used.When text is omitted following a sentence, a normal full stop (period) terminates the sentence, and then a separate three-dot ellipsis is commonly used to indicate one or more subsequent omitted sentences before continuing a longer quotation. Business Insider magazine suggests this style and it is also used in many academic journals. The Associated Press Stylebook favors this approach. In writing In her book on the ellipsis, Ellipsis in English Literature: Signs of Omission (Cambridge University Press, 2015), Anne Toner suggests that the first use of the punctuation in the English language dates to a 1588 translation of Terences Andria, by Maurice Kyffin. In this case, however, the ellipsis consists not of dots but of short dashes. "Subpuncting" of medieval manuscripts also denotes omitted meaning and may be related.Occasionally, it would be used in pulp fiction and other works of early 20th-century fiction to denote expletives that would otherwise have been censored.An ellipsis may also imply an unstated alternative indicated by context. For example, "I never drink wine ..." implies that the speaker does drink something else—such as vodka. In reported speech, the ellipsis can be used to represent an intentional silence. In poetry, an ellipsis is used as a thought-pause or line break at the caesura or this is used to highlight sarcasm or make the reader think about the last points in the poem. In news reporting, often put inside square brackets, it is used to indicate that a quotation has been condensed for space, brevity or relevance, as in "The President said that [...] he would not be satisfied", where the exact quotation was "The President said that, for as long as this situation continued, he would not be satisfied". Herb Caen, Pulitzer-prize-winning columnist for the San Francisco Chronicle, became famous for his "three-dot journalism". In different languages In English American English The Chicago Manual of Style suggests the use of an ellipsis for any omitted word, phrase, line, or paragraph from within but not at the end of a quoted passage. There are two commonly used methods of using ellipses: one uses three dots for any omission, while the second one makes a distinction between omissions within a sentence (using three dots: . . .) and omissions between sentences (using a period and a space followed by three dots: . ...). The Chicago Style Q&A recommends that writers avoid using the precomposed … (U+2026) character in manuscripts and to place three periods plus two nonbreaking spaces (. . .) instead, leaving the editor, publisher, or typographer to replace them later.The Modern Language Association (MLA) used to indicate that an ellipsis must include spaces before and after each dot in all uses. If an ellipsis is meant to represent an omission, square brackets must surround the ellipsis to make it clear that there was no pause in the original quote: [ . . . ]. Currently, the MLA has removed the requirement of brackets in its style handbooks. However, some maintain that the use of brackets is still correct because it clears confusion.The MLA now indicates that a three-dot, spaced ellipsis . . . should be used for removing material from within one sentence within a quote. When crossing sentences (when the omitted text contains a period, so that omitting the end of a sentence counts), a four-dot, spaced (except for before the first dot) ellipsis . . . . should be used. When ellipsis points are used in the original text, ellipsis points that are not in the original text should be distinguished by enclosing them in square brackets (e.g. text [...] text).According to the Associated Press, the ellipsis should be used to condense quotations. It is less commonly used to indicate a pause in speech or an unfinished thought or to separate items in material such as show business gossip. The stylebook indicates that if the shortened sentence before the mark can stand as a sentence, it should do so, with an ellipsis placed after the period or other ending punctuation. When material is omitted at the end of a paragraph and also immediately following it, an ellipsis goes both at the end of that paragraph and at the beginning of the next, according to this style.According to Robert Bringhursts Elements of Typographic Style, the details of typesetting ellipses depend on the character and size of the font being set and the typographers preference. Bringhurst writes that a full space between each dot is "another Victorian eccentricity. In most contexts, the Chicago ellipsis is much too wide"—he recommends using flush dots (with a normal word space before and after), or thin-spaced dots (up to one-fifth of an em), or the prefabricated ellipsis character U+2026 … HORIZONTAL ELLIPSIS (…, &mldr;). Bringhurst suggests that normally an ellipsis should be spaced fore-and-aft to separate it from the text, but when it combines with other punctuation, the leading space disappears and the other punctuation follows. This is the usual practice in typesetting. He provides the following examples: In legal writing in the United States, Rule 5.3 in the Bluebook citation guide governs the use of ellipses and requires a space before the first dot and between the two subsequent dots. If an ellipsis ends the sentence, then there are three dots, each separated by a space, followed by the final punctuation (e.g. Hah . . . ?). In some legal writing, an ellipsis is written as three asterisks, *** or * * , to make it obvious that text has been omitted or to signal that the omitted text extends beyond the end of the paragraph. British English The Oxford Style Guide recommends setting the ellipsis as a single character … or as a series of three (narrow) spaced dots surrounded by spaces, thus: . . . . If there is an ellipsis at the end of an incomplete sentence, the final full stop is omitted. However, it is retained if the following ellipsis represents an omission between two complete sentences. Contrary to The Oxford Style Guide, the University of Oxford Style Guide demands an ellipsis not to be surrounded by spaces, except when it stands for a pause; then, a space has to be set after the ellipsis (but not before). An ellipsis is never preceded or followed by a full stop. In Polish When applied in Polish syntax, the ellipsis is called wielokropek, literally multidot. The word wielokropek distinguishes the ellipsis of Polish syntax from that of mathematical notation, in which it is known as an elipsa. When an ellipsis replaces a fragment omitted from a quotation, the ellipsis is enclosed in parentheses or square brackets. An unbracketed ellipsis indicates an interruption or pause in speech. The syntactic rules for ellipses are standardized by the 1983 Polska Norma document PN-83/P-55366, Zasady składania tekstów w języku polskim (Rules for Setting Texts in Polish). In Russian The combination "ellipsis+period" is replaced by the ellipsis. The combinations "ellipsis+exclamation mark" and "ellipsis+question mark" are written in this way: !.. ?.. In Japanese The most common character corresponding to an ellipsis is called 3-ten rīdā ("3-dot leaders", …). 2-ten rīdā exists as a character, but it is used less commonly. In writing, the ellipsis consists usually of six dots (two 3-ten rīdā characters, ……). Three dots (one 3-ten rīdā character) may be used where space is limited, such as in a header. However, variations in the number of dots exist. In horizontally written text the dots are commonly vertically centered within the text height (between the baseline and the ascent line), as in the standard Japanese Windows fonts; in vertically written text the dots are always centered horizontally. As the Japanese word for dot is pronounced "ten", the dots are colloquially called "ten-ten-ten" (てんてんてん, akin to the English "dot dot dot").In text in Japanese media, such as in manga or video games, ellipses are much more frequent than in English, and are often changed to another punctuation sign in translation. The ellipsis by itself represents speechlessness, or a "pregnant pause". Depending on the context, this could be anything from an admission of guilt to an expression of being dumbfounded at another persons words or actions. As a device, the ten-ten-ten is intended to focus the reader on a character while allowing the character to not speak any dialogue. This conveys to the reader a focus of the narrative "camera" on the silent subject, implying an expectation of some motion or action. It is not unheard of to see inanimate objects "speaking" the ellipsis. In Chinese In Chinese, the ellipsis is six dots (in two groups of three dots, occupying the same horizontal or vertical space as two characters) (i.e. ……). In Spanish In Spanish, the ellipsis is commonly used as a substitute of et cetera at the end of unfinished lists. So it means "and so forth" or "and other things". Other use is the suspension of a part of a text, or a paragraph, or a phrase or a part of a word because it is obvious, or unnecessary, or implied. For instance, sometimes the ellipsis is used to avoid the complete use of expletives. When the ellipsis is placed alone into a parenthesis (...) or—less often—between brackets [...], which is what happens usually within a text transcription, it means the original text had more contents on the same position but are not useful to our target in the transcription. When the suppressed text is at the beginning or at the end of a text, the ellipsis does not need to be placed in a parenthesis. The number of dots is three and only three. In French In French, the ellipsis is commonly used at the end of lists to represent et cetera. In French typography, the ellipsis is written immediately after the preceding word, but has a space after it, for example: comme ça... pas comme ceci. If, exceptionally, it begins a sentence, there is a space before and after, for example: Lui ? ... vaut rien, je crois... . However, any omitted word, phrase or line at the end of a quoted passage would be indicated as follows: [...] (space before and after the square brackets but not inside), for example: ... à Paris, Nice, Nantes, Toulouse [...]. In German In German, the ellipsis in general is surrounded by spaces, if it stands for one or more omitted words. On the other side there is no space between a letter or (part of) a word and an ellipsis, if it stands for one or more omitted letters, that should stick to the written letter or letters. Example for both cases, using German style: The first el...is stands for omitted letters, the second ... for an omitted word. If the ellipsis is at the end of a sentence, the final full stop is omitted.Example: I think that ... In Italian The Accademia della Crusca suggests the use of an ellipsis ("puntini di sospensione") to indicate a pause longer than a period and, when placed between brackets, the omission of letters, words or phrases. "Tra le cose più preziose possedute da Andrea Sperelli era una coperta di seta fina, d’un colore azzurro disfatto, intorno a cui giravano i dodici segni dello Zodiaco in ricamo, con le denominazioni […] a caratteri gotici." (Gabriele D’Annunzio, Il piacere) Usage in computer system menus In computer menu functions or buttons, an ellipsis means that upon selection more options (sometimes in the form of a dialog box) will be displayed, where the user can or must make a choice. If the ellipsis is absent, the function is immediately executed upon selection. For example, the menu item "Save" indicates that the file will be overwritten without further input, whereas "Save as..." indicates that a dialog follows where the user can, for example, select another location, file name, or format. Ellipses are also used as a separate button (particularly considering the limited screen area of mobile apps) to represent partially or completely hidden options. This usage may alternatively be described as a "More button" (see also hamburger button signifying completely hidden options). In mobile, web, and general application design, the vertical ellipsis, ⋮, is sometimes used as an interface element, where it is sometimes called a kebab icon. The element typically indicates that a navigation menu can be accessed when the element is activated, and is a smaller version of the hamburger icon (≡) which is a stylized rendering of a menu. In mathematical notation An ellipsis is also often used in mathematics to mean "and so forth". In a list, between commas, or following a comma, a normal ellipsis is used, as in: 1 , 2 , 3 , … , 100 {\displaystyle 1,2,3,\ldots ,100} or to mean an infinite list, as: 1 , 2 , 3 , … {\displaystyle 1,2,3,\ldots } To indicate the omission of values in a repeated operation, an ellipsis raised to the center of the line is used between two operation symbols or following the last operation symbol, as in: 1 + 2 + 3 + ⋯ + 100 {\displaystyle 1+2+3+\cdots +100} Sometimes, e.g. in Russian mathematical texts, normal, non-raised, ellipses are used even in repeated summations.The latter formula means the sum of all natural numbers from 1 to 100. However, it is not a formally defined mathematical symbol. Repeated summations or products may similarly be denoted using capital sigma and capital pi notation, respectively: 1 + 2 + 3 + ⋯ + 100 = ∑ n = 1 100 n = 100 ? {\displaystyle 1+2+3+\cdots +100\ =\sum _{n=1}^{100}n=100?} (see termial) 1 × 2 × 3 × ⋯ × 100 = ∏ n = 1 100 n = 100 ! {\displaystyle 1\times 2\times 3\times \cdots \times 100\ =\prod _{n=1}^{100}n=100!} (see factorial)Normally dots should be used only where the pattern to be followed is clear, the exception being to show the indefinite continuation of an irrational number such as: π = 3.14159265 … {\displaystyle \pi =3.14159265\ldots } Sometimes, it is useful to display a formula compactly, for example: 1 + 4 + 9 + ⋯ + n 2 + ⋯ + 400 {\displaystyle 1+4+9+\cdots +n^{2}+\cdots +400} Another example is the set of positive zeros of the cosine function: { π 2 , 3 π 2 , 5 π 2 , … } {\displaystyle \left\{{\frac {\pi }{2}},{\frac {3\pi }{2}},{\frac {5\pi }{2}},\ldots \right\}} There are many related uses of the ellipsis in set notation. The diagonal and vertical forms of the ellipsis are particularly useful for showing missing terms in matrices, such as the size-n identity matrix: I n = [ 1 0 ⋯ 0 0 1 ⋯ 0 ⋮ ⋮ ⋱ ⋮ 0 0 ⋯ 1 ] {\displaystyle I_{n}={\begin{bmatrix}1&0&\cdots &0\\0&1&\cdots &0\\\vdots &\vdots &\ddots &\vdots \\0&0&\cdots &1\end{bmatrix}}} Computer science Programming languages A two- or three-dot ellipsis is used as an operator in some programming languages. One of its most common uses is in defining ranges or sequences, for instance 1..10 means all the numbers from 1 through 10. This is used in many languages, including Pascal, Modula, Oberon, Ada, Haskell, Perl, Ruby, Rust, Swift, Kotlin, Bash shell and F#. It is also used to indicate variadic functions in the C, C++ and Java languages. See Ellipsis (programming operator). HTML and CSS The CSS text-overflow property can be set to ellipsis, which cuts off text with an ellipsis when it overflows the content area. On Internet chat rooms and in text messaging The ellipsis is a non-verbal cue that is often used in computer-mediated interactions, in particular in synchronous genres, such as chat. The reason behind its popularity is the fact that it allows people to indicate in writing several functions: The sign of ellipsis can function as a floor holding device, and signal that more is to come, for instance when people break up longer turns in chat. Dot-dot-dot can be used systematically to enact linguistic politeness, for instance indicating topic change or hesitation. Suspension dots can be turn construction units to signal silence, for example when indicating disagreement, disapproval or confusion.Although an ellipsis is technically complete with three periods (...), its rise in popularity as a "trailing-off" or "silence" indicator, particularly in mid-20th-century comic strip and comic book prose writing, has led to expanded uses online. Today, extended ellipses anywhere from two to dozens of periods have become common constructions in Internet chat rooms and text messages. The extent of repetition in itself might serve as an additional contextualization or paralinguistic cue, to "extend the lexical meaning of the words, add character to the sentences, and allow fine-tuning and personalisation of the message". Computer representations In computing, several ellipsis characters have been codified, depending on the system used. In the Unicode standard, there are the following characters: Unicode recognizes a series of three period characters (U+002E) as compatibility equivalent (though not canonical) to the horizontal ellipsis character.In HTML, the horizontal ellipsis character may be represented by the entity reference … (since HTML 4.0), and the vertical ellipsis character by the entity reference &vellip; (since HTML 5.0). Alternatively, in HTML, XML, and SGML, a numeric character reference such as … or … can be used. In the TeX typesetting system, the following types of ellipsis are available: In LaTeX, note that the reverse orientation of \ddots can be achieved with \reflectbox provided by the graphicx package: \reflectbox{\ddots} yields . With the amsmath package from AMS-LaTeX, more specific ellipses are provided for math mode. The horizontal ellipsis character also appears in the following older character maps: in Windows-1250—Windows-1258 and in IBM/MS-DOS Code page 874, at code 85 (hexadecimal) in Mac-Roman, Mac-CentEuro and several other Macintosh encodings, at code C9 (hexadecimal) in Ventura International encoding at code C1 (hexadecimal)Note that ISO/IEC 8859 encoding series provides no code point for ellipsis. As with all characters, especially those outside the ASCII range, the author, sender and receiver of an encoded ellipsis must be in agreement upon what bytes are being used to represent the character. Naive text processing software may improperly assume that a particular encoding is being used, resulting in mojibake. In Abstract Syntax Notation One (ASN.1), the ellipsis is used as an extension marker to indicate the possibility of type extensions in future revisions of a protocol specification. In a type constraint expression like A ::= INTEGER (0..127, ..., 256..511) an ellipsis is used to separate the extension root from extension additions. The definition of type A in version 1 system of the form A ::= INTEGER (0..127, ...) and the definition of type A in version 2 system of the form A ::= INTEGER (0..127, ..., 256..511) constitute an extension series of the same type A in different versions of the same specification. The ellipsis can also be used in compound type definitions to separate the set of fields belonging to the extension root from the set of fields constituting extension additions. Here is an example: B ::= SEQUENCE { a INTEGER, b INTEGER, ..., c INTEGER } Input In Windows, the horizontal ellipsis can be inserted with Alt+0133, using the numeric keypad. In macOS, it can be inserted with ⌥ Opt+; (on an English language keyboard). In some Linux distributions, it can be inserted with AltGr+. (this produces an interpunct on other systems), or Compose... In Chinese and sometimes in Japanese, ellipsis characters are made by entering two consecutive horizontal ellipses, each with Unicode code point U+2026. In vertical texts, the application should rotate the symbol accordingly. See also Aposiopesis – Figure of speech: an unfinished sentence Caesura – Pause or break in poetry or music Code folding or holophrasting -- switching between full text and an ellipsis Cohesion (linguistics) – Grammatical and lexical linking in text Dinkus – Typographic symbol ( * * ) – a row of three dots (usually widely separated) alone in the middle of a gap between two paragraphs, to indicate a sub-chapter. An em dash — is sometimes used instead of an ellipsis, especially in written dialogue. Elision – Omission of sounds in words or phrases. In written text, this is sometimes denoted using the horizontal ellipsis. Leader (typography) – Row of dots used in tables of contents Leiden Conventions – Textual conventions for representing dubious, illegible or missing characters in manuscripts. Line break (poetry) – Subdivision of a poem References Further reading External links The dictionary definition of ellipsis at Wiktionary Media related to Ellipses (punctuation) at Wikimedia Commons
Sofosbuvir	Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used to treat hepatitis C. It is taken by mouth.Common side effects include fatigue, headache, nausea, and trouble sleeping. Side effects are generally more common in interferon-containing regimens.: 7 Sofosbuvir may reactivate hepatitis B in those who have been previously infected. In combination with ledipasvir, daclatasvir or simeprevir, it is not recommended with amiodarone due to the risk of an abnormally slow heartbeat. Sofosbuvir is in the nucleotide analog family of medications and works by blocking the hepatitis C NS5B protein.Sofosbuvir was discovered in 2007 and approved for medical use in the United States in 2013. It is on the World Health Organizations List of Essential Medicines. Medical uses Initial HCV treatment In 2016, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America jointly published a recommendation for the management of hepatitis C. In this recommendation, sofosbuvir used in combination with other drugs is part of all first-line treatments for HCV genotypes 1, 2, 3, 4, 5, and 6, and is also part of some second-line treatments. Sofosbuvir in combination with velpatasvir is recommended for all genotypes with a cure rate greater than 90%, and close to 100% in most cases. The duration of treatment is typically 12 weeks.Sofosbuvir is also used with other medications and longer treatment durations, depending on specific circumstances, genotype and cost-effectiveness–based perspective. For example, for the treatment of genotypes 1, 4, 5, and 6 hepatitis C infections, sofosbuvir can be used in combination with the viral NS5A inhibitor ledipasvir. In genotype 2 and 3 HCV infections, sofosbuvir can be used in combination with daclatasvir. For the treatment of cases with cirrhosis or liver transplant patients, weight-based ribavirin is sometimes added. Peginterferon with or without sofosbuvir is not recommended in an initial HCV treatment.Compared to previous treatments, sofosbuvir-based regimens provide a higher cure rate, fewer side effects, and a two- to four-fold reduction in therapy duration. Sofosbuvir allows most people to be treated successfully without the use of peginterferon, an injectable drug with severe side effects that is a key component of older drug combinations for the treatment of hepatitis C virus. Prior failed treatment For people who have experienced treatment failure with some form of combination therapy for hepatitis C infection, one of the next possible steps would be retreatment with sofosbuvir and either ledipasvir or daclatasvir, with or without weight-based ribavirin. The genotype and particular combination therapy a person was on when the initial treatment failed are also taken into consideration when deciding which combination to use next. The duration of retreatment can range from 12 weeks to 24 weeks depending on several factors, including which medications are used for the retreatment, whether the person has liver cirrhosis or not, and whether the liver damage is classified as compensated cirrhosis or decompensated cirrhosis. Pregnancy and breastfeeding No adequate human data are available to establish whether or not sofosbuvir poses a risk to pregnancy outcomes. However, ribavirin, a medication that is often given together with sofosbuvir to treat hepatitis C, is assigned a Pregnancy Category X (contraindicated in pregnancy) by the FDA. Pregnant women with hepatitis C who take ribavirin have shown some cases of birth defects and death in their fetus. It is recommended that sofosbuvir/ribarivin combinations be avoided in pregnant females and their male sexual partners in order to reduce harmful fetal defects caused by ribavirin. Females who could potentially become pregnant should undergo a pregnancy test 2 months prior to starting the sofosbuvir/ribavirin/peginterferon combination treatment, monthly throughout the duration of the treatment, and six months post-treatment to reduce the risk of fetal harm in case of accidental pregnancy.It is unknown whether sofosbuvir and ribavirin pass into breastmilk; therefore, it is recommended that the mother does not breastfeed during treatment with sofosbuvir alone or in combination with ribavirin. Contraindications There are no specific contraindications for sofosbuvir when used alone. However, when used in combination with ribavirin or peginterferon alfa/ribavirin, or others, the contraindications applicable to these agents are applied. Side effects Sofosbuvir used alone and in combination with other drugs such as ribavirin with or without a peginterferon has a good safety profile. Common side effects are fatigue, headache, nausea, rash, irritability, dizziness, back pain, and anemia. Most side effects are more common in interferon-containing regimens as compared to interferon-free regimens. For example, fatigue and headache are nearly reduced by half, influenza-like symptoms are reduced to 3–6% as compared to 16–18%, and neutropenia is almost absent in interferon-free treatment.: 7 Sofosbuvir may reactivate hepatitis B in those who have been previously infected. The European Medicines Agency (EMA) has recommended screening all people for hepatitis B before starting sofosbuvir for hepatitis C in order to minimize the risk of hepatitis B reactivation. Interactions Sofosbuvir (in combination with ledipasvir, daclatasvir or simeprevir) should not be used with amiodarone due to the risk of abnormally slow heartbeats.Sofosbuvir is a substrate of P-glycoprotein, a transporter protein that pumps drugs and other substances from intestinal epithelium cells back into the gut. Therefore, inducers of intestinal P-glycoprotein, such as rifampicin and St. Johns wort, could reduce the absorption of sofosbuvir.In addition, coadministration of sofosbuvir with anticonvulsants (carbamazepine, phenytoin, phenobarbital, oxcarbazepine), antimycobacterials (rifampin, rifabutin, rifapentine), and the HIV protease inhibitor tipranavir and ritonavir is expected to decrease sofosbuvir concentration. Thus, coadministration is not recommended.The interaction between sofosbuvir and a number of other drugs, such as ciclosporin, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil, were evaluated in clinical trials and no dose adjustment is needed for any of these drugs. Pharmacology Mechanism of action Sofosbuvir inhibits the hepatitis C NS5B protein. Sofosbuvir appears to have a high barrier to the development of resistance.Sofosbuvir is a prodrug of the Protide type, whereby the active phosphorylated nucleotide is granted cell permeability and oral bioavailability. It is metabolized to the active antiviral agent GS-461203 (2-deoxy-2-α-fluoro-β-C-methyluridine-5-triphosphate). GS-461203 serves as a defective substrate for the NS5B protein, which is the viral RNA polymerase, thus acts as an inhibitor of viral RNA synthesis. Although sofosbuvir has a 3 hydroxyl group to act as a nucleophile for an incoming NTP, a similar nucleotide analogue, 2-deoxy-2-α-fluoro-β-C-methylcytidine, is proposed to act as a chain terminator because the 2 methyl group of the nucleotide analogue causes a steric clash with an incoming NTP. Sofosbuvir would act in a similar way. Pharmacokinetics Sofosbuvir is only administered orally. The peak concentration after oral administration is 0.5–2 hours post-dose, regardless of initial dose. Peak plasma concentration of the main circulating metabolite GS-331077 occurs 2–4 hours post-dose. GS-331077 is the pharmacologically inactive nucleoside.Plasma protein binding of sofosbuvir is 61–65%, while GS-331077 has minimal binding.Sofosbuvir is activated in the liver to the triphosphate GS-461203 by hydrolysis of the carboxylate ester by either of the enzymes cathepsin A or carboxylesterase 1, followed by cleaving of the phosphoramidate by the enzyme histidine triad nucleotide-binding protein 1 (HINT1), and subsequent repeated phosphorylation. Dephosphorylation creates the inactive metabolite GS-331077. The half life of sofosbuvir is 0.4 hours, and the half life of GS-331077 is 27 hours.Following a single 400 mg oral dose of sofosbuvir, 80% is excreted in urine, 14% in feces, and 2.5% in expired air recovery. However, of the urine recovery 78% was the metabolite (GS-331077) and 3.5% was sofosbuvir. Chemistry Prior to the discovery of sofosbuvir, a variety of nucleoside analogs had been examined as antihepatitis C treatments, but these exhibited relatively low potency. This low potency arose in part because the enzymatic addition of the first of the three phosphate groups of the triphosphate is slow. The design of sofosbuvir, based on the ProTide approach, avoids this slow step by building the first phosphate group into the structure of the drug during synthesis. Additional groups are attached to the phosphorus to temporarily mask the two negative charges of the phosphate group, thereby facilitating entry of the drug into the infected cell. The NS5B protein is a RNA-dependent RNA polymerase critical for the viral reproduction cycle. History Sofosbuvir was discovered in 2007 by Michael Sofia, a scientist at Pharmasset, and the drug was first tested in people in 2010. In 2011, Gilead Sciences bought Pharmasset for about $11 billion. Gilead submitted the New Drug Application for sofosbuvir in combination with ribavirin in April 2013, and in October 2013 it received the FDAs Breakthrough Therapy Designation. In December 2013, the FDA approved sofosbuvir in combination with ribavirin for oral dual therapy of HCV genotypes 2 and 3, and for triple therapy with injected pegylated interferon (pegIFN) and RBV for treatment-naive people with HCV genotypes 1 and 4. Two months before, the FDA had approved another drug, simeprevir, as a hepatitis C treatment.In 2014, the fixed dose combination drug sofosbuvir/ledipasvir, the latter a viral NS5A inhibitor, was approved; it had also been granted breakthrough status.Prior to the availability of sofosbuvir, hepatitis C treatments involved 6 to 12 months of treatment with an interferon-based regimen. This regimen provided cure rates of 70% or less and was associated with severe side effects, including anemia, depression, severe rash, nausea, diarrhea, and fatigue. As sofosbuvir clinical development progressed, physicians began to "warehouse" people in anticipation of its availability. Sofosbuvirs U.S. launch was the fastest of any new drug in history. Society and culture Sofosbuvir is on the World Health Organizations List of Essential Medicines. Economics Following its approval by the FDA in 2013, the price of sofosbuvir as quoted in various media sources in 2014 ranged from $84,000 to $168,000 depending on course of treatment in the U.S. and £35,000 in the United Kingdom for a 12-week regimine, causing considerable controversy. Sofosbuvir was more affordable in Japan and South Korea at approximately $300 and $5900 respectively for a 12-week treatment, with each government covering 99% and 70% of the cost respectively. In 2014, Gilead announced it would work with generic manufacturers in 91 developing countries to produce and sell sofosbuvir, and that it would sell a name brand version of the product in India for approximately $300 per course of treatment; it had signed agreements with generic manufacturers by September 2015. United States Since its launch, the price of sofosbuvir declined as more competitors entered the direct-acting antiviral (DAA) market. In 2020, the price for a course of sofosbuvir was $64,693 in the United States. In 2014, the list price of a 12-week combination treatment with a sofosbuvir-based regimen ranged from US$84,000 to $94,000. In April 2014, U.S. House Democrats Henry Waxman, Frank Pallone Jr., and Diana DeGette wrote Gilead Sciences Inc. questioning the $84,000 price for sofosbuvir. They specifically asked Gilead CEO John Martin to "explain how the drug was priced, what discounts are being made available to low-income patients and government health programs, and the potential impact to public health by insurers blocking or delaying access to the medicine because of its cost." Sofosbuvir is cited as an example of how specialty drugs present both benefits and challenges. Sofosbuvir also is an excellent example of both the benefit and the challenge of specialty medications. On one hand, this agent offers up to a 95% response rate as part of an interferon-free treatment regimen for hepatitis C. Generally speaking, it is more effective and better tolerated than alternative treatments. Unfortunately, the current per pill cost—$1,000—results in an $84,000 treatment course, creating barriers to therapy for many. Patients, providers, and payors alike have expressed outrage, and the debate has even drawn the attention of the US Congress. Despite these concerns, sofosbuvir rapidly has become a top seller in the United States... In February 2015, Gilead announced that due in part to negotiated discounts with pharmacy benefit managers and legally mandated discounts to government payers, the average discount-to-list price in 2014 was 22%. The company estimated that the average discount in 2015 would be 46%. According to the California Technology Assessment Forum, a panel of academic pharmacoeconomic experts, representatives of managed care organizations, and advocates for people with hepatitis, a 46% discount would bring the average price of treatment to about $40,000, at which price sofosbuvir-based treatment regimens represent a "high value" for people and healthcare systems.Because of sofosbuvirs high price in the United States, by 2017, some states—such as Louisiana—were withholding the medicine from Medicaid patients with hepatitis until their livers were severely damaged. This puts "patients at increased risk of medical complications" and contributes to the "transmission of the hepatitis C virus". In an article published in May 2016 in Health Affairs, the authors proposed the invocation of the federal "government patent use" law which would enable the government to procure "important patent-protected" drugs at lower prices while compensating "the patent-holding companies reasonable royalties ... for research and development." By July 2017, Louisianas health secretary Rebekah Gee, who described Louisiana as Americas "public-health-crisis cradle", was investigating the use of the "government patent use" as a strategy. Japan and South Korea Unlike other comparable Western developed countries, sofosbuvir is far more affordable in Japan and South Korea at approximately $300 and $2165 cost to patients respectively for a 12-week treatment, as each government covers 99% and 70% of the original cost respectively. Germany In Germany, negotiations between Gilead and health insurers led to a price of €41,000 for 12 weeks of treatment. This is the same price previously negotiated with the national healthcare system in France, except that additional discounts and rebates apply in France depending on the volume of sales and the number of treatment failures. Switzerland In Switzerland, the price is fixed by the government every three years. The price in 2016 was CHF 16,102.50 for 24 pills of 400 mg. United Kingdom In 2020, the originator price per course of sofosbuvir was £35,443. In 2013, the price in the United Kingdom was expected to be £35,000 for a 12-weeks course. NHS England established 22 Operational Delivery Networks to roll out delivery, which was approved by the National Institute for Health and Care Excellence in 2015, and proposes to fund 10,000 courses of treatment in 2016–17. Each was given a "run rate" of how many people they were allowed to treat, and this was the NHSs single biggest new treatment investment in 2016. Croatia As of 2015, sofosbuvir is included on the list of essential medications in Croatia and its cost is fully covered by the Croatian Health Insurance Fund. As a result of negotiations with the manufacturer, only therapies with successful outcome would be paid by the Fund with the rest being covered by the manufacturer. India In July 2014, Gilead Sciences filed a patent for sofosbuvir in India. If the office of the controller general of patents had granted it, Gilead would have obtained exclusive rights to produce and sell sofosbuvir in the country. However, in January 2015, the Indian Patent Office rejected Gileads application. Gileads lawyers moved the Delhi High Court against this decision. That decision was overturned on appeal in February 2015. In the meantime, it granted Indian companies voluntary licenses (VLs), which allowed them to make and sell in a selected few countries at a discounted price. This agreement also granted 7% of the royalties to Gilead. However, the list of countries open to Indian firms under this agreement excluded 73 million people with hepatitis C. Developing world In 2014, Gilead announced it would seek generic licensing agreements with manufacturers to produce sofosbuvir in 91 developing countries, which contained 54% of the worlds HCV-infected population. Gilead also said it would sell a name brand version of the product in India for $300 per course of treatment, approximately double a third party estimate of the minimum achievable cost of manufacture. It had signed licenses with generic manufacturers by September 2015. The leader of one Indian activist group called this move inadequate, but nine companies launched products, which "unleashed a fierce marketing war", according to Indias The Economic Times.In Egypt, which had the worlds highest incidence of hepatitis C, Gilead offered sofosbuvir at the discounted price of $900 to the Egyptian government. The government in turn made it free to patients. Later, Gilead licensed a generic version to be available in Egypt.The Access to Medicine Index ranked Gilead first among the worlds 20 largest pharmaceutical countries in the Pricing, Manufacturing and Distribution category in both 2013 and 2014, citing Gileads "leading performance in equitable pricing." In contrast, Jennifer Cohn of Doctors Without Borders and the organization Doctors of the World criticized the price of sofosbuvir as reflecting "corporate greed" and ignoring the needs of people in developing countries.In Algeria, as of 2011 about 70,000 people were infected with hepatitis C. As of August 2015, Gilead had licensed its partners in India to sell sofosbuvir in Algeria. It had been criticized for not making the drug available in middle-income countries including Algeria prior to that. Controversies The price has generated considerable controversy. In 2017, the range of costs per treatment varied from about $84,000 to about $50. Patent challenges In February 2015, it was reported that Doctors of the World had submitted an objection to Gileads patent at the European Patent Office, claiming that the structure of sofosbuvir is based on already known molecules. In particular, Doctors of the World argued that the Protide technology powering sofosbuvir was previously invented by the Chris McGuigan team at Cardiff University in the UK, and that the Gilead drug is not therefore inventive. The group filed challenges in other developing countries as well. These challenges were unsuccessful and the court recognized the innovative step in pro-drug design and application to the specific example of sofosbuvir. Medical tourism Due to the high cost of sofosbuvir in the U.S., as of 2016 increasing numbers of Americans with hepatitis C were traveling to India to purchase the drug. Similarly, increasing numbers of Chinese were also traveling to India to purchase sofosbuvir, which had not yet been approved for sale in China by the countrys State Food and Drug Administration (SFDA). Research Combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir, ledipasvir or velpatasvir, have shown sustained virological response rates of up to 100% in people infected with HCV. Most studies indicate that the efficacy rate is between 94% and 97%; much higher than previous treatment options. That treatments could be conducted at very low costs was demonstrated by Hill and coworkers who presented data on 1,160 patients who used generic versions of solfosbuvir, ledipasvir, plus daclatasvir from suppliers in India, Egypt, China and other countries and reported over 90% success at costs of about $50 per therapy.Sofosbuvir has also been tested against other viruses such as the Zika virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). See also AT-527—a similar drug developed for the treatment of SARS-CoV-2 Tenofovir alafenamide—a nucleotide reverse-transcriptase inhibitor that uses similar phosphoramidate prodrug technology Remdesivir—a nucleotide analogue RNA polymerase inhibitor originally intended to treat hepatitis C that uses similar phosphoramidate prodrug technology and displays very similar PK. References Further reading Dean L (2017). "Sofosbuvir Therapy and IFNL4 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520377. Bookshelf ID: NBK409960. External links "Sofosbuvir". Drug Information Portal. U.S. National Library of Medicine.
Capreomycin	Capreomycin is an antibiotic which is given in combination with other antibiotics for the treatment of tuberculosis. Specifically it is a second line treatment used for active drug resistant tuberculosis. It is given by injection into a vein or muscle.Common side effects include kidney problems, hearing problems, poor balance, and pain at the site of injection. Other side effects include paralysis resulting in the inability to breathe. It is not recommended with streptomycin or other medications that may damage the auditory vestibular nerve. It is not recommended during pregnancy as it may cause kidney or hearing problems in the baby. Capreomycin is commonly grouped with the aminoglycoside family of medications. How it works is unclear.Capreomycin was discovered from Streptomyces capreolus in 1960. It was removed from the World Health Organizations List of Essential Medicines in 2019. Spectrum of susceptibility Capreomycin is most commonly used to treat Mycobacterium tuberculosis infections. Mycobacterium tuberculosis growth has been found to be inhibited at a concentration of 2.5 μg/mL. Side effects High incidence: hematuria, urine output or urinary frequency significantly increased or decreased, loss of appetite or extreme thirst (hypokalemia, renal toxicity). Less incidence: hearing loss, tinnitus, gait instability, dizziness, dyspnea, lethargy, extreme weakness (neuromuscular blockade, renal toxicity, hypokalemia), nausea or vomiting. Significant renal toxicity: blood creatinine increase, blood urea nitrogen increase, poor creatinine clearance, proteinuria (need routine blood monitoring of renal functions and urine analysis) during usage of this medication. Damaging to the 8th cranial nerve . There can be vestibular dysfunction, such as some minor hearing loss after using the medication for 2 to 4 months. A certain block effect of neuromuscular. Can cause allergic reactions: rash, drug fever, facial flushing or pale, asthma, palpitations, sense of suppression in the chest, abdominal pain, anaphylactic shock. Interactions Combined with an aminoglycoside, it can increase the possibility of ototoxicity, nephrotoxicity and neuromuscular blockage, result in some hearing loss or can continue to deafness. It could be a temporary symptom, but often be permanent. Neuromuscular blockade can lead to skeletal muscle weakness and respiratory depression or paralysis (apnea). Using anti-cholinesterase or calcium salts may release this block. Combined with amphotericin B, vancomycin, bacitracin, paromomycin, cyclosporine, kanamycin, cisplatin, bumetanide, etoric acid, furosemide: Would Increase the possibility of ototoxicity and nephrotoxicity. Combined with antihistamines, buclizine, cyclizine, meclizine, phenothiazines, thioketones, trimethamine, and capreomycin: can ameliorate the symptoms of tinnitus, dizziness or vertigo and other ototoxic symptoms. Combined with anti-neuromuscular block drugs: can antagonize the effect of the anti-neuromuscular block drugs on the skeletal muscle (so need to adjust the dose of the drugs for anti-muscle weakness. Combined with ethyl sulfide isoniazid: may increase the side effects. Combined with methoxyflurane or polymyxin injection: may increase renal toxicity or neuromuscular blockade effect. Combined with opioid: The effect of central respiratory inhibition may increase, lead to prolonged respiratory inhibition or respiratory paralysis (apnea). History Capreomycin, an antiphlogistic antibiotic which was produced in the United States in 1960, and be applied in clinic in 1968. In 1979, capreomycin was used in the area of antituberculosis by inhibiting the growth of mycobacterium tuberculosis. References External links "Capreomycin". Drug Information Portal. U.S. National Library of Medicine.
