<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Sildenafil and can you explain it in depth? [/INST] Sildenafil, sold under the brand name Viagra, among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. It is unclear if it is effective for treating sexual dysfunction in women. It is taken by mouth or by injection into a vein. Onset is typically within twenty minutes and lasts for about two hours.Common side effects include headaches, heartburn, and flushed skin. Caution is advised in those with cardiovascular disease. Rare but serious side effects include a prolonged erection (priapism) that can lead to damage to the penis, vision problems, and hearing loss. Sildenafil should not be taken by people on nitrates such as nitroglycerin (glycerin trinitrate), as this may result in a serious drop in blood pressure. Sildenafil should not be taken within four hours of taking an alpha blocker.
Sildenafil acts by blocking phosphodiesterase 5 (PDE5), an enzyme that promotes breakdown of cGMP, which regulates blood flow in the penis. It requires sexual arousal to work. It also results in dilation of the blood vessels in the lungs.Pfizer originally discovered the medication in 1989 while looking for a treatment for heart-related chest pain. It was approved for medical use in the United States and in the European Union in 1998. In 2017, it was the 217th-most commonly prescribed medication in the United States, with more than two million prescriptions. That same year, it also became available as a generic medication after final patents by Pfizer expired. In the United Kingdom, it is available over the counter. Most of the Active Pharmaceutical Ingredient (API) in Sildenafil, Sildenafil citrate, is produced in Pfizers Ringaskiddy complex, County Cork, which is Pfizers largest production facility outside of the United States.

Medical uses
Sexual dysfunction
The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete sexual intercourse). Its use is now one of the standard treatments for erectile dysfunction, including for men with diabetes mellitus.

Antidepressant-associated sexual dysfunction
Tentative evidence suggests that sildenafil may help men who experience antidepressant-induced erectile dysfunction.

Pulmonary hypertension
While sildenafil improves some markers of disease in people with pulmonary arterial hypertension, it does not appear to affect the risk of death or serious side effects.

Raynauds phenomenon
Sildenafil and other PDE5 inhibitors are used off-label to alleviate vasospasm and treat severe ischemia and ulcers in fingers and toes for people with secondary Raynauds phenomenon; these drugs have moderate efficacy for reducing the frequency and duration of vasospastic episodes. As of 2016, their role more generally in Raynauds was not clear.

High-altitude pulmonary edema
Sildenafil has been studied for high-altitude pulmonary edema, but its use is currently not recommended for that indication.

Adverse effects
In clinical trials, the most common adverse effects of sildenafil use included headache, flushing, indigestion, nasal congestion, and impaired vision, including photophobia and blurred vision. Some sildenafil users have complained of seeing everything tinted blue (cyanopsia). This cyanopsia can be explained because Sildenafil, while selective for PDE5, does have a minor level of selectivity for PDE6, which is the phosphodiesterase found in the retina. Patients thus taking the drug may experience colorvision abnormalities. Some complained of blurriness and loss of peripheral vision. In July 2005, the U.S. Food and Drug Administration (FDA) found that sildenafil could lead to vision impairment in rare cases, and a number of studies have linked sildenafil use with non-arteritic anterior ischemic optic neuropathy.Rare but serious adverse effects found through postmarketing surveillance include prolonged erections, severe low blood pressure, myocardial infarction (heart attack), ventricular arrhythmias, stroke, increased intraocular pressure, and sudden hearing loss. In October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including sildenafil, required a more prominent warning of the potential risk of sudden hearing loss.

Interactions
Care should be exercised by people who are also taking protease inhibitors for the treatment of HIV infection. Protease inhibitors inhibit the metabolism of sildenafil, effectively multiplying the plasma levels of sildenafil, increasing the incidence and severity of side effects. Those using protease inhibitors are recommended to limit their use of sildenafil to no more than one 25 mg dose every 48 hours. Other drugs that interfere with the metabolism of sildenafil include erythromycin and cimetidine, both of which can also lead to prolonged plasma half-life levels.The use of sildenafil and an α1 blocker (typically prescribed for hypertension or for urologic conditions, such as benign prostatic hypertrophy) at the same time may lead to low blood pressure, but this effect does not occur if they are taken at least 4 hours apart.