Nirmatrelvir/ritonavir	Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged oral medication used as a treatment for COVID-19. It contains the antiviral medications nirmatrelvir and ritonavir.In December 2021, nirmatrelvir/ritonavir was granted emergency use authorization by the United States Food and Drug Administration (FDA) for the treatment of COVID-19. It is not authorized for the pre-exposure or post-exposure prevention of COVID-19 or for initiation of treatment in those requiring hospitalization due to severe or critical COVID-19. It was approved in the United Kingdom later that month, and in the European Union and Canada in January 2022. Medical uses The co-packaged medication is indicated for the treatment of mild to moderate COVID-19 in people aged twelve years of age and older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. If administered within five days of symptom onset, the efficacy of the co-packaged medication against hospitalization or death in unvaccinated adults is about 88% (95% CI, 75–94%).As of May 2022, the effectiveness among vaccinated people and the effectiveness against long COVID were unknown. The drug does not prevent infection in people who live with an infected person.In the European Union, the co-packaged medication is indicated for the treatment of COVID-19 in adults who do not require supplemental oxygen and who are at increased risk for progressing to severe COVID-19. Contraindications The co-packaged medication is not authorized for the pre-exposure prophylaxis or post-exposure prophylaxis of COVID-19 nor for treatment in those requiring hospitalization due to severe or critical COVID-19, nor for use for longer than 5 consecutive days. The drug is contraindicated in those with hypersensitivity to the two main components, and in those with severely reduced kidney or liver function. During pregnancy The co-packaged medication is not recommended during pregnancy and in women who can become pregnant and who are not using contraception. Breastfeeding should be interrupted during treatment. These recommendations are because laboratory studies in animals suggest that high doses of the co-packaged medication may affect the growth of the fetus.There are no human data on the use of nirmatrelvir during pregnancy related to the risk of birth defects, spontaneous abortions (miscarriage), or adverse outcomes. There are also no human data on the presence of nirmatrelvir in human milk, its effects on milk production or the infant. In pregnant rabbits, a reduction in fetal body weight was observed with systemic exposure ten times higher than the authorized human dose of the co-packaged medication. A temporary reduction in body weight was observed in the offspring of nursing rats. Interactions and side effects Co-administration with certain drugs may have serious effects and may sometimes be fatal. The drug is contraindicated when co-administered with certain drugs, such as drugs dependent on CYP3A for removal, for which a raised concentration results in serious reactions, or those with potent CYP3A inducers, for which reduced blood concentration of the two main components may result in loss of effect against the virus and possible resistance, among others. Co-administration also affects the concentration of several drugs, sometimes requiring changing the dose or careful monitoring. Many of these drugs are widely prescribed to people at high risk from COVID-19. With the extension of the emergency authorization in August 2022, the FDA updated a checklist to help evaluate potential drug interactions and other patient factors before prescribing Paxlovid, including more than 120 drugs which are either contraindicated, should be avoided or held from use, or require dose adjustments or special monitoring.Adverse events of the co-packaged medication, regardless of causality, observed in the phase II-III EPIC-HR study included: dysgeusia (4.8–6%), diarrhea (3–3.9%), vomiting (1.3%), hypertension (1%), and myalgia (1%).There is no specific antidote for overdose with the co-packaged medication. Treatment consists of supportive measures such as monitoring of vital signs and observation of clinical status. Rebound An additional analysis of the original EPIC-HR clinical trial data (Delta variant) showed that about 2% of both the treatment and placebo groups experienced a symptomatic rebound after the 5 day treatment, meaning they felt ill again and tested positive again (antigen test and PCR test) after testing negative. This is important, because people with rebound cannot go back to work or school. The exact cause is unknown. It may be due to virus reservoirs in tissues that are not reached by the medication, or reinfection. In May 2022, Pfizer suggested repeating the treatment, but the FDA said there has been no evidence of benefit.In a 2022 US case report of 10 people with rebound while the Omicron variant has been circulating, viral load during relapse was comparable to levels during initial infection and high enough to cause secondary transmission. Also, sequencing of SARS CoV2 in three patients showed that rebound was a relapse with the same strain as it was not due to a mutation during treatment nor an infection with a different viral strain. As of September 2022, it is unknown how common rebound is among people after Paxlovid treatment, but study author David Ho thinks it is not uncommon. Besides him, President Joe Biden, First Lady Jill Biden, Anthony Fauci and Peter Hotez are known to have experienced rebound. As of September 2022, Pfizer is studying the phenomenon in a new trial it calls EPIC-SR (standard risk) while the omicron variant is circulating.As of July 2022, no Paxlovid drug resistant SARS CoV2 has been observed in clinical context. The engineering of a nirmaltrevir-resistant chimera of Vesicular Stomatitis Virus under laboratory conditions was published without formal peer review in July 2022. Manufacturing Pfizer selected its largest oral tablet factory in Freiburg as the launch facility for the manufacturing of the co-packaged medication. Nirmatrelvir, the novel portion of the co-packaged medication, was first developed in the United States and was initially manufactured in small amounts in Groton, Connecticut, to support clinical trials, but the Freiburg facility in Germany was responsible for figuring out how to mass-produce the co-packaged medication on an industrial scale. Pfizer selected another factory in Ascoli Piceno, Italy, to assist the Freiburg factory with packaging tablets into blister packs. History The primary data supporting the US Food and Drug Administration (FDA) emergency use authorization for nirmatrelvir/ritonavir are from EPIC-HR, a randomized, double-blind, placebo-controlled clinical trial studying nirmatrelvir/ritonavir for the treatment of non-hospitalized symptomatic adults with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Participants were adults 18 years of age and older with a prespecified risk factor for progression to severe disease or were 60 years and older regardless of prespecified chronic medical conditions. All participants had not received a COVID-19 vaccine and had not been previously infected with COVID-19. The main outcome measured in the trial was the proportion of people who were hospitalized due to COVID-19 or died due to any cause during 28 days of follow-up. Nirmatrelvir/ritonavir significantly reduced the proportion of people with COVID-19 related hospitalization or death from any cause by 88% compared to placebo among participants treated within five days of symptom onset and who did not receive COVID-19 therapeutic monoclonal antibody treatment. In this analysis, 1,039 participants had received nirmatrelvir/ritonavir, and 1,046 participants had received placebo and among these participants, 0.8% who received nirmatrelvir/ritonavir were hospitalized or died during 28 days of follow-up compared to 6% of the participants who received placebo.In September 2021, Pfizer began a phase II/III trial of nirmatrelvir combined with ritonavir.In December 2021, Pfizer completed a Phase III study of nirmatrelvir combined with ritonavir, and on 14 December, Pfizer announced that the Phase II/III study of nirmatrelvir combined with ritonavir showed a reduced risk of hospitalization or death. In December 2021, nirmatrelvir/ritonavir was granted emergency use authorization by the United States Food and Drug Administration (FDA) for the treatment of COVID-19. On 31 December, the United Kingdoms Medicines and Healthcare products Regulatory Agency (MHRA) approved the use of nirmatrelvir combined with ritonavir for adults with mild to moderate infection and at high risk of their illness worsening.The efficacy of the co-packaged medication against hospitalization or death in high-risk adults when administered within five days of symptom onset is about 88% (95% CI, 75–94%).In 2022, the PANORAMIC trial started testing the effectiveness of nirmatrelvir/ritonavir for treating COVID-19 infections.Pfizer also conducted a Phase II/III study in standard-risk patients called EPIC-SR, which began in December 2021. This study did not find a statistically significant reduction in the risk of hospitalization or death (treatment: 5/576; placebo: 10/569), nor did it achieve its primary goal of sustained alleviation of symptoms. However, it did find a 62% decrease in COVID-19–related medical visits (p=0.023), which was consistent with the 67% reduction from the EPIC-HR (high-risk patients) study. Pfizer discontinued enrollment in the study because of the low rate of hospitalization and death in this population. Society and culture Legal status On 16 November 2021, Pfizer submitted an application to the US Food and Drug Administration (FDA) for emergency use authorization for the co-packaged medication. The authorization was granted on 22 December 2021, for adults and children ages 12 and older who are infected with Covid and at risk. The European Medicines Agency (EMA) issued guidance about the use of the co-packaged medication for the treatment of COVID-19 in the EU on 16 December 2021. The Israeli Ministry of Health approved the use of the co-packaged medication on 26 December 2021. South Korea approved the use of the co-packaged medication on 27 December 2021.The UK Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional approval of the co-packaged medication in December 2021. Health Canada approved the use of the co-packaged medication in January 2022. The Singapore Health Sciences Authority approved the use of the co-packaged medication for treating adults in February 2022. In February 2022, China approved the medication for the treatment of adults who have mild to moderate COVID-19 and are at a high risk of progressing to a severe condition. Economics In December 2021, the German government ordered 1 million doses of, but by August 2022, only around 43,000 had been delivered by wholesalers to pharmacies. In Germany, paxlovid is by prescription through physicians only and German physicians have been reluctant to prescribe it. Hence health minister Karl Lauterbach decided that general practitioners can stock 5 Paxlovid courses in their practice and dispense it directly to patients, that a prescription would be remunerated with 15 euros and that every nursing home should appoint a vaccination officer as well as a Paxlovid officer. As of August 2022 the treatment guidelines, which German family doctors follow, have not been updated since February 2022 and recommend Paxlovid only in unvaccinated risk patients, i.e. in only a few people.As of April 2022, the United States ordered a total of 20 million Paxlovid courses. As of July 2022, the United States Department of Health and Human Services set up at least 2,200 sites where people could receive Paxlovid as soon as they test positive for the virus, including pharmacies, community health centers and long-term care facilities. In July 2022, the US FDA allowed state-licensed pharmacists to prescribe it to people with COVID-19 at high risk of progressing to severe disease. Comparison to ivermectin The co-packaged medication is sometimes falsely claimed to be a repackaged version of the antiparasitic drug ivermectin, which has been promoted as a COVID-19 therapeutic. Such claims, sometimes using the nickname "Pfizermectin", rely on superficial similarities between the mechanism of action of both drugs and the claim that Pfizer is suppressing the benefits of ivermectin. References External links Halford B (January 2022). "How Pfizer scientists transformed an old drug lead into a COVID-19 antiviral". Chemical & Engineering News. Vol. 100, no. 3. Regalado A (February 2022). "How Pfizer made an effective anti-covid pill". MIT Technology Review. COVID 19 Drug interaction check tool University of Liverpool
Lanreotide	Lanreotide, sold under the brand name Somatuline among others, is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. It is a long-acting analogue of somatostatin, like octreotide. Lanreotide (as lanreotide acetate) is manufactured by Ipsen. It is available in several countries, including the United Kingdom, Australia and Canada, and was approved for sale in the United States by the Food and Drug Administration (FDA) on August 30, 2007. Medical uses Lanreotide is used in the treatment of acromegaly, due to both pituitary and non-pituitary growth hormone-secreting tumors, and the management of symptoms caused by neuroendocrine tumors, particularly carcinoid tumors and VIPomas. In the United States and Canada, lanreotide is only indicated for the treatment of acromegaly. In the United Kingdom, it is also indicated in the treatment of thyrotrophic adenoma, a rare tumor of the pituitary gland which secretes TSH. Lanreotide also shows activity against non-endocrine tumors, and, along with other somatostatin analogues, is being studied as a possible general antitumor agent.In December 2014, the US FDA approved lanreotide for the treatment of people with unresectable, well or moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs).It is used for polycystic liver disease. It has also been shown that it reduces the volume by 264mls on average. Side effects The main side effects of lanreotide treatment are mild to moderate pain at the injection site and gastrointestinal disturbances, such as diarrhea, nausea and vomiting. Isolated cases of gallstone formation have been associated with use of lanreotide, particularly over long periods of time. Pharmacology Lanreotide is a synthetic analogue of somatostatin, a naturally occurring inhibitory hormone which blocks the release of several other hormones, including growth hormone, thyroid-stimulating hormone (TSH), insulin and glucagon. Lanreotide binds to the same receptors as somatostatin, although with higher affinity to peripheral receptors, and has similar activity. However, while somatostatin is quickly broken down in the body (within minutes), lanreotide has a much longer half-life, and produces far more prolonged effects. Formulations Lanreotide is available in two formulations: a sustained release formulation (sold under the trade name Somatuline LA), which is injected intramuscularly every ten or fourteen days, and an extended release formulation (UK trade name Somatuline Autogel, or Somatuline Depot in the US), which is administered subcutaneously once a month. Self-assembling properties Lanreotide has been shown to spontaneously self-assemble into monodisperse nanotubes of 24.4 nm diameter and has been thereafter used as a fruitful and versatile model system in several biophysical studies. References External links "Lanreotide". Drug Information Portal. U.S. National Library of Medicine.
Theophylline	Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the xanthine family, it bears structural and pharmacological similarity to theobromine and caffeine, and is readily found in nature, being present in tea (Camellia sinensis) and cocoa (Theobroma cacao). A small amount of theophylline is one of the products of caffeine metabolic processing in the liver.Acebrophylline, an airway mucoregulator and anti-inflammatory agent is a combination product of ambroxol and theophylline 7 acetic acid. Medical uses The main actions of theophylline involve: relaxing bronchial smooth muscle increasing heart muscle contractility and efficiency (positive inotrope) increasing heart rate (positive chronotropic) increasing blood pressure increasing renal blood flow anti-inflammatory effects central nervous system stimulatory effect mainly on the medullary respiratory center.The main therapeutic uses of theophylline are aimed at: chronic obstructive pulmonary disease (COPD) asthma infant apnea Blocks the action of adenosine; an inhibitory neurotransmitter that induces sleep, contracts the smooth muscles and relaxes the cardiac muscle. Treatment of post-dural puncture headache. Uses under investigation A clinical study reported in 2008 that theophylline was helpful in improving the sense of smell in study subjects with anosmia.In 2004, a small clinical study compared theophylline to methylphenidate for the treatment of attention-deficit hyperactivity disorder in children and adolescents. Adverse effects The use of theophylline is complicated by its interaction with various drugs and by the fact that it has a narrow therapeutic window (<20 mcg/mL). Its use must be monitored by direct measurement of serum theophylline levels to avoid toxicity. It can also cause nausea, diarrhea, increase in heart rate, abnormal heart rhythms, and CNS excitation (headaches, insomnia, irritability, dizziness and lightheadedness). Seizures can also occur in severe cases of toxicity, and are considered to be a neurological emergency. Its toxicity is increased by erythromycin, cimetidine, and fluoroquinolones, such as ciprofloxacin. Some lipid-based formulations of theophylline can result in toxic theophylline levels when taken with fatty meals, an effect called dose dumping, but this does not occur with most formulations of theophylline. Theophylline toxicity can be treated with beta blockers. In addition to seizures, tachyarrhythmias are a major concern. Theophylline should not be used in combination with the SSRI fluvoxamine. Spectroscopy UV-visible spectroscopy Theophylline is soluble in 0.1N NaOH and absorbs maximally at 277 nm with an extinction coefficient of 10,200 (cm−1 M−1). Proton nuclear magnetic resonance spectroscopy (1H-NMR) The characteristic signals, distinguishing theophylline from related methylxanthines, are approximately 3.23δ and 3.41δ, corresponding to the unique methylation possessed by theophylline. The remaining proton signal, at 8.01δ, corresponds to the proton on the imidazole ring, not transferred between the nitrogen. The transferred proton between the nitrogen is a variable proton and only exhibits a signal under certain conditions. Carbon nuclear magnetic resonance spectroscopy (13C-NMR) The unique methylation of theophylline corresponds to the following signals: 27.7δ and 29.9δ. The remaining signals correspond to carbons characteristic of the xanthine backbone. Natural occurrences Theophylline is naturally found in cocoa beans. Amounts as high as 3.7 mg/g have been reported in Criollo cocoa beans.Trace amounts of theophylline are also found in brewed tea, although brewed tea provides only about 1 mg/L, which is significantly less than a therapeutic dose. Trace amounts of theophylline are also found in guarana (Paullinia cupana) and in kola nuts cola (plant). Pharmacology Pharmacodynamics Like other methylated xanthine derivatives, theophylline is both a competitive nonselective phosphodiesterase inhibitor, which raises intracellular cAMP, activates PKA, inhibits TNF-alpha and inhibits leukotriene synthesis, and reduces inflammation and innate immunity nonselective adenosine receptor antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effectsTheophylline has been shown to inhibit TGF-beta-mediated conversion of pulmonary fibroblasts into myofibroblasts in COPD and asthma via cAMP-PKA pathway and suppresses COL1 mRNA, which codes for the protein collagen.It has been shown that theophylline may reverse the clinical observations of steroid insensitivity in patients with COPD and asthmatics who are active smokers (a condition resulting in oxidative stress) via a distinctly separate mechanism. Theophylline in vitro can restore the reduced HDAC (histone deacetylase) activity that is induced by oxidative stress (i.e., in smokers), returning steroid responsiveness toward normal. Furthermore, theophylline has been shown to directly activate HDAC2. (Corticosteroids switch off the inflammatory response by blocking the expression of inflammatory mediators through deacetylation of histones, an effect mediated via histone deacetylase-2 (HDAC2). Once deacetylated, DNA is repackaged so that the promoter regions of inflammatory genes are unavailable for binding of transcription factors such as NF-κB that act to turn on inflammatory activity. It has recently been shown that the oxidative stress associated with cigarette smoke can inhibit the activity of HDAC2, thereby blocking the anti-inflammatory effects of corticosteroids.) Pharmacokinetics Absorption When theophylline is administered intravenously, bioavailability is 100%. Distribution Theophylline is distributed in the extracellular fluid, in the placenta, in the mothers milk and in the central nervous system. The volume of distribution is 0.5 L/kg. The protein binding is 40%. The volume of distribution may increase in neonates and those suffering from cirrhosis or malnutrition, whereas the volume of distribution may decrease in those who are obese. Metabolism Theophylline is metabolized extensively in the liver (up to 70%). It undergoes N-demethylation via cytochrome P450 1A2. It is metabolized by parallel first order and Michaelis-Menten pathways. Metabolism may become saturated (non-linear), even within the therapeutic range. Small dose increases may result in disproportionately large increases in serum concentration. Methylation to caffeine is also important in the infant population. Smokers and people with hepatic (liver) impairment metabolize it differently. Both THC and nicotine have been shown to increase the rate of theophylline metabolism. Excretion Theophylline is excreted unchanged in the urine (up to 10%). Clearance of the drug is increased in children (age 1 to 12), teenagers (12 to 16), adult smokers, elderly smokers, as well as in cystic fibrosis, and hyperthyroidism. Clearance of the drug is decreased in these conditions: elderly, acute congestive heart failure, cirrhosis, hypothyroidism and febrile viral illnesses.The elimination half-life varies: 30 hours for premature neonates, 24 hours for neonates, 3.5 hours for children ages 1 to 9, 8 hours for adult non-smokers, 5 hours for adult smokers, 24 hours for those with hepatic impairment, 12 hours for those with congestive heart failure NYHA class I-II, 24 hours for those with congestive heart failure NYHA class III-IV, 12 hours for the elderly. History Theophylline was first extracted from tea leaves and chemically identified around 1888 by the German biologist Albrecht Kossel. Seven years later, a chemical synthesis starting with 1,3-dimethyluric acid was described by Emil Fischer and Lorenz Ach. The Traube purine synthesis, an alternative method to synthesize theophylline, was introduced in 1900 by another German scientist, Wilhelm Traube. Theophyllines first clinical use came in 1902 as a diuretic. It took an additional 20 years until it was first reported as an asthma treatment. The drug was prescribed in a syrup up to the 1970s as Theostat 20 and Theostat 80, and by the early 1980s in a tablet form called Quibron. References == External links ==
Pseudoephedrine	Pseudoephedrine (PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent in higher doses.It was first characterized in 1889, by the German chemists Ladenburg and Oelschlägel, who used a sample that had been isolated from Ephedra vulgaris by the Merck pharmaceutical corporation of Darmstadt, Germany. The salts pseudoephedrine hydrochloride and pseudoephedrine sulfate are found in many over-the-counter preparations, either as a single ingredient or (more commonly) in a fixed-dose combination with one or more additional active ingredients such as antihistamines, guaifenesin, dextromethorphan, paracetamol (acetaminophen) or an NSAID (such as aspirin or ibuprofen). Medical uses Pseudoephedrine is a stimulant, but it is well known for shrinking swollen nasal mucous membranes, so it is often used as a decongestant. It reduces tissue hyperemia, edema, and nasal congestion commonly associated with colds or allergies. Other beneficial effects may include increasing the drainage of sinus secretions, and opening of obstructed Eustachian tubes. The same vasoconstriction action can also result in hypertension, which is a noted side effect of pseudoephedrine. Pseudoephedrine can be used either as oral or as topical decongestant. Due to its stimulating qualities, however, the oral preparation is more likely to cause adverse effects, including urinary retention. According to one study, pseudoephedrine may show effectiveness as an antitussive drug (suppression of cough).Pseudoephedrine is indicated for the treatment of nasal congestion, sinus congestion and Eustachian tube congestion. Pseudoephedrine is also indicated for vasomotor rhinitis, and as an adjunct to other agents in the optimum treatment of allergic rhinitis, croup, sinusitis, otitis media, and tracheobronchitis.Pseudoephedrine is also used as a first-line prophylactic for recurrent priapism. Erection is largely a parasympathetic response, so the sympathetic action of pseudoephedrine may serve to relieve this condition. Treatment for urinary incontinence is an off-label use ("unlabeled use") for these medications. Adverse effects Common adverse drug reactions (ADRs) associated with pseudoephedrine therapy include central nervous system stimulation, insomnia, nervousness, excitability, dizziness and anxiety. Infrequent ADRs include tachycardia or palpitations. Rarely, pseudoephedrine therapy may be associated with mydriasis (dilated pupils), hallucinations, arrhythmias, hypertension, seizures and ischemic colitis; as well as severe skin reactions known as recurrent pseudo-scarlatina, systemic contact dermatitis, and nonpigmenting fixed drug eruption. Pseudoephedrine, particularly when combined with other drugs including narcotics, may also play a role in the precipitation of episodes of paranoid psychosis. It has also been reported that pseudoephedrine, among other sympathomimetic agents, may be associated with the occurrence of stroke. Precautions and contraindications Pseudoephedrine is contraindicated in patients with diabetes mellitus, cardiovascular disease, severe or uncontrolled hypertension, severe coronary artery disease, prostatic hypertrophy, hyperthyroidism, closed angle glaucoma, or by pregnant women. The safety and effectiveness of nasal decongestant use in children is unclear. Interactions Concomitant or recent (previous fourteen days) monoamine oxidase inhibitor use can lead to hypertensive reactions, including hypertensive crises.The antihypertensive effects of methyldopa, mecamylamine, reserpine and veratrum alkaloids may be reduced by sympathomimetics. Beta-adrenergic antagonists may also interact with sympathomimetics. Increase of ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis. Antacids increase the rate of pseudoephedrine absorption, while kaolin decreases it. Mechanism of action Pseudoephedrine is a sympathomimetic amine. Its principal mechanism of action relies on its direct action on the adrenergic receptor system. The vasoconstriction that pseudoephedrine produces is believed to be principally an α-adrenergic receptor response.Pseudoephedrine acts on α- and β2-adrenergic receptors, to cause vasoconstriction and relaxation of smooth muscle in the bronchi, respectively. α-Adrenergic receptors are located on the muscles lining the walls of blood vessels. When these receptors are activated, the muscles contract, causing the blood vessels to constrict (vasoconstriction). The constricted blood vessels now allow less fluid to leave the blood vessels and enter the nose, throat and sinus linings, which results in decreased inflammation of nasal membranes, as well as decreased mucus production. Thus, by constriction of blood vessels, mainly those located in the nasal passages, pseudoephedrine causes a decrease in the symptoms of nasal congestion. Activation of β2-adrenergic receptors produces relaxation of smooth muscle of the bronchi, causing bronchial dilation and in turn decreasing congestion (although not fluid) and difficulty breathing. Other uses There have been reports of off-label uses of pseudoephedrine for its stimulant properties. Long-distance truck drivers and athletes, for example, have reportedly used pseudoephedrine as a stimulant to increase their state of alertness/awareness.A study has also found that pseudoephedrine can reduce milk production in breastfeeding women. Manufacture of amphetamines Its membership in the amphetamine class has made pseudoephedrine a sought-after chemical precursor in the illicit manufacture of methamphetamine and methcathinone. As a result of the increasing regulatory restrictions on the sale and distribution of pseudoephedrine, many pharmaceutical firms have reformulated, or are in the process of reformulating medications to use alternative, but less effective, decongestants, such as phenylephrine. In the United States, federal laws control the sale of pseudoephedrine-containing products. Many retailers in the US have created corporate policies restricting the sale of pseudoephedrine-containing products. Their policies restrict sales by limiting purchase quantities and requiring a minimum age and government issued photographic identification. These requirements are similar to and sometimes more stringent than existing law. Internationally, pseudoephedrine is listed as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances. Sports Pseudoephedrine was on the International Olympic Committees (IOC) banned substances list until 2004, when the World Anti-Doping Agency (WADA) list replaced the IOC list. Although WADA initially only monitored pseudoephedrine, it went back onto the "banned" list on January 1, 2010.Pseudoephedrine is excreted through urine, and concentration in urine of this drug shows a large inter-individual spread; that is, the same dose can give a vast difference in urine concentration for different individuals. Pseudoephedrine is approved to be taken up to 240 mg per day. In seven healthy male subjects this dose yielded a urine concentration range of 62.8 to 294.4 microgram per milliliter (µg/ml) with mean ± standard deviation 149 ± 72 µg/ml. Thus, normal dosage of 240 mg pseudoephedrine per day can result in urine concentration levels exceeding the limit of 150 µg/ml set by WADA for about half of all users. Furthermore, hydration status does not affect urinary concentration of pseudoephedrine.Canadian rower Silken Laumann was stripped of her 1995 Pan American Games team gold medal after testing positive for pseudoephedrine.In February 2000, Elena Berezhnaya and Anton Sikharulidze won gold at the 2000 European Figure Skating Championships but were stripped of their medals after Berezhnaya tested positive. This resulted in a three-month disqualification from the date of the test, and the medal being stripped. She stated that she had taken cold medication approved by a doctor but had failed to inform the ISU as required. The pair missed the World Championships that year as a result of the disqualification. Romanian gymnast Andreea Răducan was stripped of her gold medal at the 2000 Summer Olympic Games after testing positive. She took two pills given to her by the team coach for a cold. Although she was stripped of the overall gold medal, she kept her other medals, and, unlike in most other doping cases, was not banned from competing again; only the team doctor was banned for a number of years. Ion Ţiriac, the president of the Romanian Olympic Committee, resigned over the scandal.In the 2010 Winter Olympic Games, the IOC issued a reprimand against the Slovak ice hockey player Lubomir Visnovsky for usage of pseudoephedrine.In the 2014 Winter Olympic Games Team Sweden and Washington Capitals ice hockey player Nicklas Bäckström was prevented from playing in the final for usage of pseudoephedrine. Bäckström claimed he was using it as allergy medication. In March 2014, the IOC Disciplinary Commission decided that Bäckström would be awarded the silver medal. In January 2015 Bäckström, the IOC, WADA and the IIHF agreed to a settlement in which he accepted a reprimand but was cleared of attempting to enhance his performance. Detection of use Pseudoephedrine may be quantified in blood, plasma, or urine to monitor any possible performance-enhancing use by athletes, confirm a diagnosis of poisoning, or to assist in a medicolegal death investigation. Many commercial immunoassay screening tests directed at the amphetamines cross-react appreciably with pseudoephedrine, but chromatographic techniques can easily distinguish pseudoephedrine from other phenethylamine derivatives. Blood or plasma pseudoephedrine concentrations are typically in the 50–300 µg/l range in persons taking the drug therapeutically, 500–3000 µg/l in people with substance use disorder involving pseudoephedrine, or poisoned patients and 10–70 mg/l in cases of acute fatal overdose. Chemistry Pseudoephedrine is a diastereomer of ephedrine and is readily reduced into methamphetamine or oxidized into methcathinone. Nomenclatures The dextrorotary (+)- or d- enantiomer is (1S,2S)-pseudoephedrine, whereas the levorotating (−)- or l- form is (1R,2R)-pseudoephedrine. In the outdated D/L system (+)-pseudoephedrine is also referred to as L-pseudoephedrine and (−)-pseudoephedrine as D-pseudoephedrine (in the Fisher projection then the phenyl ring is drawn at bottom).Often the D/L system (with small caps) and the d/l system (with lower-case) are confused. The result is that the dextrorotary d-pseudoephedrine is wrongly named D-pseudoephedrine and the levorotary l-ephedrine (the diastereomer) wrongly L-ephedrine. The IUPAC names of the two enantiomers are (1S,2S)- respectively (1R,2R)-2-methylamino-1-phenylpropan-1-ol. Synonyms for both are psi-ephedrine and threo-ephedrine. Pseudoephedrine is the International Nonproprietary Name of the (+)-form, when used as pharmaceutical substance. Society and culture Brand names The following is a list of consumer medicines that either contain pseudoephedrine or have switched to a less-regulated alternative such as phenylephrine. Actifed (made by GlaxoSmithKline) — contains 60 mg pseudoephedrine and 2.5 mg triprolidine in certain countries. Advil Cold & Sinus (made by Pfizer Canada Inc.) — contains 30 mg pseudoephedrine hydrochloride and 200 mg Ibuprofen. Aleve-D Sinus & Cold (made by Bayer Healthcare) — contains 120 mg pseudoephedrine hydrochloride (also 220 mg naproxen). Allegra-D (made by Sanofi Aventis) — contains 120 mg of pseudoephedrine hydrochloride (also 60 mg of fexofenadine). Allerclear-D (made by Kirkland Signature) — contains 240 mg of pseudoephedrine sulfate (also 10 mg of loratadine). Benadryl Plus (made by McNeil Consumer Healthcare, a Johnson & Johnson company) — contains 60 mg pseudoephedrine hydrochloride (also 8 mg acrivastine) Cirrus (made by UCB) — contains 120 mg pseudoephedrine hydrochloride (also 5 mg cetirizine). Claritin-D (made by Bayer Healthcare) — contains 120 mg of pseudoephedrine sulfate (also 5 mg of loratadine). Claritin-D 24 Hour (made by Bayer Healthcare) — contains 240 mg of pseudoephedrine sulfate (also 10 mg of loratadine). Codral (made by Asia-Pacific subsidiary of Johnson & Johnson) — Codral Original contains pseudoephedrine, Codral New Formula substitutes phenylephrine for pseudoephedrine. Congestal (made by SIGMA Pharmaceutical Industries) — contains 60 mg pseudoephedrine hydrochloride (also 650 mg paracetamol and 4 mg chlorpheniramine). Contac (made by GlaxoSmithKline) — previously contained pseudoephedrine, now contains phenylephrine. As at Nov 2014 UK version still contains 30 mg pseudoephedrine hydrochloride per tablet. Demazin (made by Bayer Healthcare) — contains pseudoephedrine sulfate and chlorpheniramine maleate Eltor (made by Sanofi Aventis) — contains pseudoephedrine hydrochloride. Mucinex D (made by Reckitt Benckiser) — contains 60 mg pseudoephedrine hydrochloride (also 1200 mg guaifenesin). Nexafed (made by Acura Pharmaceuticals) — contains 30 mg pseudoephedrine per tablet, formulated with Impede Meth-Deterrent technology. Nurofen Cold & Flu (made by Reckitt Benckiser) — contains 30 mg pseudoephedrine hydrochloride (also 200 mg ibuprofen). Respidina – contains 120 mg of pseudoephedrine in the form of extended release tablets. Rhinex Flash (made by Pharma Product Manufacturing, Cambodia) — contains pseudoephedrine combined with paracetamol and triprolidine. Rhinos SR (made by Dexa Medica) — contains 120 mg of pseudoephedrine hydrochloride (also 5 mg loratadine). Rino-Ebastel (made by Almirall) – contains 120 mg of pseudoephedrine hydrochloride (also 10 mg ebastine). Sinufed (made by Trima) — contains 60 mg pseudoephedrine hydrochloride. Sinutab (made by McNeil Consumer Healthcare, a Johnson & Johnson company) — contains 500 mg paracetamol and 30 mg pseudoephedrine hydrochloride. Sudafed Decongestant (made by McNeil Consumer Healthcare, a Johnson & Johnson company) — contains 60 mg of pseudoephedrine hydrochloride. Theraflu (made by Novartis) — previously contained pseudoephedrine, now contains phenylephrine. Unifed (made by United Pharmaceutical Manufacturer, Jordan) — contains pseudoephedrine hydrochloride (also triprolidine and guaifenesin). Zyrtec-D 12 Hour (made by McNeil Consumer Healthcare, a Johnson & Johnson company) — contains 120 mg pseudoephedrine hydrochloride (also 5 mg of cetirizine). Zephrex-D (made by Westport Pharmaceuticals) – a special meth-resistant form of pseudoephedrine that becomes gooey when heated Legal status Australia Illicit diversion of pseudoephedrine in Australia has caused significant changes to the way the products are regulated. As of 2006, all products containing pseudoephedrine have been rescheduled as either "Pharmacist Only Medicines" (Schedule 3) or "Prescription Only Medicines" (Schedule 4), depending on the amount of pseudoephedrine in the product. A Pharmacist Only Medicine may only be sold to the public if a pharmacist is directly involved in the transaction. These medicines must be kept behind the counter, away from public access. Pharmacists are also encouraged (and in some states required) to log purchases with the online database Project STOP. This system aims to prevent individuals from purchasing small quantities of pseudoephedrine from many different pharmacies. As a result, many pharmacies no longer stock Sudafed, the common brand of pseudoephedrine cold/sinus tablets, opting instead to sell Sudafed PE, a phenylephrine product that has not been proven effective in clinical trials. Canada Health Canada has investigated the risks and benefits of pseudoephedrine and ephedrine/Ephedra. Near the end of the study, Health Canada issued a warning on their website stating that those who are under the age of 12, or who have heart disease and may have strokes, should avoid taking pseudoephedrine and ephedrine. Also, they warned that everyone should avoid taking ephedrine or pseudoephrine with other stimulants like caffeine. They also banned all products that contain both ephedrine (or pseudoephedrine) and caffeine.Products whose only medicinal ingredient is pseudoephedrine must be kept behind the pharmacy counter. Products containing pseudoephedrine along with other medicinal ingredients may be displayed on store shelves but may be sold only in a pharmacy when a pharmacist is present. Colombia The Colombian government prohibited the trade of pseudoephedrine in 2010. Japan Medications that contain more than 10% pseudoephedrine are prohibited under the Stimulants Control Law in Japan. Mexico On 23 November 2007, the use and trade of pseudoephedrine in Mexico was made illegal as it was argued that it was extremely popular as a precursor in the synthesis of methamphetamine. Netherlands Pseudoephedrine was withdrawn from sale in 1989 due to concerns about adverse cardiac side effects. New Zealand In New Zealand, pseudoephedrine is currently classified as a Class B Part II controlled drug in the Misuse of Drugs Act 1975, making it illegal to supply or possess except on prescription.Pseudoephedrine, ephedrine, and any product containing these substances, e.g. cold and flu medicines, were first classified in October 2004 as Class C Part III (partially exempted) controlled drugs, due to being the principal ingredient in methamphetamine. New Zealand Customs and police officers continued to make large interceptions of precursor substances believed to be destined for methamphetamine production. On 9 October 2009, Prime Minister John Key announced pseudoephedrine-based cold and flu tablets would become prescription-only drugs and reclassified as a class B2 drug. The law was amended by The Misuse of Drugs Amendment Bill 2010, which passed in August 2011. Turkey In Turkey, medications containing pseudoephedrine are available with prescription only. United Kingdom In the UK, pseudoephedrine is available over the counter under the supervision of a qualified pharmacist, or on prescription. In 2007, the MHRA reacted to concerns over diversion of ephedrine and pseudoephedrine for the illicit manufacture of methamphetamine by introducing voluntary restrictions limiting over the counter sales to one box containing no more than 720 mg of pseudoephedrine in total per transaction. These restrictions became law in April 2008. No form of ID is required. United States Federal The United States Congress has recognized that pseudoephedrine is used in the illegal manufacture of methamphetamine. In 2005, the Committee on Education and the Workforce heard testimony concerning education programs and state legislation designed to curb this illegal practice. Attempts to control the sale of the drug date back to 1986, when federal officials at the Drug Enforcement Administration (DEA) first drafted legislation, later proposed by Senator Bob Dole, that would have placed a number of chemicals used in the manufacture of illicit drugs under the Controlled Substances Act. The bill would have required each transaction involving pseudoephedrine to be reported to the government, and federal approval of all imports and exports. Fearing this would limit legitimate use of the drug, lobbyists from over the counter drug manufacturing associations sought to stop this legislation from moving forward, and were successful in exempting from the regulations all chemicals that had been turned into a legal final product, such as Sudafed.Prior to the passage of the Combat Methamphetamine Epidemic Act of 2005, sales of the drug became increasingly regulated, as DEA regulators and pharmaceutical companies continued to fight for their respective positions. The DEA continued to make greater progress in their attempts to control pseudoephedrine as methamphetamine production skyrocketed, becoming a serious problem in the western United States. When purity dropped, so did the number of people in rehab and people admitted to emergency rooms with methamphetamine in their systems. This reduction in purity was usually short lived, however, as methamphetamine producers eventually found a way around the new regulations.Congress passed the Combat Methamphetamine Epidemic Act of 2005 ("CMEA") as an amendment to the renewal of the USA Patriot Act. Signed into law by president George W. Bush on March 6, 2006, the act amended 21 U.S.C. § 830, concerning the sale of pseudoephedrine-containing products. The law mandated two phases, the first needing to be implemented by April 8, 2006, and the second to be completed by September 30, 2006. The first phase dealt primarily with implementing the new buying restrictions based on amount, while the second phase encompassed the requirements of storage, employee training, and record keeping. Though the law was mainly directed at pseudoephedrine products it also applies to all over-the-counter products containing ephedrine, pseudoephedrine, and phenylpropanolamine, their salts, optical isomers, and salts of optical isomers. Pseudoephedrine was defined as a "scheduled listed chemical product" under 21 U.S.C. § 802(45(A)). The act included the following requirements for merchants ("regulated sellers") who sell such products: Required a retrievable record of all purchases, identifying the name and address of each party, to be kept for two years Required verification of proof of identity of all purchasers Required protection and disclosure methods in the collection of personal information Required reports to the Attorney General of any suspicious payments or disappearances of the regulated products Required training of employees with regard to the requirements of the CMEA. Retailers must self-certify as to training and compliance. The non-liquid dose form of regulated products may only be sold in unit dose blister packs Regulated products must be stored behind the counter or in a locked cabinet in such a way as to restrict public access Sales limits (per customer): Daily sales limit—must not exceed 3.6 grams of pseudoephedrine base without regard to the number of transactions 30-day (not monthly) sales limit—must not exceed 7.5 grams of pseudoephedrine base if sold by mail order or "mobile retail vendor" 30-day purchase limit—must not exceed 9 grams of pseudoephedrine base. (A misdemeanor possession offense under 21 U.S.C. § 844a for the person who buys it.)In regards to the identification that may be used by an individual buying pseudoephedrine products the following constitute acceptable forms of identification: US passport Alien registration or permanent resident card Unexpired foreign passport with temporary I-551 stamp Unexpired Employment Authorization Document Drivers License or Government issued identification card (including Canadian drivers license) School ID with picture Voters Registration card US Military Card Native American tribal documentsThe requirements were revised in the Methamphetamine Production Prevention Act of 2008 to require that a regulated seller of scheduled listed chemical products may not sell such a product unless the purchaser: Presents a government issued photographic identification; and Signs the written logbook with their name, address, and time and date of the sale State Most states also have laws regulating pseudoephedrine.The states of Alabama, Arizona, Arkansas, California, Colorado, Delaware, Florida, Georgia, Hawaii (as of May 1, 2009) Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana (as of August 15, 2009), Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Montana, Nebraska, Nevada, New Jersey, North Carolina, Ohio, Oklahoma, Oregon, Pennsylvania, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia and Wisconsin have laws requiring pharmacies to sell pseudoephedrine "behind the counter". Though the drug can be purchased without a prescription, states can limit the number of units sold and can collect personal information from purchasers. The states of Oregon and Mississippi previously required a prescription for the purchase of products containing pseudoephedrine. However as of January 1, 2022 these restrictions have been repealed The state of Oregon reduced the number of methamphetamine lab seizures from 467 in 2004 (the final full year before implementation of the prescription only law) to a new low of 12 in 2009. The decrease in meth lab incidents in Oregon occurred largely before the prescription-only law took effect, according to a NAMSDL report titled Pseudoephedrine Prescription Laws in Oregon and Mississippi. The report posits that the decline in meth lab incidents in both states may be due to other factors: "Mexican traffickers may have contributed to the decline in meth labs in Mississippi and Oregon (and surrounding states) as they were able to provide ample supply of equal or greater quality meth at competitive prices". Additionally, similar decreases in meth lab incidents were seen in surrounding states, according to the report, and meth-related deaths in Oregon have dramatically risen since 2007. Some municipalities in Missouri have enacted similar ordinances, including Washington, Union, New Haven, Cape Girardeau and Ozark. Certain pharmacies in Terre Haute, Indiana do so as well.Another approach to controlling the drug on the state level mandated by some state governments to control the purchases of their citizens is the use of electronic tracking systems, which require the electronic submission of specified purchaser information by all retailers who sell pseudoephedrine. Thirty-two states now require the National Precursor Log Exchange (NPLEx) to be used for every pseudoephedrine and ephedrine OTC purchase, and ten of the eleven largest pharmacy chains in the US voluntarily contribute all of their similar transactions to NPLEx. These states have seen dramatic results in reducing the number of methamphetamine laboratory seizures. Prior to implementation of the system in Tennessee in 2005, methamphetamine laboratory seizures totaled 1,497 in 2004, but were reduced to 955 in 2005, and 589 in 2009. Kentuckys program was implemented statewide in 2008, and since statewide implementation, the number of laboratory seizures has significantly decreased. Oklahoma initially experienced success with their tracking system after implementation in 2006, as the number of seizures dropped in that year and again in 2007. In 2008, however, seizures began rising again, and have continued to rise in 2009. Nonetheless, when Oklahoma adopted NPLEx, their lab seizures also dropped significantly. NPLEx appears to be successful by requiring the real-time submission of transactions, thereby enabling the relevant laws to be enforced at the point of sale. By creating a multi-state database and the ability to compare all transactions quickly, NPLEx enables pharmacies to deny purchases that would be illegal based on gram limits, age, or even to convicted meth offenders in some states.
Pseudoephedrine	NPLEx also enforces the federal gram limits across state lines, which was impossible with state-operated systems. Access to the records is by law enforcement agencies only, through an online secure portal. In popular culture In the pilot episode of Breaking Bad, Walter White first synthesizes methamphetamine through the Nagai route, using red phosphorus and iodine to reduce pseudoephedrine. In the episode "Vitamin D" of Glee, Terri takes a job as the school nurse to stop her husband, Will Schuester, from becoming closer to guidance counsellor Emma Pillsbury (Jayma Mays), but is fired after giving the students performance-enhancing pseudoephedrine tablets. In her 2013 single "Avant Gardener", Australian rock musician Courtney Barnett refers to the effects of pseudoephedrine: "Reminds me of the time / When I was really sick and I / Had too much pseudoephedrine and I / Couldnt sleep at night". In her 2017 album Melodrama, pop artist Lorde references pseudoephedrine on the song "Writer in the Dark". The lyric reads: "I still feel you, now and then / Slow like pseudoephedrine / When you see me, will you say Ive changed?" Synthesis Although pseudoephedrine occurs naturally as an alkaloid in certain plant species (for example, as a constituent of extracts from the Ephedra species, also known as ma huang, in which it occurs together with other isomers of ephedrine), the majority of pseudoephedrine produced for commercial use is derived from yeast fermentation of dextrose in the presence of benzaldehyde. In this process, specialized strains of yeast (typically a variety of Candida utilis or Saccharomyces cerevisiae) are added to large vats containing water, dextrose and the enzyme pyruvate decarboxylase (such as found in beets and other plants). After the yeast has begun fermenting the dextrose, the benzaldehyde is added to the vats, and in this environment the yeast converts the ingredients to the precursor l-phenylacetylcarbinol (L-PAC). L-PAC is then chemically converted to pseudoephedrine via reductive amination.The bulk of pseudoephedrine is produced by commercial pharmaceutical manufacturers in India and China, where economic and industrial conditions favor its mass production for export. See also References External links "Pseudoephedrine". Drug Information Portal. U.S. National Library of Medicine.
Antithrombin	Antithrombin (AT) is a small glycoprotein that inactivates several enzymes of the coagulation system. It is a 432-amino-acid protein produced by the liver. It contains three disulfide bonds and a total of four possible glycosylation sites. α-Antithrombin is the dominant form of antithrombin found in blood plasma and has an oligosaccharide occupying each of its four glycosylation sites. A single glycosylation site remains consistently un-occupied in the minor form of antithrombin, β-antithrombin. Its activity is increased manyfold by the anticoagulant drug heparin, which enhances the binding of antithrombin to factor IIa (prothrombin) and factor Xa. Nomenclature Antithrombin is also termed antithrombin III (AT III). The designations antithrombin I through to antithrombin IV originate in early studies carried out in the 1950s by Seegers, Johnson and Fell.Antithrombin I (AT I) refers to the absorption of thrombin onto fibrin after thrombin has activated fibrinogen. Antithrombin II (AT II) refers to a cofactor in plasma, which together with heparin interferes with the interaction of thrombin and fibrinogen. Antithrombin III (AT III) refers to a substance in plasma that inactivates thrombin. Antithrombin IV (AT IV) refers to an antithrombin that becomes activated during and shortly after blood coagulation. Only AT III and possibly AT I are medically significant. AT III is generally referred to solely as "antithrombin" and it is antithrombin III that is discussed in this article. Structure Antithrombin has a half-life in blood plasma of around 3 days. The normal antithrombin concentration in human blood plasma is high at approximately 0.12 mg/ml, which is equivalent to a molar concentration of 2.3 μM. Antithrombin has been isolated from the plasma of a large number of species additional to humans. As deduced from protein and cDNA sequencing, cow, sheep, rabbit and mouse antithrombins are all 433 amino acids in length, which is one amino acid longer than human antithrombin. The extra amino acid is thought to occur at amino acid position 6. Cow, sheep, rabbit, mouse, and human antithrombins share between 84 and 89% amino acid sequence identity. Six of the amino acids form three intramolecular disulfide bonds, Cys8-Cys128, Cys21-Cys95, and Cys248-Cys430. They all have four potential N-glycosylation sites. These occur at asparagine (Asn) amino acid numbers 96, 135, 155, and 192 in humans and at similar amino acid numbers in other species. All these sites are occupied by covalently attached oligosaccharide side-chains in the predominant form of human antithrombin, α-antithrombin, resulting in a molecular weight for this form of antithrombin of 58,200. The potential glycosylation site at asparagine 135 is not occupied in a minor form (around 10%) of antithrombin, β-antithrombin (see Figure 1).Recombinant antithrombins with properties similar to those of normal human antithrombin have been produced using baculovirus-infected insect cells and mammalian cell lines grown in cell culture. These recombinant antithrombins generally have different glycosylation patterns to normal antithrombin and are typically used in antithrombin structural studies. For this reason many of the antithrombin structures stored in the protein data bank and presented in this article show variable glycosylation patterns. Antithrombin begins in its native state, which has a higher free energy compared to the latent state, which it decays to on average after 3 days. The latent state has the same form as the activated state - that is, when it is inhibiting thrombin. As such it is a classic example of the utility of kinetic vs thermodynamic control of protein folding. Function Antithrombin is a serpin (serine protease inhibitor) and is thus similar in structure to most other plasma protease inhibitors, such as alpha 1-antichymotrypsin, alpha 2-antiplasmin and Heparin cofactor II. The physiological target proteases of antithrombin are those of the contact activation pathway (formerly known as the intrinsic pathway), namely the activated forms of Factor X (Xa), Factor IX (IXa), Factor XI (XIa), Factor XII (XIIa) and, to a greater extent, Factor II (thrombin) (IIa), and also the activated form of Factor VII (VIIa) from the tissue factor pathway (formerly known as the extrinsic pathway). The inhibitor also inactivates kallikrein and plasmin, also involved in blood coagulation. However it inactivates certain other serine proteases that are not involved in coagulation such as trypsin and the C1s subunit of the enzyme C1 involved in the classical complement pathway.Protease inactivation results as a consequence of trapping the protease in an equimolar complex with antithrombin in which the active site of the protease enzyme is inaccessible to its usual substrate. The formation of an antithrombin-protease complex involves an interaction between the protease and a specific reactive peptide bond within antithrombin. In human antithrombin this bond is between arginine (arg) 393 and serine (ser) 394 (see Figure 2 and Figure 3).It is thought that protease enzymes become trapped in inactive antithrombin-protease complexes as a consequence of their attack on the reactive bond. Although attacking a similar bond within the normal protease substrate results in rapid proteolytic cleavage of the substrate, initiating an attack on the antithrombin reactive bond causes antithrombin to become activated and trap the enzyme at an intermediate stage of the proteolytic process. Given time, thrombin is able to cleave the reactive bond within antithrombin and an inactive antithrombin-thrombin complex will dissociate, however the time it takes for this to occur may be greater than 3 days. However, bonds P3-P4 and P1-P2 can be rapidly cleaved by neutrophil elastase and the bacterial enzyme thermolysin, respectively, resulting in inactive antithrombins no longer able to inhibit thrombin activity.The rate of antithrombins inhibition of protease activity is greatly enhanced by its additional binding to heparin, as is its inactivation by neutrophil elastase. Antithrombin and heparin Antithrombin inactivates its physiological target enzymes, Thrombin, Factor Xa and Factor IXa with rate constants of 7–11 x 103, 2.5 x 103 M−1 s−1 and 1 x 10 M−1 s−1 respectively. The rate of antithrombin-thrombin inactivation increases to 1.5 - 4 x 107 M−1 s−1 in the presence of heparin, i.e. the reaction is accelerated 2000-4000 fold. Factor Xa inhibition is accelerated by only 500 to 1000 fold in the presence of heparin and the maximal rate constant is 10 fold lower than that of thrombin inhibition. The rate enhancement of antithrombin-Factor IXa inhibition shows an approximate 1 million fold enhancement in the presence of heparin and physiological levels of calcium.AT-III binds to a specific pentasaccharide sulfation sequence contained within the heparin polymer GlcNAc/NS(6S)-GlcA-GlcNS(3S,6S)-IdoA(2S)-GlcNS(6S) Upon binding to this pentasaccharide sequence, inhibition of protease activity is increased by heparin as a result of two distinct mechanisms. In one mechanism heparin stimulation of Factor IXa and Xa inhibition depends on a conformational change within antithrombin involving the reactive site loop and is thus allosteric. In another mechanism stimulation of thrombin inhibition depends on the formation of a ternary complex between AT-III, thrombin, and heparin. Allosteric activation Increased Factor IXa and Xa inhibition requires the minimal heparin pentasaccharide sequence. The conformational changes that occur within antithrombin in response to pentasaccharide binding are well documented.In the absence of heparin, amino acids P14 and P15 (see Figure 3) from the reactive site loop are embedded within the main body of the protein (specifically the top of beta sheet A). This feature is in common with other serpins such as heparin cofactor II, alpha 1-antichymotrypsin and MENT. The conformational change most relevant for Factor IXa and Xa inhibition involves the P14 and P15 amino acids within the N-terminal region of the reactive site loop (circled in Figure 4 model B). This region has been termed the hinge region. The conformational change within the hinge region in response to heparin binding results in the expulsion of P14 and P15 from the main body of the protein and it has been shown that by preventing this conformational change, increased Factor IXa and Xa inhibition does not occur. It is thought that the increased flexibility given to the reactive site loop as a result of the hinge region conformational change is a key factor in influencing increased Factor IXa and Xa inhibition. It has been calculated that in the absence of the pentasaccharide only one in every 400 antithrombin molecules (0.25%) is in an active conformation with the P14 and P15 amino acids expelled. Non-allosteric activation Increased thrombin inhibition requires the minimal heparin pentasaccharide plus at least an additional 13 monomeric units. This is thought to be due to a requirement that antithrombin and thrombin must bind to the same heparin chain adjacent to each other. This can be seen in the series of models shown in Figure 5. In the structures shown in Figure 5 the C-terminal portion (P side) of the reactive site loop is in an extended conformation when compared with other un-activated or heparin activated antithrombin structures. The P region of antithrombin is unusually long relative to the P region of other serpins and in un-activated or heparin activated antithrombin structures forms a tightly hydrogen bonded β-turn. P elongation occurs through the breaking of all hydrogen bonds involved in the β-turn.The hinge region of antithrombin in the Figure 5 complex could not be modelled due to its conformational flexibility, and amino acids P9-P14 are not seen in this structure. This conformational flexibility indicates an equilibrium may exist within the complex between a P14 P15 reactive site loop inserted antithrombin conformation and a P14 P15 reactive site loop expelled conformation. In support of this, analysis of the positioning of P15 Gly in the Figure 5 complex (labelled in model B) shows it to be inserted into beta sheet A (see model C). Effect of glycosylation on activity α-Antithrombin and β-antithrombin differ in their affinity for heparin. The difference in dissociation constant between the two is threefold for the pentasaccharide shown in Figure 3 and greater than tenfold for full length heparin, with β-antithrombin having a higher affinity. The higher affinity of β-antithrombin is thought to be due to the increased rate at which subsequent conformational changes occur within the protein upon initial heparin binding. For α-antithrombin, the additional glycosylation at Asn-135 is not thought to interfere with initial heparin binding, but rather to inhibit any resulting conformational changes.Even though it is present at only 5–10% the levels of α-antithrombin, due to its increased heparin affinity, it is thought that β-antithrombin is more important than α-antithrombin in controlling thrombogenic events resulting from tissue injury. Indeed, thrombin inhibition after injury to the aorta has been attributed solely to β-antithrombin. Role in disease Evidence for the important role antithrombin plays in regulating normal blood coagulation is demonstrated by the correlation between inherited or acquired antithrombin deficiencies and an increased risk of any affected individual developing thrombotic disease. Antithrombin deficiency generally comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism. Acquired antithrombin deficiency Acquired antithrombin deficiency occurs as a result of three distinctly different mechanisms. The first mechanism is increased excretion which may occur with renal failure associated with proteinuria nephrotic syndrome. The second mechanism results from decreased production as seen in liver failure or cirrhosis or an immature liver secondary to premature birth. The third mechanism results from accelerated consumption which is most pronounced as consequence of severe injury trauma but also may be seen on a lesser scale as a result of interventions such as major surgery or cardiopulmonary bypass. Inherited antithrombin deficiency The incidence of inherited antithrombin deficiency has been estimated at between 1:2000 and 1:5000 in the normal population, with the first family suffering from inherited antithrombin deficiency being described in 1965. Subsequently, it was proposed that the classification of inherited antithrombin deficiency be designated as either type I or type II, based upon functional and immunochemical antithrombin analyses. Maintenance of an adequate level of antithrombin activity, which is at least 70% that of a normal functional level, is essential to ensure effective inhibition of blood coagulation proteases. Typically as a result of type I or type II antithrombin deficiency, functional antithrombin levels are reduced to below 50% of normal. Type I antithrombin deficiency Type I antithrombin deficiency is characterized by a decrease in both antithrombin activity and antithrombin concentration in the blood of affected individuals. Type I deficiency was originally further divided into two subgroups, Ia and Ib, based upon heparin affinity. The antithrombin of subgroup Ia individuals showed a normal affinity for heparin while the antithrombin of subgroup Ib individuals showed a reduced affinity for heparin. Subsequent functional analysis of a group of 1b cases found them not only to have reduced heparin affinity but multiple or pleiotrophic abnormalities affecting the reactive site, the heparin binding site and antithrombin blood concentration. In a revised system of classification adopted by the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis, type Ib cases are now designated as type II PE, Pleiotrophic effect.Most cases of type I deficiency are due to point mutations, deletions or minor insertions within the antithrombin gene. These genetic mutations result in type I deficiency through a variety of mechanisms: Mutations may produce unstable antithrombins that either may be not exported into the blood correctly upon completion biosynthesis or exist in the blood for a shortened period of time, e.g., the deletion of 6 base pairs in codons 106–108. Mutations may affect mRNA processing of the antithrombin gene. Minor insertions or deletions may lead to frame shift mutations and premature termination of the antithrombin gene. Point mutations may also result in the premature generation of a termination or stop codon e.g. the mutation of codon 129, CGA→TGA (UGA after transcription), replaces a normal codon for arginine with a termination codon. Type II antithrombin deficiency Type II antithrombin deficiency is characterized by normal antithrombin levels but reduced antithrombin activity in the blood of affected individuals. It was originally proposed that type II deficiency be further divided into three subgroups (IIa, IIb, and IIc) depending on which antithrombin functional activity is reduced or retained. Subgroup IIa - Decreased thrombin inactivation, decreased factor Xa inactivation and decreased heparin affinity. Subgroup IIb - Decreased thrombin inactivation and normal heparin affinity. Subgroup IIc - Normal thrombin inactivation, normal factor Xa inactivation and decreased heparin affinity.In the revised system of classification again adopted by the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis, type II antithrombin deficiency remains subdivided into three subgroups: the already mentioned type II PE, along with type II RS, where mutations effect the reactive site and type II HBS, where mutations effect the antithrombin heparin binding site. For the purposes of an antithrombin mutational database compiled by members of the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis, type IIa cases are now classified as type II PE, type IIb cases as type II RS and type IIc cases as type II HBS. Toponyms Presently it is relatively easy to characterise a specific antithrombin genetic mutation. However prior to the use of modern characterisation techniques investigators named mutations for the town or city where the individual suffering from the deficiency resided i.e. the antithrombin mutation was designated a toponym. Modern mutational characterisation has since shown that many individual antithrombin toponyms are actually the result of the same genetic mutation, for example antithrombin-Toyama, is equivalent to antithrombin-Kumamoto, -Amien, -Tours, -Paris-1, -Paris-2, -Alger, -Padua-2 and -Barcelona. Medical uses Antithrombin is used as a protein therapeutic that can be purified from human plasma or produced recombinantly (for example Atryn, which is produced in the milk of genetically modified goats). It is approved by the FDA as an anticoagulant for the prevention of clots before, during, or after surgery or birthing in patients with hereditary antithrombin deficiency.It has been studied in sepsis to reduce diffuse intravascular coagulation and other outcomes. It has not been found to confer any benefit in critically ill people with sepsis. Cleaved and latent antithrombin Cleavage at the reactive site results in entrapment of the thrombin protease, with movement of the cleaved reactive site loop together with the bound protease, such that the loop forms an extra sixth strand in the middle of beta sheet A. This movement of the reactive site loop can also be induced without cleavage, with the resulting crystallographic structure being identical to that of the physiologically latent conformation of plasminogen activator inhibitor-1 (PAI-1). For this reason the conformation of antithrombin in which the reactive site loop is incorporated uncleaved into the main body of the protein is referred to as latent antithrombin. In contrast to PAI-1 the transition for antithrombin from a normal or native conformation to a latent conformation is irreversible. Native antithrombin can be converted to latent antithrombin (L-antithrombin) by heating alone or heating in the presence of citrate. However, without extreme heating and at 37 °C (body temperature) 10% of all antithrombin circulating in the blood is converted to the L-antithrombin over a 24-hour period. The structure of L-antithrombin is shown in Figure 6. The 3-dimensional structure of native antithrombin was first determined in 1994. Unexpectedly the protein crystallized as a heterodimer composed of one molecule of native antithrombin and one molecule of latent antithrombin. Latent antithrombin on formation immediately links to a molecule of native antithrombin to form the heterodimer, and it is not until the concentration of latent antithrombin exceeds 50% of the total antithrombin that it can be detected analytically. Not only is the latent form of antithrombin inactive against its target coagulation proteases, but its dimerisation with an otherwise active native antithrombin molecule also results in the native molecules inactivation. The physiological impact of the loss of antithrombin activity either through latent antithrombin formation or through subsequent dimer formation is exacerbated by the preference for dimerisation to occur between heparin activated β-antithrombin and latent antithrombin as opposed to α-antithrombin.A form of antithrombin that is an intermediate in the conversion between native and latent forms of antithrombin has also been isolated and this has been termed prelatent antithrombin. Antiangiogenic antithrombin Angiogenesis is a physiological process involving the growth of new blood vessels from pre-existing vessels. Under normal physiological conditions angiogenesis is tightly regulated and is controlled by a balance of angiogenic stimulators and angiogenic inhibitors. Tumor growth is dependent upon angiogenesis and during tumor development a sustained production of angiogenic stimulatory factors is required along with a reduction in the quantity of angiogenic inhibitory factors tumor cells produce. The cleaved and latent form of antithrombin potently inhibit angiogenesis and tumor growth in animal models. The prelatent form of antithrombin has been shown to inhibit angiogenesis in-vitro but to date has not been tested in experimental animal models. References Further reading Panzer-Heinig, Sabine (2009). Antithrombin (III) - Establishing Pediatric Reference Values, Relevance for DIC 1992 versus 2007 (Thesis). Medizinische Fakultät Charité - Universitätsmedizin Berlin. External links The MEROPS online database for peptidases and their inhibitors: I04.018 Antithrombin+III at the US National Library of Medicine Medical Subject Headings (MeSH) Human SERPINC1 genome location and SERPINC1 gene details page in the UCSC Genome Browser.
Phendimetrazine	Phendimetrazine (Bontril, Adipost, Anorex-SR, Appecon, Melfiat, Obezine, Phendiet, Plegine, Prelu-2, Statobex) is a stimulant drug of the morpholine chemical class used as an appetite suppressant. Pharmacology Phendimetrazine functions as a prodrug to phenmetrazine; approximately 30 percent of an oral dose is converted into it. Phendimetrazine can essentially be thought of as an extended-release formulation of phenmetrazine with less potential for abuse. Phendimetrazine is an anorectic drug which acts as a norepinephrine-dopamine releasing agent (NDRA).As an amphetamine congener, its structure incorporates the backbone of methamphetamine, a potent CNS stimulant. While the addition of an N-methyl group to amphetamine significantly increases its potency and bioavailability, methylation of phenmetrazine renders the compound virtually inactive. However, phendimetrazine is a prodrug for phenmetrazine which acts as the active metabolite. Phendimetrazine possesses preferable pharmacokinetics over phenmetrazine as a therapeutic agent because its metabolization by demethylases produces a more steady and prolonged exposure of active drug within the body. This decreases abuse potential as the peak blood-concentration of active phenmetrazine thats produced from a single dose of phendimetrazine is lower than a single therapeutically equivalent dose of phenmetrazine. Indicated as a short-term secondary treatment for exogenous obesity, phendimetrazine immediate-release 35mg tablets are typically consumed one hour before meals, not to exceed three doses daily. Phendimetrazine is also manufactured as a 105mg extended-release capsule for once daily dosing, typically consumed 30 to 60 minutes before a morning meal. Whereas the immediate-release formulation has a maximum daily dosage of 210mg (6 tablets), the extended-release capsules have a maximum daily dosage of 105mg (one capsule). Legality According to the List of Psychotropic Substances under International Control published by the International Narcotics Control Board, phendimetrazine is a Schedule III controlled substance under the Convention on Psychotropic Substances. See also 2-Phenyl-3,6-dimethylmorpholine 3-Fluorophenmetrazine Fenbutrazate G-130 Morazone Manifaxine Radafaxine Phenmetrazine Fenmetramide == References ==
Degarelix	Degarelix, sold under the brand name Firmagon among others, is a hormonal therapy used in the treatment of prostate cancer.Testosterone is a male hormone that promotes growth of many prostate tumours and therefore reducing circulating testosterone to very low (castration) levels is often the treatment goal in the management of advanced prostate cancer. Degarelix has an immediate onset of action, binding to gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland and blocking their interaction with GnRH. This induces a fast and profound reduction in luteinizing hormone (LH), follicle-stimulating hormone (FSH) and in turn, testosterone suppression. Medical uses The GnRH antagonist degarelix, through its ability to reduce serum testosterone, is used to treat hormone-sensitive prostate cancer. Side effects As with all hormonal therapies, degarelix is commonly associated with hormonal side effects such as hot flashes and weight gain. Due to its mode of administration (subcutaneous injection), degarelix is also associated with injection-site reactions such as injection-site pain, erythema or swelling. Injection-site reactions are usually mild or moderate in intensity and occur predominantly after the first dose, decreasing in frequency thereafter. Less common: Anemia. Diarrhea, nausea. Hyperhidrosis including night sweats, rash. Gynecomastia, testicular atrophy, erectile dysfunction. Increased transaminases. Musculoskeletal pain and discomfort. Dizziness, headache. Insomnia. Weight gain. Chills, fever, fatigue, flu-like illness. Pharmacology GnRH antagonists (receptor blockers) such as degarelix are synthetic peptide derivatives of the natural GnRH decapeptide – a hormone that is made by neurons in the hypothalamus. GnRH antagonists compete with natural GnRH for binding to GnRH receptors in the pituitary gland. This reversible binding blocks the release of LH and FSH from the pituitary. The reduction in LH subsequently leads to a rapid and sustained suppression of testosterone release from the testes and subsequently reduces the size and growth of the prostate cancer. This in turn results in a reduction in prostate-specific antigen (PSA) levels in the patients blood. Measuring PSA levels helps to monitor how patients with prostate cancer are responding to treatment.Unlike GnRH agonists, which cause an initial stimulation of the hypothalamic-pituitary-gonadal axis (HPGA), leading to a surge in testosterone levels, and under certain circumstances, a flare-up of the tumour, GnRH antagonists do not cause a surge in testosterone or clinical flare. Clinical flare is a phenomenon that occurs in patients with advanced disease, which can precipitate a range of clinical symptoms such as bone pain, urethral obstruction, and spinal cord compression. Drug agencies have issued boxed warnings regarding this phenomenon in the prescribing information for GnRH agonists. As testosterone surge does not occur with GnRH antagonists, there is no need for patients to receive an antiandrogen as flare protection during prostate cancer treatment. GnRH agonists also induce an increase in testosterone levels after each reinjection of the drug – a phenomenon that does not occur with GnRH antagonists such as degarelix.GnRH antagonists have an immediate onset of action leading to a fast and profound suppression of testosterone and are therefore especially valuable in the treatment of patients with prostate cancer where fast control of disease is needed. History In December 2008, the US Food and Drug Administration (FDA) approved degarelix for the treatment of patients with advanced prostate cancer in the United States. It was subsequently approved by the European Commission at the recommendation of the European Medicines Agency (EMA) in February 2009, for use in adult males with advanced, hormone-dependent prostate cancer. Ferring Pharmaceuticals markets the drug under the name Firmagon. Research Degarelix is studied for use as a chemical castration agent on sex offenders in Sweden. A study published on April 29, 2020, in JAMA Psychiatry demonstrated a reduced the risk score for committing child sexual abuse in men with pedophilic disorder two weeks after initial injection. See also Gonadotropin-releasing hormone receptor § Antagonists References External links "Degarelix". Drug Information Portal. U.S. National Library of Medicine.
Neostigmine	Neostigmine, sold under the brand name Bloxiverz, among others, is a medication used to treat myasthenia gravis, Ogilvie syndrome, and urinary retention without the presence of a blockage. It is also used in anaesthesia to end the effects of non-depolarising neuromuscular blocking medication. It is given by injection either into a vein, muscle, or under the skin. After injection effects are generally greatest within 30 minutes and last up to 4 hours.Common side effects include nausea, increased saliva, crampy abdominal pain, and slow heart rate. More severe side effects include low blood pressure, weakness, and allergic reactions. It is unclear if use in pregnancy is safe for the baby. Neostigmine is in the cholinergic family of medications. It works by blocking the action of acetylcholinesterase and therefore increases the levels of acetylcholine.Neostigmine was patented in 1931. It is on the World Health Organizations List of Essential Medicines. The term is from Greek neos, meaning "new", and "-stigmine", in reference to its parent molecule, physostigmine, on which it is based. Medical uses It is used to improve muscle tone in people with myasthenia gravis, and also to reverse the effects of non-depolarizing muscle relaxants such as rocuronium and vecuronium at the end of an operation.Another indication for use is the conservative management of acute colonic pseudo-obstruction, or Ogilvies syndrome, in which patients get massive colonic dilatation in the absence of a true mechanical obstruction.Hospitals sometimes administer a solution containing neostigmine intravenously to delay the effects of envenomation through snakebite. Some promising research results have also been reported for administering the drug nasally as a snakebite treatment. Side effects Neostigmine can induce generic ocular side effects including: headache, brow pain, blurred vision, phacodonesis, pericorneal injection, congestive iritis, various allergic reactions, and rarely, retinal detachment.: 114 Neostigmine is often prescribed for underactive urinary bladder.Neostigmine has a wide variety of side-effects such as reduced heart rate (bradycardia), due to the increase of acetylcholine at nerve terminals. For this reason it is usually given along with an anti-cholinergic drug such as atropine or glycopyrrolate.Gastrointestinal symptoms occur earliest after ingestion and include anorexia, nausea, vomiting, abdominal cramps, and diarrhea.: 109 Pharmacology By interfering with the breakdown of acetylcholine, neostigmine indirectly stimulates both nicotinic and muscarinic receptors. Unlike physostigmine, neostigmine has a quaternary nitrogen; hence, it is more polar. It does not cross the blood–brain barrier and enter the CNS. However, it does cross the placenta. Its effect on skeletal muscle is greater than that of physostigmine. Neostigmine has moderate duration of action – usually two to four hours. Neostigmine binds to the anionic and ester site of acetylcholinesterase, which blocks the enzyme from breaking down the acetylcholine molecules before they reach the postsynaptic membrane receptors. This allows for the threshold to be reached so a new impulse can be triggered in the next neuron. In myasthenia gravis there are too few acetylcholine receptors so with the acetylcholinesterase blocked, acetylcholine can bind to the few receptors and trigger a muscular contraction. Chemistry Neostigmine, which can be viewed as a simplified analog of physostigmine, is made by reacting 3-dimethylaminophenol with N-dimethylcarbamoyl chloride, which forms the dimethylcarbamate, and its subsequent alkylation using dimethyl sulfate forming the desired compound. Spectral data Neostigmine shows notable UV/VIS absorption at 261 nm, 267 nm, and 225 nm.Neostigmines 1H NMR Spectroscopy reveals shifts at: 7.8, 7.7, 7.4, 7.4, 3.8, and 3.1 parts per million. The higher shifts are due to the aromatic hydrogens. The lower shifts at 3.8 ppm and 3.1 ppm are due to the electronic withdrawing nature of the tertiary and quaternary nitrogen, respectively. History Neostigmine was first synthesized by Aeschlimann and Reinert in 1931 and was patented by Aeschlimann in 1933.Neostigmine is made by first reacting 3-dimethylaminophenol with N-dimethylcarbamoyl chloride, which forms a dimethylcarbamate. Next, that product is alkylated using dimethyl sulfate, which forms neostigmine.: 103 References External links "Neostigmine". Drug Information Portal. U.S. National Library of Medicine. "Neostigmine methylsulfate". Drug Information Portal. U.S. National Library of Medicine. "Neostigmine bromide". Drug Information Portal. U.S. National Library of Medicine.
Interferon alfa-2b	Interferon alfa-2b is an antiviral or antineoplastic drug. It is a recombinant form of the protein Interferon alpha-2 that was originally sequenced and produced recombinantly in E. coli in the laboratory of Charles Weissmann at the University of Zurich, in 1980. It was developed at Biogen, and ultimately marketed by Schering-Plough under the trade name Intron-A. It was also produced in 1986 in recombinant human form, in the Center for Genetic Engineering and Biotechnology of Havana, Cuba, under the name Heberon Alfa R.It has been used for a wide range of indications, including viral infections and cancers. This drug is approved around the world for the treatment of chronic hepatitis C, chronic hepatitis B, hairy cell leukemia, Behçets disease, chronic myelogenous leukemia, multiple myeloma, follicular lymphoma, carcinoid tumor, mastocytosis and malignant melanoma.The medication is being used in clinical trials to treat patients with SARS-CoV-2 and there are published results in the peer-reviewed scientific literature.So far, two non-peer reviewed research articles have been published. One study at the University of Texas Medical Branch, Galveston, showed evidence of a direct anti-viral effect of Interferon alpha against novel Coronavirus in vitro. The study demonstrated around 10,000 fold reduction in the quantity of virus that was pre-treated with Interferon alpha 48 hours earlier. A second study by universities in China, Australia and Canada analysed 77 moderate COVID-19 subjects in Wuhan and observed that those who received Interferon alpha-2b showed a significant reduction in the duration of virus shedding period and even in levels of the inflammatory cytokine, IL-6. This drug is also used off-label in cats and dogs, both by injection and orally. The cross-species nature of IFN-α allow it to work in non-human animals, but the period of usefulness is limited by the production of antibodies against this foreign protein. See also Interferon Ropeginterferon alfa-2b References External links Intron-A Summary of Product Characteristics Nagata S, Taira H, Hall A, et al. (Mar 1980). "Synthesis in E. coli of a polypeptide with human leukocyte interferon activity". Nature. 284 (5754): 316–20. Bibcode:1980Natur.284..316N. doi:10.1038/284316a0. PMID 6987533. S2CID 4310807.
Norco	Norco may refer to: Places Norco, California, U.S. Norco Hills, or La Sierra Heights, section of the Temescal Mountains Norco, Louisiana, U.S. Other uses Norco Bicycles, a Canadian bicycle manufacturer Norco Co-operative, an agricultural supply and marketing co-operative, New South Wales, Australia Northern Co-operative Society (Norco), a defunct Aberdeen, Scotland co-operative society Norco, a brand name for the fixed-dose combination opioid pain medication hydrocodone/paracetamol NORCO (video game), a point-and-click video game set in a fictional version of Norco, Louisiana See also Norco shootout
Ethionamide	Ethionamide is an antibiotic used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, to treat active multidrug-resistant tuberculosis. It is no longer recommended for leprosy. It is taken by mouth.Ethionamide has a high rate of side effects. Common side effects include nausea, diarrhea, abdominal pain, and loss of appetite. Serious side effects may include liver inflammation and depression. It should not be used in people with significant liver problems. Use in pregnancy is not recommended as safety is unclear. Ethionamide is in the thioamides family of medications. It is believed to work by interfering with the use of mycolic acid.Ethionamide was discovered in 1956 and approved for medical use in the United States in 1965. It is on the World Health Organizations List of Essential Medicines. Medical uses Ethionamide is used in combination with other antituberculosis agents as part of a second-line regimen for active tuberculosis.Ethionamide is well absorbed orally with or without food, but is often administered with food to improve tolerance. It crosses the blood brain barrier to achieve concentrations in the cerebral-spinal fluid equivalent to plasma.The antimicrobial spectrum of ethionamide includes M. tuberculosis, M. bovis and M. segmatis. It also is used rarely against infections with M. leprae and other nontuberculous mycobacteria such as M. avium and M. kansasii. While working in a similar manner to isoniazid, cross resistance is only seen in 13% of strains, since they are both prodrugs but activated by different pathways. Resistance can emerge from mutations in ethA, which is needed to activate the drug, or ethR, which can be overexpressed to repress ethA. Mutations in inhA or the promoter of inhA can also lead to resistance through changing the binding site or overexpression.The FDA has placed it in pregnancy category C, because it has caused birth defects in animal studies. It is not known whether ethionamide is excreted into breast milk. Adverse effects Ethionamide frequently causes gastrointestinal distress with nausea and vomiting which can lead patients to stop taking it. This can sometimes be improved by taking it with food.Ethionamide can cause hepatocellular toxicity and is contraindicated in patients with severe liver impairment. Patients on ethionamide should have regular monitoring of their liver function tests. Liver toxicity occurs in up to 5% of patients and follows a pattern similar to isoniazid, usually arising in the first 1 to 3 months of therapy, but can occur even after more than 6 months of therapy. The pattern of liver function test derangement is often a rise in the ALT and AST.Both central neurological side effects such as psychiatric disturbances and encephalopathy, along with peripheral neuropathy have been reported. Administering pyridoxine along with ethionamide may reduce these effects and is recommended.Ethionamide is structurally similar to methimazole, which is used to inhibit thyroid hormone synthesis, and has been linked to hypothyroidism in several TB patients. Periodic monitoring of thyroid function while on ethionamide is recommended. Interactions Ethionamide may worsen the adverse effects of other antituberculous drugs being taken at the same time. It boosts levels of isoniazid when taken together and can lead to increased rates of peripheral neuropathy and hepatotoxicity. When taken with cycloserine, seizures have been reported. High rates of hepatotoxicty have been reported when taken with rifampicin. The drugs labeling cautions against excessive alcohol ingestion as it may provoke a psychotic reaction. Mechanism of action Ethionamide is a prodrug which is activated by the enzyme ethA, a mono-oxygenase in Mycobacterium tuberculosis, and then binds NAD+ to form an adduct which inhibits InhA in the same way as isoniazid. The mechanism of action is thought to be through disruption of mycolic acid.Expression of the ethA gene is controlled by ethR, a transcriptional repressor. It is thought that improving ethA expression will increase the efficacy of ethionamide and prompting interest by drug developers in EthR inhibitors as a co-drug. Other names 1314 2-ethylisothionicotinamide amidazine thioamide iridocinIt is sold under the brand name Trecator by Wyeth Pharmaceuticals which was purchased by Pfizer in 2009. References External links "Ethionamide". Drug Information Portal. U.S. National Library of Medicine. Ethionamide (PIM 224)
Hexamethylenetetramine	Hexamethylenetetramine, also known as methenamine, hexamine, or urotropin, is a heterocyclic organic compound with the formula (CH2)6N4. This white crystalline compound is highly soluble in water and polar organic solvents. It has a cage-like structure similar to adamantane. It is useful in the synthesis of other organic compounds, including plastics, pharmaceuticals, and rubber additives. It sublimes in vacuum at 280 °C. Synthesis, structure, reactivity Hexamethylenetetramine was discovered by Aleksandr Butlerov in 1859. It is prepared industrially by combining formaldehyde and ammonia: The reaction can be conducted in gas phase and in solution. The molecule has a tetrahedral cage-like structure, similar to adamantane. Four vertices are occupied by nitrogen atoms, which are linked by methylene groups. Although the molecular shape defines a cage, no void space is available at the interior for binding other atoms or molecules, unlike crown ethers or larger cryptand structures. The molecule behaves like an amine base, undergoing protonation and N-alkylation (e.g. quaternium-15). Applications The dominant use of hexamethylenetetramine is in the production of powdery or liquid preparations of phenolic resins and phenolic resin moulding compounds, where it is added as a hardening component. These products are used as binders, e.g. in brake and clutch linings, abrasive products, non-woven textiles, formed parts produced by moulding processes, and fireproof materials. Medical uses As the mandelic acid salt (methenamine mandelate) or the hippuric acid salt (methenamine hippurate), it is used for the treatment of urinary tract infection. In an acidic environment, methenamine is believed to act as an antimicrobial by converting to formaldehyde. A systematic review of its use for this purpose in adult women found there was insufficient evidence of benefit and further research is needed.Methenamine acts as an over-the-counter antiperspirant due to the astringent property of formaldehyde. Histological stains Methenamine silver stains are used for staining in histology, including the following types: Grocotts methenamine silver stain, used widely as a screen for fungal organisms. Jones stain, a methenamine silver-Periodic acid-Schiff that stains for basement membrane, availing to view the "spiked" Glomerular basement membrane associated with membranous glomerulonephritis. Solid fuel Together with 1,3,5-trioxane, hexamethylenetetramine is a component of hexamine fuel tablets used by campers, hobbyists, the military and relief organizations for heating camping food or military rations. It burns smokelessly, has a high energy density of 30.0 megajoules per kilogram (MJ/kg), does not liquify while burning, and leaves no ashes, although its fumes are toxic. Standardized 0.149 g tablets of methenamine (hexamine) are used by fire-protection laboratories as a clean and reproducible fire source to test the flammability of carpets and rugs. Food additive Hexamethylene tetramine or hexamine is also used as a food additive as a preservative (INS number 239). It is approved for usage for this purpose in the EU, where it is listed under E number E239, however it is not approved in the USA, Russia, Australia, or New Zealand. Reagent in organic chemistry Hexamethylenetetramine is a versatile reagent in organic synthesis. It is used in the Duff reaction (formylation of arenes), the Sommelet reaction (converting benzyl halides to aldehydes), and in the Delepine reaction (synthesis of amines from alkyl halides). Explosives Hexamethylenetetramine is the base component to produce RDX and, consequently, C-4 as well as Octogen, hexamine dinitrate, hexamine diperchlorate and HMTD. Historical uses Hexamethylenetetramine was first introduced into the medical setting in 1895 as a urinary antiseptic. However, it was only used in cases of acidic urine, whereas boric acid was used to treat urinary tract infections with alkaline urine. Scientist De Eds found that there was a direct correlation between the acidity of hexamethylenetetramines environment and the rate of its decomposition. Therefore, its effectiveness as a drug depended greatly on the acidity of the urine rather than the amount of the drug administered. In an alkaline environment, hexamethylenetetramine was found to be almost completely inactive.Hexamethylenetetramine was also used as a method of treatment for soldiers exposed to phosgene in World War I. Subsequent studies have shown that large doses of hexamethylenetetramine provide some protection if taken before phosgene exposure but none if taken afterwards. Producers Since 1990 the number of European producers has been declining. The French SNPE factory closed in 1990; in 1993, the production of hexamethylenetetramine in Leuna, Germany ceased; in 1996, the Italian facility of Agrolinz closed down; in 2001, the UK producer Borden closed; in 2006, production at Chemko, Slovak Republic, was closed. Remaining producers include INEOS in Germany, Caldic in the Netherlands, and Hexion in Italy. In the US, Eli Lilly and Company stopped producing methenamine tablets in 2002. In Australia, Hexamine Tablets for fuel are made by Thales Australia Ltd. In México, Hexamine is produced by Abiya. == References ==
Lisinopril/hydrochlorothiazide	Lisinopril/hydrochlorothiazide, sold under the brand name Zestoretic among others, is a fixed-dose combination medication used for the treatment of high blood pressure. It contains lisinopril, an ACE inhibitor, and hydrochlorothiazide, a diuretic. Typically, it becomes an option once a person is doing well on the individual components. It is taken by mouth.Common side effects include dizziness, headache, cough, and feeling tired. Severe side effects may include angioedema and low blood pressure. Use during pregnancy may harm the baby.The combination was approved for medical use in the United States in 1989. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2020, it was the 50th most commonly prescribed medication in the United States, with more than 13 million prescriptions. References External links "Hydrochlorothiazide mixture with lisinopril". Drug Information Portal. U.S. National Library of Medicine.
Esomeprazole	Esomeprazole, sold under the brand name Nexium among others, is a medication which reduces stomach acid. It is used to treat gastroesophageal reflux disease, peptic ulcer disease, and Zollinger–Ellison syndrome. Effectiveness is similar to other proton pump inhibitors (PPIs). It is taken by mouth or injection into a vein.Common side effects include headache, constipation, dry mouth, and abdominal pain. Serious side effects may include angioedema, Clostridium difficile infection, and pneumonia. Use in pregnancy appears to be safe, while safety during breastfeeding is unclear. Esomeprazole is the (S)-(−)-isomer of omeprazole. It works by blocking H+/K+-ATPase in the parietal cells of the stomach.It was patented in 1993 and approved for medical use in 2000. It is available as a generic medication and sold over the counter in a number of countries. In 2019, it was the 127th most commonly prescribed medication in the United States, with more than 5 million prescriptions. It is also available without a prescription in the United States. Medical use The primary uses of esomeprazole are gastroesophageal reflux disease, treatment and maintenance of erosive esophagitis, treatment of duodenal ulcers caused by H. pylori, prevention of gastric ulcers in those on chronic NSAID therapy, and treatment of gastrointestinal ulcers associated with Crohns disease. Gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) is a condition in which the digestive acid in the stomach comes in contact with the esophagus. The irritation caused by this disorder is known as heartburn. Long-term contact between gastric acids and the esophagus can cause permanent damage to the esophagus. Esomeprazole reduces the production of digestive acids, thus reducing their effect on the esophagus. Duodenal ulcers Esomeprazole is combined with the antibiotics clarithromycin and amoxicillin (or metronidazole instead of amoxicillin in penicillin-hypersensitive patients) in a 10-day eradication triple therapy for Helicobacter pylori. Infection by H. pylori is a causative factor in the majority of peptic and duodenal ulcers. Efficacy A 2006 meta analysis concluded that compared to other proton pump inhibitors, esomeprazole confers a modest overall benefit in esophageal healing and symptom relief. When broken down by disease severity, the benefit of esomeprazole relative to other proton pump inhibitors was negligible in people with mild disease (number needed to treat 50), but appeared more in those with severe disease (number needed to treat 8). A second meta analysis also found increases in erosive esophageal healing (>95% healing rate) when compared to standardized doses in broadly selected patient populations. A 2017 study found esomeprazole to be among a number of effective doses of PPIs. Adverse effects Common side effects include headache, diarrhea, nausea, flatulence, decreased appetite, constipation, dry mouth, and abdominal pain. More severe side effects are severe allergic reactions, chest pain, dark urine, fast heartbeat, fever, paresthesia, persistent sore throat, severe stomach pain, unusual bruising or bleeding, unusual tiredness, and yellowing of the eyes or skin.Proton pump inhibitors may be associated with a greater risk of hip fractures and Clostridium difficile-associated diarrhoea. Patients are frequently administered the drugs in intensive care as a protective measure against ulcers, but this use is also associated with a 30% increase in occurrence of pneumonia.Long-term use of proton pump inhibitors in patients treated for Helicobacter pylori has been shown to dramatically increase the risk of gastric cancer.Acute tubulointerstitial nephritis is a possible adverse reaction when using proton pump inhibitors. Interactions Esomeprazole is a competitive inhibitor of the enzyme CYP2C19, and may therefore interact with drugs that depend on it for metabolism, such as diazepam and warfarin; the concentrations of these drugs may increase if they are used concomitantly with esomeprazole. Conversely, clopidogrel (Plavix) is an inactive prodrug that partially depends on CYP2C19 for conversion to its active form; inhibition of CYP2C19 blocks the activation of clopidogrel, thus reducing its effects.Drugs that depend on stomach pH for absorption may interact with omeprazole; drugs that depend on an acidic environment (such as ketoconazole or atazanavir) will be poorly absorbed, whereas drugs that are broken down in acidic environments (such as erythromycin) will be absorbed to a greater extent than normal. Pharmacokinetics Single 20 to 40 mg oral doses generally give rise to peak plasma esomeprazole concentrations of 0.5-1.0 mg/L within 1–4 hours, but after several days of once-daily administration, these levels may increase by about 50%. A 30-minute intravenous infusion of a similar dose usually produces peak plasma levels on the order of 1–3 mg/L. The drug is rapidly cleared from the body, largely by urinary excretion of pharmacologically inactive metabolites such as 5-hydroxymethylesomeprazole and 5-carboxyesomeprazole. Esomeprazole and its metabolites are analytically indistinguishable from omeprazole and the corresponding omeprazole metabolites unless chiral techniques are employed. Dosage forms Esomeprazole is available as delayed-release capsules in the United States or as delayed-release tablets in Australia, the United Kingdom, and Canada (containing esomeprazole magnesium) in strengths of 20 and 40 mg, as delayed-release capsules in the United States (containing esomeprazole strontium) in a 49.3 mg strength (delivering the equivalent of 40 mg of esomeprazole, and as esomeprazole sodium for intravenous injection/infusion. Oral esomeprazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic conditions of the stomach. This is achieved by formulating capsules using the multiple-unit pellet system. The combination naproxen/esomeprazole magnesium (brand name Vimovo) is used for the prevention of gastric ulcers associated with chronic NSAID therapy. Vimovo is available in two dosage strengths: 500/20 mg and 375/20 mg. Clinical trials of naproxen/esomeprazole demonstrated an incidence of GI ulcer in 24% of patients on naproxen (alone) versus 7% on naproxen/esomeprazole. The FDA has added warnings to the label for Vimovo concerning acute interstitial nephritis and risk of kidney problems in some patients. Multiple-unit pellet system Esomeprazole capsules, as well as Losec/Prilosec tablets, are formulated as a "multiple-unit pellet system" (MUPS). Essentially, the capsule consists of extremely small enteric-coated granules (pellets) of the esomeprazole formulation inside an outer shell. When the capsule is immersed in an aqueous solution, as happens when the capsule reaches the stomach, water enters the capsule by osmosis. The contents swell from water absorption, causing the shell to burst, and releasing the enteric-coated granules. For most patients, the multiple-unit pellet system is of no advantage over conventional enteric-coated preparations. Patients for whom the formulation is of benefit include those requiring nasogastric tube feeding and those with difficulty swallowing (dysphagia). Society and culture Global distribution In 2010, AstraZeneca announced a co-promotion agreement with Daiichi Sankyo to distribute Nexium in Japan. In September 2011, Nexium was approved for sale and was launched by Daiichi Sankyo in Japan. Esomeprazole was approved for use in the United States in February 2001. Economics Between the launch of esomeprazole in 2001 and 2005, the drug netted AstraZeneca about $14.4 billion. Controversy There has been some controversy about AstraZenecas behaviour in creating, patenting, and marketing the drug. Esomeprazoles successful predecessor, omeprazole, is a mixture of two mirror-imaged molecules (esomeprazole which is the S-enantiomer, and R-omeprazole); critics said the company was trying to "evergreen" its omeprazole patent by patenting the pure esomeprazole and aggressively marketing to doctors that it is more effective than the mixture.Thomas A. Scully, head of the Centers for Medicare and Medicaid Services (CMS), also criticized AstraZeneca for their aggressive marketing of Nexium. At a conference of the American Medical Association (AMA), he said that Astra was using the new drug to overcharge consumers and insurance companies. Brand names Generic versions of esomeprazole magnesium are available worldwide. It is available over-the-counter under the brand name Nexium in the United States and the UK. Other uses Esomeprazole can be used as a parasiticide. Gokmen et al., 2016 screen for efficacy against Trichomonas vaginalis isolates from horses. They found esomeprazole to be effective as a veterinary antiparasitic. References Further reading Dean L (2012). "Esomeprazole Therapy and CYP2C19 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520354. Bookshelf ID: NBK100896. External links "Esomeprazole". Drug Information Portal. U.S. National Library of Medicine. "Esomeprazole sodium". Drug Information Portal. U.S. National Library of Medicine.