Contraindications
Contraindications include:
Concomitant use of nitric oxide donors, organic nitrites and nitrates, such as:
nitroglycerin
isosorbide mononitrate
isosorbide dinitrate
sodium nitroprusside
alkyl nitrites (commonly known as "poppers")
Concomitant use of soluble guanylyl cyclase stimulators, such as riociguat
Known hypersensitivity to sildenafilSildenafil should not be used if sexual activity is inadvisable due to underlying cardiovascular risk factors.

Nonmedical use
Recreational use
Sildenafils popularity with young adults has increased over the years. Sildenafils trade name, Viagra, is widely recognized in popular culture, and the drugs association with treating erectile dysfunction has led to its recreational use. The reasons behind such use include the belief that the drug increases libido, improves sexual performance, or permanently increases penis size. Studies on the effects of sildenafil when used recreationally are limited, but suggest it has little effect when used by those who do not have erectile dysfunction. In one study, a 25 mg dose was shown to cause no significant change in erectile quality, but did reduce the postejaculatory refractory time. This study also noted a significant placebo effect in the control group.Unprescribed recreational use of sildenafil and other PDE5 inhibitors is noted as particularly high among users of illegal drugs. Sildenafil is sometimes used to counteract the effects of other substances, often illicit. Some users mix it with methylenedioxymethamphetamine (MDMA, ecstasy), other stimulants, or opiates in an attempt to compensate for the common side effect of erectile dysfunction, a combination known as "sextasy", "rockin and rollin" or "trail mix". Mixing it with amyl nitrite, another vasodilator, is particularly dangerous and potentially fatal.

Jet lag research
The 2007 Ig Nobel Prize in Aviation went to Patricia V. Agostino, Santiago A. Plano, and Diego A. Golombek of Universidad Nacional de Quilmes, Argentina, for their discovery that sildenafil helps treat jet lag recovery in hamsters.

Sports
Professional athletes have been documented using sildenafil, believing the opening of their blood vessels will enrich their muscles. In turn, they believe it will enhance their performances.

Analogs
Acetildenafil and other synthetic structural analogs of sildenafil which are PDE5 inhibitors have been found as adulterants in a number of "herbal" aphrodisiac products sold over-the-counter. These analogs have not undergone any of the rigorous testing that drugs like sildenafil have passed, and thus have unknown side-effect profiles. Some attempts have been made to ban these drugs, but progress has been slow so far, as, even in those jurisdictions that have laws targeting designer drugs, the laws are drafted to ban analogs of illegal drugs of abuse, rather than analogs of prescription medicines. However, at least one court case has resulted in a product being taken off the market.The U.S. Food and Drug Administration (FDA) has banned numerous products claiming to be Eurycoma longifolia that, in fact, contain only analogs of sildenafil. Sellers of such fake herbals typically respond by just changing the names of their products.

Detection in biological fluids
Sildenafil and/or N-desmethylsildenafil, its major active metabolite, may be quantified in plasma, serum, or whole blood to assess pharmacokinetic status in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdose.

Mechanism of action
Sildenafil protects cyclic guanosine monophosphate (cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum. Nitric oxide (NO) in the corpus cavernosum of the penis binds to guanylate cyclase receptors, which results in increased levels of cGMP, leading to smooth muscle relaxation (vasodilation) of the intimal cushions of the helicine arteries. This smooth muscle relaxation leads to vasodilation and increased inflow of blood into the spongy tissue of the penis, causing an erection. Robert F. Furchgott, Ferid Murad, and Louis Ignarro won the Nobel Prize in Physiology or Medicine in 1998 for their independent study of the metabolic pathway of nitric oxide in smooth muscle vasodilation.
The molecular mechanism of smooth muscle relaxation involves the enzyme CGMP-dependent protein kinase, also known as PKG. This kinase is activated by cGMP and it phosphorylates multiple targets in the smooth muscle cells, namely myosin light chain phosphatase, RhoA, IP3 receptor, phospholipase C, and others. Overall, this results in a decrease in intracellular calcium and desensitizing proteins to the effects of calcium, engendering smooth muscle relaxation.Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. The molecular structure of sildenafil is similar to that of cGMP and acts as a competitive binding agent of PDE5 in the corpus cavernosum, resulting in more cGMP and increased penile response to sexual stimulation. Without sexual stimulation, and therefore lack of activation of the NO/cGMP system, sildenafil should not cause an erection. Other drugs that operate by the same mechanism include tadalafil (Cialis) and vardenafil (Levitra).
Sildenafil is broken down in the liver by hepatic metabolism using cytochrome p450 enzymes, mainly CYP450 3A4 (major route), but also by CYP2C9 (minor route) hepatic isoenzymes. The major product of metabolisation by these enzymes is N-desmethylated sildenafil, which is metabolised further. This metabolite also has an affinity for the PDE receptors, about 40% of that of sildenafil. Thus, the metabolite is responsible for about 20% of sildenafils action. Sildenafil is excreted as metabolites predominantly in the feces (about 80% of administered oral dose) and to a lesser extent in the urine (around 13% of the administered oral dose).  If taken with a high-fat meal, absorption is reduced; the time taken to reach the maximum plasma concentration increases by around one hour, and the maximum concentration itself is decreased by nearly one-third.