Carbidopa/levodopa/entacapone	Carbidopa/levodopa/entacapone, sold under the brand name Stalevo among others, is a dopaminergic fixed-dose combination medication that contains carbidopa, levodopa, and entacapone for the treatment of Parkinsons disease. It is marketed by Swiss-based Novartis Pharmaceuticals and manufactured by Finnish drugmaker Orion Corporation. Medical uses Carbidopa/levodopa/entacapone was approved by the U.S. Food and Drug Administration (FDA) in June 2003, to treat adults with Parkinsons disease of unknown cause in two scenarios. First, to substitute with equivalent strength of each of the three components for immediate-release carbidopa/levodopa and entacapone previously administered as individual products. Second, to replace immediate-release carbidopa/levodopa therapy (without entacapone) when people experience the signs and symptoms of end-of-dose "wearing-off" but only for people taking a total daily dose of levodopa of 600 mg or less and not experiencing dyskinesias.It may help decrease a change of response to Parkinsons medications.In the European Union it is indicated for the treatment of adults with Parkinsons disease and end-of-dose motor fluctuations not stabilized on levodopa/dopa decarboxylase (DDC) inhibitor treatment. Side effects Sometimes a wearing off effect may occur at the end of the dosing interval, where a patient may feel Parkinsons symptoms. Urine, saliva, or sweat may be discolored (dark color such as red, brown, or black) after taking carbidopa/levodopa/entacapone. Prostate cancer On March 31, 2010, the United States Food and Drug Administration (FDA) stated it was evaluating long-term clinical data from STRIDE-PD which found that a greater number of patients taking Stalevo had prostate cancer compared to those taking carbidopa/levodopa. Other controlled clinical trials evaluating carbidopa/levodopa/entacapone or entacapone did not find an increased risk of prostate cancer. FDA is still reviewing the available information and has not concluded that carbidopa/levodopa/entacapone increases the risk of developing prostate cancer. Healthcare professionals were advised to be aware of this possible risk and follow current guidelines for prostate cancer screening. FDA recommended that healthcare professionals follow the recommendations in the drug label when prescribing carbidopa/levodopa/entacapone and Comtan. Patients were directed to not stop taking their medication unless directed to do so by their healthcare professional. Cardiovascular risks On August 20, 2010, the United States Food and Drug Administration stated meta-analysis of several studies "appeared to show an increase in the risk of heart attack, stroke, and cardiovascular death for people taking the drug" but also stated "findings were not clear." Heart problems are not uncommon in Parkinsons patients and the FDA will investigate the concerns. Drug interactions Carbidopa/levodopa/entacapone is contraindicated in patients taking a class of antidepressant drugs known as non-selective monoamine oxidase (MAO) inhibitors such as phenelzine and tranylcypromine. Combining carbidopa/levodopa/entacapone with these drugs could cause serious—possibly life-threatening—side effects. MAO inhibitors should be stopped at least two weeks before starting therapy with carbidopa/levodopa/entacapone. Carbidopa/levodopa/entacapone may be combined with the drugs rasagiline or selegiline. These drugs are a different type of MAO inhibitor known as selective MAO inhibitors that are often prescribed for Parkinsons disease. Many drug interactions involving selegiline are theoretical, primarily based on interactions with non-selective MAO inhibitors; at oral doses the risk of these interactions may be very low. However, transdermal selegiline, known by its trade name Emsam, is still contraindicated. Transdermal selegiline results in higher plasma levels at which it behaves like a non-selective MAO inhibitor. Concominant use of entacapone, a component of carbidopa/levodopa/entacapone, with MAO inhibitors may increase toxicity of MAO inhibitors. Levodopa, also a component of carbidopa/levodopa/entacapone, in combination with MAO inhibitors may result in hypertensive reactions. Mechanism of action Levodopa is the immediate precursor to dopamine. Entacapone is a selective, reversible catechol-O-methyltransferase (COMT) inhibitor that prevents the degradation of levodopa. Entacapone does not cross the blood–brain barrier. Carbidopa is a peripheral aromatic L-amino acid decarboxylase (AADC) inhibitor. Carbidopa, which also does not cross the blood–brain barrier, is combined with levodopa to prevent its conversion to dopamine in the periphery. Society and culture Extension As of 2010, applications for extending the indication of carbidopa/levodopa/entacapone to people requiring initiation of levodopa therapy have been under review by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), based on the favorable results from FIRST-STEP, a study conducted in North America and Europe by Novartis from 2005, to 2007 (see below). References External links "Carbidopa mixture with entacapone and levodopa". Drug Information Portal. U.S. National Library of Medicine. "Entacapone/Carbidopa/Levodopa (marketed as Stalevo) Information". U.S. Food and Drug Administration (FDA). 6 April 2017.
H5N1 vaccine	A H5N1 vaccine is an influenza vaccine intended to provide immunization to influenza A virus subtype H5N1. Vaccines have been formulated against several of the avian H5N1 influenza varieties. Vaccination of poultry against the H5N1 epizootic is widespread in certain countries. Some vaccines also exist for use in humans, and others are in testing, but none have been made available to civilian populations, nor produced in quantities sufficient to protect more than a tiny fraction of the Earths population in the event of an H5N1 pandemic. In January 2020, the U.S. Food and Drug Administration (FDA) approved Audenz, an adjuvanted influenza A (H5N1) monovalent vaccine. Audenz is a vaccine indicated for active immunization for the prevention of disease caused by the influenza A virus H5N1 subtype contained in the vaccine. Audenz is approved for use in persons six months of age and older at increased risk of exposure to the influenza A virus H5N1 subtype contained in the vaccine.Some older, egg-based H5N1 vaccines for humans that have been licensed are: Sanofi Pasteurs vaccine approved by the United States in April 2007, GlaxoSmithKlines vaccine Prepandrix approved by the European Union in May 2008, with reactive AS03 (containing squalene) adjuvant. and CSL Limiteds vaccine Panvax approved by Australia in June 2008.Other licensed H5N1 vaccines include: Adjupanrix, approved for medical use in the European Union in October 2009. Adjupanrix contains the flu strain A/VietNam/1194/2004 NIBRG 14 (H5N1). Foclivia, approved for medical use in the European Union in October 2009. Foclivia contains the flu strain A/Vietnam/1194/2004 (H5N1). Aflunov, approved for medical use in the European Union in November 2010. Aflunov contains the flu strain A/turkey/Turkey/1/2005 (H5N1)-like strain (NIBRG-23) (clade 2.2.1). Pumarix, approved for medical use in the European Union in March 2011.In November 2013, the U.S. Food and Drug Administration (FDA) approved an experimental H5N1 bird flu vaccine to be held in stockpiles. In a clinical trial including 3,400 adults, 91% of people age 18-64 and 74% of people age 65 or older formed an immune response sufficient to provide protection. Reported adverse effects were generally mild, with pain at the injection site being the most common adverse effect.H5N1 continually mutates, meaning vaccines based on current samples of avian H5N1 cannot be depended upon to work in the case of a future pandemic of H5N1. While there can be some cross-protection against related flu strains, the best protection would be from a vaccine specifically produced for any future pandemic flu virus strain. Daniel R. Lucey, co-director of the Biohazardous Threats and Emerging Diseases graduate program at Georgetown University, has made this point, "There is no H5N1 pandemic so there can be no pandemic vaccine." However, "pre-pandemic vaccines" have been created; are being refined and tested; and do have some promise both in furthering research and preparedness for the next pandemic. Vaccine manufacturing companies are being encouraged to increase capacity so that if a pandemic vaccine is needed, facilities will be available for rapid production of large amounts of a vaccine specific to a new pandemic strain.Problems with H5N1 vaccine production include: lack of overall production capacity lack of surge production capacity (it is impractical to develop a system that depends on hundreds of millions of 11-day-old specialized eggs on a standby basis) the pandemic H5N1 might be lethal to chickensCell culture (cell-based) manufacturing technology can be applied to influenza vaccines as they are with most viral vaccines and thereby solve the problems associated with creating flu vaccines using chicken eggs. Vaccine production capacity: The protective immune response generated by influenza vaccines is largely based on viral hemagglutinin (HA) and neuraminidase (NA) antigens in the vaccine. As a consequence, the basis of influenza vaccine manufacturing is growing massive quantities of virus in order to have sufficient amounts of these protein antigens to stimulate immune responses. Influenza vaccines used in the United States and around world are manufactured by growing virus in fertilized hens eggs, a commercial process that has been in place for decades. To achieve vaccine production targets millions of 11-day-old fertilized eggs must be available every day of production.In the near term, further expansion of these systems will provide additional capacity for the U.S.-based production of both seasonal and pandemic vaccines, however, the surge capacity that will be needed for a pandemic response cannot be met by egg-based vaccine production alone, as it is impractical to develop a system that depends on hundreds of millions of 11-day-old specialized eggs on a standby basis. In addition, because a pandemic could result from an avian influenza strain that is lethal to chickens, it is impossible to ensure that eggs will be available to produce vaccine when needed.In contrast, cell culture manufacturing technology can be applied to influenza vaccines as they are with most viral vaccines (e.g., polio vaccine, measles-mumps-rubella vaccine, chickenpox vaccine). In this system, viruses are grown in closed systems such as bioreactors containing large numbers of cells in growth media rather than eggs. The surge capacity afforded by cell-based technology is insensitive to seasons and can be adjusted to vaccine demand, as capacity can be increased or decreased by the number of bioreactors or the volume used within a bioreactor. In addition to supporting basic research on cell-based influenza vaccine development, HHS is currently supporting a number of vaccine manufacturers in the advanced development of cell-based influenza vaccines with the goal of developing U.S.-licensed cell-based influenza vaccines produced in the United States. The US government has purchased from Sanofi Pasteur and Chiron Corporation several million doses of vaccine meant to be used in case of an influenza pandemic of H5N1 avian influenza and is conducting clinical trials with these vaccines. Researchers at the University of Pittsburgh have had success with a genetically engineered vaccine that took only a month to make and completely protected chickens from the highly pathogenic H5N1 virus.According to the United States Department of Health & Human Services: In addition to supporting basic research on cell-based influenza vaccine development, HHS is currently supporting a number of vaccine manufacturers in the advanced development of cell-based influenza vaccines with the goal of developing U.S.-licensed cell-based influenza vaccines produced in the United States. Dose-sparing technologies. Current U.S.-licensed vaccines stimulate an immune response based on the quantity of HA (hemagglutinin) antigen included in the dose. Methods to stimulate a strong immune response using less HA antigen are being studied in H5N1 and H9N2 vaccine trials. These include changing the mode of delivery from intramuscular to intradermal and the addition of immune-enhancing adjuvant to the vaccine formulation. Additionally, HHS is soliciting contract proposals from manufacturers of vaccines, adjuvants, and medical devices for the development and licensure of influenza vaccines that will provide dose-sparing alternative strategies.Chiron Corporation is now recertified and under contract with the National Institutes of Health to produce 8,000–10,000 investigational doses of Avian Flu (H5N1) vaccine. MedImmune and Aventis Pasteur are under similar contracts. The United States government hopes to obtain enough vaccine in 2006 to treat 4 million people. However, it is unclear whether this vaccine would be effective against a hypothetical mutated strain that would be easily transmitted through human populations, and the shelf life of stockpiled doses has yet to be determined.The New England Journal of Medicine reported on March 30, 2006, on one of dozens of vaccine studies being conducted. The Treanor et al. study was on vaccine produced from the human isolate (A/Vietnam/1203/2004 H5N1) of a virulent clade 1 influenza A (H5N1) virus with the use of a plasmid rescue system, with only the hemagglutinin and neuraminidase genes expressed and administered without adjuvant. "The rest of the genes were derived from an avirulent egg-adapted influenza A/PR/8/34 strain. The hemagglutinin gene was further modified to replace six basic amino acids associated with high pathogenicity in birds at the cleavage site between hemagglutinin 1 and hemagglutinin 2. Immunogenicity was assessed by microneutralization and hemagglutination-inhibition assays with the use of the vaccine virus, although a subgroup of samples were tested with the use of the wild-type influenza A/Vietnam/1203/2004 (H5N1) virus." The results of this study combined with others scheduled to be completed by spring 2007 is hoped will provide a highly immunogenic vaccine that is cross-protective against heterologous influenza strains.On August 18, 2006. the World Health Organization (WHO) changed the H5N1 strains recommended for candidate vaccines for the first time since 2004. "The WHOs new prototype strains, prepared by reverse genetics, include three new H5N1 subclades. The hemagglutinin sequences of most of the H5N1 avian influenza viruses circulating in the past few years fall into two genetic groups, or clades. Clade 1 includes human and bird isolates from Vietnam, Thailand, and Cambodia and bird isolates from Laos and Malaysia. Clade 2 viruses were first identified in bird isolates from China, Indonesia, Japan, and South Korea before spreading westward to the Middle East, Europe, and Africa. The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO. Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections: Subclade 1, Indonesia Subclade 2, Middle East, Europe, and Africa Subclade 3, ChinaOn the basis of the three subclades, the WHO is offering companies and other groups that are interested in pandemic vaccine development these three new prototype strains: An A/Indonesia/2/2005-like virus An A/Bar headed goose/Quinghai/1A/2005-like virus An A/Anhui/1/2005-like virus[...] Until now, researchers have been working on prepandemic vaccines for H5N1 viruses in clade 1. In March, the first clinical trial of a U.S. vaccine for H5N1 showed modest results. In May, French researchers showed somewhat better results in a clinical trial of an H5N1 vaccine that included an adjuvant. Vaccine experts arent sure if a vaccine effective against known H5N1 viral strains would be effective against future strains. Although the new viruses will now be available for vaccine research, WHO said clinical trials using the clade 1 viruses should continue as an essential step in pandemic preparedness, because the trials yield useful information on priming, cross-reactivity, and cross-protection by vaccine viruses from different clades and subclades."</ref>As of November 2006, the United States Department of Health and Human Services (HHS) had enough H5N1 pre-pandemic vaccine to treat about 3 million people (5.9 million full-potency doses) in spite of 0.2 million doses used for research and 1.4 million doses that have begun to lose potency (from the original 7.5 million full-potency doses purchased from Sanofi Pasteur and Chiron Corp.). The expected shelf life of seasonal flu vaccine is about a year so the fact that most of the H5N1 pre-pandemic stockpile is still good after about two years is considered encouraging. Clinical trials H5N1 clinical trials are clinical trials concerning H5N1 vaccines. They are intended to discover pharmacological effects and identify any adverse reactions the vaccines may achieve in humans. References Further reading Khurana S, Suguitan AL, Rivera Y, Simmons CP, Lanzavecchia A, Sallusto F, Manischewitz J, King LR, Subbarao K, Golding H (April 2009). "Antigenic fingerprinting of H5N1 avian influenza using convalescent sera and monoclonal antibodies reveals potential vaccine and diagnostic targets". PLOS Med. 6 (4): e1000049. doi:10.1371/journal.pmed.1000049. PMC 2661249. PMID 19381279. External links "Diagnostic Targets and Potential Vaccine Against H5n1 Avian Influenza". U.S. Food and Drug Administration (FDA). 2019-10-21. US patent 8778847, "Immunogenic peptides of influenza virus", published 2010-11-11, issued 2014-06-25 "Pandemic Influenza". HHS.gov. 2016-07-14.
Tarka	Tarka may refer to: Tarka, also Chhaunk, in Indian cuisine is a method of seasoning food with spices heated in oil or ghee Tarka, Nigeria, a Local Government Area in Benue State, Nigeria Tarka, Niger Tarka the Otter, a 1927 novel by Henry Williamson Tarka Line, a railway line in Devon, England Tarka Trail, a series of footpaths assembled from former railway lines Tarka (medication), a brand name for an antihypertensive medication Tarka (flute), also tharqa, a traditional flute of the Andes David Tarka (born 1983), Australian football player Taharqa, Nubian pharaoh of the twenty-fifth Dynasty of Egypt Tarka (film), a 1988 Kannada language movie Taarka, an Oregonian quartet Tarka Cordell (1968–2008), British musician, writer and record producer Wiesław Tarka (born 1964), Polish diplomat The Tarka, an alien race in the video game Sword of the Stars See also Tarka sastra, an Indian science of dialectics, logic and reasoning
Fenoprofen	Fenoprofen is a nonsteroidal anti-inflammatory drug (NSAID). Fenoprofen calcium is used for symptomatic relief for rheumatoid arthritis, osteoarthritis, and mild to moderate pain. It has also been used to treat postoperative pain. Fenoprofen is marketed in the US as Nalfon. Pharmacology Decreases inflammation, pain, and fever, probably through inhibition of cyclooxygenase (COX-2 inhibitor) activity and prostaglandin synthesis. Chirality and biological activity Fenoprofen is chiral drug with one stereogenic center and exists as chiral twins. (S)-enantiomer has the desired pharmacological action where as the (R)-isomer is less active. It is observed that there is stereoselective bioconversion of the (R)- to (S)-fenoprofen. This stereoselective conversion is called chiral inversion. Contraindications History of significantly impaired renal function; patients with known hypersensitivity to any component of the product; patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs; treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. 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. Drug interactions Aminoglycosides (e.g. gentamicin): Plasma aminoglycoside levels may be elevated. Angiotensin-converting enzyme (ACE) inhibitors: Antihypertensive effect of ACE inhibitors may be diminished. Anticoagulants: Coadministration may prolong prothrombin time. Aspirin: Fenoprofen Cl may be increased; coadministration is not recommended. Diuretics: Patients treated with fenoprofen may be resistant to the effects of loop diuretics and thiazides. Hydantoins, sulfonamides, sulfonylureas: Fenoprofen may displace these drugs from their binding site. Lithium: Renal Cl of lithium may be reduced and plasma levels may be elevated, which may increase the risk of lithium toxicity. Methotrexate: May increase methotrexate levels. Phenobarbital: May decrease fenoprofen t 1⁄2 . Dosage adjustments of fenoprofen may be required if phenobarbital is added or withdrawn. SSRIs (e.g. fluoxetine, citalopram): The risk of GI effects may be increased. Laboratory test interactions False elevation in free and total serum T 3 as measured by Amerlex-M kit. Brand names UK - Fenopron (Typharm Limited) See also Ibuprofen Ketoprofen Thalidomide Chirality Chiral drugs Chiral inversion References External links Fenoprofen info from Drugs.com
Rifaximin	Rifaximin, is a non-absorbable, broad spectrum antibiotic mainly used to treat travelers diarrhea. It is based on the rifamycin antibiotics family. Since its approval in Italy in 1987, it has been licensed in over more than 30 countries for the treatment of a variety of gastrointestinal diseases like irritable bowel syndrome, and hepatic encephalopathy. It acts by inhibiting RNA synthesis in susceptible bacteria by binding to the RNA polymerase enzyme. This binding blocks translocation, which stops transcription. It is marketed under the brand name Xifaxan by Salix Pharmaceuticals. Medical uses Travelers’ Diarrhea (TD) Rifaximin is used to treat travelers diarrhea caused by certain bacteria (E. coli) in adults and children at least 12 years of age. It treats travelers diarrhea by stopping the growth of the bacteria that cause diarrhea. Rifaximin will not work to treat travelers diarrhea that is bloody or occurs with fever. Irritable Bowel Syndrome (IBS) Rifaximin is used for the treatment of irritable bowel syndrome. It possesses anti-inflammatory and antibacterial properties, and is a nonabsorbable antibiotic that acts locally in the gut. These properties make it efficacious in relieving chronic functional symptoms of non-constipation type irritable bowel syndrome (IBS). It appears to retain its therapeutic properties for this indication, even after repeated courses. It is particularly indicated where small intestine bacterial overgrowth is suspected of involvement in a persons IBS. Symptom relief or improvement can be obtained for global IBS symptoms, including: abdominal pain, flatulence, bloating, and stool consistency. A drawback is that repeated courses may be necessary for relapse of symptoms. Clostridium difficile Infection (CDI) Rifaximin may also be a useful addition to vancomycin when treating patients with relapsing C. difficile infection. However, the quality of evidence of these studies was judged to be low. Because exposure to rifamycins in the past may increase risk for resistance, rifaximin should be avoided in such cases. Hepatic Encephalopathy (HE) Rifaximin is used to prevent episodes of hepatic encephalopathy (changes in thinking, behavior, and personality caused by a build-up of toxins in the brain in people who have liver disease) in adults who have liver disease. It treats hepatic encephalopathy by stopping the growth of bacteria that produce toxins and that may worsen the liver disease. Although high-quality evidence is still lacking, it appears to be as effective as, or more effective than, other available treatments for hepatic encephalopathy (such as lactulose), is better tolerated, and may work faster. It prevents reoccurring encephalopathy and is associated with high patient satisfaction. People are more compliant and satisfied to take this medication than any other due to minimal side effects, prolonged remission, and overall cost. The drawbacks are increased cost, and lack of robust clinical trials for HE without combination lactulose therapy. Other uses Other uses include treatment of: infectious diarrhea, small intestinal bacterial overgrowth, inflammatory bowel disease, and diverticular disease. It is effective in treating small intestinal bacterial overgrowth regardless of whether it is associated with irritable bowel syndrome or not. It has also shown efficacy with rosacea, ocular rosacea which also presents as dry eyes for patients with co-occurrence with small intestinal bacterial overgrowth (SIBO). Special caution Patients should avoid Rifaximin usage if they are allergic to Rifabutin, Rifampin and Rifapentine. It may cause attenuated vaccines (such as typhoid vaccine) to not work well. Health care professionals should be informed about its usage before having any immunizations. Pregnant or breastfeeding women should avoid taking it as it is a pregnancy category C drug and can harm the foetus. Cautious use is required in individuals with cirrhosis of the liver who have a Child-Pugh score of class C severity. Side effects Rifaximin has an excellent safety profile due to its lack of systemic absorption. Clinical trials did not show any serious adverse events while using the drug. There were no deaths while using it in the clinical trials.The most common side effects includes nausea, stomach pain, dizziness, fatigue, headaches, muscle tightening and joint pain. It may also cause reddish discoloration of urine.The most serious side effects of Rifaximin are: Clostridium difficile-associated diarrhea (CDAD) Drug-resistant bacterial superinfection Severe allergic reactions including hives, rashes and itching Interactions As Rifaximin is not significantly absorbed from the gut, the great majority of these drug interactions are negligible in people with healthy liver function, so healthcare providers usually do not worry about drug interactions unless liver impairment is present. It may decrease the effectiveness of warfarin, a commonly prescribed anticoagulant, in people with liver problems. Pharmacology Rifaximin is a semisynthetic broad spectrum antibacterial drug, derived through chemical modification of the natural antibiotic rifamycin. It has very low bioavailability due to its poor absorption after oral administration. Because of this local action within the gut and the lack of horizontal transfer of resistant genes, the development of bacterial resistance is rare, and most of the drug taken orally stays in the gastrointestinal tract where the infection takes place. Mechanism of action Rifaximin interferes with transcription by binding to the β-subunit of bacterial RNA polymerase. This results in the blockage of the translocation step that normally follows the formation of the first phosphodiester bond, which occurs in the transcription process. This in turn results in a reduction of bacteria populations, including gas-producing bacteria, which may reduce mucosal inflammation, epithelial dysfunction, and visceral hypersensitivity. Rifaximin has broad spectrum antibacterial properties against both gram positive and gram negative anaerobic and aerobic bacteria. As a result of bile acid solubility, its antibacterial action is limited mostly to the small intestine and less so the colon. A resetting of the bacterial composition has also been suggested as a possible mechanism of action for relief of IBS symptoms. Additionally, rifaximin may have a direct anti-inflammatory effect on gut mucosa via modulation of the pregnane X receptor. Other mechanisms for its therapeutic properties include inhibition of bacterial translocation across the epithelial lining of the intestine, inhibition of adherence of bacteria to the epithelial cells, and a reduction in the expression of proinflammatory cytokines. Availability In the United States, Salix Pharmaceuticals holds a US Patent for rifaximin and markets the drug under the name Xifaxan. In addition to receiving FDA approval for travelers diarrhea and (marketing approved for) hepatic encephalopathy, rifaximin received FDA approval for IBS in May 2015. No generic formulation is available in the US and none has appeared due to the fact that the FDA approval process was ongoing. If rifaximin receives full FDA approval for hepatic encephalopathy it is likely that Salix will maintain marketing exclusivity and be protected from generic formulations until March 24, 2017. In 2018, a patent dispute with Teva was settled which delayed a generic in the United States, with the patent set to expire in 2029.Rifaximin is approved in 33 countries for GI disorders. On August 13, 2013, Health Canada issued a Notice of Compliance to Salix Pharmaceuticals Inc. for the drug product Zaxine. In India, it is available under the brand names Ciboz and Xifapill. In Russia and Ukraine the drug is sold under the name Alfa Normix (Альфа Нормикс), produced by Alfa Wassermann S.p.A. (Italy). In 2018, the FDA approved a similar drug by Cosmos Pharmaceuticals called Aemcolo for travelers diarrhea. References External links "Rifaximin". Drug Information Portal. U.S. National Library of Medicine.
Miltefosine	Miltefosine, sold under the trade name Impavido among others, is a medication mainly used to treat leishmaniasis and free-living amoeba infections such as Naegleria fowleri and Balamuthia mandrillaris. This includes the three forms of leishmaniasis: cutaneous, visceral and mucosal. It may be used with liposomal amphotericin B or paromomycin. It is taken by mouth.Common side effects include vomiting, abdominal pain, fever, headaches, and decreased kidney function. More severe side effects may include Stevens–Johnson syndrome or low blood platelets. Use during pregnancy appears to cause harm to the baby and use during breastfeeding is not recommended. How it works is not entirely clear.Miltefosine was first made in the early 1980s and studied as a treatment for cancer. A few years later it was found to be useful for leishmaniasis and was approved for this use in 2002 in India. It is on the World Health Organizations List of Essential Medicines. Medical uses Leishmaniasis Miltefosine is primarily used for the treatment of visceral and New World cutaneous leishmaniasis, and is undergoing clinical trials for this use in several countries. This drug is now listed as a core medication for the treatment of leishmaniasis under the WHO Model List of Essential Medicines. Several medical agents have some efficacy against visceral or cutaneous leishmaniasis, however, a 2005 survey concluded that miltefosine is the only effective oral treatment for both forms of leishmaniasis. Amoeba infections Miltefosine has been used successfully in some cases of the very rare, but highly lethal, brain infection by the amoeba, Naegleria fowleri, acquired through water entering the nose during a plunge in contaminated water. It has orphan drug status in the United States for acanthamoeba keratitis and primary amebic meningoencephalitis (PAM). Pregnancy and breastfeeding Miltefosine is listed as pregnancy category D by the FDA. This means there is evidence-based adverse reaction data from investigational or marketing experience or studies in humans of harm to the human fetus. Despite this evidence, the potential benefits of miltefosine may warrant use of the drug in pregnant women despite potential risks. A pregnancy test should be done prior to starting treatment. Effective birth control should be used while on miltefosine and 5 months after discontinuation of treatment. Its use during breast feeding is most likely unsafe. Contraindications Miltefosine is contraindicated in individuals who have a hypersensitivity to this medication, pregnant women, and people who have the Sjögren-Larsson syndrome. It is embryotoxic and fetotoxic in rats and rabbits, and teratogenic in rats but not in rabbits. It is therefore contraindicated for use during pregnancy, and contraception is required beyond the end of treatment in women of child-bearing age. Side effects Common side effects from miltefosine treatment are nausea and vomiting, which occur in 60% of people. Other common side effects are dizziness, headache, and daytime sleepiness.Serious side effects include rash, diarrhea, and arthritis. The side effects are more severe in women and young children. The overall effects are quite mild and easily reversed. Mechanism of action Miltefosine primarily acts on Leishmania by affecting the speciess promastigote and amastigote stages. Miltefosine exerts its activity by interacting with lipids, inhibiting cytochrome c oxidase and causing apoptosis-like cell death. This may affect membrane integrity and mitochondrial function of the parasite. History Cancer While initially studied as a cancer medication, due to side effects it was never used for this purpose.Phospholipid group alkylphosphocholine were known since the early 1980s, particularly in terms of their binding affinity with cobra venom. In 1987 the phospholipids were found to be potent toxins on leukemic cell culture. Initial in vivo investigation on the antineoplastic activity showed positive result, but then only at high dosage and at high toxicity. At the same time in Germany, Hansjörg Eibl, at the Max Planck Institute for Biophysical Chemistry, and Clemens Unger, at the University of Göttingen, demonstrated that the antineoplastic activity of the phospholipid analogue miltefosine (at the time known as hexadecylphosphocholine) was indeed tumour-specific. It was highly effective against methylnitrosourea-induced mammary carcinoma, but less so on transplantable mammary carcinomas and autochthonous benzo(a)pyrene-induced sarcomas, and relatively inactive on Walker 256 carcinosarcoma and autochthonous acetoxymethylmethylnitrosamine-induced colonic tumors of rats. It was subsequently found that miltefosine was structurally unique among lipids having anticancer property in that it lacks the glycerol group, is highly selective on cell types and acts through different mechanism. Leishmaniasis In the same year as the discovery of the anticancer property, miltefosine was reported by S. L. Croft and his team at the London School of Hygiene and Tropical Medicine as having antileishmanial effect as well. The compound was effective against Leishmania donovani amastigotes in cultured mouse peritoneal macrophages at a dose of 12.8 mg/kg/day in a five-day course. However, priority was given to the development of the compound for cutaneous metastases of breast cancer. In 1992 a new research was reported in which the compound was highly effective in mouse against different life cycle stages of different Leishmania species, and in fact, more potent than the conventional sodium stibogluconate therapy by a factor of more than 600. Results of the first clinical trial in humans were reported from Indian patients with chronic leishmaniasis with high degree of success and safety. This promising development promulgated a unique public–private partnership collaboration between ASTA Medica (later Zentaris GmbH), the World Health Organization (WHO) Special Programme for Research and Training in Tropical Diseases, and the Government of India. Eventually, several successful Phase II and III trials led to the approval of miltefosine in 2002 as the first and only oral drug for leishmaniasis. Naegleria fowleri and Acanthamoeba In 2013, the US Centers for Disease Control and Prevention recommended miltefosine for the treatment of free-living amoeba infections such as granulomatous amoebic encephalitis and primary amoebic meningoencephalitis, two fatal protozoal diseases. Historically, only four survivors have been recorded out of 138 confirmed infections in North America. One American survived the infection in 1978 and one individual from Mexico in 2003. In 2013, two children survived and recovered from primary amoebic meningoencephalitis after treatment with miltefosine. In 2016 after treatment that included miltefosine, another child became the fourth person in the United States to survive Naegleria fowleri infection. Society and culture Availability Since 2017 Miltefosine is commercially available in the United States through Profounda. Previously one could only get it from the CDC for emergency use under an expanded access IND protocol for treatment of free-living amoeba (FLA) infections: primary amoebic meningoencephalitis caused by Naegleria fowleri and granulomatous amoebic encephalitis caused by Balamuthia mandrillaris and Acanthamoeba species. Miltefosine is almost exclusively produced by Profounda, a private pharmaceutical company. Economics In the developing world a course of treatment costs US$65 to $150. In the developed world treatment may be 10 to 50 times greater. Further research It is active against some bacteria and fungi, as well as human trematode Schistosoma mansoni and the snail that spreads it Biomphalaria alexandrina. Antiprotozoal and antifungal activities Miltefosine is being investigated by researchers interested in finding treatments for infections which have become resistant to existing drugs. Animal and in vitro studies suggest it may have broad anti-protozoal and anti-fungal properties: Animal studies suggest miltefosine may also be effective against Trypanosoma cruzi, the parasite responsible for Chagas disease. Several studies have found the drug to be effective against types of fungus: Cryptococcus neoformans, Candida, Aspergillus and Fusarium. A 2006 in vitro study found that miltefosine is effective against metronidazole-resistant variants of Trichomonas vaginalis, a sexually transmitted protozoal disease. Cetrimonium bromide, a compound related to miltefosine, was demonstrated in 2007 to exhibit potent in vitro activity against Plasmodium falciparum. An in vitro test in 2006 showed that miltefosine is effective against the deadly protozoan pathogens, Naegleria fowleri, Balamuthia mandrillaris, and Acanthamoeba. However, later studies showed that it is not as potent as other drugs, such as chlorpromazine and diminazene aceturate (Berenil). In 2013, there were reports of failure of miltefosine in the treatment of leishmaniasis. Although drug resistance was suspected, studies in 2014 reported that miltefosine is not so effective in children, most probably related to a lack of drug exposure in children. Moverover, males appeared to have a higher probability of relapse as well. A 2012 in vitro study found that miltefosine had promising activity against Candida albicans biofilms. Anti-HIV activity Miltefosine targets HIV infected macrophages, which play a role in vivo as long-lived HIV-1 reservoirs. The HIV protein Tat activates pro-survival PI3K/Akt pathway in primary human macrophages. Miltefosine acts by inhibiting the PI3K/Akt pathway, thus removing the infected macrophages from circulation, without affecting healthy cells. It significantly reduces replication of HIV-1 in cocultures of human dendritic cells (DCs) and CD4+ T cells, which is due to a rapid secretion of soluble factors and is associated with induction of type-I interferon (IFN) in the human cells. References External links "Miltefosine". Drug Information Portal. U.S. National Library of Medicine. Max Planck Innovation FDA Panel Endorses Miltefosine for Leishmaniasis Med India Drugs.com
Lutetium (177Lu) oxodotreotide	Lutetium (177Lu) oxodotreotide (INN) or 177Lu DOTA-TATE, trade name Lutathera, is a chelated complex of a radioisotope of the element lutetium with DOTA-TATE, used in peptide receptor radionuclide therapy (PRRT). Specifically, it is used in the treatment of cancers which express somatostatin receptors.Alternatives to 177Lu-DOTATE include yttrium-90 DOTATATE or DOTATOC. The longer range of the beta particles emitted by 90Y, which deliver the therapeutic effect, may make it more suitable for large tumors with 177Lu reserved for smaller volumesThe U.S. Food and Drug Administration (FDA) considers 177Lu dotatate to be a first-in-class medication. Clinical trials and drug approval The European Commission approved lutetium (177Lu) oxodotreotide (trade name Lutathera) "for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs) in adults" in September 2017.177Lu DOTA-TATE was approved in the United States for the treatment of SSTR positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut and hindgut neuroendocrine tumors in adults, in January 2018. This was the first time a radiopharmaceutical had been approved for the treatment of GEP-NETs in the United States.The U.S. Food and Drug Administration (FDA) approved 177Lu dotatate based primarily on evidence from one clinical trial, NETTER-1 of 229 participants with somatostatin-receptor positive midgut GEP-NETs. Enrolled participants had tumors which could not be surgically removed and were worsening while receiving treatment with octreotide.Participants were randomly assigned to receive either 177Lu dotatate with long-acting octreotide or long-acting octreotide, at a higher dose, alone. 177Lu dotatate was injected through the vein and long-acting octreotide was injected in the muscle. Both, participants and health care providers knew which treatment was given. The benefit of 177Lu dotatate was evaluated by measuring the length of time that tumors did not grow after treatment and compared it to the control group (progression free survival).The FDA considered additional data from a second study based on data from 1,214 participants with somatostatin receptor-positive tumors, including GEP-NETS, who received 177Lu dotatate at a single site in the Netherlands, Erasmus MC. All participants received 177Lu dotatate with octreotide. Participants and health care providers knew which treatment was given. The benefit of 177Lu dotatate was evaluated by measuring if and how much the tumor size changed during treatment (the overall response rate). Complete or partial tumor shrinkage was reported in 16 percent of a subset of 360 participants with GEP-NETs who were evaluated for response by the FDA. Participants initially enrolled in the study received 177Lu dotatate as part of an expanded access program.The FDA granted the application for 177Lu dotatate priority review designation and orphan drug designation. The FDA granted the approval of Lutathera to Advanced Accelerator Applications. Adverse effects The therapeutic effect of 177Lu derives from the ionizing beta radiation it emits, however this can also be harmful to healthy tissue and organs. The kidneys are particularly at risk as they help to remove 177Lu DOTA-TATE from the body. To protect them, an amino acid solution (arginine/lysine) is administered by slow infusion, starting before the radioactive administration and normally continuing for several hours afterwards. References External links "Lutetium Lu 177 dotatate". Drug Information Portal. U.S. National Library of Medicine.
Triamcinolone acetonide	Triamcinolone acetonide is a synthetic corticosteroid medication used topically to treat various skin conditions, to relieve the discomfort of mouth sores, and intra-articularly by proceduralists to treat various joint conditions. It is also injected intralesionally (inside a lesion) to treat inflammation in some parts of the body, particularly the skin. In nasal spray form, it is used to treat allergic rhinitis. It is a more potent derivative of triamcinolone, and is about eight times as potent as prednisone. It is used for the treatment of macular edema associated with uveitis.It is also known under the brand names Kenalog (topical) and Volon A as an injection, to treat allergies, arthritis, eye diseases, intestinal problems, and skin diseases. In 2014, the U.S. Food and Drug Administration (FDA) made triamcinolone acetonide an over-the-counter drug in the United States in nasal spray form under the brand name Nasacort. Medical uses Triamcinolone acetonide as an intra-articular injectable has been used to treat a variety of musculoskeletal conditions. When applied to the skin as a topical ointment, it is used to mitigate blistering from poison ivy, oak, and sumac. When combined with nystatin, it is used to treat skin infections with discomfort from fungus, though it should not be used on the eyes. It provides relatively immediate relief and is used before using oral prednisone. Oral and dental paste preparations are used for treating aphthous ulcers. As an intravitreal injection, triamcinolone acetonide has been used to treat various eye diseases and has been found useful in reducing macular edema. Drug trials have found it to be as efficient as anti-VEGF drugs in eyes with artificial lenses over a two-year period. A systematic review did not find any evidence of any benefit in preventing vision loss in eyes treated with triamcinolone acetonide over placebo, for patients with age-related macular degeneration.Triamcinolone acetonide is also administered via intralesional injection in the treatment of hypertrophic and keloid scars.Uncommonly, intramuscular injection of triamcinolone acetonide may be indicated for the control of severe or incapacitating allergic states for which conventional treatments have failed, such as asthma, atopic dermatitis, contact dermatitis, perennial or seasonal allergic rhinitis, serum sickness, and transfusion and drug hypersensitivity reactions. Contraindications Evidence suggests that usage of triamcinolone acetonide or other steroids to treat macular edema increases the risk of increasing intraocular pressure in patients.Triamcinolone acetonide should not be used by those with tuberculosis or untreated fungal, bacterial, systemic viral or herpes simplex infections without consulting a doctor first. Pharmacology Pharmacodynamics Triamcinolone acetonide is a corticosteroid. It is specifically a glucocorticoid, or an agonist of the glucocorticoid receptor, that is about five times as potent as cortisol. It has very little mineralocorticoid effects. The affinities of triamcinolone acetonide for the androgen and estrogen receptors are both <0.1% (relative to testosterone and estradiol). However, triamcinolone acetonide has 15% of the affinity of progesterone for the progesterone receptor. In relation to this, triamcinolone acetonide can produce endocrine side effects like ovulation inhibition and menstrual irregularities. Chemistry Triamcinolone acetonide, also known as 9α-fluoro-16α-hydroxyprednisolone 16α,17α-acetonide or as 9α-fluoro-11β,16α-17α,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone, is a synthetic halogenated cyclic ketal pregnane corticosteroid. It is the C16α,17α acetonide of triamcinolone. Veterinary use Triamcinolone acetonide is also used in veterinary medicine as an ingredient in topical ointments and in topical sprays for control of pruritus in dogs. A series of injections with triamcinolone acetonide or another corticosteroid may reduce keloid size and irritation. It is used as a preinductor and/or inductor of birth in cows. It was also used in the horse racing industry, but it is now a banned substance if found in a horses system on race day. See also Topical steroid References External links "Triamcinolone acetonide". Drug Information Portal. U.S. National Library of Medicine. "Triamcinolone". MedlinePlus. "Triamcinolone Nasal Spray". MedlinePlus.
Daunorubicin/cytarabine	Daunorubicin/cytarabine is a fixed-dose combination medication used for the treatment of acute myeloid leukemia. It contains the liposomal bound daunorubicin, an anthracycline topoisomerase inhibitor, and cytarabine, a nucleoside metabolic inhibitor. Medical uses Daunorubicin/cytarabine is indicated for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in people aged one year of age and older. References External links "Cytarabine mixture with daunorubicin". Drug Information Portal. U.S. National Library of Medicine.
Caffeine/ergotamine	Caffeine/ergotamine (trade name Cafergot) is the proprietary name of a medication consisting of ergotamine tartrate and caffeine. This combination is used for the treatment of headaches, such as migraine headache. Use Correct timing of use is important. Cafergot is an abortive headache treatment, which prevents the development of the headache, rather than a treatment for an established headache. The medication should be administered at the first sign of headache. There exist some limitations as to the maximum number of tablets that can be taken per day per week. Different sources of drug information may carry different information, and patients are encouraged to ask their pharmacist or prescriber about such details. Cafergot is currently available as a generic drug (ergotamine tartrate/caffeine) Mechanism of action According to a topic review on UpToDate, "ergotamine and dihydroergotamine (DHE 45) bind to 5HT 1b/d receptors, just as triptans do." This along with binding to other serotonergic and dopaminergic receptors is their presumed mechanism of action in treating migraine. Adverse effects Because the vasoconstrictive effects of ergotamine and caffeine are not selective for the brain, adverse effects due to systemic vasoconstriction can occur. Cold feet or hands, angina pectoris, myocardial infarction, or dizziness are some examples. == References ==
Methyltestosterone	Methyltestosterone, sold under the brand names Android, Metandren, and Testred among others, is an androgen and anabolic steroid (AAS) medication which is used in the treatment of low testosterone levels in men, delayed puberty in boys, at low doses as a component of menopausal hormone therapy for menopausal symptoms like hot flashes, osteoporosis, and low sexual desire in women, and to treat breast cancer in women. It is taken by mouth or held in the cheek or under the tongue.Side effects of methyltestosterone include symptoms of masculinization like acne, increased hair growth, voice changes, and increased sexual desire. It can also cause estrogenic effects like fluid retention, breast tenderness, and breast enlargement in men and liver damage. The drug is a synthetic androgen and anabolic steroid and hence is an agonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has moderate androgenic effects and moderate anabolic effects, which make it useful for producing masculinization.Methyltestosterone was discovered in 1935 and was introduced for medical use in 1936. It was made shortly after the discovery of testosterone and was one of the first synthetic AAS to be developed. In addition to its medical use, methyltestosterone is used to improve physique and performance, although it is not as commonly used as other AAS for such purposes due to its androgenic effects, estrogenic effects, and risk of liver damage. The drug is a controlled substance in many countries and so non-medical use is generally illicit. Uses Medical Methyltestosterone is or has been used in the treatment of delayed puberty, hypogonadism, cryptorchidism, and erectile dysfunction in males, and in low doses to treat menopausal symptoms (specifically for osteoporosis, hot flashes, and to increase libido and energy), postpartum breast pain and engorgement, and breast cancer in women. It is specifically approved in the United States for the treatment of hypogonadism and delayed puberty in males and the treatment of advanced inoperable breast cancer in females. It was also approved in low doses in combination with esterified estrogens for the treatment of moderate to severe vasomotor symptoms associated with menopause in women in the United States, but this formulation was discontinued and hence is no longer used.Methyltestosterone is less effective in inducing masculinization than testosterone, but is useful for maintaining established masculinization in adults.The dosages of methyltestosterone used are 10 to 50 mg/day in men for common medical uses like hypogonadism and delayed puberty as well as physique- and performance-enhancing purposes and 2.5 mg/day in women for menopausal symptoms. Higher dosages of 50 to 200 mg/day have been used to treat women with inoperable breast cancer that has failed to respond to other therapies, although such dosages are associated with severe irreversible virilization. Non-medical Methyltestosterone is used for physique- and performance-enhancing purposes by competitive athletes, bodybuilders, and powerlifters, although it is not commonly used relative to other AAS for such purposes. Available forms Methyltestosterone is typically used as an oral medication. It is also available under the brand names Metandren and Oreton Methyl for use specifically by buccal or sublingual administration. Methyltestosterone is available in the form of 2, 5, 10, and 25 mg oral tablets. It was also available in combination with estrogens as esterified estrogens/methyltestosterone (0.625 mg/1.25 mg, 1.25 mg/2.5 mg) and conjugated estrogens/methyltestosterone (0.625 mg/5.0 mg, 1.25 mg/10 mg). Contraindications Methyltestosterone should be used with caution in women and children, as it can cause irreversible virilization. Due to its estrogenicity, methyltestosterone can also accelerate epiphyseal closure and thereby produce short stature in children and adolescents. It can worsen symptoms in men with benign prostatic hyperplasia. Methyltestosterone should not be used in men with prostate cancer, as androgens can accelerate tumor progression. The drug should be used with caution in patients with pre-existing hepatotoxicity, due to its own potential for hepatotoxicity. Side effects Adverse effects of methyltestosterone include androgenic side effects like oily skin, acne, seborrhea, increased facial/body hair growth, scalp hair loss, increased aggressiveness and sex drive, and spontaneous erections, as well as estrogenic side effects like breast tenderness, gynecomastia, fluid retention, and edema. In women, methyltestosterone can cause partially irreversible virilization, for instance voice deepening, hirsutism, clitoromegaly, breast atrophy, and muscle hypertrophy, as well as menstrual disturbances and reversible infertility. In men, the drug may also cause hypogonadism, testicular atrophy, and reversible infertility at sufficiently high dosages.Methyltestosterone can sometimes cause hepatotoxicity, for instance elevated liver enzymes, cholestatic jaundice, peliosis hepatis, hepatomas, and hepatocellular carcinoma, with extended use. It can also have adverse effects on the cardiovascular system. AAS like methyltestosterone stimulate erythropoiesis (red blood cell production) and increase hematocrit levels and at high dosages can cause polycythemia (overproduction of red blood cells), which can greatly increase the risk of thrombic events such as embolism and stroke. With long-term treatment, AAS can increase the risk of benign prostatic hyperplasia and prostate cancer. Violent and even homicidal behavior, hypomania/mania, depression, suicidality, delusions, and psychosis have all been associated with very high dosages of AAS. Interactions Aromatase inhibitors can be used to reduce or prevent the estrogenic effects of methyltestosterone and 5α-reductase inhibitors can be used to prevent its potentiation in so-called "androgenic" tissues and thereby improve its ratio of anabolic to androgenic activity and reduce its rate of androgenic side effects. Antiandrogens like bicalutamide and cyproterone acetate can block both the anabolic and androgenic effects of AAS like methyltestosterone. Pharmacology Pharmacodynamics As an AAS, methyltestosterone is an agonist of the androgen receptor (AR), similarly to androgens like testosterone and dihydrotestosterone (DHT). It is a substrate for 5α-reductase like testosterone, and so is potentiated analogously in so-called "androgenic" tissues like the skin, hair follicles, and prostate gland via transformation into the more potent AR agonist mestanolone (17α-methyl-DHT). As such, methyltestosterone has a relatively low ratio of anabolic to androgenic activity, with a similar ratio to that of testosterone (close to 1:1), and this makes it among the most androgenic AAS. Due to efficient aromatization into the potent and metabolism-resistant estrogen methylestradiol (17α-methylestradiol), methyltestosterone has relatively high estrogenicity and hence potential for estrogenic side effects such as gynecomastia and fluid retention. The drug possesses negligible progestogenic activity.Due to its combined disadvantages of a relatively poor ratio of anabolic to androgenic activity, unusually high estrogenicity, and the potential for hepatotoxicity (as with other 17α-alkylated AAS), methyltestosterone has not been used as commonly as many other AAS either in medicine or for physique- or performance-enhancing purposes. Pharmacokinetics Absorption Methyltestosterone has dramatically improved oral bioavailability and metabolic stability relative to testosterone. This difference is due to the C17α methyl group, which results in steric hindrance and prevents metabolism. The oral bioavailability of methyltestosterone is about 70%, and it is well-absorbed from the gastrointestinal tract. Methyltestosterone can also be taken buccally or sublingually. Although effective orally, methyltestosterone is more effective by these non-oral routes, which are said to approximately double its bioavailability and require half the oral dosage.Circulating levels of methyltestosterone with administration of 1.25 to 2.5 mg/day oral methyltestosterone in women are in the range of 20 to 30 ng/dL. For comparison to testosterone, methyltestosterone is at least as potent as an AAS. However, due to the large decrease in sex hormone-binding globulin (SHBG) levels and hence increase in free unbound testosterone caused by methyltestosterone, androgenic effects may be greater than reflected merely by methyltestosterone levels. Distribution Methyltestosterone is highly protein-bound, by approximately 98%. The medication has low but significant affinity for human serum sex hormone-binding globulin (SHBG), about 25% of that of testosterone and 5% of that of DHT. Metabolism The biological half-life of methyltestosterone is approximately 3 hours (range 2.5–3.5 hours). The duration of action of methyltestosterone is said to be 1 to 3 days, and is described as relatively short among AAS. Excretion Methyltestosterone is excreted 90% in the urine as conjugates and other metabolites, and 6% in feces. Chemistry Methyltestosterone, also known as 17α-methyltestosterone or as 17α-methylandrost-4-en-17β-ol-3-one, is a synthetic, 17α-alkylated androstane steroid and a derivative of testosterone differing from it only in the presence of a methyl group at the C17α position. Close synthetic relatives of methyltestosterone include metandienone (17α-methyl-δ1-testosterone) and fluoxymesterone (9α-fluoro-11β-hydroxy-17α-methyltestosterone). Derivatives Methyltestosterone and ethyltestosterone (17α-ethyltestosterone) are the parent structures of all 17α-alkylated AAS. Major 17α-alkylated AAS include the testosterone derivatives fluoxymesterone, metandienone (methandrostenolone), and methyltestosterone and the DHT derivatives oxandrolone, oxymetholone, and stanozolol. Synthesis A chemical synthesis of methyltestosterone from dehydroepiandrosterone (DHEA) with methandriol as an intermediate proceeds as follows: History Methyltestosterone was first synthesized in 1935 along with methandriol and mestanolone. It was the second synthetic AAS to be developed, following mesterolone (1α-methyl-DHT) in 1934, and was the first 17α-alkylated AAS to be synthesized. The drug was introduced for medical use in 1936. Society and culture Generic names Methyltestosterone is the INN, USAN, USP, BAN, and JAN of the drug and its generic name in English and Japanese, while méthyltestostérone is its DCF and French name and metiltestosterone is its DCIT and Italian name. The generic name of the drug is methyltestosterone in Latin, methyltestosteron in German, and metiltestosterona in Spanish. Methyltestosterone is also known by its former developmental code name NSC-9701. Brand names Brand names under which methyltestosterone is or has been marketed for medical use include Afro, Agovirin, Android, Androral, Mesteron, Metandren, Methitest, Methyltestosterone, Methyl Testosterone, Oraviron, Oreton, Oreton Methyl, Testormon, Testovis, Testred, and Virilon, among others. With an estrogen Methyltestosterone is available at a low-dose in combination with esterified estrogens for the treatment of menopausal symptoms like hot flashes in women under the brand names Covaryx, Essian, Estratest, Menogen, and Syntest. Availability United States Although it is not commonly used, methyltestosterone is one of the few AAS that remains available for medical use in the United States. The others are testosterone, testosterone cypionate, testosterone enanthate, testosterone undecanoate, oxandrolone, oxymetholone, and fluoxymesterone. Other countries Methyltestosterone has also been marketed in many other countries throughout the world. Legal status Methyltestosterone, along with other AAS, is a schedule III controlled substance in the United States under the Controlled Substances Act and a schedule IV controlled substance in Canada under the Controlled Drugs and Substances Act. See also Esterified estrogens/methyltestosterone Conjugated estrogens/methyltestosterone References Further reading Phillips EH, Ryan S, Ferrari R, Green C (2003). "Estratest and Estratest HS (esterified estrogens and methyltestosterone) therapy: a summary of safety surveillance data, January 1989 to August 2002". Clin Ther. 25 (12): 3027–43. doi:10.1016/s0149-2918(03)90090-7. PMID 14749144. Kabat GC, Kamensky V, Heo M, Bea JW, Hou L, Lane DS, Liu S, Qi L, Simon MS, Wactawski-Wende J, Rohan TE (2014). "Combined conjugated esterified estrogen plus methyltestosterone supplementation and risk of breast cancer in postmenopausal women". Maturitas. 79 (1): 70–6. doi:10.1016/j.maturitas.2014.06.006. PMID 25011395. El-Desoky el-SI, Reyad M, Afsah EM, Dawidar AA (2016). "Synthesis and chemical reactions of the steroidal hormone 17α-methyltestosterone". Steroids. 105: 68–95. doi:10.1016/j.steroids.2015.11.004. PMID 26639430. S2CID 32620483. External links Methyltestosterone - William Llewellyns Anabolic.org
Potassium chloride (medical use)	Potassium chloride, also known as potassium salt, is used as a medication to treat and prevent low blood potassium. Low blood potassium may occur due to vomiting, diarrhea, or certain medications. The concentrated version should be diluted before use. It is given by slow injection into a vein or by mouth.Side effects may include heart problems if given too quickly by injection into a vein. By mouth it can result in abdominal pain, peptic ulcer disease, or gastrointestinal bleeding. Greater care is recommended in those with kidney problems. As long as high blood potassium does not occur, use in pregnancy or breastfeeding is believed to be safe for the baby. Generally, the strength of the formulation for injection into a vein should not be greater than 40 mmol/L (3 mg/L).Potassium chloride came into large scale commercial use as a fertilizer in 1861 and has been used medically since the 1950s. It is on the World Health Organizations List of Essential Medicines. Potassium chloride is available as a generic medication. In 2020, it was the 33rd most commonly prescribed medication in the United States, with more than 17 million prescriptions. Medical use Potassium chloride is used in the treatment of hypokalemia as an electrolyte replenisher. With a molecular weight of approximately 75 and a valence of 1, the use of KCl for electrolytes makes 75 mg the equivalent of 1 mEq. Some cardiac surgery procedures cannot be carried out on the beating heart. For these procedures, the surgical team will bypass the heart with a heart-lung machine and inject potassium chloride into the heart muscle to stop the heartbeat. Side effects Side effects can include gastrointestinal discomfort, including nausea and vomiting, diarrhea, and bleeding of the digestive tract. Overdoses cause hyperkalemia, which can lead to paresthesia, cardiac conduction blocks, fibrillation, arrhythmias, and sclerosis.Because of the risk of small-bowel lesions, the US FDA requires some potassium salts containing more than 99 mg (about 1.3 mEq) to be labeled with a warning, while recommending an adult daily intake of 4700 mg (about 63 mEq). History Slow-K is a 1950s development where the medicine is formulated to enter the bloodstream at delayed intervals. It was first only prescribed to British military forces to balance their diets while serving in Korea. Society Brand names Brand names include K-Dur, Klor-Con, Micro-K, Slow-K, Sando-K, and Kaon Cl, most of which are extended release medicine by mouth. Lethal injection Potassium chloride is used in lethal injection as the third of a three-drug combination. KCl is also sometimes used in fetal intracardiac injections in second- and third-trimester induced abortions. Jack Kevorkians thanatron machine injected a lethal dose of potassium chloride into the patient, which caused the heart to stop functioning, after a sodium thiopental-induced coma was achieved.Cardiac arrest induced by potassium has been used in political assassinations in Iran, by injection or by inserting a potassium suppository into the victims rectum. References External links "Potassium chloride". Drug Information Portal. U.S. National Library of Medicine.
Lixisenatide	Lixisenatide (trade name Lyxumia in the European Union and Adlyxin in the U.S. and manufactured by Sanofi) is a once-daily injectable GLP-1 receptor agonist for the treatment of type 2 diabetes. Medical use Lixisenatide is used as adjunct to diet and exercise to treat type 2 diabetes. In the European Union, its use is limited to complementing insulin therapy. As of 2017 it is unclear if they affect a persons risk of death.It is provided in an autoinjector containing fourteen doses and is injected subcutaneously.Lixisenatide should not be used for people who have problems with stomach emptying. Lixisenatide delays emptying of the stomach, which may change how quickly other drugs that are taken by mouth take effect. Lixisenatide in neurodegenerative diseases Results from a research work which was done by McClean PL et al. demonstrated that the GLP-1 receptor agonists liraglutide and lixisenatide which are on the market as treatments for type 2 diabetes show promise as potential drug treatments of Alzheimer disease AD. Lixisenatide was equally effective at a lower dose compared to liraglutide in some of the measured parameters after ten weeks of daily intraperitoneal injections with liraglutide (2.5 or 25 nmol/kg) or lixisenatide (1 or 10 nmol/kg) or saline of APP/PS1 mice at an age when amyloid plaques had already formed. When analyzing synaptic plasticity in the hippocampus, LTP was strongly increased in APP/PS1 mice by either drug, with more effectiveness accomplished with lixisenatide. The reduction of synapse numbers seen in APP/PS1 mice was prevented by the two drugs. The amyloid plaque load and dense-core Congo red positive plaque load in the cortex were reduced by both drugs at all doses. The chronic inflammation response (microglial activation) was also reduced by all treatments Cai HY et al. demonstrated in a study that lixisenatide could reduce amyloid plaques, neurofibrillary tangles and neuroinflammation in the hippocampi of 12-month-old APP/PS1/tau female mice; activation of PKA-CREB signaling pathway and inhibition of p38-MAPK might be the important mechanisms in the neuroprotective function of lixisenatide. So, lixisenatide might have the potential to be developed as a novel therapy for AD Liu Wet al found an interesting results when comparing exendin-4 (10 nmol/kg), liraglutide (25 nmol/kg) and lixisenatide (10 nmol/kg), it was found that exendin-4 showed no protective effects at the dose chosen, while both liraglutide and lixisenatide showed effects in preventing the MPTP-induced motor impairment (Rotarod, open-field locomotion, catalepsy test), reduction in tyrosine hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, a reduction of the pro-apoptotic signaling molecule BAX and an increase in the anti-apoptotic signaling molecule B-cell lymphoma-2. The previous results demonstrate that both liraglutide and lixisenatide are superior to exendin-4, and both drugs show promise as a novel treatment of Parkinson disease Another study done by Kerry Hunter et al. profiled the GLP-1 receptor agonists liraglutide and lixisenatide. The kinetics of crossing the blood brain barrier (BBB), activation of the GLP-1R by measuring cAMP levels, and physiological effects in the brain on neuronal stem cell proliferation and neurogenesis were evaluated. Both drugs were able to cross the BBB. Lixisenatide crossed the BBB at all doses tested (2.5, 25, or 250 nmol/kg ip.) when measured 30 min post-injection and at 2.5-25 nmol/kg ip. 3 h post-injection. Lixisenatide also enhanced neurogenesis in the brain. Liraglutide crossed the BBB at 25 and 250 nmol/kg ip. but no increase was detectable at 2.5 nmol/kg ip. 30 min post-injection, and at 250 nmol/kg ip. at 3 h post-injection. Liraglutide and lixisenatide enhanced cAMP levels in the brain, with lixisenatide being more effective. The previous results suggest that these novel incretin analogues cross the BBB showing physiological activity and neurogenesis in the brain, which makes them good candidates to be used as a treatment of neurodegenerative diseases. Adverse effects In about 0.1% of cases people have had anaphylactic reactions to lixisenatide and in about 0.2% of cases the drug has caused pancreatitis. Use with insulin or sulfonylurea may cause hypoglycemia. In some cases, people with no kidney disease have had acute kidney injury and in some people with existing kidney disease the condition has gotten worse. Because lixisenatide is a peptide people can and do develop an immune response to it that will eventually make the drug ineffective; people who have developed antibodies to lixisenatide tend to have more inflammation at the injection site.At least 5% of people had nausea, vomiting, diarrhea, headache, or dizziness after taking lixisenatide. Mechanism of action Lixisenatide is a member of the class of glucagon-like peptide-1 receptor agonist drugs, each of which activates the GLP-1 receptor. GLP-1 is a hormone that helps pancreatic beta cells to secrete insulin in response to high blood sugar. Because it works like the normal hormone, insulin is only secreted when blood sugar is high. Like GLP-1, it also slows gastric emptying. Chemistry Lixisenatide is a peptide made of 44 amino acids, with an amide group on its C terminus.has been described as "des-38-proline-exendin-4 (Heloderma suspectum)-(1–39)-peptidylpenta-L-lysyl-L-lysinamide", meaning it is derived from the first 39 amino acids in the sequence of the peptide exendin-4, that was isolated from the Gila monster venom, omitting proline at position 38 and adding six lysine residues. Its complete sequence is: H–His–Gly–Glu–Gly–Thr–Phe–Thr–Ser–Asp–Leu–Ser–Lys–Gln–Met–Glu–Glu–Glu–Ala–Val–Arg–Leu–Phe–Ile–Glu–Trp–Leu–Lys–Asn–Gly–Gly–Pro–Ser–Ser–Gly–Ala–Pro–Pro–Ser–Lys–Lys–Lys–Lys–Lys–Lys–NH2 History It was created by Zealand Pharma A/S of Denmark; in 2003 Zealand licensed it to Sanofi which developed the drug. Lixisenatide was approved by the European Commission on February 1, 2013. Sanofi submitted an NDA in the US, which was accepted for review by the US FDA in February 2013 but after discussions with the FDA about the cardiovascular safety data included in the package (starting in 2008, the FDA had required stronger CV safety data for new anti-diabetes drugs, following the controversy around the risks of Avandia) Sanofi decided to withdraw the NDA and wait for the results of a Phase III study that was scheduled to be completed in 2015. Because the drug was the first GLP-1 agonist that could be taken once a day, sales projections in 2013 were €500M per year by 2018. Sanofi resubmitted the application which the FDA accepted in September 2015, by which time Sanofi had lost the lead in the field of anti-diabetic drugs to Novo Nordisk. Lixisenatide received FDA approval on July 28, 2016.In 2010, Zeland and Sanofi extended their license agreement to allow Sanofi to develop a combination therapy of lixisenatide with insulin glargine, which was Sanofis best selling drug at the time, with sales of around €3 billion in 2009. Sanofi planned to start the Phase III trial that year. Sanofi submitted the NDA in December 2015 for the combination, called LixiLan and it was considered by the same Endocrinologic and Metabolic Drugs Advisory FDA Committee that was considering lixisenatide as a single agent. In May 2016 by a vote of 12–2, with several members of the committee expressing reservations about Sanofis plans to offer two pens with different ratios of insulin glargine and lixisenatide - one for people who had never taken insulin before and one for people who had; there was also concern about how to handle dosing when switching people from a single drug regimen to the combination drug. In August 2016 the FDA told Sanofi that it was delaying a final decision for three months, and asked Sanofi for more data on how people used the delivery devices.Patent protection for lixisenatide expires in 2020. References External links "Lixisenatide". Drug Information Portal. U.S. National Library of Medicine.
Oxybuprocaine	Oxybuprocaine (INN), also known as benoxinate or BNX, is an ester-type local anesthetic, which is used especially in ophthalmology and otolaryngology. Oxybuprocaine is sold by Novartis under the brand names Novesine or Novesin. Safety for use in pregnancy and lactation has not been established. Uses In ophthalmology in order to numb the surface of the eye (the outermost layers of the cornea and conjunctiva) for the following purposes:in order to perform a contact/applanation tonometry, for small operations, in order to remove small foreign objects from the uppermost layer of the cornea or conjunctiva; in otolaryngology for numbing the mucous membranes of the nostrils and pharynx, for diagnostic purposes and small operations, for numbing the mucous membranes of bronchi, for example in bronchoscopy, Pharmacokinetics Anaesthesia starts with a latency of 30 to 50 seconds and lasts for about 10 to 30 minutes, depending on perfusion. The drug is metabolised by esterases in blood plasma and liver. Adverse effects When used excessively, oxybuprocaine like any other topical anesthetic used in the eye and on mucous membranes (like for example tetracaine, proxymetacaine and proparacaine) can cause irritation, hypersensitivity, anaphylaxis, irreversible corneal damage and even complete destruction of the cornea. (Excessive use means several times a day during several days or even weeks.) Interactions Oxybuprocaine is incompatible with silver and mercury salts, as well as basic substances. It also reduces the antimicrobial action of sulfonamides. See also Topical anesthetic == References ==
Ibuprofen/paracetamol	Ibuprofen/paracetamol, sold under the brand name Combiflam among others, is a fixed-dose combination of the two medications, ibuprofen, and paracetamol (acetaminophen). It is available in India, the United States, and Australia. It may be used for fever, headache, muscle pain and menstrual cramps. Ibuprofen belongs to nonsteroidal anti-inflammatory drug (NSAID) class of drugs. There is evidence that paracetamol combined with an NSAID provides pain relief better than either drug used alone. Adverse effects References External links "Acetaminophen mixture with ibuprofen". Drug Information Portal. U.S. National Library of Medicine.
Teduglutide	Teduglutide (brand names Gattex in the US and Revestive in Europe) is a 33-membered polypeptide and glucagon-like peptide-2 (GLP-2) analog that is used for the treatment of short bowel syndrome. It works by promoting mucosal growth and possibly restoring gastric emptying and secretion. In Europe it has been granted orphan drug status and is marketed under the brand Revestive by Nycomed. It was approved by the United States under the name Gattex on 21 December 2012, where it was given status as an orphan drug. Medical uses Up to a certain point, the gut can adapt to partial resections that result in short bowel syndrome. Still, parenteral substitution of water, minerals and vitamins (depending on which part of the gut has been removed) is often necessary. Teduglutide may reduce or shorten the necessity of such infusions by improving the intestinal mucosa and possibly by other mechanisms. Adverse effects Common adverse effects in clinical studies included abdominal discomfort (49% of patients), respiratory infections (28%), nausea (27%) and vomiting (14%), local reactions at the injection site (21%), and headache (17%). Chemistry and mechanism of action Teduglutide differs from natural GLP-2 by a single amino acid: an alanine is replaced with a glycine. This blocks breaking down of the molecule by dipeptidyl peptidase and increases its half-life from seven minutes (GLP-2) to about two hours, while retaining its biological actions. These include maintenance of the intestinal mucosa, increasing intestinal blood flow, reducing gastrointestinal motility and secretion of gastric acid. == References ==
Thymoglobulin	Thymoglobulin (manufactured by Sanofi) is an anti-human thymocyte immunoglobulin preparation made of purified polyclonal antibodies derived from rabbits. While these antibodies have a variety of specificities, their main mechanism of immunosuppression is through depletion of T cells. Thymoglobulin is currently approved for clinical use in Europe and the United States for renal allograft rejection, prevention of graft-vs.-host disease, and conditions involving bone marrow failure, including aplastic anemia and has additional off-label uses. History of antithymocyte globulin Antithymocyte globulin (ATG) was originally developed as one of various tested preparations of antilymphocyte globulin (ALG) specifically generated against human lymphocytes within the thymus, or thymocytes. The purpose of this research was largely to produce an effective immunosuppressive agent safe for use in humans. Since the discovery of a link between antilymphocyte serum (ALS) and lymphocyte depletion by Metchnikoff in 1899, various studies have demonstrated the immunosuppressive ability of ALG and ATG. Experiments on ALS that confirmed its efficacy in lymphocyte depletion led to testing of different types of preparations including ALG, which were ALS produced against human lymphocytes, and ATG.A number of studies conducted in the 1960s, including studies by Starzl et al. and Mathe et al., resulted in promising data for the clinical use of ALG for preserving short-term and long-term kidney function in patients immediately after human kidney transplantation. Use of equine ALG was also found to be efficacious in preventing acute graft-vs.-host-disease in patients’ post-allogeneic bone marrow transplantation. Experimentation with ALG and ATG preparations from different sources followed, leading to testing of ATG derived from rabbit serum. Thymoglobulin was the first commercial rabbit-derived ATG to be introduced in Europe and the US in the 1980s. Due to its demonstrated efficacy as an immunosuppressive agent, it remains a commonly used ATG for induction therapy and treatment of other associated conditions, such as graft-vs.-host disease and aplastic anemia. Mechanism of immunosuppression As an rATG, thymoglobulin consists of polyclonal antibodies, which, unlike monoclonal antibodies, target a large variety of immune cell surface proteins, including B and T lymphocyte, natural killer cell, and plasma cell surface antigens. However, its efficacy as an immunosuppressive agent is primarily through rapid induced apoptosis of CD3+ T cells present in the bloodstream. Even at low levels of concentration (up to 1 ug/mL), rATG T-cell depletive ability is still sound, but higher concentrations of ATG can induce lysis of T lymphocytes through the classical complement pathway along with B cell and NK cell depletion as well . Thymoglobulin has also demonstrated the ability to induce expression of a number of regulatory cell markers in vitro, including CD25, GITR, and CTLA-4 (aka CD152, functions as immune checkpoint, downregulates immune response). Recent research has suggested that Thymoglobulin may also contribute to T-cell anergy, in which T-cells remain inactive, though further research must be done to confirm this interaction. Clinical applications Thymoglobulin is commonly used to prevent and treat acute rejection and increase graft survival in solid organ transplantation (SOT), especially kidney, liver, pancreas, and heart transplantation. As multiple studies have demonstrated both its efficacy and safety in a clinical setting, it is also used in different minimization regimens to reduce the application of higher risk immunosuppressive agents such as corticosteroids and calcineurin inhibitors (CNIs) in solid organ transplantation. Because both corticosteroids and CNIs have been found to potentially cause long-term adverse effects in the body, a multitude of studies have been conducted to examine the efficacy of thymoglobulin in SOT either with minimal usage or without the use of either agent. Findings have indicated that use of thymoglobulin alone minimizes risk of adverse effects and thus improves long-term outcomes for transplant patients.Thymoglobulin is also an effective agent for preventing graft-vs.-host disease in patients receiving haematopoietic stem cell transplantation (HSCT). GVHD is a condition in which immune cells within the graft attack host cells and cause tissue damage. It is considered a major obstacle to successful HSCT. The T-cell depleting activity of thymoglobulin has proved to be useful in preventing GVHD. Multiple studies have indicated that thymoglobulin is favored in comparison to other induction agents for patients who have increased risk of developing post-transplant complications, such as elderly patients, patients undergoing a repeat transplantation, and patients in which minimization of use of steroids or CNIs post-operation is recommended. == References ==
Palonosetron	Palonosetron, sold under the brand name Aloxi, is used for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV). It is a 5-HT3 antagonist.Palonosetron is administered intravenously, or as a single oral capsule. It has a longer duration of action than other 5-HT3 antagonists. The oral formulation was approved on August 22, 2008, for prevention of acute CINV alone, as a large clinical trial did not show oral administration to be as effective as intravenous use against delayed CINV. It is on the World Health Organizations List of Essential Medicines.The oral combination netupitant/palonosetron is approved for both acute and delayed CINV. Adverse effects The most common adverse effects are headache, which occurs in 4–11% of patients, and constipation in up to 6% of patients. In less than 1% of patients, other gastrointestinal disorders occur, as well as sleeplessness, first- and second-degree atrioventricular block, muscle pain and shortness of breath. Palonosetron is similarly well tolerated as other 5-HT3 antagonists, and slightly less than placebo. Interactions Palonosetron does not relevantly inhibit or induce cytochrome P450 liver enzymes. There are case reports about serotonin syndrome when the drug is combined with serotonergic substances such as selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), two common types of antidepressants. Pharmacology Mechanism of action Palonosetron is a 5-HT3 antagonist, commonly known as a setron. These drugs act by blocking serotonin from binding to the 5-HT3 receptor. Pharmacokinetics Orally taken palonosetron is absorbed well from the gut and has a bioavailability of 97%. Highest blood plasma levels are reached after 5.1±1.7 hours, independently of food intake, and plasma protein binding is 62%. 40% of the substance are eliminated in the unchanged form, and a further 45–50% are metabolized by the liver enzyme CYP2D6 and to a lesser extent by CYP3A4 and CYP1A2. The two main metabolites, the N-oxide and a hydroxy derivative, have less than 1% of palonosetrons antagonistic effect and are thus practically inactive.Palonosetron and its metabolites are mainly (to 80–93%) eliminated via the kidney. Biological half-life in healthy persons was 37±12 hours in a study, and 48±19 hours in cancer patients. In 10% of patients, half-life is over 100 hours. Most other marketed setrons have half-lives in the range of about two to 15 hours. Chemistry The substance is solid at room temperature and melts at 87 to 88 °C (189 to 190 °F). The infusions and capsules contain palonosetron hydrochloride, which is also a solid. The hydrochloride is easily soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and isopropyl alcohol.The molecule has two asymmetric carbon atoms. It is used in form of the pure (S,S)-stereoisomer. References External links "Palonosetron". Drug Information Portal. U.S. National Library of Medicine.
Prothrombin complex concentrate	Prothrombin complex concentrate (PCC), also known as factor IX complex, is a medication made up of blood clotting factors II, IX, and X. Some versions also contain factor VII. It is used to treat and prevent bleeding in hemophilia B if pure factor IX is not available. It may also be used for reversal of warfarin therapy. It is given by slow injection into a vein.Common side effects include allergic reactions, headache, vomiting, and sleepiness. Other serious side effects include blood clots which may result in a heart attack, stroke, pulmonary embolism, or deep vein thrombosis. Antibodies may form after long term use such that future doses are less effective.Prothrombin complex concentrate came into medical use in the 1960s. It is on the World Health Organizations List of Essential Medicines. It is made from human plasma. Recombinant factor IX is also available in a stand-alone preparation. In the United States a dose of PCC costs about US$900. A number of different formulations are available globally. Medical uses Prothrombin complex concentrate reverses the effects of warfarin and other vitamin K antagonist anti-coagulants and is used in cases of significant bleeding in people with a coagulopathy. It is also used when such a person must undergo an emergency operation. Other uses include a deficiency of one of the included clotting factors, either congenital or due to liver disease, and hemophilia. Several guidelines, including those from the American College of Chest Physicians, recommend prothrombin complex concentrate for warfarin reversal in people with serious bleeding.For rapid anticoagulation reversal for surgery, four-factor prothrombin complex concentrate reduces international normalized ratio (INR) and decreases bleeding during surgery when compared with administration of fresh frozen plasma. No differences in thromboembolic event was found. Contraindications The package insert states that prothrombin complex concentrate is contraindicated in patients with disseminated intravascular coagulation, a pathological activation of coagulation, because giving clotting factors would only further fuel this process. However, if the PCC is given because factor levels are low, it can restore normal coagulation. As PCC products contain heparin, they are contraindicated in patients with heparin-induced thrombocytopenia. Chemistry Prothrombin complex concentrate contains a number of blood clotting factors. Typically this includes factor II, IX, and X. Some versions also contain factor VII, protein C, and protein S. Heparin may be added to stop early activation of the factors. History The U.S. Food and Drug Administration (FDA) announced its approval in 2013. The FDA approved Kcentras orphan drug status in December 2012. References Further reading External links "Prothrombin complex concentrate". Drug Information Portal. U.S. National Library of Medicine.
Sulfasalazine	Sulfasalazine (SSZ), sold under the trade name Azulfidine among others, is a medication used to treat rheumatoid arthritis, ulcerative colitis, and Crohns disease. It is considered by some to be a first-line treatment in rheumatoid arthritis. It is taken by mouth.Significant side effects occur in about 25% of people. Commonly these include loss of appetite, nausea, headache, and rash. Severe side effects include bone marrow suppression, liver problems, Stevens–Johnson syndrome, and kidney problems. It should not be used in people allergic to aspirin or sulfonamide. Use during pregnancy appears to be safe for the baby.Sulfasalazine is in the disease-modifying antirheumatic drugs (DMARDs) family of medications. It is unclear exactly how it works. One proposed mechanism is the inhibition of prostaglandins, resulting in local anti-inflammatory effects in the colon. The medication is broken down by intestinal bacteria into sulfapyridine and 5-aminosalicylic acid. That which is absorbed is excreted by the kidneys and in the bile.Sulfasalazine was approved for medical use in the United States in 1950. It is on the World Health Organizations List of Essential Medicines. Sulfasalazine is available as a generic medication. Medical uses Sulfasalazine is used in the treatment of inflammatory bowel disease, including ulcerative colitis and Crohns disease. It is also indicated for use in rheumatoid arthritis and used in other types of inflammatory arthritis (e.g. psoriatic arthritis and reactive arthritis).It is usually not given to children under two years of age. Side effects Use of sulfasalazine is contraindicated in people with sulfa allergies and in those with urinary tract obstructions, intestinal obstructions, and severe liver or kidney problems.Sulfasalazine metabolizes to sulfapyridine. Serum levels should be monitored every three months, and more frequently at the outset. Serum levels above 50 μg/L are associated with side effects. In rare cases, sulfasalazine can cause severe depression in young males. It can also cause oligospermia and temporary infertility. Immune thrombocytopenia has been reported.Sulfasalazine inhibits dihydropteroate synthase, and can cause folate deficiency and megaloblastic anemia. and various other undesirable effects.Sulfasalazine can cause hemolytic anemia in people with G6PD deficiency.Sulfasalazine can cause kidney stones. Sulfasalazine may cause stomach upset, nausea, vomiting, loss of appetite, headache, dizziness, or unusual tiredness. Skin and urine can become orange, with occasional allergic reactions.Sulfasalazine may cause sulfhemoglobinemia. Pharmacology Around 90% of a dose of sulfasalazine reaches the colon, where most of it is metabolized by bacteria into sulfapyridine and mesalazine (also known as 5-aminosalicylic acid or 5-ASA). Both metabolites are active; most of the sulfapyridine is absorbed and then further metabolized, but most mesalazine is not, and remains in the colon.A mix of unchanged, hydroxylated, and glucuronidated sulfapyridine is eliminated in urine, as is acetylated mesalazine and unmetabolized sulfasalazine.The mechanism of action is not clear, but it appears that sulfasalazine and its metabolites have immunosuppressive, antibacterial, and anti-inflammatory effects. It also appears to inhibit the cystine-glutamate antiporter. Chemistry It is a codrug which is a combination of sulfapyridine and 5-aminosalicylic acid coupled with an azo linkage. Cost In people with rheumatoid arthritis, the cost-effectiveness of sulfasalazine is improved by combining it with other drugs. It is commonly used in treating inflammatory bowel disease in part due to its cost effectiveness. Research Sulfasalazine has been studied in cirrhosis, psoriasis, idiopathic urticaria, and amyloidosis. References External links "Sulfasalazine". Drug Information Portal. U.S. National Library of Medicine.
Praziquantel	Praziquantel (PZQ), sold under the brandname Biltricide among others, is a medication used to treat a number of types of parasitic worm infections in mammals, birds, amphibians, reptiles, and fish. In humans specifically, it is used to treat schistosomiasis, clonorchiasis, opisthorchiasis, tapeworm infections, cysticercosis, hydatid disease, and other fluke infections. It should not be used for worm infections of the eye. It is taken by mouth.Side effects in humans may include poor coordination, abdominal pain, vomiting, headache, and allergic reactions. While it may be used during pregnancy, it is not recommended for use during breastfeeding. Praziquantel is in the anthelmintic class of medications. It works partly by affecting the function of the worms sucker.Praziquantel was approved for medical use in the United States in 1982. It is on the World Health Organizations List of Essential Medicines. Medical uses Praziquantel is used to treat diseases caused by infection with several types of internal/gastrointestinal, and external parasites, including: Hydatid disease caused by infection of various organs with larval stages of tapeworms of the genus Echinococcus Cysticercosis caused by infection of the brain and/or muscles with the eggs and larvae of the pork tapeworm Taenia solium (though it has been judged less effective than albendazole in treatment of neurocysticercosis) In dogs and cats, whose gastrointestinal tracts are infected with the tapeworms Dipylidium caninum or Taenia taeniaeformis, respectively; praziquantel is also often used in fixed combination with pyrantel embonate against the roundworms (ascarids): Toxocara cati and Toxascaris leonina. Praziquantel is also effective against Echinococcus multilocularis. Schistosomiasis caused by trematodes of the genus Schistosoma: As of 2005, praziquantel is the primary treatment for human schistosomiasis, for which it is usually effective in a single dose. Clonorchiasis brought on by the Chinese liver fluke Clonorchis sinensis Paragonimiasis caused by infection with lung flukes, mostly of the species Paragonimus westermani Fasciolopsiasis caused by intestinal fluke Fasciolopsis buski Side effects The majority of side effects develop due to the release of the contents of the parasites as they are killed and the consequent host immune reaction. The heavier the parasite burden, the heavier and more frequent the side effects normally are. Central nervous system (CNS): Frequently occurring side effects are dizziness, headache, and malaise. Drowsiness, somnolence, fatigue, and vertigo have also been seen. Almost all patients with cerebral cysticercosis experience CNS side effects related to the cell-death of the parasites (headache, worsening of pre-existing neurological problems, seizures, arachnoiditis, and meningism). These side effects may be life-threatening and can be reduced by coadministration of corticosteroids. All patients with cerebral cysticercosis are strongly recommended to be hospitalized during treatment. Gastrointestinal tract: About 90% of all patients have abdominal pain or cramps with or without nausea and vomiting. Diarrhea may develop and may be severe with colic. Sweating, fever, and sometimes bloody stools may occur together with diarrhea. Liver: Asymptomatic and transient increases of liver enzymes (AST and ALT) are noted frequently (up to 27%). No case of symptomatic liver damage has been seen so far. Sensitivity reactions: Urticaria, rash, pruritus and eosinophilia in white blood cell counts Other locations/body as a whole: Lower back pain, myalgia, arthralgia, fever, sweating, various cardiac arrhythmias, and hypotension Pregnancy The WHO states praziquantel is safe during pregnancy. Animal studies have failed to reveal evidence of fetal harm. Praziquantel is effective in reducing schistosomiasis during pregnancy. Another trial found that treatment with praziquantel did not increase the rates of low birthweight, fetal death, or congenital anomalies. Drug interactions The antibiotic rifampicin decreases plasma concentrations of praziquantel.Carbamazepine and phenytoin are reported to reduce the bioavailability of praziquantel. Chloroquine also reduces its bioavailability.The drug cimetidine heightens praziquantel bioavailability. Mechanism of action The drugs mode of action is not exactly known at present, but experimental evidence indicates praziquantel increases the permeability of the membranes of schistosome cells towards calcium ions. The drug thereby induces contraction of the parasites muscle, resulting in paralysis in the contracted state. The dying parasites are dislodged from their site of action in the host organism and may enter systemic circulation or may be destroyed by host immune reaction (phagocytosis). Additional mechanisms including focal disintegrations and disturbances of oviposition (laying of eggs) are seen in other types of sensitive parasites. Another hypothesis regarding the mechanism of action is that it interferes with adenosine uptake in worms. This effect may have therapeutical relevance given that the schistosome, as the Taenia and the Echinococcus (other praziquantel-sensitive parasites), is unable to synthesize purines, such as adenosine, de novo. Bayers Animal Health Division website states, "Praziquantel is active against cestodes (tapeworms). Praziquantel is absorbed, metabolized in the liver, and excreted in the bile. Upon entering the digestive tract from the bile, cestocidal activity is exhibited. Following exposure to praziquantel, the tapeworm loses its ability to resist digestion by the mammalian host. Because of this, whole tapeworms, including the scolices (plural of "scolex"), are very rarely passed after administration of praziquantel. In many instances, only disintegrated and partially digested pieces of tapeworms will be seen in the stool. The majority of tapeworms are digested and are not found in the feces."Praziquantel is administered as a racemate, but only the (R)-enantiomer is biologically active; the enantiomers may be separated using a resolution of an amine obtained from praziquantel. Pharmacokinetics Praziquantel is well absorbed (about 80%) from the gastrointestinal tract. However, due to extensive first-pass metabolism, only a relatively small amount enters systemic circulation. Praziquantel has a serum half-life of 0.8 to 1.5 hours in adults with normal renal and liver function. Metabolites have a half-life of 4 to 5 hours. In patients with significantly impaired liver function (Child-Pugh score B and C), the serum half-life is increased to 3 to 8 hours. Praziquantel and its metabolites are mainly excreted renally; within 24 h after a single oral dose, 70 to 80% is found in urine, but less than 0.1% as the unchanged drug. Praziquantel is metabolized through the cytochrome P450 pathway via CYP3A4. Agents that induce or inhibit CYP3A4 such as phenytoin, rifampin, and azole antifungals will affect the metabolism of praziquantel. Praziquantel has a particularly dramatic effect on patients with schistosomiasis. Studies of those treated have shown that within six months of receiving a dose of praziquantel, up to 90% of the damage done to internal organs due to schistosomiasis infection can be reversed. History Praziquantel was developed in the laboratories for parasitological research of Bayer AG and Merck KGaA in Germany (Elberfeld and Darmstadt) in the mid-1970s. Society and culture Brand names Biltricide (Bayer) Tablets (for human use) Cesol (Merck) Tablets Cestoved (Vedco) both tablets and injectable for veterinary use Cysticide (Merck) Tablets Distocide (Shin Poong Pharm. Co., Ltd.) tablet (for human use) Distoside (Chandra Bhagat Pharma Pvt Ltd) tablet (for human use) Droncit (Bayer) for veterinary use Drontal (combination with pyrantel pamoate) (Bayer) for veterinary use D-Worm (Farnum) for veterinary use; note that D-Worm also makes roundworm medicine containing piperidine which is not effective against tapeworms. Fish Tapes (Thomas Labs) for aquarium use Interceptor Plus chewable tablets (combination with milbemycin) (Elanco) for veterinary use. Note regular Interceptor only has milbemycin and does not contain praziquantel. Kaicide (Taiwan) Milbemax (combination with milbemycin oxime) (Novartis) for veterinary use Popantel (Jurox) PraziPro (Hikari) for aquarium use Praz-Tastic (NFP/National Fish Pharmaceuticals) for aquarium use Pure Prazi (COTS Koi/Children of the Sun Koi) for aquarium use PraziPure (J.K.O., Inc. d/b/a Kodama Koi Farm & Kodama Koi Garden; licensed by COTS Koi) for aquarium use Profender (combination with emodepside) (Bayer) for veterinary use Tape Worm Tabs (Trade Winds) for veterinary use Zentozide (Berich (Thailand) Co) Regulatory approval Praziquantel is on the World Health Organizations List of Essential Medicines.Praziquantel is not licensed for use in humans in the UK, but it can be imported when necessary on a named-patient basis. It is available in the UK as a veterinary anthelmintic. Praziquantel is FDA approved in the US for the treatment of schistosomiasis and liver flukes, although it is effective in other infections. Veterinary medicine Salmon poisoning disease Diplozoon paradoxum and other Trematoda infections of many fish speciesIt may cause problems in dogs with MDR1 mutations. See also Fenbendazole Oxfendazole Nocodazole References External links "Praziquantel (Rx) Biltricide". Medscape. WebMD. Retrieved 2015-11-01. "Praziquantel". Drug Information Portal. U.S. National Library of Medicine.