Route of administration
When taken by mouth sildenafil for erectile dysfunction results in an average time to onset of erections of 27 minutes (ranging from 12 to 70 minutes).
Under the tongue use of sildenafil for erectile dysfunction results in an average onset of action of 15 minutes and lasting for an average of 40 minutes.
There are also mouth spray preparations of sildenafil for faster onset of action.

Chemical synthesis
The preparation steps for synthesis of sildenafil are:
Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate
Hydrolysis with aqueous sodium hydroxide (NaOH) to free acid
Nitration with oleum/fuming nitric acid
Carboxamide formation with refluxing thionyl chloride/NH4OH
Reduction of nitro group to amino group
Acylation with 2-ethoxybenzoyl chloride
Cyclization
Sulfonation to the chlorosulfonyl derivative
Condensation with 1-methylpiperazine.

History
Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizers Sandwich, Kent, research facility in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a symptom of ischaemic heart disease). The first clinical trials were conducted in Morriston Hospital in Swansea.  Phase I clinical trials under the direction of Ian Osterloh suggested the drug had little effect on angina, but it could induce marked penile erections. Pfizer therefore decided to market it for erectile dysfunction, rather than for angina; this decision became an often-cited example of drug repositioning. The drug was patented in 1996, approved for use in erectile dysfunction by the FDA on 27 March 1998, becoming the first oral treatment approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year. It soon became a great success: annual sales of Viagra peaked in 2008 at US$1.934 billion.

Society and culture
Marketing and sales
In the US, even though sildenafil is available only by prescription from a doctor, it was advertised directly to consumers on TV (famously being endorsed by former United States Senator Bob Dole and football star Pelé). Numerous sites on the Internet offer Viagra for sale after an "online consultation", often a simple web questionnaire. The Viagra name has become so well known that many fake aphrodisiacs now call themselves "herbal viagra" or are presented as blue tablets imitating the shape and colour of Pfizers product. Viagra is also informally known as "vitamin V", "the blue pill", or "blue diamond", as well as various other nicknames.
In 2000, Viagra sales accounted for 92% of the global market for prescribed erectile dysfunction pills. By 2007, Viagras global share had plunged to about 50% due to several factors, including the entry of Cialis and Levitra, along with several counterfeits and clones, and reports of vision loss in people taking PDE5 inhibitors. In 2008, the FDA forced Pfizer to remove Viva Cruiser, an advergame for Viagra, from appearing on Forbes.com, after the game failed to disclose risk information about the drug.In February 2007, it was announced that Boots, the UK pharmacy chain, would try over-the-counter sales of Viagra in stores in Manchester, England. Men between the ages of 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist. In 2017, the Medicines and Healthcare products Regulatory Agency (MHRA) enacted legislation that expanded this nationwide, allowing a particular branded formulation of Sildenafil, Viagra Connect (50 mg), to be sold over the counter and without a prescription throughout the UK from early 2018. While the sale remains subject to a consultation with a pharmacist, the other restrictions from the trial have been removed, allowing customers over the age of 18 to purchase an unlimited number of pills. The decision was made, in part, to reduce online sales of counterfeit and potentially dangerous erectile dysfunction treatments.
On 6 May 2013, Pfizer, which manufactures Viagra, told the Associated Press they will begin selling the drug directly to people on its website.Pfizers patents on Viagra expired outside the US in 2012; in the US they were set to expire, but Pfizer settled litigation with each of Mylan and Teva which agreed that both companies could introduce generics in the US on 11 December 2017. In December 2017, Pfizer released its own generic version of Viagra.As of 2018, the U.S. Food and Drug Administration has approved fifteen drug manufacturers to market generic sildenafil in the United States. Seven of these companies are based in India. This is likely to lead to dramatic price reductions.