Oxandrolone	Oxandrolone, sold under the brand names Oxandrin and Anavar, among others, is an androgen and anabolic steroid (AAS) medication which is used to help promote weight gain in various situations, to help offset protein catabolism caused by long-term corticosteroid therapy, to support recovery from severe burns, to treat bone pain associated with osteoporosis, to aid in the development of girls with Turner syndrome, and for other indications. It is taken by mouth.Side effects of oxandrolone include symptoms of masculinization such as acne, increased hair growth, voice changes, and increased sexual desire. The drug is a synthetic androgen and anabolic steroid, hence is an agonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone. It has strong anabolic effects and weak androgenic effects, which give it a mild side effect profile and make it especially suitable for use in women.Oxandrolone was first described in 1962 and was introduced for medical use in 1964. It is used mostly in the United States. In addition to its medical use, oxandrolone is used to improve physique and performance. The drug is a controlled substance in many countries, so nonmedical use is generally illicit. Medical uses Oxandrolone has been researched and prescribed as a treatment for a wide variety of conditions. It is FDA-approved for treating bone pain associated with osteoporosis, aiding weight gain following surgery or physical trauma, during chronic infection, or in the context of unexplained weight loss, and counteracting the catabolic effect of long-term corticosteroid therapy.As of 2016, it is often prescribed off-label to quicken recovery from severe burns, aid the development of girls with Turner syndrome, and counteract HIV/AIDS-induced wasting. Oxandrolone improves both short-term and long-term outcomes in people recovering from severe burns and is well-established as a safe treatment for this indication. It is also used in the treatment of idiopathic short stature, anemia, hereditary angioedema, alcoholic hepatitis, and hypogonadism.Medical research has established the effectiveness of oxandrolone in aiding the development of girls with Turner syndrome. Although oxandrolone has long been used to accelerate growth in children with idiopathic short stature, it is unlikely to increase adult height, and in some cases may even decrease it. Oxandrolone has, therefore, largely been replaced by growth hormone for this use. Children with idiopathic short stature or Turner syndrome are given doses of oxandrolone far smaller than those given to people with burns to minimize the likelihood of virilization and premature maturation. Non-medical uses Many bodybuilders and athletes use oxandrolone illicitly for its muscle-building effects. It is much more anabolic than androgenic, so women and those seeking less intense steroid regimens use it particularly often. Many also value oxandrolones low hepatotoxicity relative to most other orally active AASs. Contraindications Like other AASs, oxandrolone may worsen hypercalcemia by increasing osteolytic bone resorption. When taken by pregnant women, oxandrolone may have unintended effects such as masculinization on the fetus. Side effects Women who are administered oxandrolone may experience virilization, irreversible development of masculine features such as voice deepening, hirsutism, menstruation abnormalities, male-pattern hair loss, and clitoral enlargement. Oxandrolone may disrupt growth in children, reducing their adult height. Because of these side effects, doses given to women and children are minimized and people are usually monitored for virilization and growth abnormalities. Like other androgens, oxandrolone can cause or worsen acne and priapism (unwanted or prolonged erections). Oxandrolone can also reduce males fertility, another side effect common among androgens. In an attempt to compensate for the exogenous increase in androgens, the body may reduce testosterone production via testicular atrophy and inhibition of gonadotropic activity.Unlike some AASs, oxandrolone does not generally cause gynecomastia because it is not aromatized into estrogenic metabolites. However, although no reports of gynecomastia were made in spite of widespread use, oxandrolone was reported in a publication in 1991 to have been associated with 33 cases of gynecomastia in adolescent boys treated with it for short stature. The gynecomastia developed during oxandrolone therapy in 19 of the boys and after the therapy was completed in 14 of the boys, and 10 of the boys had transient gynecomastia, while 23 had persistent gynecomastia that necessitated mastectomy. Though transient gynecomastia is a natural and common occurrence in pubertal boys, the gynecomastia associated with oxandrolone was of a late/delayed onset and was persistent in a high percentage of the cases. As such, the researchers stated, "although oxandrolone cannot be implicated as stimulatory [in] gynecomastia", a possible relationship should be considered in clinicians using oxandrolone in adolescents for growth stimulation.Uniquely among 17α-alkylated AASs, oxandrolone shows little to no hepatotoxicity, even at high doses. No cases of severe hepatotoxicity have been singularly attributed to oxandrolone. However, elevated liver enzymes have been observed in some people, particularly with high doses and/or prolonged treatment, although they return to normal ranges following discontinuation. Interactions Oxandrolone greatly increases warfarins blood-thinning effect, sometimes dangerously so. In April 2004, Savient Pharmaceuticals published a safety alert through the FDA warning healthcare professionals of this. Oxandrolone can also inhibit the metabolism of oral hypoglycemic agents. It may worsen edema when taken alongside corticosteroids or adrenocorticotropic hormone. Pharmacology Pharmacodynamics Like other AASs, oxandrolone is an agonist of the androgen receptor, similar to androgens such as testosterone and DHT. The relative binding affinity of oxandrolone for the androgen receptor is about 0.8% of that of metribolone. Activation of the androgen receptor stimulates protein synthesis, which increases muscle growth, lean body mass, and bone mineral density.Compared to testosterone and many other AASs, oxandrolone is less androgenic relative to its strength as an anabolic. Oxandrolone has about 322 to 633% of the anabolic potency and 24% of the androgenic potency of methyltestosterone. Similarly, oxandrolone has as much as 6 times the anabolic potency of testosterone and has significantly reduced androgenic potency in comparison. The reduced ratio of anabolic to androgenic activity of oxandrolone often motivates its medical use in children and women because less androgenic effect implies less risk of virilization. The bodybuilding community also considers this fact when choosing between AASs.As oxandrolone is already 5α-reduced, it is not a substrate for 5α-reductase, hence is not potentiated in androgenic tissues such as the skin, hair follicles, and prostate gland. This is involved in its reduced ratio of anabolic to androgenic activity. Due to the substitution of one of the carbon atoms with an oxygen atom at the C2 position in the A ring, oxandrolone is resistant to inactivation by 3α-hydroxysteroid dehydrogenase in skeletal muscle. This is in contrast to DHT, and is thought to underlie the preserved anabolic potency with oxandrolone. Because it is 5α-reduced, oxandrolone is not a substrate for aromatase, hence cannot be aromatized into metabolites with estrogenic activity. Oxandrolone similarly possesses no progestogenic activity.Oxandrolone is, uniquely, far less hepatotoxic than other 17α-alkylated AASs, which may be due to differences in metabolism. Pharmacokinetics The oral bioavailability of oxandrolone is 97%. Its plasma protein binding is 94 to 97%. The drug is metabolized primarily by the kidneys and to a lesser extent by the liver. Oxandrolone is the only AAS that is not primarily or extensively metabolized by the liver, and this is thought to be related to its diminished hepatotoxicity relative to other AASs. Its elimination half-life is reported as 9.4 to 10.4 hours, but is extended to 13.3 hours in the elderly. About 28% of an oral dose of oxandrolone is eliminated unchanged in the urine and 3% is excreted in the feces. Chemistry Oxandrolone is a synthetic androstane steroid and a 17α-alkylated derivative of DHT. It is also known as 2-oxa-17α-methyl-5α-dihydrotestosterone (2-oxa-17α-methyl-DHT) or as 2-oxa-17α-methyl-5α-androstan-17β-ol-3-one, and is DHT with a methyl group at the C17α position and the C2 carbon replaced with an oxygen atom. Closely related AASs include the marketed AAS mestanolone (17α-methyl-DHT), oxymetholone (2-hydroxymethylene-17α-methyl-DHT), and stanozolol (a 2,3-pyrazole A ring-fused derivative of 17α-methyl-DHT) and the never-marketed/designer AAS desoxymethyltestosterone (3-deketo-17α-methyl-δ2-DHT), methasterone (2α,17α-dimethyl-DHT), methyl-1-testosterone (17α-methyl-δ1-DHT), and methylstenbolone (2,17α-dimethyl-δ1-DHT). History Oxandrolone was first made by Raphael Pappo and Christopher J. Jung while at Searle Laboratories (now part of Pfizer). The researchers first described the drug in 1962. They were immediately interested in oxandrolones very weak androgenic effects relative to its anabolic effects. It was introduced as a pharmaceutical drug in the United States in 1964.The drug was prescribed to promote muscle regrowth in disorders which cause involuntary weight loss, and is used as part of treatment for HIV/AIDS. It had also been shown to be partially successful in treating cases of osteoporosis. However, in part due to bad publicity from its illicit use by bodybuilders, production of Anavar was discontinued by Searle Laboratories in 1989. It was picked up by Bio-Technology General Corporation, which changed its name to Savient Pharmaceuticals, which following successful clinical trials in 1995, released it under the brand name Oxandrin. BTG subsequently won approvals for orphan drug status by the Food and Drug Administration for treating alcoholic hepatitis, Turner syndrome, and HIV-induced weight loss. It is also indicated as an offset to protein catabolism caused by long-term administration of corticosteroids. Society and culture Generic names Oxandrolone is the generic name of the drug and its INN, USAN, USP, BAN, DCF, DCIT, and JAN, while ossandrolone is or was formerly the DCIT. Brand names The original brand name of oxandrolone was Anavar, which was marketed in the United States and the Netherlands. This product was eventually discontinued and replaced in the United States with a new product named Oxandrin, which is the sole remaining brand name for oxandrolone in the United States. Oxandrolone has also been sold under the brand names Antitriol (Spain), Anatrophill (France), Lipidex (Brazil), Lonavar (Argentina, Australia, Italy), Protivar, and Vasorome (Japan), among others. Additional brand names exist for products that are manufactured for the steroid black market.Among those using oxandrolone for nonmedical purposes, it is often referred to colloquially as "Var", a shortened form of the brand name Anavar. Availability United States Oxandrolone is one of the few AASs that remains available for medical use in the United States. The others (as of November 2017) are testosterone, testosterone cypionate, testosterone enanthate, testosterone undecanoate, methyltestosterone, fluoxymesterone, and oxymetholone. Other countries Outside of the United States, the availability of oxandrolone is quite limited. With the exception of Moldova, it is no longer available in Europe. Oxandrolone is available in some less-regulated markets in Asia such as Malaysia. It is also available in Mexico. Historically, oxandrolone has been marketed in Argentina, Australia, Brazil, France, Italy, Japan, and Spain, but it appears to no longer be available in these countries. Legal status In the United States, oxandrolone is categorized as a Schedule III controlled substance under the Controlled Substances Act along with many other AASs. It is a Schedule IV controlled substance in Canada, and a Schedule 4 controlled drug in the United Kingdom. Doping in sports Oxandrolone is sometimes used as a doping agent in sports. Cases of doping with oxandrolone by professional athletes have been reported. References External links Oxandrin Homepage, savientpharma.com (via archive.org) Oxandrin Label, fda.gov (retrieved 23 October 2009) "Oxandrolone Side Effects, Interactions and Information". drugs.com.
Oxycodone/aspirin	Oxycodone/aspirin (trade name Percodan) is a combination drug marketed by Endo Pharmaceuticals. It is a tablet containing a mixture of 325 mg (5 grains) of aspirin and 4.8355 mg of oxycodone HCl (equivalent to 4.3346 mg of oxycodone as the free base); it is an opioid/non-opioid combination used to treat moderate to moderately severe pain. The safety of the combination during pregnancy has not been established, although aspirin is generally contraindicated during pregnancy, and the drug has been placed in pregnancy category D. Inactive ingredients include D&C Yellow 10, FD&C Yellow 6, microcrystalline cellulose, and corn starch. Percodan was first marketed by DuPont Pharmaceuticals and prescribed in the United States in 1950. Once a widely prescribed painkiller, it has largely been replaced by alternative oxycodone compounds containing paracetamol (acetaminophen) instead of aspirin, such as Percocet. Adverse effects Pharmacology The oxycodone component in the combination is technically 14-hydroxy-7,8-dihydrocodein-6-one, a white odorless, crystalline powder which is synthesized from the opium alkaloid thebaine. Thebaine by itself has no therapeutic value. Oxycodone is metabolized into oxymorphone. Unlike morphine and like codeine, oxycodone has a good oral potency. Prior to the introduction of paracetamol, Percodan was the mainstay in post-operative oral pain treatment due to the potency and long half-life of oxycodone. It originally contained a small amount of caffeine. Reformulation Percodan was reformulated in 2005; prior to 2005, it contained two oxycodone salts—4.62 mg of oxycodone hydrochloride and 0.38 mg of oxycodone terephthalate. Since the latter salt is unusual in the pharmacopeia, the manufacturer increased the amount of oxycodone hydrochloride to 4.8355 mg and discontinued the oxycodone terephthalate. Miscellaneous The combination oxycodone/aspirin is also sold under the brand name Endodan. All products containing oxycodone (including Percodan, Percocet, OxyContin) have the potential to be habit-forming. Oxycodone can produce drug dependence of the morphine type and, therefore, has the potential for being addictive. See also Embeda Hypnorm Percocet Targin Vicodin Vicoprofen References External links Percodan Prescribing Information from Endo Pharmaceuticals. Search "Percodan" in FDA Archives; shows approval in 1950.
Cholic acid	Cholic acid, also known as 3α,7α,12α-trihydroxy-5β-cholan-24-oic acid is a primary bile acid that is insoluble in water (soluble in alcohol and acetic acid), it is a white crystalline substance. Salts of cholic acid are called cholates. Cholic acid, along with chenodeoxycholic acid, is one of the two major bile acids produced by the liver, where it is synthesized from cholesterol. These two major bile acids are roughly equal in concentration in humans. Derivatives are made from cholyl-CoA, which exchanges its CoA with either glycine, or taurine, yielding glycocholic and taurocholic acid, respectively.Cholic acid downregulates cholesterol-7-α-hydroxylase (rate-limiting step in bile acid synthesis), and cholesterol does the opposite. This is why chenodeoxycholic acid, and not cholic acid, can be used to treat gallstones (because decreasing bile acid synthesis would supersaturate the stones even more).Cholic acid and chenodeoxycholic acid are the most important human bile acids. Other species may synthesize different bile acids as their predominant primary bile acids. Medical uses Cholic acid, sold under the brand name Cholbam, is approved for use in the United States and is indicated as a treatment for children and adults with bile acid synthesis disorders due to single enzyme defects, and for peroxisomal disorders (such as Zellweger syndrome).It was approved for use in the European Union in September 2013, and is sold under the brand name Orphacol. It is indicated for the treatment of inborn errors in primary bile-acid synthesis due to 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency or Δ4-3-oxosteroid-5β-reductase deficiency in infants, children and adolescents aged one month to 18 years and adults.Cholic acid FGK (Kolbam) was approved for medical use in the European Union in November 2015. It is indicated for the treatment of inborn errors of primary bile acid synthesis, in infants from one month of age for continuous lifelong treatment through adulthood, encompassing the following single enzyme defects: sterol 27-hydroxylase deficiency (presenting as cerebrotendinous xanthomatosis, CTX); 2- (or alpha-) methylacyl-CoA racemase (AMACR) deficiency; cholesterol 7 alpha-hydroxylase (CYP7A1) deficiency.The most common side effects include peripheral neuropathy (nerve damage in the hands and feet), diarrhea, nausea (feeling sick), acid reflux (stomach acid flowing up into the mouth), esophagitis (inflammation of the food pipe), jaundice (yellowing of the skin and eyes), skin problems (lesions) and malaise (feeling unwell). Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. References External links "Cholic acid". Drug Information Portal. U.S. National Library of Medicine.
Brimonidine	Brimonidine is a medication used to treat open-angle glaucoma, ocular hypertension, and rosacea. In rosacea it improves the redness. It is used as eye drops or applied to the skin.Common side effects when used in the eyes include itchiness, redness, and a dry mouth. Common side effects when used on the skin include redness, burning, and headaches. More significant side effects may include allergic reactions and low blood pressure. Use in pregnancy appears to be safe. When applied to the eye it works by decreasing the amount of aqueous humor made while increasing the amount that drains from the eye. When applied to the skin it works by causing blood vessels to contract.Brimonidine was patented in 1972 and came into medical use in 1996. It is available as a generic medication. In 2019, it was the 217th most commonly prescribed medication in the United States, with more than 2 million prescriptions. Medical uses Brimonidine is indicated for the lowering of intraocular pressure in patients with open-angle glaucoma or ocular hypertension. It is also the active ingredient of brimonidine/timolol along with timolol maleate. A 2017 Cochrane review found insufficient evidence to determine if brimonidine slows optic nerve damage.In 2013, the FDA approved topical application of brimonidine 0.33% gel for persistent facial redness of rosacea. Mechanism of action Brimonidine is an α2 adrenergic agonist.α2 agonists, through the activation of a G protein-coupled receptor, inhibit the activity of adenylate cyclase. This reduces cAMP and hence aqueous humour production by the ciliary body. Peripheral α2 agonist activity results in vasoconstriction of blood vessels (as opposed to central α2 agonist activity that decreases sympathetic tone, as can be seen by the medication clonidine). This vasoconstriction may explain the acute reduction in aqueous humor flow. The increased uveoscleral outflow from prolonged use may be explained by increased prostaglandin release due to α adrenergic stimulation. This may lead to relaxed ciliary muscle and increased uveoscleral outflow. Society and culture Names It is sold under the brand names Alphagan, Alphagan-P, Mirvaso, Lumify, Brymont, and others. Over the counter In July 2018, Bausch and Lomb began to market over the counter (OTC) eye drops, using brimonidines tartrate formulation in a concentration of 0.025%, as an ophthalmic vasoconstrictor under the brand name Lumify. Intended to relieve redness in the sclerae of the eyes for periods of up to eight hours at a time through its vasoconstrictive effects, Lumify was marketed as an alternative to Visine, the brand of tetrahydrozoline hydrochloride solution most commonly used for that purpose. References Further reading Oh DJ, Chen JL, Vajaranant TS, Dikopf MS (January 2019). "Brimonidine tartrate for the treatment of glaucoma". Expert Opin Pharmacother. 20 (1): 115–122. doi:10.1080/14656566.2018.1544241. PMID 30407890. S2CID 53240954. External links "Brimonidine". Drug Information Portal. U.S. National Library of Medicine. "Brimonidine tartrate". Drug Information Portal. U.S. National Library of Medicine.
Obeticholic acid	Obeticholic acid (OCA), sold under the brand name Ocaliva, is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It is used as a medication used to treat primary biliary cholangitis. Intercept Pharmaceuticals Inc. hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma. Invention and development The natural bile acid chenodeoxycholic acid was identified in 1999 as the most active physiological ligand for the farnesoid X receptor (FXR), which is involved in many physiological and pathological processes. A series of alkylated bile acid analogues were designed, studied and patented by Roberto Pellicciari and colleagues at the University of Perugia, with 6α-ethyl-chenodeoxycholic acid emerging as the most highly potent FXR agonist. FXR-dependent processes in liver and intestine were proposed as therapeutic targets in human diseases. Obeticholic acid is the first FXR agonist to be used in human drug studies. Clinical studies Obeticholic acid is undergoing development in phase II and III studies for specific liver and gastrointestinal conditions. The U.S. Food and Drug Administration (FDA) approved obeticholic acid on May 27, 2016, for the treatment of primary biliary cholangitis. It was approved as an orphan drug based on its reduction in the level of the biomarker alkaline phosphatase as a surrogate endpoint for clinical benefit. It is indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA. Additional studies are being required to prove its clinical benefit. Primary biliary cholangitis Primary biliary cholangitis (PBC), also known as primary biliary cirrhosis, is an auto-immune, inflammatory liver disease which produces bile duct injury, fibrosis, cholestasis and eventual cirrhosis. It is much more common in women than men and can cause jaundice, itching (pruritus) and fatigue. Ursodeoxycholic acid therapy is beneficial, but the disease often progresses and may require liver transplantation. Animal studies suggested that treatment with FXR agonists should be beneficial in cholestatic diseases such as PBC. OCA at doses between 10 mg and 50 mg was shown to provide significant biochemical benefit, but pruritus was more frequent with higher doses. The results of a randomized, double-blind phase III study of OCA, 5 mg or 10 mg, compared to placebo (POISE) were presented in April 2014, and showed that the drug met the trials primary endpoint of a significant reduction in serum alkaline phosphatase, a biomarker predictive of disease progression, liver transplantation or death. Nonalcoholic steatohepatitis (NASH) Non-alcoholic steatohepatitis is a common cause of abnormal liver function with histological features of fatty liver, inflammation and fibrosis. It may progress to cirrhosis and is becoming an increasing indication for liver transplantation. It is increasing in prevalence. OCA is proposed to treat NASH. A phase II trial published in 2013, showed that administration of OCA at 25 mg or 50 mg daily for six weeks reduced markers of liver inflammation and fibrosis and increased insulin sensitivity.The Farnesoid X Receptor Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis Treatment (FLINT) trial, sponsored by NIDDK, was halted early in January 2014, after about half of the 283 subjects had completed the study, when a planned interim analysis showed that a) the primary endpoint had been met and b) lipid abnormalities were detected and arose safety concerns. Treatment with OCA (25 mg/day for 72 weeks) resulted in a highly statistically significant improvement in the primary histological endpoint, defined as a decrease in the NAFLD Activity Score of at least two points, with no worsening of fibrosis. 45% (50 of 110) of the treated group had this improvement compared with 21% (23 of 109) of the placebo-treated controls. However concerns about longterm safety issues such as increased cholesterol and adverse cardiovascular events may warrant the concomitant use of statins in OCA-treated patients. Portal hypertension Animal studies suggest that OCA improves intrahepatic vascular resistance and so may be of therapeutic benefit in portal hypertension. An open label phase IIa clinical study is under way. Bile acid diarrhea Bile acid diarrhea (also called bile acid malabsorption) can be secondary to Crohns disease or be a primary condition. Reduced median levels of FGF19, an ileal hormone that regulates increased hepatic bile acid synthesis, have been found in this condition. FGF19 is potently stimulated by bile acids and especially by OCA. A proof of concept study of OCA (25 mg/d) has shown clinical and biochemical benefit. FDA Label Update On February 1, 2018, the FDA updated label warnings for obeticholic acid to better explain recommended dosing. According to the agency, a misunderstanding led some health care professionals to improperly dose the drug on a daily basis rather than weekly, which can increase the risk of liver damage. References External links "Obeticholic acid". Drug Information Portal. U.S. National Library of Medicine.
Estramustine phosphate	Estramustine phosphate (EMP), also known as estradiol normustine phosphate and sold under the brand names Emcyt and Estracyt, is a dual estrogen and chemotherapy medication which is used in the treatment of prostate cancer in men. It is taken multiple times a day by mouth or by injection into a vein.Side effects of EMP include nausea, vomiting, gynecomastia, feminization, demasculinization, sexual dysfunction, blood clots, and cardiovascular complications. EMP is a dual cytostatic and hence chemotherapeutic agent and a hormonal anticancer agent of the estrogen type. It is a prodrug of estramustine and estromustine in terms of its cytostatic effects and a prodrug of estradiol in relation to its estrogenic effects. EMP has strong estrogenic effects at typical clinical dosages, and consequently has marked antigonadotropic and functional antiandrogenic effects.EMP was introduced for medical use in the early 1970s. It is available in the United States, Canada, the United Kingdom, other European countries, and elsewhere in the world. Medical uses EMP is indicated, in the United States, for the palliative treatment of metastatic and/or progressive prostate cancer, whereas in the United Kingdom it is indicated for the treatment of unresponsive or relapsing prostate cancer. The medication is usually reserved for use in hormone-refractory cases of prostate cancer, although it has been used as a first-line monotherapy as well. Response rates with EMP in prostate cancer are said to be equivalent to conventional high-dose estrogen therapy.Due to its relatively severe side effects and toxicity, EMP has rarely been used in the treatment of prostate cancer. This is especially true in Western countries today. As a result, and also due to the scarce side effects of gonadotropin-releasing hormone modulators (GnRH modulators) like leuprorelin, EMP was almost abandoned. However, encouraging clinical research findings resulted in renewed interest of EMP for the treatment of prostate cancer.EMP has been used at doses of 140 to 1,400 mg/day orally in the treatment of prostate cancer. However, oral EMP is most commonly used at a dose of 560 to 640 mg/day (280–320 mg twice daily). The recommended dosage of oral EMP in the Food and Drug Administration (FDA) label for Emcyt is 14 mg per kg of body weight (i.e., one 140 mg oral capsule for each 10 kg or 22 lbs of body weight) given in 3 or 4 divided doses per day. The label states that most patients in studies of oral EMP in the United States have received 10 to 16 mg per kg per day. This would be about 900 to 1,440 mg/day for a 90-kg or 200-lb man. Lower doses of oral EMP, such as 280 mg/day, have been found to have comparable effectiveness as higher doses but with improved tolerability and reduced toxicity. Doses of 140 mg/day have been described as a very low dosage. EMP has been used at doses of 240 to 450 mg/day intravenously.EMP and other estrogens such as polyestradiol phosphate and ethinylestradiol are far less costly than newer therapies such as GnRH modulators, abiraterone acetate, and enzalutamide. In addition, estrogens may offer significant benefits over other means of androgen deprivation therapy, for instance in terms of bone loss and fractures, hot flashes, cognition, and metabolic status.EMP has been used to prevent the testosterone flare at the start of GnRH agonist therapy in men with prostate cancer. Available forms EMP is or has been available in the form of both capsules (140 mg, 280 mg) for oral administration and aqueous solutions (300 mg) for intravenous injection. Contraindications EMP is contraindicated when used in children, patients hypersensitive to estrogens or nitrogen mustards, those with peptic ulcer (an ulcer in the digestive tract), those with severely compromised liver function, those with weak heart muscle (also known as myocardial insufficiency) and those with thromboembolic disorders or complications related to fluid retention. Side effects The side effects of EMP overall have been described as relatively severe. The most common side effects of EMP have been reported to be gastrointestinal side effects like nausea, vomiting, and diarrhea, with nausea and vomiting occurring in 40% of men. They are usually mild or moderate in severity, and the nausea and vomiting can be managed with prophylactic antiemetic medications. Nonetheless, severe cases of gastrointestinal side effects with EMP may require dose reduction or discontinuation of therapy. Although nausea and vomiting have been reported to be the most common side effects of EMP, gynecomastia (male breast development) has been found to occur in as many as 83% of men treated with EMP, and the incidence of erectile dysfunction is possibly similar to or slightly less than the risk of gynecomastia. As a rule, feminization, a gynoid fat distribution, demasculinization, and impotence are said to occur in virtually or nearly 100% of men treated with high-dose estrogen therapy. Decreased sexual activity has also been reported in men treated with EMP. These side effects are due to high estrogen levels and low testosterone levels. Prophylactic irradiation of the breasts can be used to decrease the incidence and severity of gynecomastia with estrogens.Severe adverse effects of EMP are thromboembolic and cardiovascular complications including pulmonary embolism, deep vein thrombosis, stroke, thrombophlebitis, coronary artery disease (ischemic heart disease; e.g., myocardial infarction), thrombophlebitis, and congestive heart failure with fluid retention. EMP produces cardiovascular toxicity similarly to diethylstilbestrol, but to a lesser extent in comparison at low doses (e.g., 280 mg/day oral EMP vs. 1 mg/day oral diethylstilbestrol). The prostate cancer disease state also increases the risk of thromboembolism, and combination with docetaxel may exacerbate the risk of thromboembolism as well. Meta-analyses of clinical trials have found that the overall risk of thromboembolism with EMP is 4 to 7%, relative to 0.4% for chemotherapy regimens without EMP. Thromboembolism is the major toxicity-related cause of discontinuation of EMP. Anticoagulant therapy with medications such as aspirin, warfarin, unfractionated and low-molecular-weight heparin, and vitamin K antagonists can be useful for decreasing the risk of thromboembolism with EMP and other estrogens like diethylstilbestrol and ethinylestradiol.Adverse liver function tests are commonly seen with EMP, but severe liver dysfunction is rare with the medication. Central nervous system side effects are rarely seen with EMP, although enlarged ventricles and neuronal pigmentation have been reported in monkeys treated with very high doses of EMP (20–140 mg/kg/day) for 3 to 6 months. EMP does not appear to have cytostatic effects in normal brain tissue. In women treated with EMP in clinical studies, a few instances of minor gynecological hemorrhages have been observed. EMP is described as relatively well tolerated among cytostatic antineoplastic and nitrogen-mustard agents, rarely or not at all being associated with significant hematologic toxicity such as myelosuppression (bone marrow suppression), gastrointestinal toxicity, or other more marked toxicity associated with such agents. In contrast to most other cytostatic agents, which often cause myelosuppression, leukopenia (decreased white blood cell count), and neutropenia (decreased neutrophil count), EMP actually produces leukocytosis (increased white blood cell count) as a side effect.In a small low-dose study using 280 mg/day oral EMP for 150 days, tolerability was significantly improved, with gastrointestinal irritation occurring in only 15% of men, and there was no incidence of severe cardiovascular toxicity or deep vein thrombosis. In addition, no other side effects besides slight transient elevated liver enzymes were observed. These findings suggest that lower doses of oral EMP may be a safer option than higher doses for the treatment of prostate cancer. However, a subsequent 2004 meta-analysis of 23 studies of thromboembolic events with EMP found substantial incidence of thromboembolic events regardless of dosage and no association of EMP dose with risk of these complications. Overdose There has been no clinical experience with overdose of EMP. Overdose of EMP may result in pronounced manifestations of the known adverse effects of the medication. There is no specific antidote for overdose of EMP. In the event of overdose, gastric lavage should be used to evacuate gastric contents as necessary and treatment should be symptom-based and supportive. In the case of dangerously low counts of red blood cells, white blood cells, or platelets, whole blood may be given as needed. Liver function should be monitored with EMP overdose. After an overdose of EMP, hematological and hepatic parameters should continue to be monitored for at least 6 weeks.EMP has been used at high doses of as much as 1,260 mg/day by the oral route and 240 to 450 mg/day by intravenous injection. Interactions EMP has been reported to increase the efficacy and toxicity of tricyclic antidepressants like amitriptyline and imipramine. When products containing calcium, aluminium, and/or magnesium, such as dairy products like milk, various foods dietary supplements, and antacids, are consumed concomitantly with EMP, an insoluble chelate complex/phosphate salt between EMP and these metals can be formed, and this can markedly impair the absorption and hence oral bioavailability of EMP. There may be an increased risk of angioedema in those concurrently taking ACE inhibitors. Pharmacology Pharmacodynamics EMP, also known as estradiol normustine phosphate, is a combined estrogen ester and nitrogen mustard ester. It consists of estradiol, an estrogen, linked with a phosphate ester as well as an ester of normustine, a nitrogen mustard. In terms of its pharmacodynamic effects, EMP is a prodrug of estramustine, estromustine, and estradiol. As a prodrug of estradiol, EMP is an estrogen and hence an agonist of the estrogen receptors. EMP itself has only very weak affinity for the estrogen receptors. The medication is of about 91% higher molecular weight than estradiol due to the presence of its C3 normustine and C17β phosphate esters. Because EMP is a prodrug of estradiol, it may be considered to be a natural and bioidentical form of estrogen, although it does have additional cytostatic activity via estramustine and estromustine.EMP acts by a dual mechanism of action: 1) direct cytostatic activity via a number of actions; and 2) as a form of high-dose estrogen therapy via estrogen receptor-mediated antigonadotropic and functional antiandrogenic effects. The antigonadotropic and functional antiandrogenic effects of EMP consist of strong suppression of gonadal androgen production and hence circulating levels of androgens such as testosterone; greatly increased levels of sex hormone-binding globulin and hence a decreased fraction of free androgens in the circulation; and direct antiandrogenic actions in prostate cells. The free androgen index with oral EMP has been found to be on average 4.6-fold lower than with orchiectomy. As such, EMP therapy results in considerably stronger androgen deprivation than orchiectomy. Metabolites of EMP, including estramustine, estromustine, estradiol, and estrone, have been found to act as weak antagonists of the androgen receptor (EC50 = 0.5–3.1 μM), although the clinical significance of this is unknown.Extremely high levels of estradiol and estrone occur during EMP therapy. The estrogenic metabolites of EMP are responsible for its most common adverse effects and its cardiovascular toxicity. EMP has been described as having relatively weak estrogenic effects in some publications. However, it has shown essentially the same rates and degrees of estrogenic effects, such as breast tenderness, gynecomastia, cardiovascular toxicity, changes in liver protein synthesis, and testosterone suppression, as high-dose diethylstilbestrol and ethinylestradiol in clinical studies. The notion that EMP has relatively weak estrogen activity may have been based on animal research, which found that EMP had 100-fold lower uterotrophic effects than estradiol in rats, and may also not have taken into account the very high doses of EMP used clinically in humans.The mechanism of action of the cytostatic effects of EMP is complex and only partially understood. EMP is considered to mainly be a mitotic inhibitor, inhibiting mechanisms involved in the mitosis phase of the cell cycle. Specifically, it binds to microtubule-associated proteins and/or to tubulin and produces depolymerization of microtubules (Kd = 10–20 μM for estramustine), resulting in the arrest of cell division in the G2/M phase (specifically metaphase). EMP was originally thought to mediate its cytostatic effects as a prodrug of normustine, a nitrogen mustard, and hence was thought to be an alkylating antineoplastic agent. However, subsequent research has found that EMP is devoid of alkylating actions, and that the influence of EMP on microtubules is mediated by intact estramustine and estromustine, with normustine or estradiol alone having only minor or negligible effects. As such, the unique properties of the estramustine and estromustine structures, containing a carbamate-ester bond, appear to be responsible for the cytostatic effects of EMP. In addition to its antimitotic actions, EMP has also been found to produce other cytostatic effects, including induction of apoptosis, interference with DNA synthesis, nuclear matrix interaction, cell membrane alterations, induction of reactive oxygen species (free oxygen radicals), and possibly additional mechanisms. EMP has been found to have a radiosensitizing effect in prostate cancer and glioma cells, improving sensitivity to radiation therapy as well.The cytostatic metabolites of EMP are accumulated in tissues in a selective manner, for instance in prostate cancer cells. This may be due to the presence of a specific estramustine-binding protein (EMBP) (Kd = 10–35 nM for estramustine), also known as prostatin or prostatic secretion protein (PSP), which has been detected in prostate cancer, glioma, melanoma, and breast cancer cells. Because of its tissue selectivity, EMP is said to produce minimal cytostatic effects in healthy tissues, and its tissue selectivity may be responsible for its therapeutic cytostatic efficacy against prostate cancer cells.EMP was originally developed as a dual ester prodrug of an estrogen and normustine as a nitrogen mustard alkylating antineoplastic agent which, due to the affinity of the estrogen moiety for estrogen receptors, would be selectively accumulated in estrogen target tissues and hence estrogen receptor-positive tumor cells. Consequentially, it was thought that EMP would preferentially deliver the alkylating normustine moiety to these tissues, allowing for reduced cytostatic effects in healthy tissues and hence improved efficacy and tolerability. However, subsequent research found that there is very limited and slow cleavage of the normustine ester and that EMP is devoid of alkylating activity. In addition, it appears that estramustine and estromustine may be preferentially accumulated in estrogen target tissues not due to affinity for the estrogen receptors, but instead due to affinity for the distinct EMBP.Extremely high, pregnancy-like levels of estradiol may be responsible for the leukocytosis (increased white blood cell count) that is observed in individuals treated with EMP. This side effect is in contrast to most other cytotoxic agents, which instead cause myelosuppression (bone marrow suppression), leukopenia (decreased white blood cell count), and neutropenia (decreased neutrophil count). Antigonadotropic effects EMP at a dosage 280 mg/day has been found to suppress testosterone levels in men into the castrate range (to 30 ng/dL) within 20 days and to the low castrate range (to 10 ng/dL) within 30 days. Similarly, a dosage of 70 mg/day EMP suppressed testosterone levels into the castrate range within 4 weeks. Pharmacokinetics Upon oral ingestion, EMP is rapidly and completely dephosphorylated by phosphatases into estramustine during the first pass in the gastrointestinal tract. Estramustine is also partially but considerably oxidized into estromustine by 17β-hydroxysteroid dehydrogenases during the first pass. As such, EMP reaches the circulation as estramustine and estromustine, and the major metabolite of EMP is estromustine. A limited quantity of approximately 10 to 15% of estramustine and estromustine is further slowly metabolized via hydrolysis of the normustine ester into estradiol and estrone, respectively. This reaction is believed to be catalyzed by carbamidases, although the genes encoding the responsible enzymes have not been characterized. The circulating levels of normustine formed from EMP are insignificant. Release of nitrogen mustard gas from normustine via cleavage of the carboxylic acid group has not been demonstrated and does not seem to occur.The oral bioavailability of EMP is low, which is due to profound first-pass metabolism; specifically, dephosphorylation of EMP. The oral bioavailability of EMP specifically as estramustine and estromustine is 44 to 75%, suggesting that absorption may be incomplete. In any case, there is a linear relationship between the oral dose of EMP and circulating levels of estramustine and estromustine. Consumption of calcium, aluminium, or magnesium with oral EMP can markedly impair its bioavailability due to diminished absorption from the intestines, and this may interfere with its therapeutic effectiveness at low doses.Following a single oral dose of 420 mg EMP in men with prostate cancer, maximal levels of estromustine were 310 to 475 ng/mL (475,000 pg/mL) and occurred after 2 to 3 hours. Estradiol levels with 280 mg/day oral EMP have been found to increase to very high concentrations within one week of therapy. In one study, levels of estradiol were over 20,000 pg/mL after 10 days, were about 30,000 pg/mL after 30 days, and peaked at about 40,000 pg/mL at 50 days. Another study found lower estradiol levels of 4,900 to 9,000 pg/mL during chronic therapy with 560 mg/day oral EMP. An additional study found estradiol levels of about 17,000 pg/mL with 140 mg/day oral EMP and 38,000 pg/mL with 280 mg/day oral EMP. The circulating levels of estradiol and estrone during EMP therapy have been reported to exceed normal levels in men by more than 100- and 1,000-fold, respectively. Levels of estramustine and estradiol in the circulation are markedly lower than those of estromustine and estrone, respectively, with a ratio of about 1:10 in both cases. Nonetheless, estradiol levels during EMP therapy appear to be similar to those that occur in mid-to-late pregnancy, which range from 5,000 to 40,000 pg/mL. No unchanged EMP is seen in the circulation with oral administration.The pharmacokinetics of EMP are different with intravenous injection. Following a single intravenous injection of 300 mg EMP, levels of EMP were higher than those of its metabolites for the first 8 hours. This is likely due to the bypassing of first-pass metabolism. However, by 24 hours after the dose, unchanged EMP could no longer be detected in the circulation. The clearance of EMP from blood plasma is 4.85 ± 0.684 L/h. The volumes of distribution of EMP with intravenous injection were small; under a two-compartment model, the volume of distribution for the central compartment was 0.043 L/kg and for the peripheral compartment was 0.11 L/kg. The plasma protein binding of EMP is high. Estramustine is accumulated in tumor tissue, for instance prostate cancer and glioma tissue, with estramustine levels much higher in these tissues than in plasma (e.g., 6.3- and 15.9-fold, respectively). Conversely, levels of estromustine in tumor versus plasma are similar (1.0- and 0.5-fold, respectively). Estramustine and estromustine appear to accumulate in adipose tissue.The elimination half-life of estromustine with oral EMP was 13.6 hours on average, with a range of 8.8 to 22.7 hours. Conversely, the elimination half-life of estromustine with intravenous injection was 10.3 hours, with a range of 7.36 to 12.3 hours. For comparison, the corresponding elimination half-lives of estrone were 16.5 and 14.7 hours for oral and intravenous administration, respectively. Estramustine and estromustine are mainly excreted in bile and hence in feces. They are not believed to be excreted in urine. Chemistry EMP, also known as estradiol 3-normustine 17β-phosphate or as estradiol 3-(bis(2-chloroethyl)carbamate) 17β-(dihydrogen phosphate), is a synthetic estrane steroid and a derivative of estradiol. It is an estrogen ester; specifically, EMP is a diester of estradiol with a C3 normustine (nitrogen mustard–carbamate moiety) ester and a C17β phosphate ester. EMP is provided as the sodium or meglumine salt. EMP is similar as a compound to other estradiol esters such as estradiol sulfate and estradiol valerate, but differs in the presence of its nitrogen mustard ester moiety. Antineoplastic agents related to EMP, although none of them were marketed, include alestramustine, atrimustine, cytestrol acetate, estradiol mustard, ICI-85966, and phenestrol.Due to its hydrophilic phosphate ester moiety, EMP is a readily water-soluble compound. This is in contrast to most other estradiol esters, which are fatty acid esters and lipophilic compounds that are not particularly soluble in water. Unlike EMP, estramustine is highly lipophilic, practically insoluble in water, and non-ionizable. The phosphate ester of EMP was incorporated into the molecule in order to increase its water solubility and allow for intravenous administration.The molecular weight of EMP sodium is 564.3 g/mol, of EMP meglumine is 715.6 g/mol, of EMP is 520.4 g/mol, of estramustine is 440.4 g/mol, and of estradiol is 272.4 g/mol. As a result of these differences in molecular weights, EMP contains about 52%, EMP sodium about 48%, and EMP meglumine about 38% of the amount of estradiol within their structures as does an equal-mass quantity of estradiol. History EMP was first synthesized in the mid-1960s and was patented in 1967. It was initially developed for the treatment of breast cancer. The idea for EMP was inspired by the uptake and accumulation of radiolabeled estrogens into breast cancer tissue. However, initial clinical findings of EMP in women with breast cancer were disappointing. Subsequently, radiolabeled EMP was found to be taken up into and accumulated rat prostate gland, and this finding culminated in the medication being repurposed for the treatment of prostate cancer. EMP was introduced for medical use in the treatment of this condition in the early 1970s, and was approved in the United States for this indication in 1981. EMP was originally introduced for use by intravenous injection. Subsequently, an oral formulation was introduced, and the intravenous preparation was almost abandoned in favor of the oral version. Society and culture Generic names EMP is provided as the sodium salt for oral administration, which has the generic names estramustine phosphate sodium (USAN) and estramustine sodium phosphate (BANM, JAN), and as the meglumine salt for intravenous administration, which has the generic name estramustine phosphate meglumine. The INNM is estramustine phosphate. The name estramustine phosphate is a contraction of estradiol normustine phosphate. EMP is also known by its former developmental code names Leo 299, Ro 21-8837, and Ro 21-8837/001. Brand names EMP is most commonly marketed under the brand names Estracyt and Emcyt, but has also been sold under a number of other brand names, including Amsupros, Biasetyl, Cellmustin, Estramustin HEXAL, Estramustina Filaxis, Estranovag, Multosin, Multosin Injekt, Proesta, Prostamustin, and Suloprost. Availability EMP is marketed in the United States, Canada, and Mexico under the brand name Emcyt, whereas the medication is marketed under the brand name Estracyt in the United Kingdom and elsewhere throughout Europe as well as in Argentina, Chile, and Hong Kong. It has been discontinued in a number of countries, including Australia, Brazil, Ireland, and Norway. Research EMP has been studied in the treatment of other cancers such as glioma and breast cancer. It has been found to slightly improve quality of life in people with glioma during the first 3 months of therapy. References == Further reading ==
Trimethoprim	Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers diarrhea. With sulfamethoxazole or dapsone it may be used for Pneumocystis pneumonia in people with HIV/AIDS. It is taken by mouth.Common side effects include nausea, changes in taste, and rash. Rarely it may result in blood problems such as not enough platelets or white blood cells. Trimethoprim may cause sun sensitivity. There is evidence of potential harm during pregnancy in some animals but not humans. It works by blocking folate metabolism via dihydrofolate reductase in some bacteria which results in their death.Trimethoprim was first used in 1962. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. Medical uses It is primarily used in the treatment of urinary tract infections, although it may be used against any susceptible aerobic bacterial species. It may also be used to treat and prevent Pneumocystis jirovecii pneumonia. It is generally not recommended for the treatment of anaerobic infections such as Clostridium difficile colitis (the leading cause of antibiotic-induced diarrhea). Trimethoprim has been used in trials to treat retinitis.Resistance to trimethoprim is increasing, but it is still a first line antibiotic in many countries. Spectrum of susceptibility Cultures and susceptibility tests should be done to make sure bacteria are treated by trimethoprim. Escherichia coli Proteus mirabilis Klebsiella pneumoniae Enterobacter species Coagulase-negative Staphylococcus species, including S. saprophyticus Streptococcus pneumoniae Haemophilus influenzae Side effects Common Nauseas Change in taste Vomiting Diarrhea Rashes Sun sensitivity Itchiness Rare Can cause thrombocytopenia (low levels of platelets) by lowering folic acid levels; this may also cause megaloblastic anemia. Trimethoprim antagonizes the epithelial sodium channel in the distal tubule, thus acting like amiloride. This can cause increased potassium levels in the body (hyperkalemia). Can compete with creatinine for secretion into the renal tubule. This can cause an artificial rise in the serum creatinine. Use in EHEC infections may lead to an increase in expression of Shiga toxin. Contraindications Known hypersensitivity to trimethoprim History of megaloblastic anemia due to folate deficiency Pregnancy Based on the studies that show that trimethoprim crosses the placenta and can affect folate metabolism, there has been growing evidence of the risk of structural birth defects associated with trimethoprim, especially during the first trimester of pregnancy. It may be involved in a reaction similar to disulfiram when alcohol is consumed after it is used, in particular when used in combination with sulfamethoxazole. The trophoblasts in the early fetus are sensitive to changes in the folate cycle. A recent study has found a doubling in the risk of miscarriage in women exposed to trimethoprim in the early pregnancy. Mechanism of action Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF). THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis. Trimethoprims affinity for bacterial dihydrofolate reductase is several thousand times greater than its affinity for human dihydrofolate reductase. Sulfamethoxazole inhibits dihydropteroate synthase, an enzyme involved further upstream in the same pathway. Trimethoprim and sulfamethoxazole are commonly used in combination due to possible synergistic effects, and reduced development of resistance. This benefit has been questioned. History Trimethoprim was first used in 1962. In 1972, it was used as a prophylactic treatment for urinary tract infections in Finland.Its name is derived from trimethyloxy-pyrimidine. See also Tetroxoprim Iclaprim References External links "Trimethoprim". Drug Information Portal. U.S. National Library of Medicine.