Counterfeits
Counterfeit Viagra,  despite generally being cheaper, can contain harmful substances or substances that affect how Viagra works, such as blue printer ink, amphetamines, metronidazole, boric acid, and rat poison.Viagra is one of the worlds most counterfeited medicines. According to a Pfizer study, around 80% of sites claiming to sell Viagra were selling counterfeits.

Regional issues
Brazil
Pfizers patent on sildenafil citrate expired in Brazil in 2010.

Canada
In Canada, Pfizers patent 2,324,324 for Revatio (sildenafil used to treat pulmonary hypertension) was found invalid by the Federal Court in June 2010, on an application by Ratiopharm Inc.On 8 November 2012, the Supreme Court of Canada ruled that Pfizers patent 2,163,446 on Viagra was invalid from the beginning because the company did not provide full disclosure in its application. The decision, Teva Canada Ltd. v. Pfizer Canada Inc., pointed to section 27(3)(b) of The Patent Act which requires that disclosure must include sufficient information "to enable any person skilled in the art or science to which it pertains" to produce it. It added further: "As a matter of policy and sound statutory interpretation, patentees cannot be allowed to game the system in this way. This, in my view, is the key issue in this appeal."Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision. To remain competitive, Pfizer then reduced the price of Viagra in Canada. However, on 9 November 2012, Pfizer filed a motion for a re-hearing of the appeal in the Supreme Court of Canada, on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent. Finally, on 22 April 2013, the Supreme Court of Canada invalidated Pfizers patent altogether.

China
Manufacture and sale of sildenafil citrate drugs is common in China, where Pfizers patent claim is not widely enforced.

Egypt
Egypt approved Viagra for sale in 2002, but soon afterwards allowed local companies to produce generic versions of the drug, citing the interests of poor people who would not be able to afford Pfizers price.

European Union
Pfizers patent on sildenafil citrate expired in some member countries of the EU, Austria, Denmark, France, Germany, Ireland, Italy, The Netherlands, Spain, Sweden, the United Kingdom and Switzerland on 21 June 2013.  A UK patent held by Pfizer on the use of PDE5 inhibitors (see below) as treatment of impotence was invalidated in 2000 because of obviousness; this decision was upheld on appeal in 2002.

India
Manufacture and sale of sildenafil citrate drugs known as "generic Viagra" is common in India, where Pfizers patent claim does not apply. Trade names include Kamagra (Ajanta Pharma), Silagra (Cipla), Edegra (Sun Pharmaceutical), Penegra (Zydus Cadila), Manly (Cooper Pharma) and Zenegra (Alkem Laboratories).

New Zealand
Sildenafil was reclassified in New Zealand in 2014 so it could be bought over the counter from a pharmacist. It is thought that this reduced sales over the Internet and was safer as men could be referred for medical advice if appropriate.

South Korea
In 1999 South Korea granted two patents to Pfizer related to sildenafil. The first document guaranteed sole production and sale of the substance until 2012, while the second gave Pfizer the exclusive use to treating erectile dysfunction with sildenafil until 2014. In 2011 Hanmi Pharmaceutical and CJ CheilJedang launched a suit against the exclusive use patent. The Korean Court system made a ruling against Pfizer in June 2012, allowing for the unhindered domestic production of generic prescription sildenafil.During 2012 Viagra lost its position as the top selling erectile dysfunction treatment in South Korea. This development was credited largely "due to the introduction of generic products." Generic sildenafil became publicly available in May. Sales of PalPal by Hanmi Pharmaceuticals totalled ₩22 billion or about 86% the market share of Viagra that year. By 2017 there were over 50 generic sildenafil pills available. During that year Viagra sales slumped to 38% that of Palpal.

United Kingdom
There were 2,958,199 prescriptions for Sildenafil in 2016 in England, compared with 1,042,431 in 2006.In 2018, Viagra Connect, a particular formulation of Sildenafil marketed by Pfizer, became available for sale without a prescription in the UK, in an attempt to widen availability and reduce demand for counterfeit products.

United States
Sildenafil is available as a generic drug in the United States, labeled for pulmonary arterial hypertension. As of 2016 branded pills cost about 50 times more than generic ones. In the United States as of 2015 the branded 50 mg pill cost is between 25.17 and US$37.88.In the United States, Pfizer received two patents for sildenafil: one for its indication to treat cardiovascular disease (marketed as Revatio) and another for its indication to treat erectile dysfunction (marketed as Viagra). The substance is the same under both trade names.In 1992, Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases. This would be marketed as Revatio. The patent was published in 1993 and expired in 2012. The patent on Revatio (indicated for pulmonary arterial hypertension rather than erectile dysfunction) expired in late 2012. Generic versions of this low-dose form of sildenafil have been available in the U.S. from a number of manufacturers, including Greenstone, Mylan, and Watson, since early 2013. Health care providers may prescribe generic sildenafil for erectile dysfunction. However, the generic is not available in the same dosages as branded Viagra, so using dosages typically required for treating ED requires patients to take multiple pills.In 1994, Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Clocortolone and can you explain it in depth? [/INST] Clocortolone (Cloderm) is a topical steroid. It is used in the form of an ester, clocortolone pivalate, and applied as a cream. It is used for the treatment of dermatitis and is considered a medium-strength corticosteroid. It is unusual among steroids in that it contains a chlorine atom and a fluorine atom.

Pharmacology
Clocortolone is an upper-mid potency topical corticosteroid formulation. It is rated at a class 4 potency on a scale of 1 (highest potency) to 7 (lowest potency). Most patients are treated with mid-potency topical corticosteroids, for they are an effective medium between safety and efficacy for short and long-term conditions.
Vital to the pharmacological action of clocortolone is the presence and location of its functional groups. There were several molecular modifications done to create clocortolone pivalate, including beta-hydroxylation at C-11, methylation at C-16, double bonds at C-12, esterification at C-21, and halogenation at C-6 and C-9. It is common in the medical community to associate halogenation of topical corticosteroids with adverse effects. This notion is, in fact, incorrect—it is both the presence and location of halogenation in steroids that matter. In comparison to all other topical corticosteroids, the combination of the chlorine at C-9 and the fluorine at C-6 is unique to clocortolone. Clocortolone pivalate, due to its unique nature, has both upper-mid potency and the safety profile associated with a lower potency topical corticosteroid. This versatility allows for Cloderm cream to be a treatment option for a variety of patients.

Cream vehicle
Clocortolone pivalate 0.1% is formulated in a cream that contains three ingredients which assist in stratum corneum permeability barrier integrity: white petrolatum (occlusive), mineral oil (humectant), and stearyl alcohol (long-chain fatty alcohol emollient). This cream does not contain lanolin, fragrance, nor propylene glycol, all of which have been known to be problematic for some patients.

Clinical studies
In Phase III trials, Cloderm was found to be especially useful in treating eczema, atopic dermatitis, and psoriasis. Phase III trials also showed rapid action and relief for the majority of the patients involved. There is no age restriction on the use of clocortolone pivalate 0.1% cream. Clinical trials comparing clocortolone pivalate 0.1% topical cream with vehicle in atopic dermatitis/eczematous dermatitis, psoriasis, and contact dermatitis included pediatric patients (N=44). The mean age of pediatric subjects was 10 years (range 3–14 years). Clocortolone pivalate 0.1% cream was efficacious for the majority (75%) of the pediatric patients in these trials, with no serious adverse effects occurring in either group.In six parallel, double-blind, placebo-controlled trials, patients with atopic dermatitis/eczematous dermatitis were randomized to treatment with clocortolone pivalate 0.1% topical cream (total n=109) or vehicle (total n=100), applied three times daily over a duration of 14 days. According to evaluations completed by the physician investigators, a significantly higher proportion of patients in the clocortolone pivalate group than patients in the vehicle group demonstrated a good or excellent response at Days 4, 7, and 14.Due to the chronic and lengthy nature of some steroid responsive dermatoses such as atopic dermatitis and psoriasis, a study of 27 patients was conducted, wherein these patients were treated with Cloderm from 30 days up to 7 months. The results of these treatments showed a low rate of adverse reactions and no signs of striae, atrophy, or hypopigmentation. Adverse reactions that were experienced included burning, itching, irritation, dryness, and/or folliculitis.Additionally, a clinical study investigated the potential of hypothalamic–pituitary–adrenal (HPA) axis suppression. Ten men with no major health issues applied 30g of clocortolone pivalate 0.1% cream twice a day for 21 days while wearing a plastic sweat suit for twelve hours per day </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Fostemsavir and can you explain it in depth? [/INST] Fostemsavir, sold under the brand name Rukobia, is an antiretroviral medication for adults living with HIV/AIDS who have tried multiple HIV medications and whose HIV infection cannot be successfully treated with other therapies because of resistance, intolerance or safety considerations.The most common adverse reaction is nausea. Severe adverse reactions included elevations in liver enzymes among participants also infected with hepatitis B or C virus, and changes in the immune system (immune reconstitution syndrome).Fostemsavir is an HIV entry inhibitor and a prodrug of temsavir (BMS-626529). Fostemsavir is a human immunodeficiency virus type 1 (HIV-1) gp120-directed attachment inhibitor.It was approved for medical use in the United States in July 2020, and in the European Union in February 2021. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.