Pretomanid	Pretomanid is an antibiotic medication used for the treatment of multi-drug-resistant tuberculosis affecting the lungs. It is generally used together with bedaquiline and linezolid. It is taken by mouth.The most common side effects include nerve damage, acne, vomiting, headache, low blood sugar, diarrhea, and liver inflammation. It is in the nitroimidazole class of medications.Pretomanid was approved for medical use in the United States in August 2019, and in the European Union in July 2020. Pretomanid was developed by TB Alliance. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Medical uses Pretomanid is indicated in combination with bedaquiline and linezolid, in adults, for the treatment of pulmonary extensively drug resistant (XDR), or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB). History Pretomanid is the generic, nonproprietary name for the novel anti-bacterial drug compound formerly called PA-824. Pretomanid is referred to as "Pa" in regimen abbreviations, such as BPaL. The "preto" part of the compounds name honors Pretoria, South Africa, the home of a TB Alliance clinical development office where much of the drugs development took place, while the "-manid" stem designates compounds with similar chemical structures. This class of drug is variously referred to as nitroimidazoles or nitroimidazooxazines. Development of this compound was initiated because of the urgent need for new antibacterial drugs effective against resistant strains of tuberculosis. Also, current anti-TB drugs are mainly effective against replicating and metabolically active bacteria, creating a need for drugs effective against persisting or latent bacterial infections as often occur in patients with tuberculosis. Discovery and pre-clinical development Pretomanid was first identified in 2000, in a series of 100 nitroimidazopyran derivatives synthesized and tested for antitubercular activity, by PathoGenesis (now a subsidiary of Novartis). Importantly, pretomanid has activity against static M. tuberculosis isolates that survive under anaerobic conditions, with bactericidal activity comparable to that of the existing drug metronidazole. Pretomanid requires metabolic activation by Mycobacterium for antibacterial activity. Pretomanid was not the most potent compound in the series against cultures of M. tuberculosis, but it was the most active in infected mice after oral administration. Oral pretomanid was active against tuberculosis in mice and guinea pigs at safely tolerated dosages for up to 28 days. Limited FDA approval The U.S. Food and Drug Administration (FDA) approved pretomanid only in combination with bedaquiline and linezolid for treatment of a limited and specific population of adults with extensively drug resistant, treatment-intolerant or nonresponsive multidrug resistant pulmonary tuberculosis. Pretomanid was approved under the Limited Population Pathway (LPAD pathway) for antibacterial and antifungal drugs. The LPAD Pathway was established by Congress under the 21st Century Cures Act to expedite development and approval of antibacterial and antifungal drugs to treat serious or life-threatening infections in a limited population of patients with unmet need. Pretomanid is only the third tuberculosis drug to receive FDA approval in more than 40 years.The FDA granted Pretomanid priority review and orphan drug designation. The FDA granted The Global Alliance for TB Drug Development (TB Alliance) the approval of Pretomanid and a Tropical Disease Priority Review Voucher. References External links "Pretomanid". Drug Information Portal. U.S. National Library of Medicine.
Ethinylestradiol/desogestrel	Desogestrel/ethinylestradiol (EE/DSG), sold under the brand name Marvelon among others, is a fixed-dose combination of desogestrel (DSG), a progestin, and ethinylestradiol (EE), an estrogen, which is used as a birth control pill to prevent pregnancy in women. It is taken by mouth.It was approved for medical use in the United Kingdom in 1981, and in the United States in 1992. In 2019, it was the 128th most commonly prescribed medication in the United States, with more than 5 million prescriptions. See also List of combined sex-hormonal preparations § Estrogens and progestogens == References ==
Ofloxacin	Ofloxacin is a quinolone antibiotic useful for the treatment of a number of bacterial infections. When taken by mouth or injection into a vein, these include pneumonia, cellulitis, urinary tract infections, prostatitis, plague, and certain types of infectious diarrhea. Other uses, along with other medications, include treating multidrug resistant tuberculosis. An eye drop may be used for a superficial bacterial infection of the eye and an ear drop may be used for otitis media when a hole in the ear drum is present.When taken by mouth, common side effects include vomiting, diarrhea, headache, and rash. Other serious side effect include tendon rupture, numbness due to nerve damage, seizures, and psychosis. Use in pregnancy is typically not recommended. Ofloxacin is in the fluoroquinolone family of medications. It works by interfering with the bacteriums DNA.Ofloxacin was patented in 1980 and approved for medical use in 1985. It is on the World Health Organizations List of Essential Medicines. Ofloxacin is available as a generic medication. In 2017, it was the 278th most commonly prescribed medication in the United States, with more than one million prescriptions. Medical uses Ofloxacin is used in the treatment of bacterial infections such as: Acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) Community-acquired pneumonia Uncomplicated skin and skin structure infections Nongonococcal urethritis and cervicitis Epididymitis Mixed Infections of the urethra and cervix Acute pelvic inflammatory disease Uncomplicated cystitis Complicated urinary tract infections Prostatitis Acute, uncomplicated urethral and cervical gonorrheaOfloxacin has not been shown to be effective in the treatment of syphilis. Ofloxacin is no longer considered a first-line treatment for gonorrhea, because of bacterial resistance. Susceptible bacteria According to the product package insert, ofloxacin is effective against these microorganisms:Aerobic Gram-positive microorganisms: Staphylococcus aureus (methicillin-susceptible strains) Streptococcus pneumoniae (penicillin-susceptible strains) Streptococcus pyogenesAerobic Gram-negative microorganisms Citrobacter koseri (Citrobacter diversus) Enterobacter aerogenes Escherichia coli Haemophilus influenzae Klebsiella pneumoniae Neisseria gonorrhoeae Proteus mirabilis Pseudomonas aeruginosaOther microorganisms: Chlamydia trachomatis Adverse effects In general, fluoroquinolones are well tolerated, with most side effects being mild to moderate. On occasion, serious adverse effects occur. Common side effects include gastrointestinal effects such as nausea, vomiting, and diarrhea, as well as headache and insomnia. The overall rate of adverse events in patients treated with fluoroquinolones is roughly similar to that seen in patients treated with other antibiotic classes. A U.S. Centers for Disease Control study found patients treated with fluoroquinolones experienced adverse events severe enough to lead to an emergency department visit more frequently than those treated with cephalosporins or macrolides, but less frequently than those treated with penicillins, clindamycin, sulfonamides, or vancomycin.Postmarketing surveillance has revealed a variety of relatively rare but serious adverse effects associated with all members of the fluoroquinolone antibacterial class. Among these, tendon problems and exacerbation of the symptoms of the neurological disorder myasthenia gravis are the subject of "black box" warnings in the United States. The most severe form of tendonopathy associated with fluoroquinolone administration is tendon rupture, which in the great majority of cases involves the Achilles tendon. Younger people typically experience good recovery, but permanent disability is possible, and is more likely in older patients. The overall frequency of fluoroquinolone-associated Achilles tendon rupture in patients treated with ciprofloxacin or levofloxacin has been estimated at 17 per 100,000 treatments. Risk is substantially elevated in the elderly and in those with recent exposure to topical or systemic corticosteroid therapy. Simultaneous use of corticosteroids is present in almost one-third of quinolone-associated tendon rupture. Tendon damage may manifest during and up to a year after fluoroquinolone therapy has been completed.Fluoroquinolones prolong the QT interval by blocking voltage-gated potassium channels. Prolongation of the QT interval can lead to torsades de pointes, a life-threatening arrhythmia, but in practice, this appears relatively uncommon in part because the most widely prescribed fluoroquinolones (ciprofloxacin and levofloxacin) only minimally prolong the QT interval.Clostridium difficile-associated diarrhea may occur in connection with the use of any antibacterial drug, especially those with a broad spectrum of activity such as clindamycin, cephalosporins, and fluoroquinolones. Fluoroquinoline treatment is associated with risk similar to or less than that associated with broad spectrum cephalosporins. Fluoroquinoline administration may be associated with the acquisition and outgrowth of a particularly virulent Clostridium strain.The U.S. prescribing information contains a warning regarding uncommon cases of peripheral neuropathy, which can be permanent. Other nervous system effects include insomnia, restlessness, and rarely, seizure, convulsions, and psychosis Other rare and serious adverse events have been observed with varying degrees of evidence for causation.Events that may occur in acute overdose are rare, and include kidney failure and seizure. Susceptible groups of patients, such as children and the elderly, are at greater risk of adverse reactions during therapeutic use.Ofloxacin, like some other fluoroquinolones, may inhibit drug-metabolizing enzymes, and thereby increase blood levels of other drugs such as cyclosporine, theophylline, and warfarin, among others. These increased blood levels may result in a greater risk of side effects. Careful monitoring of serum glucose is advised when ofloxacin or other fluorquinolones are used by people who are taking sulfonylurea antidiabetes drugs. The concomitant administration of a nonsteroidal anti-inflammatory drug with a quinolone, including ofloxacin, may increase the risk of central nervous system stimulation and convulsive seizures. The fluoroquinolones have been shown to increase the anticoagulant effect of acenocoumarol, anisindione, and dicumarol. Additionally, the risk of cardiotoxicity and arrhythmias is increased when co-administered with drugs such as dihydroquinidine barbiturate, quinidine, and quinidine barbiturate.Current or past treatment with oral corticosteroids is associated with an increased risk of Achilles tendon rupture, especially in elderly patients who are also taking the fluoroquinolones. Contraindications As noted above, under licensed use, ofloxacin is now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance. Caution should be used in people with liver disease. The excretion of ofloxacin may be reduced in patients with severe liver function disorders (e.g., cirrhosis with or without ascites). Ofloxacin is also considered to be contraindicated within the pediatric population, pregnancy, nursing mothers, patients with psychiatric illnesses and in patients with epilepsy or other seizure disorders. Pregnancy Ofloxacin has not been shown to have any teratogenic effects at oral doses as high as 810 mg/kg/day (11 times the recommended maximum human dose based on mg/m2 or 50 times based on mg/kg) and 160 mg/kg/day (four times the recommended maximum human dose based on mg/m2 or 10 times based on mg/kg) when administered to pregnant rats and rabbits, respectively. Additional studies in rats with oral doses up to 360 mg/kg/day (five times the recommended maximum human dose based on mg/m2 or 23 times based on mg/kg) demonstrated no adverse effect on late fetal development, labor, delivery, lactation, neonatal viability, or growth of the newborn. Doses equivalent to 50 and 10 times the recommended maximum human dose of ofloxacin (based on mg/kg) were fetotoxic (i.e., decreased fetal body weight and increased fetal mortality) in rats and rabbits, respectively. Minor skeletal variations were reported in rats receiving doses of 810 mg/kg/day, which is more than 10 times higher than the recommended maximum human dose based on mg/m2.There are, however, no adequate and well-controlled studies in pregnant women. Ofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Children Oral and intravenous ofloxacin are not licensed for use in children, except as noted above, due to the risk of musculoskeletal injury. In one study, 1534 juvenile patients (age 6 months to 16 years) treated with levofloxacin as part of three efficacy trials were followed up to assess all musculoskeletal events occurring up to 12 months after treatment. At 12 months follow-up, the cumulative incidence of musculoskeletal adverse events was 3.4%, compared to 1.8% among 893 patients treated with other antibiotics. In the levafloxacin-treated group, about two-thirds of these musculoskeletal adverse events occurred in the first 60 days, 86% were mild, 17% were moderate, and all resolved without long-term sequelae. In a study comparing the safety and efficacy of levofloxacin to that of azithromycin or ceftriaxone in 712 children with community-acquired pneumonia, adverse events were experienced by 6% of those treated with levofloxacin and 4% of those treated with comparator antibiotics. Most of these adverse events were thought to be unrelated or doubtfully related to the levofloxacin. Two deaths were observed in the levofloxacin group, neither of which was thought to be treatment-related. Spontaneous reports to the FDA Adverse Effects Reporting System at the time of the 20 September 2011 FDA Pediatric Drugs Advisory Committee include musculoskeletal events (39, including five cases of tendon rupture) and central nervous system events (19, including five cases of seizures) as the most common spontaneous reports between April 2005 and March 2008. An estimated 130,000 pediatric prescriptions for levofloxacin were filled on behalf of 112,000 pediatric patients during that period. Overdose Limited information is available on overdose with ofloxacin. Advice for the management of an acute overdose of ofloxacin is emptying of the stomach, along with close observation, and making sure that the patient is appropriately hydrated. Hemodialysis or peritoneal dialysis is of only limited effectiveness. Overdose may result in central nervous system toxicity, cardiovascular toxicity, tendon/articular toxicity, and hepatic toxicity as well as kidney failure and seizure. Both seizures and severe psychiatric reactions have, however, been reported to occur at therapeutic dosage. Pharmacokinetics The bioavailability of ofloxacin in the tablet form is roughly 98% following oral administration, reaching maximum serum concentrations within one to two hours. Between 65% and 80% of an administered oral dose of ofloxacin is excreted unchanged via the kidneys within 48 hours of dosing. Therefore, elimination is mainly by renal excretion. However, 4-8% of an ofloxacin dose is excreted in the feces. This would indicate a small degree of biliary excretion, as well. Plasma elimination half-life is around 4 to 5 hours in patients and 6.4 to 7.4 hours in elderly patients.Ofloxacin is a racemic mixture, which consists of 50% levofloxacin (the biologically active component) and 50% of its “mirror image” or enantiomer dextrofloxacin."After multiple-dose administration of 200 mg and 300 mg doses, peak serum levels of 2.2 and 3.6 μg/ml, respectively, are predicted at steady-state. In vitro, approximately 32% of the drug in plasma is protein bound. Floxin is widely distributed to body tissues. Ofloxacin has been detected in blister fluid, cervix, lung tissue, ovary, prostatic fluid, prostatic tissue, skin, and sputum. Pyridobenzoxazine ring appears to decrease the extent of parent compound metabolism. Less than 5% is eliminated by the kidneys as desmethyl or N-oxide metabolites; 4% to 8% by feces."A number of the endogenous compounds have been reported to be affected by ofloxacin as inhibitors, alteraters, and depletors. See the latest package insert for ofloxacin for additional details. Mode of action Ofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting two bacterial type II topoisomerases, DNA gyrase and topoisomerase IV. Topoisomerase IV is an enzyme necessary to separate (mostly in prokaryotes, in bacteria in particular) replicated DNA, thereby inhibiting bacterial cell division. History Ofloxacin is a second-generation fluoroquinolone, being a broader-spectrum analog of norfloxacin, and was synthesized and developed by scientists at Daiichi Seiyaku.It was first approved for marketing in Japan in 1985, for oral administration, and Daiichi marketed it there under the brand name Tarvid. Daiichi, working with Johnson & Johnson, obtained FDA approval in December 1990, under the brand name Floxin, labelled for use in adults with lower respiratory tract infections, skin and skin structure infections, urinary tract infections, prostatitis, and sexually transmitted diseases. By 1991, it was also marketed as Tarvid by Hoechst in the UK, Germany, Belgium, and Portugal; as Oflocet in France, Portugal, Tunisia, and several African countries by Roussel-Uclaf, as Oflocin by Glaxo in Italy, and as Flobacin by Sigma-Tau in Italy.The market for ofloxacin was seen as difficult from its launch; it was approved as a "1C" drug, a new molecular entity with little or no therapeutic gain over existing therapies, and ciprofloxacin, which had a broader spectrum, was already on the market.By 1992, an intravenous solution was approved for marketing,In 1997, an indication for pelvic inflammatory disease was approved by the U.S. Food and Drug Administration (FDA) for the oral formulation, and in the same year, a solution for ear infections was approved under the brand Daiichi and J&J also cannibalized its own market by introducing levofloxacin, the levo-enantiomer of ofloxacin, in 1996; Johnson and Johnsons annual sales of Floxin in 2003 was about $30 million, whereas their combined sales of Levaquin/Floxin exceeded $1.15 billion in the same year. Johnson & Johnson withdrew the marketing application in 2009. Society and culture Available forms Ofloxacin for systemic use is available as a tablet (multiple strengths), an oral suspension, and an injectable solution (multiple strengths). It is also used as eye drops and ear drops and is available in combination with ornidazole. Dosage Ofloxacin should be administered as described within the Dosage Guidelines table found within the most recent package insert. The status of the patients renal function and hepatic function must also be taken into consideration to avoid an accumulation that may lead to a fatal drug overdose. Ofloxacin is eliminated primarily by renal excretion. However, the drug is also metabolized and partially cleared through the liver. Modification of the dosage is required using the table found within the package insert for those with impaired liver or kidney function (particularly for patients with severe renal dysfunction). However, since the drug is known to be substantially excreted by the kidneys, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. The duration of treatment depends upon the severity of infection and the usual duration is 7 to 14 days. Antibiotic use and bacterial resistance Resistance to ofloxacin and other fluoroquinolones may evolve rapidly, even during a course of treatment. Numerous pathogens, including Staphylococcus aureus, enterococci, and Streptococcus pyogenes now exhibit resistance worldwide.Floxacin and other fluoroquinolones had become the most commonly prescribed class of antibiotics to adults in 2002. Nearly half (42%) of these prescriptions were for conditions not approved by the U.S. Food and Drug Administration (FDA), such as acute bronchitis, otitis media, and acute upper respiratory tract infection, according to a study that was supported in part by the Agency for Healthcare Research and Quality. Additionally they are commonly prescribed for medical conditions that are not even bacterial to begin with, such as viral infections, or those to which no proven benefit exists. References External links "Ofloxacin". Drug Information Portal. U.S. National Library of Medicine.
Sodium hyaluronate	Sodium hyaluronate is the sodium salt of hyaluronic acid, a glycosaminoglycan found in various connective tissue of humans. Chemistry Sodium hyaluronate is the sodium salt of hyaluronic acid. It is a glycosaminoglycan and long-chain polymer of disaccharide units of Na-glucuronate-N-acetylglucosamine. It can bind to specific receptors for which it has a high affinity. The polyanionic form, commonly referred to as hyaluronan, is a visco-elastic polymer found in the aqueous and vitreous humour of the eye and in the fluid of articulating joints. Natural occurrence Sodium hyaluronate, as hyaluronic acid, is distributed widely in the extracellular matrix of mammalian connective, epithelial, and neural tissues, as well as the corneal endothelium. Mechanism of action Sodium hyaluronate functions as a tissue lubricant and is thought to play an important role in modulating the interactions between adjacent tissues. It forms a viscoelastic solution in water. Mechanical protection for tissues (iris, retina) and cell layers (corneal, endothelium, and epithelium) are provided by the high viscosity of the solution. Elasticity of the solution assists in absorbing mechanical stress and providing a protective buffer for tissues. In facilitating wound healing, it is thought that it acts as a protective transport vehicle, taking peptide growth factors and other structural proteins to a site of action. It is then enzymatically degraded and active proteins are released to promote tissue repair. Pharmacokinetics Sodium hyaluronate is cleared within hours of injection but appears to have residual effects on contacted cells. In the eye it is eliminated via the canal of Schlemm. Adverse effects Adverse effects are relatively rare when used to treat the joints.When used in ophthalmological procedures, sodium hyaluronate may cause postoperative inflammation, corneal edema or decompensation, and short-term increases in intraocular pressure. Medical uses Intra-articular injection It is used to treat knee pain in patients with osteoarthritis who have not received relief from other treatments. It is injected into the joint capsule, to act as both a shock absorber and a lubricant for the joint. Thus sodium hyaluronate is used as a viscosupplement, administered through a series of injections into the knee, increasing the viscosity of the synovial fluid, which helps lubricate, cushion and reduce pain in the joint. It is generally used as a last resort before surgery and provides symptomatic relief, by recovering the viscoelasticity of the articular fluid, and by stimulating new production from synovial fluid. Use of sodium hyaluronate may reduce the need for joint replacement. Injections appear to increase in effectiveness over the course of four weeks, reaching a peak at eight weeks and retaining some effectiveness at six months, with greater benefit for osteoarthritis than oral analgesics. It may also be effective when used with the ankle joint. Intraocular viscoelastic injection It is used as an aid in ophthalmic surgery acting as aqueous and vitreous humor, e.g. in cataract extraction (intra- and extracapsular), intraocular lens implantation, corneal transplant, glaucoma filtration, and retina attachment surgery and in the treatment of dry eyes. In surgical procedures in the anterior segment of eyeball, instillation of sodium hyaluronate its viscoelasticity enables maintenance of a deep chamber during surgical manipulation since the solution does not flow out of the open anterior chamber, allowing for efficient manipulation with less trauma to the corneal endothelium and other surrounding tissues. Its viscoelasticity also helps to push back the vitreous face and prevent formation of a postoperative flat chamber. In posterior segment surgery, sodium hyaluronate serves as a surgical aid to gently separate, maneuver, and hold tissues. It creates a clear field of vision, facilitating intra-operative and post-operative inspection of the retina and photocoagulation. Skin injections in plastic surgery Sodium hyaluronate is injected to reduce wrinkles on the face. As of 2017, the FDA had approved 13 hyaluronate preparations as so called dermal fillers. They are also used as a filler of lips or in other parts of the body, though not FDA approved. The filling effect is temporary and lasts for about six months or longer in most people. Topical application Topically applied sodium hyaluronate can facilitate the absorption of biomacromolecules, i.e. pharmaceuticals, and function like a nanocarrier. Its effects on skin depend on the hyaluronate formulation and skin health: In barrier-deficient skin it restricted the delivery of biomacromolecules to the stratum corneum and viable epidermis. In normal skin, low-molecular weight hyaluronate (5 kDa) enhanced penetration into the epidermis.Transepidermal water loss increased by 55.5% with low-molecular weight, and was reduced by 28% with crosslinked resilient, and by 16% with HMW. The addition to skin creams became popular in the second millennium. Its efficacy against wrinkles has not been tested in clinical trials.Dry, scaly skin, such as that caused by atopic dermatitis, may be treated with lotion or another skin product containing sodium hyaluronate as its active ingredient.After instillation into the lung, higher molecular weight hyaluronate appears to persist longer in the lung but if > 215 kD there was poor lung penetration and mucociliary clearance. Hyaluronate could allow access to lymph nodes draining the pulmonary bed. Intravesical instillation Sodium hyaluronate can be instilled into the bladder for the treatment of various forms of cystitis and associated bladder pain, by replenishing the glycosaminoglycan layer of the bladder urothelium. Contraindications Sodium hyaluronate has a very low incidence of side effects, however it is contraindicated in people who are sensitive to hyaluronate preparations. If being administered as an intra-articular injection, it should not be given when there are infections or skin disease at the injection site. History In the late 1970s and early 1980s the material was used with the brand names of Hylartin and Hylartin Vetused in human and veterinary clinical trials (race horses) to treat osteoarthritis. The first commercially sold sodium hyaluronate had been developed by Endre Alexander Balazs under the brand name of Healon, manufactured by Pharmacia AB in Sweden in 1980. In 1986, sodium hyaluronate was used as an intra-articular injection to treat osteoarthritis of the knee with the product Hyalart/Hyalgan by Fidia of Italy. See also Hyaluronic acid sodium salt Biochem/physiol Actions Hyaluronic Acid Legal Information == References ==
Carglumic acid	Carglumic acid, sold under the brand name Carbaglu among others, is used for the treatment of hyperammonaemia.Carglumic acid is a carbamoyl phosphate synthetase 1 (CPS 1) activator.The most common adverse effects include vomiting, abdominal pain, pyrexia (fever), and tonsillitis, anemia, diarrhea, ear infection, other infections, nasopharyngitis, decreased hemoglobin levels, and headache.It was approved for medical use in the United States in March 2010. Carglumic acid is an orphan drug. Medical uses Carglumic acid is indicated for the treatment of acute hyperammonemia and chronic hyperammonemia. References External links "Carglumic acid". Drug Information Portal. U.S. National Library of Medicine.
Leuprorelin	Leuprorelin, also known as leuprolide, is a manufactured version of a hormone used to treat prostate cancer, breast cancer, endometriosis, uterine fibroids, and early puberty, to perform chemical castration of violent sex offenders, or as part of transgender hormone therapy. It is given by injection into a muscle or under the skin.Leuprorelin is in the gonadotropin-releasing hormone (GnRH) analogue family of medications. It works by decreasing gonadotropin and therefore decreasing testosterone and estradiol. Common side effects include hot flashes, unstable mood, trouble sleeping, headaches, and pain at the site of injection. Other side effects may include high blood sugar, allergic reactions, and problems with the pituitary gland. Use during pregnancy may harm the baby.Leuprorelin was patented in 1973 and approved for medical use in the United States in 1985. It is on the World Health Organizations List of Essential Medicines. It is sold under the brand name Lupron among others. Medical use Leuprorelin may be used in the treatment of hormone-responsive cancers such as prostate cancer and breast cancer. It may also be used for estrogen-dependent conditions such as endometriosis or uterine fibroids. It may be used for precocious puberty in both males and females, and to prevent premature ovulation in cycles of controlled ovarian stimulation for in vitro fertilization (IVF). This use is controversial since the Lupron label advises against using the drug when one is considering pregnancy, due to a risk of birth defects.It may be used to reduce the risk of premature ovarian failure in women receiving cyclophosphamide for chemotherapy.Along with triptorelin and goserelin, it has been used to delay puberty in transgender youth until they are old enough to begin hormone replacement therapy. Researchers have recommended puberty blockers after age 12, when the person has developed to Tanner stages 2–3, and then cross-sex hormones treatment at age 16. This use of the drug is off-label, however, not having been approved by the Food and Drug Administration and without data on long-term effects of this use.They are also sometimes used as alternatives to antiandrogens like spironolactone and cyproterone acetate for suppressing testosterone production in transgender women. It also is used for suppressing estrogen production in transgender men.It is considered a possible treatment for paraphilias. Leuprorelin has been tested as a treatment for reducing sexual urges in pedophiles and other cases of paraphilia. Side effects Common side effects of leuprorelin injection include redness/burning/stinging/pain/bruising at the injection site, hot flashes (flushing), increased sweating, night sweats, tiredness, headache, upset stomach, nausea, diarrhea, impotence, testicular shrinkage, constipation, stomach pain, breast swelling or tenderness, acne, joint/muscle aches or pain, trouble sleeping (insomnia), reduced sexual interest, vaginal discomfort/dryness/itching/discharge, vaginal bleeding, swelling of the ankles/feet, increased urination at night, dizziness, breakthrough bleeding in a female child during the first two months of leuprorelin treatment, weakness, chills, clammy skin, skin redness, itching, or scaling, testicle pain, impotence, depression, or memory problems. The rates of gynecomastia with leuprorelin have been found to range from 3 to 16%. Pharmacology Mechanism of action Leuprorelin is a gonadotropin-releasing hormone (GnRH) analogue acting as an agonist at pituitary GnRH receptors. Agonism of GnRH receptors initially results in the stimulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion by the anterior pituitary ultimately leading to increased serum estradiol and testosterone levels via the normal physiology of the hypothalamic–pituitary–gonadal axis (HPG axis); however, because propagation of the HPG axis is incumbent upon pulsatile hypothalamic GnRH secretion, pituitary GnRH receptors become desensitised after several weeks of continuous leuprorelin therapy. This protracted downregulation of GnRH receptor activity is the targeted objective of leuprorelin therapy and ultimately results in decreased LH and FSH secretion, leading to hypogonadism and thus a dramatic reduction in estradiol and testosterone levels regardless of sex.In the treatment of prostate cancer, the initial increase in testosterone levels associated with the initiation of leuprorelin therapy is counterproductive to treatment goals. This effect is avoided with concurrent utilisation of 5α-reductase inhibitors, such as finasteride, or flutamide which function to block the downstream effects of testosterone. Available forms Leuprorelin is available in the following forms, among others: Short-acting daily intramuscular injection (Lupron) Long-acting depot intramuscular injection (Lupron Depot) Long-acting depot subcutaneous injection (Eligard) Long-acting subcutaneous injection (Fensolvi) Long-acting subcutaneous implant (Viadur) Long-acting leuprolide mesylate (Camcevi) for the treatment of advanced prostate cancer. Leuprolide acetate and norethindrone acetate combination pack (Lupaneta Pack) Chemistry The peptide sequence is Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt (Pyr = L-pyroglutamyl). History Leuprorelin was discovered and first patented in 1973 and was introduced for medical use in 1985. It was initially marketed only for daily injection, but a depot injection formulation was introduced in 1989. Approvals Lupron injection was approved by the FDA for treatment of advanced prostate cancer on April 9, 1985. Lupron depot for monthly intramuscular injection was approved by the FDA for palliative treatment of advanced prostate cancer on January 26, 1989. Viadur was approved by the FDA for palliative treatment of advanced prostate cancer on March 6, 2000. Eligard was approved by the FDA for palliative treatment of advanced prostate cancer on January 24, 2002. Fensolvi was approved by the FDA for children with central precocious puberty on May 4, 2020. Society and culture Legal status On 24 March 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Camcevi, intended for the treatment of the cancer of the prostate in adult men when the cancer is "hormone-dependent", which means that it responds to treatments that reduce the levels of the hormone testosterone. The applicant for this medicinal product is Accord Healthcare S.L.U. Names Leuprorelin is the generic name of the drug and its INN and BAN, while leuprorelin acetate is its BANM and JAN, leuprolide acetate is its USAN and USP, leuprorelina is its DCIT, and leuproréline is its DCF. It is also known by its developmental code names A-43818, Abbott-43818, DC-2-269, and TAP-144.Leuprorelin is marketed by Bayer AG under the brand name Viadur, by Tolmar under the brand names Eligard and Fensolvi, and by TAP Pharmaceuticals (1985–2008), by Varian Darou Pajooh under the brand name Leupromer and Abbott Laboratories (2008–present) under the brand name Lupron. Controversy In October 2001, the US Department of Justice, states attorneys general, and TAP Pharmaceutical Products, a subsidiary of Abbott Laboratories, settled criminal and civil charges against TAP related to federal and state medicare fraud and illegal marketing of the drug leuprorelin. TAP paid a total of $875 million, which was a record high at the time. The $875 million settlement broke down to $290 million for violating the Prescription Drug Marketing Act, $559.5 million to settle federal fraud charges for overcharging Medicare, and $25.5 million reimbursement to 50 states and Washington, D.C., for filing false claims with the states Medicaid programs. The case arose under the False Claims Act with claims filed by Douglas Durand, a former TAP vice president of sales, and Joseph Gerstein, a doctor at Tufts Universitys HMO practice. Durand, Gerstein, and Tufts shared $95 million of the settlement.There have since been various suits concerning leuprorelin use, none successful. They either concern the oversubscription of the drug or undue warning about the side effects. Between 2010 and 2013, the FDA updated the Lupron drug label to include new safety information on the risk of thromboembolism, loss of bone density and convulsions. The FDA then asserted that the benefits of leuprorelin outweigh its risks when used according to its approved labeling. Since 2017, the FDA has been evaluating leuprorelins connection to pain and discomfort in musculoskeletal and connective tissue. "Lupron protocol" A 2005 paper in the controversial and non-peer reviewed journal Medical Hypotheses suggested leuprorelin as a possible treatment for autism, the hypothetical method of action being the now defunct hypothesis that autism is caused by mercury, with the additional unfounded assumption that mercury binds irreversibly to testosterone and therefore leuprorelin can help cure autism by lowering the testosterone levels and thereby mercury levels. However, there is no scientifically valid or reliable research to show its effectiveness in treating autism. This use has been termed the "Lupron protocol" and Mark Geier, the proponent of the hypothesis, has frequently been barred from testifying in vaccine-autism related cases on the grounds of not being sufficiently expert in that particular issue and has had his medical license revoked. Medical experts have referred to Geiers claims as "junk science". Research As of 2006, leuprorelin was under investigation for possible use in the treatment of mild to moderate Alzheimers disease.A by mouth formulation of leuprorelin is under development for the treatment of endometriosis. It was also under development for the treatment of precocious puberty, prostate cancer, and uterine fibroids, but development for these uses was discontinued. The formulation has the tentative brand name Ovarest. As of July 2018, it is in phase II clinical trials for endometriosis. Veterinary use Leuprorelin is frequently used in ferrets for the treatment of adrenal disease. Its use has been reported in a ferret with concurrent primary hyperaldosteronism, and one with concurrent diabetes mellitus. It is also used to treat pet parrots with chronic egg laying behavior. References Further reading Shajnfeld A, Krueger RB (July 2006). "Reforming (Purportedly) Non-Punitive Responses to Sexual Offending". Developments in Mental Health Law. 25: 81. SSRN 1077282. External links "Leuprorelin". Drug Information Portal. U.S. National Library of Medicine. "Leuprolide acetate". Drug Information Portal. U.S. National Library of Medicine. "Leuprolide mesylate". Drug Information Portal. U.S. National Library of Medicine.