Medical uses
Fostemsavir in combination with other antiretroviral(s), is indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations.

Adverse effects
Fostemsavir may cause a serious condition called immune reconstitution syndrome, similar to other approved drugs for treatment of HIV-1 infection. This condition can happen at the beginning of HIV-1 treatment when the immune system may get stronger and begin to fight infections that have been hidden in the body for a long time. Other serious side effects include heart rhythm problems due to prolongation of heart electrical activity (QT prolongation) and an increase of liver enzymes in patients with hepatitis B or C virus co-infection.

History
It was under development by ViiV Healthcare / GlaxoSmithKline for use in the treatment of HIV infection. When the active form of fostemsavir binds to the gp120 protein of the virus, it prevents initial viral attachment to the host CD4+ T cell and entry into the host immune cell; its method of action is a first for HIV drugs. Because it targets a different step of the viral lifecycle, it offers promise for individuals with virus that has become highly resistant to other HIV drugs. Since the function of gp120 that this drug inhibits is highly conserved, the drug is unlikely to promote resistance to itself. Investigators found that enfuvirtide-resistant and ibalizumab-resistant HIV envelopes remained susceptible to fostemsavir. Conversely, fostemsavir-resistant HIV remained susceptible to all the entry inhibitors. Furthermore, HIV isolates that do not require the CD4 receptor for cell entry were also susceptible to fostemsavir, and the virus did not escape the attachment inhibitor by becoming CD4-independent. Prior in vitro studies showed that fostemsavir inhibits both CCR5-tropic and CXCR4-tropic HIV.

Fostemsavir was approved for medical use in the United States in July 2020.The safety and efficacy of fostemsavir, taken twice daily by mouth, were evaluated in a clinical trial of 371 heavily treatment-experienced adult participants who continued to have high levels of virus (HIV-RNA) in their blood despite being on antiretroviral drugs. Two hundred seventy-two participants were treated in the main trial arm, and an additional 99 participants received fostemsavir in a different arm of the trial. Most participants had been treated for HIV for more than 15 years (71 percent), had been exposed to five or more different HIV treatment regimens before entering the trial (85 percent) and/or had a history of AIDS (86 percent). Participants in the main cohort of the trial received either fostemsavir or a placebo twice daily for eight days, in addition to their failing antiretroviral regimen. On the eighth day, participants treated with fostemsavir had a significantly greater decrease in levels of HIV-RNA in their blood compared to those taking the placebo. After the eighth day, all participants received fostemsavir with other antiretroviral drugs. After 24 weeks of fostemsavir plus other antiretroviral drugs, 53 percent of participants achieved HIV RNA suppression, where levels of HIV were low enough to be considered undetectable. After 96 weeks, 60 percent of participants continued to have HIV RNA suppression.The clinical trial (NCT02362503) was conducted at 108 sites in 23 countries in North America, South America, Europe, Australia, Taiwan and South Africa.The U.S. Food and Drug Administration (FDA) granted the application for fostemsavir fast track, priority review, and breakthrough therapy designations. The FDA granted the approval of Rukobia to ViiV Healthcare.On 10 December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Rukobia, intended for the treatment of multi-drug resistant HIV-1 infection. The applicant for this medicinal product is ViiV Healthcare B.V. Fostemsavir was approved for medical use in the European Union in February 2021.

References
Further reading
Kozal M, Aberg J, Pialoux G, Cahn P, Thompson M, Molina JM,  et al. (March 2020). "Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection". N. Engl. J </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Stiripentol and can you explain it in depth? [/INST] Stiripentol, sold under the brand name Diacomit, is an anticonvulsant medication used for the treatment of Dravet syndrome - a serious genetic brain disorder.The most common side effects include loss of appetite, weight loss, insomnia (difficulty sleeping), drowsiness, ataxia (inability to co‑ordinate muscle movements), hypotonia (low muscle strength) and dystonia (muscle disorders).