Muromonab-CD3	Muromonab-CD3 (trade name Orthoclone OKT3, marketed by Janssen-Cilag) is an immunosuppressant drug given to reduce acute rejection in patients with organ transplants. It is a monoclonal antibody targeted at the CD3 receptor, a membrane protein on the surface of T cells. It was the first monoclonal antibody to be approved for clinical use in humans. History Muromonab-CD3 was approved by the U.S. Food and Drug Administration (FDA) in 1986, making it the first monoclonal antibody to be approved anywhere as a drug for humans. In the European Communities, it was the first drug to be approved under the directive 87/22/EWG, a precursor of the European Medicines Agency (EMEA) centralised approval system in the European Union. This process included an assessment by the Committee for Proprietary Medicinal Products (CPMP, now CHMP), and a subsequent approval by the national health agencies; in Germany, for example, in 1988 by the Paul Ehrlich Institute in Frankfurt. However, the manufacturer of muromonab-CD3 has voluntarily withdrawn it from the United States market in 2010 due to numerous side-effects, better-tolerated alternatives and declining usage. Indications Muromonab-CD3 is approved for the therapy of acute, glucocorticoid-resistant rejection of allogeneic renal, heart and liver transplants. Unlike the monoclonal antibodies basiliximab and daclizumab, it is not approved for prophylaxis of transplant rejection, although a 1996 review has found it to be safe for that purpose.It has also been investigated for use in treating T-cell acute lymphoblastic leukemia. Pharmacodynamics and chemistry T cells recognise antigens primarily via the T cell receptor (TCR).: 160 CD3 is one of the proteins that make up the TCR complex.: 166 The TCR transduces the signal for the T cell to proliferate and attack the antigen.: 160 Muromonab-CD3 is a murine (mouse) monoclonal IgG2a antibody which was created using hybridoma technology. It binds to the T cell receptor-CD3-complex (specifically the CD3 epsilon chain) on the surface of circulating T cells, initially leading to an activation, but subsequently inducing the clearance of TCR complex from cell surface and apoptosis of the T cells. This protects the transplant against the T cells. When administered for transplant induction, the drug is administered daily thereafter for up to 7 days.Newer monoclonal antibodies in development with the same mechanism of action include otelixizumab (also known as TRX4), teplizumab (also known as hOKT3γ1(Ala-Ala) ), and visilizumab (with a tentative trade name of Nuvion). They are being investigated for the treatment of other conditions like Crohns disease, ulcerative colitis, and type 1 diabetes. Further development of teplizumab is uncertain, due to one-year data from a recent Phase III trial being "disappointing". Adverse effects Especially during the first infusion, the binding of muromonab-CD3 to CD3 can activate T cells to release cytokines like tumor necrosis factor and interferon gamma. This cytokine release syndrome, or CRS, includes side effects like skin reactions, fatigue, fever, chills, myalgia, headaches, nausea and diarrhea, and could lead to life-threatening conditions like apnoea, cardiac arrest, and flash pulmonary edema. To minimize the risk of CRS and to offset some of the minor side effects patient experience, glucocorticoids (such as methylprednisolone), acetaminophen, and diphenhydramine are given before the infusion.Other adverse effects include leucopenia, as well as an increased risk for severe infections and malignancies typical of immunosuppressive therapies. Neurological side effects like aseptic meningitis and encephalopathy have been observed. Possibly, they are also caused by the T cell activation.Repeated application can result in tachyphylaxis (reduced effectiveness) due to the formation of anti-mouse antibodies in the patient, which accelerates elimination of the drug. It can also lead to an anaphylactic reaction against the mouse protein, which may be difficult to distinguish from a CRS. Contraindications Except under special circumstances, the drug is contraindicated for patients with an allergy against mouse proteins, as well as patients with uncompensated heart failure, uncontrolled arterial hypertension or epilepsy. It should not be used during pregnancy or lactation. Etymology Muromonab-CD3 was developed before the WHO nomenclature of monoclonal antibodies took effect, and consequently its name does not follow this convention. Instead, it is a contraction from "murine monoclonal antibody targeting CD3". == References ==
Felbamate	Felbamate (marketed under the brand name Felbatol by MedPointe) is an anticonvulsant used in the treatment of epilepsy. It is used to treat partial seizures (with and without generalization) in adults and partial and generalized seizures associated with Lennox–Gastaut syndrome in children. However, an increased risk of potentially fatal aplastic anemia and/or liver failure limit the drugs usage to severe refractory epilepsy. Mechanism of action Felbamate has been proposed to have a unique dual mechanism of action as a positive modulator of GABAA receptors and as a blocker of NMDA receptors, particularly isoforms containing the NR2B subunit. Although it is clear that felbamate does cause pharmacological inhibition of NMDA receptors, the relevance of NMDA receptor blockade as a strategy for the treatment of human epilepsy has been questioned. Therefore, the importance of the effects of felbamate on NMDA receptors to its therapeutic action in epilepsy is uncertain. Approval history United States August 1993. Felbamate was approved for partial seizures with and without secondary generalization in adults and for Lennox–Gastaut Syndrome, a serious form of childhood epilepsy. Over the following year 150,000 people were started on felbamate therapy and a third of these became established. August 1, 1994. It was urgently withdrawn after 10 cases of aplastic anemia. A "Dear Doctor" letter was sent to 240,000 physicians. September 27, 1994. Felbamate had a limited redemption in another "Dear Doctor" letter sent to 260,000 physicians. It was recommended that the drug remain available only for patients with severe epilepsy for whom the benefits outweigh the risks, and that changes be made to the products labelling to reflect the newly recognized risk. This redemption came with an additional warning since there had been 10 cases acute liver failure (4 of which were fatal). At this point, 10,000 to 12,000 people remained on the drug. United Kingdom The drug is only available on a limited named-patient basis. Indications and usage Adults: Monotherapy or adjunctive therapy in the treatment of partial seizures, with and without generalization. Children: Adjunctive therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome. Dosing Felbamate is available in tablets (400 mg and 600 mg) and as a peach-coloured oral suspension (600 mg/5 mL). Adults (≥ 14 years): begin with 1,200 mg daily given every 6 to 8 hours Children (2–14 years): 15 to 45 mg per kg per day given every 6 to 8 hours Side effects Adverse reactions include decreased appetite, vomiting, insomnia, nausea, dizziness, somnolence, and headache. Many patients report increased alertness with the drug. Two rare but very serious effects include aplastic anemia and serious liver damage. The risk of aplastic anemia is between 1:3,600 and 1:5,000, of which 30% of cases are fatal. The risk of liver damage is between 1:24,000 to 1:34,000, of which 40% of cases are fatal. Drug interactions Felbamate is an inhibitor of CYP2C19 - an enzyme involved in the metabolism of several commonly used medications. Felbamate interacts with several other AEDs, including phenytoin, valproate, and carbamazepine; dosage adjustments may be necessary to avoid adverse effects. Concomitant administration of felbamate and carbamazepine decreases blood levels of both drugs, while increasing the level of carbamazepine-10,11 epoxide, the active metabolite of carbamazepine. History Felbamate was discovered by Frank Berger at Wallace Laboratories. References External links Felbatol: Prescribing Information RxList: Felbamate contains extensive information including the patient warning and a sample consent form. Hard Choices with Felbamate Newer Antiepileptic Drugs: Gabapentin, Lamotrigine, Felbamate, Topiramate and Fosphenytoin MedPonte Pharmaceuticals
Metolazone	Metolazone is a thiazide-like diuretic marketed under the brand names Zytanix, Metoz, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure and high blood pressure. Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the kidney, so that blood volume decreases and urine volume increases. This lowers blood pressure and prevents excess fluid accumulation in heart failure. Metolazone is sometimes used together with loop diuretics such as furosemide or bumetanide, but these highly effective combinations can lead to dehydration and electrolyte abnormalities. It was patented in 1966 and approved for medical use in 1974. Medical uses One of the primary uses of metolazone is for treating edema (fluid retention) associated with congestive heart failure (CHF). In mild heart failure, metolazone or another diuretic may be used alone, or combined with other diuretics for moderate or severe heart failure. In addition to preventing fluid buildup, the use of metolazone may allow the patient to relax the amount of sodium restriction that is required. Although most thiazide diuretics lose their effectiveness in kidney failure, metolazone remains active even when the glomerular filtration rate (GFR) is below 30–40 mL/min (moderate chronic kidney disease). This gives it a considerable advantage over other thiazide diuretics, since renal and heart failure often coexist and contribute to fluid retention.Metolazone may also be used in kidney disease, such as chronic kidney disease or the nephrotic syndrome. Chronic kidney disease causes excess fluid retention that is often treated with diet adjustments and diuretics. Metolazone may be combined with other diuretics (typically loop diuretics) to treat diuretic resistance in congestive heart failure, chronic kidney disease, and nephrotic syndrome. Metolazone and a loop diuretic will synergistically enhance diuresis over the use of either agent alone. Using this combination, diuretic effects will occur at two different segments of the nephron; namely, the loop diuretic will act at the loop of Henle, and metolazone will act at the distal convoluted tubule. Metolazone is frequently prescribed in addition to the loop diuretic. Metolazone may be used for edema caused by liver cirrhosis as well. The other major use of metolazone is in treating hypertension (high blood pressure). Thiazide diuretics, though usually not metolazone, are very often used alone as first-line treatment for mild hypertension. They are also used in combination with other drugs for difficult-to-treat or more severe hypertension. "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" (JNC 7) recommends thiazide diuretics as the initial medication for treatment of hypertension. Hydrochlorothiazide is by far the most commonly used, as it is both better-studied and cheaper (about four times) than metolazone, although as mentioned above metolazone is used in patients with moderate chronic kidney disease. Toxicity Since thiazide diuretics affect the transport of electrolytes and water in the kidney, they can be responsible for abnormalities of water balance and electrolyte levels. Removal of too much fluid can cause volume depletion and hypotension. Various electrolyte abnormalities may result, including hyponatremia (low sodium), hypokalemia (low potassium), hypochloremia (low chloride), hypomagnesemia (low magnesium), hypercalcemia (high calcium), and hyperuricemia (high uric acid). These may result in dizziness, headache, or heart arrhythmias (palpitations). Serious, though rare, side effects include aplastic anemia, pancreatitis, agranulocytosis, and angioedema. Metolazone, like other thiazide diuretics, may unmask latent diabetes mellitus or exacerbate gout, especially by interacting with medicines used to treat gout. In addition, thiazide diuretics, including metolazone, are sulfonamides; those with hypersensitivity to sulfonamides ("sulfa allergy") may also be allergic to metolazone. Mechanism of action The primary target of all thiazide diuretics, including metolazone, is the distal convoluted tubule, part of the nephron in the kidney, where they inhibit the sodium-chloride symporter. In the kidney, blood is filtered into the lumen, or open space, of the nephron tubule. Whatever remains in the tubule will travel to the bladder as urine and eventually be excreted. The cells lining the tubule modify the fluid inside, absorbing some material and excreting others. One side of the cell (the apical side) faces the lumen; the opposite side (the basolateral side) faces the interstitial space near blood vessels. The other sides are tightly joined to neighboring cells. As with other regions, tubule cells in the distal convoluted tubule possess the ATP-powered sodium-potassium antiporter (Na+/K+-ATPase), which uses energy from ATP to transfer three sodium ions out from the basolateral surface (toward blood vessels) while simultaneously transferring two potassium ions in. The distal convoluted tubule cells also possess a sodium-chloride symporter on the apical side, which passively allows one sodium ion and one chloride ion to diffuse together in from the lumen (where urine is forming) into the cell interior. As sodium is pumped out of the cell by the ATPase, its intracellular concentration falls, and additional sodium begins to diffuse in from the tubule lumen as replacement. The symporter requires chloride to be transported in as well. Water passively follows to maintain isotonicity; excess chloride and potassium passively diffuse out the cell through basolateral channels into the interstitial space, and water accompanies them. The water and chloride, as well as the sodium pumped out by the ATPase, will be absorbed into the bloodstream. Metolazone and the other thiazide diuretics inhibit the function of the sodium-chloride symporter, preventing sodium and chloride, and therefore water too, from leaving the lumen to enter the tubule cell. As a result, water remains in the lumen and is excreted as urine, instead of being reabsorbed into the bloodstream. Since most of the sodium in the lumen has already been reabsorbed by the time the filtrate reaches the distal convoluted tubule, thiazide diuretics have limited effects on water balance and on electrolyte levels. Nevertheless, they can be associated with low sodium levels, volume depletion, and low blood pressure, among other adverse effects. Pharmacokinetics Metolazone is only available in oral preparations. Approximately 65% of the amount ingested becomes available in the bloodstream. Its half-life is approximately fourteen hours, similar to indapamide but considerably longer than hydrochlorothiazide. Metolazone is around ten times as potent as hydrochlorothiazide. The primary form of excretion is in the urine (around 80%); the remaining fifth is evenly split between biliary excretion and metabolism into inactive forms. Chemistry The use of activated anthranilic acid derivatives facilitates the preparation of the amides in those cases where the amines are either unreactive or difficult to obtain. Thus, reaction of (1) with phosgene gives the reactive the isatoic anhydride (2). Condensation of that with ortho-toluidine leads to the acylation product (3) formed with a simultaneous loss of carbon dioxide. This is then converted to the quinazolone (4) by heating with acetic anhydride. Reaction with sodium borohydride in the presence of aluminum chloride selectively reduces the double bond to yield the diuretic agent metolazone (5). Structure and classification Metolazone is a quinazoline, a derivative of the similar diuretic quinethazone, as well as a sulfonamide. It is related to analogs of 1,2,4-benzothiadizine-1,1-dioxide (benzothiadiazine). Such drugs are called benzothiadiazides, or thiazides for short; however, in terms of chemistry, metolazone is not a substituted benzothiadiazine, and therefore is not technically a thiazide. Since metolazone (as well as other drugs like indapamide) acts on the same target as thiazides and behave in a similar pharmacologic fashion, it is, however, considered a "thiazide-like diuretic." Therefore, metolazone and similar drugs are often categorized with thiazide diuretics despite not being thiazides themselves. History Metolazone was developed in the 1970s. Its creator, Indian born chemist Dr. Bola Vithal Shetty has been active in helping the U.S. Food and Drug Administration review drug applications, and in the development of new medicines. Metolazone quickly gained popularity due to its lower kidney toxicity compared to other diuretics (especially thiazides) in patients with chronic kidney disease. == References ==
Taliglucerase alfa	Taliglucerase alfa, sold under the brand name Elelyso among others, is a biopharmaceutical medication developed by Protalix and Pfizer. The drug, a recombinant glucocerebrosidase used to treat Gauchers disease, is the first plant-made pharmaceutical to win approval by the U.S. Food and Drug Administration (FDA). Each vial has 200 units of taliglucerase alfa. Approval history The U.S. FDA New Drug Application (NDA) was granted approval in May 2012, for use in adults. The U.S. FDA Supplemental New Drug Application (sNDA) for pediatric use was granted approved in August 2014. In Israel, the Israeli Ministry of Health granted approval in September 2012. In Brazil, the Brazilian Health Surveillance Agency (ANVISA) granted approval in March 2013. In Canada, Health Canada issued a Notice of Compliance in May 2014, for both adults and pediatric patients.Taliglucerase alfa is made by the Israeli biotherapeutics company Protalix and sold by the American pharmaceutical company Pfizer. Society and culture Economics For 2016, Elelyso was ranked third for pharmaceuticals with the highest cost-per-patient, with an average cost of $483,242 per year. References External links "Taliglucerase alfa". Drug Information Portal. U.S. National Library of Medicine.
Colistin	Colistin, also known as polymyxin E, is an antibiotic medication used as a last-resort treatment for multidrug-resistant Gram-negative infections including pneumonia. These may involve bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter. It comes in two forms: colistimethate sodium can be injected into a vein, injected into a muscle, or inhaled, and colistin sulfate is mainly applied to the skin or taken by mouth. Colistimethate sodium is a prodrug; it is produced by the reaction of colistin with formaldehyde and sodium bisulfite, which leads to the addition of a sulfomethyl group to the primary amines of colistin. Colistimethate sodium is less toxic than colistin when administered parenterally. In aqueous solutions it undergoes hydrolysis to form a complex mixture of partially sulfomethylated derivatives, as well as colistin. Resistance to colistin began to appear as of 2015.Common side effects of the injectable form include kidney problems and neurological problems. Other serious side effects may include anaphylaxis, muscle weakness, and Clostridium difficile-associated diarrhea. The inhaled form may result in constriction of the bronchioles. It is unclear if use during pregnancy is safe for the fetus. Colistin is in the polymyxin class of medications. It works by breaking down the cytoplasmic membrane, which generally results in bacterial cell death.Colistin was discovered in 1947 and colistimethate sodium was approved for medical use in the United States in 1970. It is on the World Health Organizations List of Essential Medicines. The World Health Organization classifies colistin as critically important for human medicine. It is available as a generic medication. It is derived from bacteria of the genus Paenibacillus. Medical uses Antibacterial spectrum Colistin has been effective in treating infections caused by Pseudomonas, Escherichia, and Klebsiella species. The following represents minimum inhibitory concentration (MIC) susceptibility data for a few medically significant microorganisms: Escherichia coli: 0.12–128 μg/mL Klebsiella pneumoniae: 0.25–128 μg/mL Pseudomonas aeruginosa: ≤0.06–16 μg/mLFor example, colistin in combination with other drugs is used to attack P. aeruginosa biofilm infection in lungs of patients with cystic fibrosis. Biofilms have a low-oxygen environment below the surface where bacteria are metabolically inactive, and colistin is highly effective in this environment. However, P. aeruginosa reside in the top layers of the biofilm, where they remain metabolically active. This is because surviving tolerant cells migrate to the top of the biofilm via pili and form new aggregates via quorum sensing. Administration and dosage Forms Two forms of colistin are available commercially: colistin sulfate and colistimethate sodium (colistin methanesulfonate sodium, colistin sulfomethate sodium). Colistin sulfate is cationic; colistimethate sodium is anionic. Colistin sulfate is stable, whereas colistimethate sodium is readily hydrolysed to a variety of methanesulfonated derivatives. Colistin sulfate and colistimethate sodium are eliminated from the body by different routes. With respect to Pseudomonas aeruginosa, colistimethate is the inactive prodrug of colistin. The two drugs are not interchangeable. Colistimethate sodium may be used to treat Pseudomonas aeruginosa infections in patients with cystic fibrosis, and it has come into recent use for treating multidrug-resistant Acinetobacter infection, although resistant forms have been reported. Colistimethate sodium has also been given intrathecally and intraventricularly in Acinetobacter baumannii and Pseudomonas aeruginosa meningitis and ventriculitis Some studies have indicated that colistin may be useful for treating infections caused by carbapenem-resistant isolates of Acinetobacter baumannii. Colistin sulfate may be used to treat intestinal infections, or to suppress colonic flora. Colistin sulfate is also used in topical creams, powders, and otic solutions. Colistin A (polymyxin E1) and colistin B (polymyxin E2) can be purified individually to research and study their effects and potencies as separate compounds. Dosage Colistin sulfate and colistimethate sodium may both be given intravenously, but the dosing is complicated. The different labeling of the parenteral products of colistin methanesulfonate in different parts of the world was noted by Li et al. Colistimethate sodium manufactured by Xellia (Colomycin injection) is prescribed in international units, whereas colistimethate sodium manufactured by Parkdale Pharmaceuticals (Coly-Mycin M Parenteral) is prescribed in milligrams of colistin base: Colomycin 1,000,000 units is 80 mg colistimethate; Coly-mycin M 150 mg colistin base is 360 mg colistimethate or 4,500,000 units.Because colistin was introduced into clinical practice over 50 years ago, it was never subject to the regulations that modern drugs are subject to, and therefore there is no standardised dosing of colistin and no detailed trials on pharmacology or pharmacokinetics. The optimal dosing of colistin for most infections is therefore unknown. Colomycin has a recommended intravenous dose of 1 to 2 million units three times daily for patients weighing 60 kg or more with normal renal function. Coly-Mycin has a recommended dose of 2.5 to 5 mg/kg colistin base a day, which is equivalent to 6 to 12 mg/kg colistimethate sodium per day. For a 60 kg man, therefore, the recommended dose for Colomycin is 240 to 480 mg of colistimethate sodium, yet the recommended dose for Coly-Mycin is 360 to 720 mg of colistimethate sodium. Likewise, the recommended "maximum" dose for each preparation is different (480 mg for Colomycin and 720 mg for Coly-Mycin). Each country has different generic preparations of colistin, and the recommended dose depends on the manufacturer. This complete absence of any regulation or standardisation of dose makes intravenous colistin dosing difficult for the physician.Colistin has been used in combination with rifampicin; evidence of in vitro synergy exists, and the combination has been used successfully in patients. There is also in vitro evidence of synergy for colistimethate sodium used in combination with other antipseudomonal antibiotics.Colistimethate sodium aerosol (Promixin; Colomycin Injection) is used to treat pulmonary infections, especially in cystic fibrosis. In the UK, the recommended adult dose is 1–2 million units (80–160 mg) nebulised colistimethate twice daily. Nebulized colistin has also been used to decrease severe exacerbations in patients with chronic obstructive pulmonary disease and infection with Pseudomonas aeruginosa. Resistance Resistance to colistin is rare, but has been described. As of 2017, no agreement exists about how to define colistin resistance. The Société Française de Microbiologie uses a MIC cut-off of 2 mg/L, whereas the British Society for Antimicrobial Chemotherapy sets a MIC cutoff of 4 mg/L or less as sensitive, and 8 mg/L or more as resistant. No standards for describing colistin sensitivity are given in the United States. The first known colistin-resistance gene in a plasmid which can be transferred between bacterial strains is mcr-1. It was found in 2011 in China on a pig farm where colistin is routinely used and became publicly known in November 2015. The presence of this plasmid-borne gene was confirmed starting December 2015 in South-East Asia, several European countries, and the United States. It is found in certain strains of the bacteria Paenibacillus polymyxa.India reported the first detailed colistin-resistance study, which mapped 13 colistin-resistant infections recorded over 18 months. It concluded that pan-drug-resistant infections, particularly those in the bloodstream, have a higher mortality. Multiple other cases were reported from other Indian hospitals. Although resistance to polymyxins is generally less than 10%, it is more frequent in the Mediterranean and South-East Asia (Korea and Singapore), where colistin resistance rates are increasing. Colistin-resistant E. coli was identified in the United States in May 2016.A recent review from 2016 to 2021 fount that E. coli is the dominant species harbouring mcr genes. Plasmid - mediated colistin resistance is also conferred upon other species that carry different genes resistant to antibiotics. The emergence of the mcr-9 gene is quite remarkable.Use of colistin to treat Acinetobacter baumannii infections has led to the development of resistant bacterial strains. They have also developed resistance to the antimicrobial compounds LL-37 and lysozyme, produced by the human immune system. This cross-resistance is caused by gain-of-function mutations to the pmrB gene, a phosphoethanolamine transferase (similar to mcr-1) located on the bacterial chromosome.Not all resistance to colistin and some other antibiotics is due to the presence of resistance genes. Heteroresistance, the phenomenon wherein apparently genetically identical microbes exhibit a range of resistance to an antibiotic, has been observed in some species of Enterobacter since at least 2016 and was observed in some strains of Klebsiella pneumoniae in 2017–2018. In some cases this phenomenon has significant clinical consequences. Inherently resistant Variable resistance Aeromonas Vibrio Prevotella Fusobacterium Escherichia coli Adverse reactions The main toxicities described with intravenous treatment are nephrotoxicity (damage to the kidneys) and neurotoxicity (damage to the nerves), but this may reflect the very high doses given, which are much higher than the doses currently recommended by any manufacturer and for which no adjustment was made for pre-existing renal disease. Neuro- and nephrotoxic effects appear to be transient and subside on discontinuation of therapy or reduction in dose.At a dose of 160 mg colistimethate IV every eight hours, very little nephrotoxicity is seen. Indeed, colistin appears to have less toxicity than the aminoglycosides that subsequently replaced it, and it has been used for extended periods up to six months with no ill effects. Colistin-induced nephrotoxicity is particularly likely in patients with hypoalbuminemia.The main toxicity described with aerosolised treatment is bronchospasm, which can be treated or prevented with the use of β2-adrenergic receptor agonists such as salbutamol or following a desensitisation protocol. Mechanism of action Colistin is a polycationic peptide and has both hydrophilic and lipophilic moieties. These cationic regions interact with the bacterial outer membrane by displacing magnesium and calcium bacterial counter ions in the lipopolysaccharide. The hydrophobic and hydrophilic regions interact with the cytoplasmic membrane just like a detergent, solubilizing the membrane in an aqueous environment. This effect is bactericidal even in an isosmolar environment.Colistin binds to lipopolysaccharides and phospholipids in the outer cell membrane of Gram-negative bacteria. It competitively displaces divalent cations (Ca2+ and Mg2+) from the phosphate groups of membrane lipids, which leads to disruption of the outer cell membrane, leakage of intracellular contents and bacterial death. Pharmacokinetics No clinically useful absorption of colistin occurs in the gastrointestinal tract. For systemic infection, colistin must therefore be given by injection. Colistimethate is eliminated by the kidneys, but colistin is eliminated by non-renal mechanism(s) that are as of yet not characterised. History Colistin was first isolated in Japan in 1949 by Y. Koyama, from a flask of fermenting Bacillus polymyxa var. colistinus, and became available for clinical use in 1959.Colistimethate sodium, a less toxic prodrug, became available for injection in 1959. In the 1980s, polymyxin use was widely discontinued because of nephro- and neurotoxicity. As multi-drug resistant bacteria became more prevalent in the 1990s, colistin started to get a second look as an emergency solution, in spite of toxicity.Colistin has also been used in agriculture, particularly in China from the 1980s onwards. Chinese production for agriculture exceeded 2700 tons in 2015. China banned colistin use for livestock growth promotion in 2016. Biosynthesis The biosynthesis of colistin requires the use of three amino acids: threonine, leucine, and 2,4-diaminobutryic acid. The linear form of colistin is synthesized before cycliziation. Non-ribosomal peptide biosynthesis begins with a loading module and then the addition of each subsequent amino acid. The subsequent amino acids are added with the help of an adenylation domain (A), a peptidyl carrier protein domain (PCP), an epimerization domain (E), and a condensation domain (C). Cyclization is accomplished by a thioesterase. The first step is to have a loading domain, 6-methylheptanoic acid, associate with the A and PCP domains. Now with a C, A, and PCP domain that is associated with 2,4-diaminobutryic acid. This continues with each amino acid until the linear peptide chain is completed. The last module will have a thioesterase to complete the cyclization and form the product colistin. References Further reading Reardon S (December 2015). "Spread of antibiotic-resistance gene does not spell bacterial apocalypse — yet". Nature. doi:10.1038/nature.2015.19037. External links "Colistimethate sodium". Drug Information Portal. U.S. National Library of Medicine. "Colistin sulfate". Drug Information Portal. U.S. National Library of Medicine. "Colistin topics page (bibliography)". Science.gov.
Oxycodone/ibuprofen	Oxycodone/ibuprofen (INNs, trade name Combunox) is an oral combination drug formulation of the opioid analgesic oxycodone and the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen that is used in the treatment of chronic and acute pain. This particular drug is supplied in a fixed dose combination tablet which contains Oxycodone Hydrochloride, USP 5 mg with Ibuprofen, USP 400 mg. Adverse effects See also Oxycodone/paracetamol Oxycodone/aspirin Hydrocodone/ibuprofen References External links "Ibuprofen mixture with oxycodone". Drug Information Portal. U.S. National Library of Medicine.
Onasemnogene abeparvovec	Onasemnogene abeparvovec, sold under the brand name Zolgensma, is a gene therapy medication used to treat spinal muscular atrophy (SMA). It is used as a one-time infusion into a vein.Onasemnogene abeparvovec works by providing a new copy of the gene that makes the human SMN protein.The treatment must be accompanied by a course of corticosteroids of at least two months. Common side effects include vomiting and increased liver enzymes.Onasemnogene abeparvovec was first approved for medical use in the United States in 2019 as a treatment for children less than two years old. It was later approved in other jurisdictions with similar scope. The approval scope in certain jurisdictions, including the European Union and Canada, is somewhat different. Medical uses Onasemnogene abeparvovec has been developed to treat spinal muscular atrophy, a disease linked to a mutation in the SMN1 gene on chromosome 5q and diagnosed predominantly in young children that causes progressive loss of muscle function and frequently death. The medication is administered as an intravenous infusion.The treatment is approved in the United States and certain other countries for use in children with spinal muscular atrophy up to the age of two, including at the presymptomatic stage of the disease. In the European Union and Canada, it is indicated for the treatment of patients with spinal muscular atrophy who either have a clinical diagnosis of spinal muscular atrophy type 1 or have up to three copies of the SMN2 gene.The medication is used with corticosteroids in an effort to protect the liver. Adverse effects Common adverse reactions may include nausea and elevated liver enzymes. Serious adverse reactions may include liver problems and low platelets. Transient elevated levels of cardiac troponin‑I were observed in clinical trials; the clinical importance of these findings is not known. However, cardiac toxicity was seen in studies of other animals.As the medication may reduce the platelet count, platelets may need to be checked before the medication is started, then weekly for the first month and every two weeks for the next two months until the level is back to baseline. Liver function should be monitored for three months after administration. Mechanism of action SMA is a neuromuscular disorder caused by a mutation in the SMN1 gene, which leads to a decrease in SMN protein, a protein necessary for survival of motor neurons. Onasemnogene abeparvovec is a biologic drug consisting of AAV9 virus capsids that contains a SMN1 transgene along with synthetic promoters. Upon administration, the AAV9 viral vector delivers the SMN1 transgene to the affected motor neurons, where it leads to an increase in SMN protein. History Onasemnogene abeparvovec was developed by the US biotechnology startup AveXis, which was acquired by Novartis in 2018, based on the work at the Institut de Myologie in France.The U.S. Food and Drug Administration (FDA) granted the application for onasemnogene abeparvovec-xioi fast track, breakthrough therapy, priority review, and orphan drug designations. The FDA also awarded the manufacturer a rare pediatric disease priority review voucher, and granted the approval of Zolgensma to AveXis Inc.In June 2015, the European Commission granted orphan designation for the drug. In July 2019, the drug was removed from the Committee for Medicinal Products for Human Use (CHMP) accelerated assessment program.In May 2019, onasemnogene abeparvovec received US FDA approval as a treatment for children less than two years old. Since 2019, the treatment has been reimbursed in Israel and Qatar. In March 2020, onasemnogene abeparvovec was granted regulatory approval in Japan with the label identical to the US one. Also in March 2020, the European Medicines Agency recommended a conditional marketing authorization for use in people with SMA type 1 or with any SMA type and having no more than three copies of the SMN2 gene. In May 2020, Onasemnogene abeparvovec was conditionally approved in Europe.In August 2020, onasemnogene abeparvovec was granted regulatory approval in Brazil by the Brazilian Health Regulatory Agency (ANVISA).In December 2020, onasemnogene abeparvovec was approved for medical use in Canada.Onasemnogene abeparvovec was approved for medical use in Australia in February 2021.An official approval in Russia was granted in December 2021. Society and culture Economics The drug carries a list price of US$2.125 million per treatment, making it the most expensive medication in the world as of 2019. In its first full quarter of sales US$160 million of medication was sold.In Japan, the drug was made available through the public health care system on 20 May 2020, making it the most expensive drug covered by the Japanese public health care system. The Central Social Insurance Medical Council, responsible for approving the universal drug fee schedule in Japan, has negotiated the price down to ¥167,077,222 (approx. USD 1,530,000) per patient. Controversy In the months leading up to the medications approval by the US Food and Drug Administration (FDA), a whistleblower informed Novartis that certain studies of the medication had been subject to data manipulation. Novartis fired two AveXis executives it determined responsible for the alleged data manipulation but informed the FDA of the data integrity issue only in June 2019, a month after the drugs approval. The delay drew strong condemnation from the FDA. In October 2019, the company admitted to not having informed the FDA and the European Medicines Agency (EMA) for seven months about toxic effects of the intravenous formulation observed in laboratory animals. Due to data manipulation issue, the EMA withdrew their decision to allow an accelerated assessment of the medication.In December 2019, Novartis announced that it would donate 100 doses of onasemnogene abeparvovec per year to children outside the US through a global lottery. The decision, which has been claimed by Novartis to be based on a recommendation by unnamed bioethicists, was received with much criticism by the European Commission, some European healthcare regulators and patient groups who see it as emotionally burdening, suboptimal, and ethically questionable. Novartis did not consult with families or doctors before announcing the scheme. Names Onasemnogene abeparvovec is the international nonproprietary name (INN) and the United States Adopted Name (USAN). References External links "Onasemnogene abeparvovec". Drug Information Portal. U.S. National Library of Medicine.
Acebutolol	Acebutolol, sold under the brand names Sectral among others, is a beta blocker for the treatment of hypertension and arrhythmias. Acebutolol is a cardioselective beta-1 blocker and has intrinsic sympathetic activity. It is commonly used in the treatment of angina. It was patented in 1967 and approved for medical use in 1973. Medical uses Hypertension Ventricular and atrial cardiac arrhythmia Acute myocardial infarction in high-risk patients Smith–Magenis syndrome Contraindications Stable or unstable angina (due to its partial agonist or ISA activity) Side effects The development of anti-nuclear antibodies (ANA) has been found in 10 to 30% of patients under treatment with acebutolol. A systemic disease with arthralgic pain and myalgias has been observed in 1%. A lupus erythematosus-like syndrome with skin rash and multiforme organ involvement is even less frequent. The incidence of both ANA and symptomatic disease under acebutolol is higher than under propranolol. Female patients are more likely to develop these symptoms than male patients. Some few cases of hepatotoxicity with increased liver enzymes (ALT, AST) have been seen. Altogether, 5 to 6% of all patients treated have to discontinue acebutolol due to intolerable side effects. When possible, the treatment should be discontinued gradually in order to avoid a withdrawal syndrome with increased frequency of angina and even precipitation of myocardial infarction. Pharmacology Acebutolol is a cardioselective beta-1 blocker which also considered a partial agonist due to its intrinsic sympathomimetic activity (ISA). This means it provides low-grade beta stimulation at rest but acting as typical beta-blockers when sympathetic activity is high. Among other drugs in the beta-blocker class, Acebutolol will provide beta-blockade effects to a lesser extent. Due to its cardioselectivity, Acebutolol is more suitable than non-cardioselective beta-blockers, in a patient with asthma or chronic obstructive pulmonary disease (COPD) who needs treatment with a beta-blocker. This cardio-specificity will minimize the anti-hypertensive effects as seen with non-specific beta blockers such as Propanalol and Nadolol. (For these reasons, it may be a beta-blocker of choice in inclusion in Polypill strategies). In doses lower than 800 mg daily its constricting effects on the bronchial system and smooth muscle vessels are only 10% to 30% of those observed under propranolol treatment, but there is experimental evidence that the cardioselective properties diminish at doses of 800 mg/day or more. The drug has lipophilic properties and therefore crosses the blood–brain barrier. Acebutolol has no negative impact on serum lipids (cholesterol and triglycerides). No HDL decrease has been observed. In this regard, it is unlike many other beta-blockers which have this unfavourable property. The drug works in hypertensive patients with high, normal, or low renin plasma concentrations, although acebutolol may be more efficient in patients with high or normal renin plasma concentrations. In clinically relevant concentrations, a membrane-stabilizing effect does not appear to play an important role. Pharmacokinetics Acebutolol is well absorbed from the GI tract, but undergoes substantial first-pass-metabolization, leading to a bioavailability of only 35% to 50%. Peak plasma levels of acebutolol are reached within 2 to 2.5 hours after oral dosing. Peak levels of the main active metabolite, diacetolol, are reached after 4 hours. Acebutolol has a half-life of 3 to 4 hours, and diacetolol a half-life of 8 to 13 hours. Acebutolol undergoes extensive hepatic metabolization resulting in the desbutyl amine acetolol which is readily converted into diacetolol. Diacetolol is as active as acebutolol (equipotency) and appears to have the same pharmacologic profile. Geriatric patients tend to have higher peak plasma levels of both acebutolol and diacetolol and a slightly prolonged excretion. Excretion is substantially prolonged in patients with renal impairment, and so a dose reduction may be needed. Liver cirrhosis does not seem to alter the pharmacokinetic profile of the parent drug and metabolite. References External links AHFS Database
Sodium nitrite	Sodium nitrite is an inorganic compound with the chemical formula NaNO2. It is a white to slightly yellowish crystalline powder that is very soluble in water and is hygroscopic. From an industrial perspective, it is the most important nitrite salt. It is a precursor to a variety of organic compounds, such as pharmaceuticals, dyes, and pesticides, but it is probably best known as a food additive used in processed meats and (in some countries) in fish products. Uses Industrial chemistry The main use of sodium nitrite is for the industrial production of organonitrogen compounds. It is a reagent for conversion of amines into diazo compounds, which are key precursors to many dyes, such as diazo dyes. Nitroso compounds are produced from nitrites. These are used in the rubber industry.It is used in a variety of metallurgical applications, for phosphatizing and detinning.Sodium nitrite is an effective corrosion inhibitor and is used as an additive in industrial greases, as an aqueous solution in closed loop cooling systems, and in a molten state as a heat transfer medium. Food additive and preservative Sodium nitrite is used to speed up the curing of meat and also impart an attractive pink color. Nitrite reacts with the meat myoglobin to cause color changes, first converting to nitrosomyoglobin (bright red), then, on heating, to nitrosohemochrome (a pink pigment).Historically, salt has been used for the preservation of meat. The salt-preserved meatproduct was usually brownish-gray in color. When sodium nitrite is added with the salt, the meat develops a red, then pink color, which is associated with cured meats such as ham, bacon, hot dogs, and bologna.In the early 1900s, irregular curing was commonplace. This led to further research surrounding the use of sodium nitrite as an additive in food, standardizing the amount present in foods to minimize the amount needed while maximizing its food additive role. Through this research, sodium nitrite has been found to give taste and color to the meat and inhibit lipid oxidation that leads to rancidity, with varying degrees of effectiveness for controlling growth of disease-causing microorganisms. The ability of sodium nitrite to address the above-mentioned issues has led to production of meat with extended storage life and has improved desirable color and taste. According to scientists working for the meat industry, nitrite has improved food safety. This view is disputed in the light of its ineffectiveness against botulism and the possible carcinogenic effects caused by adding nitrites to meat.Nitrite has the E number E250. Potassium nitrite (E249) is used in the same way. It is approved for usage in the EU, USA and Australia and New Zealand.In meat-processing, sodium nitrite is never used in a pure state but always mixed with common salt. This mixture is known as nitrited salt, curing salt or nitrited curing salt. In Europe, nitrited curing salt contains between 99.1% and 99.5% common salt and between 0.5% and 0.9% nitrite. In the US, nitrited curing salt is dosed at 6% and must be remixed with salt before use. Color and taste The appearance and taste of meat is an important component of consumer acceptance. Sodium nitrite is responsible for the desirable red color (or shaded pink) of meat. Very little nitrite is needed to induce this change. It has been reported that as little as 2 to 14 parts per million (ppm) is needed to induce this desirable color change. However, to extend the lifespan of this color change, significantly higher levels are needed. The mechanism responsible for this color change is the formation of nitrosylating agents by nitrite, which has the ability to transfer nitric oxide that subsequently reacts with myoglobin to produce the cured meat color. The unique taste associated with cured meat is also affected by the addition of sodium nitrite. However, the mechanism underlying this change in taste is still not fully understood. Inhibition of microbial growth A 2018 study by the British Meat Producers Association determined that legally permitted levels of nitrite have no effect on the growth of the Clostridium botulinum bacteria which causes botulism, in line with the UKs Advisory Committee on the Microbiological Safety of Food opinion that nitrites are not required to prevent C. botulinum growth and extend shelf life. In some countries, cured-meat products are manufactured without nitrites. For example, Parma ham, which has been produced without nitrite since 1993, was reported in 2018 to have caused no cases of botulism.Sodium nitrite has shown varying degrees of effectiveness for controlling growth of other spoilage or disease causing microorganisms. Although the inhibitory mechanisms are not well known, its effectiveness depends on several factors including residual nitrite level, pH, salt concentration, reductants present and iron content. The type of bacteria also affects sodium nitrites effectiveness. It is generally agreed that sodium nitrite is not effective for controlling Gram-negative enteric pathogens such as Salmonella and Escherichia coli.Other food additives (such as lactate and sorbate) provide similar protection against bacteria, but do not provide the desired pink color. Inhibition of lipid peroxidation Sodium nitrite is also able to effectively delay the development of oxidative rancidity. Lipid peroxidation is considered to be a major reason for the deterioration of quality of meat products (rancidity and unappetizing flavors). Sodium nitrite acts as an antioxidant in a mechanism similar to the one responsible for the coloring effect. Nitrite reacts with heme proteins and metal ions, neutralizing free radicals by nitric oxide (one of its byproducts). Neutralization of these free radicals terminates the cycle of lipid oxidation that leads to rancidity. Medication Sodium nitrite is used as a medication together with sodium thiosulfate to treat cyanide poisoning. It is recommended only in severe cases of cyanide poisoning. In those who have both cyanide poisoning and carbon monoxide poisoning sodium thiosulfate by itself is usually recommended. It is given by slow injection into a vein.Side effects can include low blood pressure, headache, shortness of breath, loss of consciousness, and vomiting. Greater care should be taken in people with underlying heart disease. The patients levels of methemoglobin should be regularly checked during treatment. While not well studied during pregnancy, there is some evidence of potential harm to the baby. Sodium nitrite is believed to work by creating methemoglobin that then binds with cyanide and thus removes it from the mitochondria.Sodium nitrite came into medical use in the 1920s and 1930s. It is on the World Health Organizations List of Essential Medicines. Suicide Several academic publications in 2020 and 2021 have discussed the toxicity of sodium nitrite, and an apparent recent increase in suicides from using sodium nitrite which had been ordered online. The usage of sodium nitrite as a suicide method has been heavily discussed on suicide forums. Sodium nitrite was also the culprit of the McCarthy et al v Amazon lawsuit alleging that Amazon knowingly assisted in the deaths of healthy children by selling them "suicide kits" as Amazons "frequently bought together" feature recommended buying sodium nitrate, an antiemetic and a suicide instruction book together. Toxicity Sodium nitrite is toxic. The LD50 in rats is 180 mg/kg and in human LDLo is 71 mg/kg. Yet, death by sodium nitrite ingestion can happen at lower dose. Sodium nitrite is sometimes used for homicide. The online marketplace eBay has globally prohibited the sale of sodium nitrite since 2019. To prevent accidental intoxication, sodium nitrite (blended with salt) sold as a food additive in the US is dyed bright pink to avoid mistaking it for plain salt or sugar. In other countries, nitrited curing salt is not dyed but is strictly regulated. Occurrence in vegetables Nitrites are not naturally occurring in vegetables in significant quantities. Boiling vegetables does not affect nitrite levels.The presence of nitrite in animal tissue is a consequence of metabolism of nitric oxide, an important neurotransmitter. Nitric oxide can be created de novo from nitric oxide synthase utilizing arginine or from ingested nitrite. Pigs Because of sodium nitrites high level of toxicity to swine (Sus scrofa) it is now being developed in Australia to control feral pigs and wild boar. The sodium nitrite induces methemoglobinemia in swine, i.e. it reduces the amount of oxygen that is released from hemoglobin, so the animal will feel faint and pass out, and then die in a humane manner after first being rendered unconscious. The Texas Parks and Wildlife Department operates a research facility at Kerr Wildlife Management Area, where they examine feral pig feeding preferences and bait tactics to administer sodium nitrite. Cancer Carcinogenicity is the ability or tendency of a chemical to induce tumors, increase their incidence or malignancy, or shorten the time of tumor occurrence.Adding nitrites to meat has been shown to generate known carcinogens such as nitrosamines; the World Health Organization (WHO) advises that each 50 g (1.8 oz) of "processed meats" eaten a day would raise the risk of getting bowel cancer by 18% over a lifetime. The World Health Organizations review of more than 400 studies concluded, in 2015, that there was sufficient evidence that "processed meats" caused cancer, particularly colon cancer; the WHOs International Agency for Research on Cancer (IARC) classified "processed meats" as carcinogenic to humans (Group 1); "processed meat" meaning meat that has been transformed through salting, curing, fermentation, smoking, or other processes to enhance flavour or improve preservation.).Nitrosamines can be formed during the curing process used to preserve meats, when sodium nitrite-treated meat is cooked, and also from the reaction of nitrite with secondary amines under acidic conditions (such as occurs in the human stomach). Dietary sources of nitrosamines include US cured meats preserved with sodium nitrite as well as the dried salted fish eaten in Japan. In the 1920s, a significant change in US meat curing practices resulted in a 69% decrease in average nitrite content. This event preceded the beginning of a dramatic decline in gastric cancer mortality. Around 1970, it was found that ascorbic acid (vitamin C), an antioxidant, inhibits nitrosamine formation. Consequently, the addition of at least 550 ppm of ascorbic acid is required in meats manufactured in the United States. Manufacturers sometimes instead use erythorbic acid, a cheaper but equally effective isomer of ascorbic acid. Additionally, manufacturers may include α-tocopherol (vitamin E) to further inhibit nitrosamine production. α-Tocopherol, ascorbic acid, and erythorbic acid all inhibit nitrosamine production by their oxidation-reduction properties. Ascorbic acid, for example, forms dehydroascorbic acid when oxidized, which when in the presence of nitrosonium, a potent nitrosating agent formed from sodium nitrite, reduces the nitrosonium into nitric oxide. The nitrosonium ion formed in acidic nitrite solutions is commonly mislabeled nitrous anhydride, an unstable nitrogen oxide that cannot exist in vitro.Ingesting nitrite under conditions that result in endogenous nitrosation has been classified as "probably carcinogenic to humans" by International Agency for Research on Cancer (IARC).Sodium nitrite consumption has also been linked to the triggering of migraines in individuals who already experience them.One study has found a correlation between highly frequent ingestion of meats cured with pink salt and the COPD form of lung disease. The studys researchers suggest that the high amount of nitrites in the meats was responsible; however, the team did not prove the nitrite theory. Additionally, the study does not prove that nitrites or cured meat caused higher rates of COPD, merely a link. The researchers did adjust for many of COPDs risk factors, but they commented they cannot rule out all possible unmeasurable causes or risks for COPD. Production Industrial production of sodium nitrite follows one of two processes, the reduction of nitrate salts, or the oxidation of lower nitrogen oxides. One method uses molten sodium nitrate as the salt, and lead which is oxidized, while a more modern method uses scrap iron filings to reduce the nitrate.A more commonly used method involves the general reaction of nitrogen oxides in alkaline aqueous solution, with the addition of a catalyst. The exact conditions depend on which nitrogen oxides are used, and what the oxidant is, as the conditions need to be carefully controlled to avoid over oxidation of the nitrogen atom.Sodium nitrite has also been produced by reduction of nitrate salts by exposure to heat, light, ionizing radiation, metals, hydrogen, and electrolytic reduction. Chemical reactions In the laboratory, sodium nitrite can be used to destroy excess sodium azide. 2 NaN 3 + 2 NaNO 2 + 4 H + ⟶ 3 N 2 + 2 NO + 4 Na + + 2 H 2 O {\displaystyle {\ce {2 NaN3 + 2 NaNO2 + 4 H^+ -> 3 N2 + 2 NO + 4 Na^+ + 2 H2O}}} Above 330 °C sodium nitrite decomposes (in air) to sodium oxide, nitric oxide and nitrogen dioxide. 2 NaNO 2 ⟶ Na 2 O + NO + NO 2 {\displaystyle {\ce {2 NaNO2 -> Na2O + NO + NO2}}} Sodium nitrite can also be used in the production of nitrous acid: 2 NaNO 2 + H 2 SO 4 ⟶ 2 HNO 2 + Na 2 SO 4 {\displaystyle {\ce {2NaNO2 + H2SO4 ->2 HNO2 + Na2SO4}}} The nitrous acid then, under normal conditions, decomposes: 2 HNO 2 ⟶ NO 2 + NO + H 2 O {\displaystyle {\ce {2 HNO2 -> NO2 + NO + H2O}}} The resulting nitrogen dioxide hydrolyzes to a mixture of nitric and nitrous acids: 2 NO 2 + H 2 O ⟶ HNO 3 + HNO 2 {\displaystyle {\ce {2 NO2 + H2O -> HNO3 + HNO2}}} Isotope labelling 15N In organic synthesis isotope enriched sodium nitrite-15N can be used instead of normal sodium nitrite as their reactivity is nearly identical in most reactions. The obtained products carry isotope 15N and hence Nitrogen NMR can be efficiently carried out. References Further reading External links Drug information portal at the U.S. National Library of Medicine International Chemical Safety Card 1120. Nitrite in Meat

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