Medical uses
In the European Union, stiripentol is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in people with severe myoclonic epilepsy in infancy (SMEI, Dravets syndrome) whose seizures are not adequately controlled with clobazam and valproate.In the United States, stiripentol is indicated for the treatment of seizures associated with Dravet syndrome in people two years of age and older taking clobazam. There are no clinical data to support the use of stiripentol as monotherapy in Dravet syndrome.It is used in some countries as an add-on therapy with sodium valproate and clobazam for treating children with Dravet syndrome whose seizures are not adequately controlled.  As of 2017, it was not known whether stiripentol remains useful as children become adolescents or adults.

Contraindications
Stiripentol must not be used in people who have had psychoses (a serious mental state with a distorted sense of reality) with attacks of delirium (a mental state with confusion, excitement, restlessness and hallucinations).

Adverse effects
Very common (more than 10% of people) adverse effects include loss of appetite, weight loss, insomnia, drowsiness, ataxia, hypotonia, and dystonia.Common (between 1% and 10% of people) adverse effects include neutropenia (sometimes severe), aggressiveness, irritability, behavior disorders, opposing behavior, hyperexcitability, sleep disorders, hyperkinesias, nausea, vomiting, and elevated gamma-glutamyltransferase.

Interactions
Stiripentol inhibits several cytochrome P450 isoenzymes and so interacts with many anticonvulsants and other medicines.

Pharmacology
As with most anticonvulsants, the precise mechanism of action is unknown. Regardless, stiripentol has been shown to have anticonvulsant effects of its own.
Stiripentol increases GABAergic activity. At clinically relevant concentrations, it enhances central GABA neurotransmission through a barbiturate-like effect, since it increases the duration of opening of GABA-A receptor channels in hippocampal slices. It has also been shown to increase GABA levels in brain tissues by interfering with its reuptake and metabolism </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Emapalumab and can you explain it in depth? [/INST] Emapalumab, sold under the brand name Gamifant, is an anti-interferon-gamma (IFNγ) antibody medication used for the treatment of hemophagocytic lymphohistiocytosis (HLH), which has no cure.The most common side effects include infections, hypertension, infusion-related reactions, and pyrexia.The U.S </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Mebendazole and can you explain it in depth? [/INST] Mebendazole (MBZ), sold under the brand name Vermox among others, is a medication used to treat a number of parasitic worm infestations. This includes ascariasis, pinworm infection, hookworm infections, guinea worm infections, hydatid disease, and giardia, among others. It is taken by mouth.Mebendazole is usually well tolerated. Common side effects include headache, vomiting, and ringing in the ears. If used at large doses it may cause bone marrow suppression. It is unclear if it is safe in pregnancy. Mebendazole is a broad-spectrum antihelminthic agent of the benzimidazole type.Mebendazole came into use in 1971, after it was developed by Janssen Pharmaceutica in Belgium. It is on the World Health Organizations List of Essential Medicines. Mebendazole is available as a generic medication.

Medical use
Mebendazole is a highly effective, broad-spectrum antihelmintic indicated for the treatment of nematode infestations, including roundworm, hookworm, whipworm, threadworm (pinworm), and the intestinal form of trichinosis prior to its spread into the tissues beyond the digestive tract. Other drugs are used to treat worm infections outside the digestive tract, as mebendazole is poorly absorbed into the bloodstream. Mebendazole is used alone in those with mild to moderate infestations. It kills parasites relatively slowly, and in those with very heavy infestations, it can cause some parasites to migrate out of the digestive system, leading to appendicitis, bile duct problems, or intestinal perforation. To avoid this, heavily infested patients may be treated with piperazine, either before or instead of mebendazole. Piperazine paralyses the parasites, causing them to pass in the feces. It is also used rarely in the treatment of cystic echinococcosis, also known as hydatid disease. Evidence for effectiveness for this disease, however, is poor.Mebendazole and other benzimidazole antithelmetics are active against both larval and adult stages of nematodes, and in the cases of roundworm and whipworm, kill the eggs, as well. Paralysis and death of the parasites occurs slowly, and elimination in the feces may require several days.

Special populations
Mebendazole has been shown to cause ill effects in pregnancy in animal models, and no adequate studies of its effects in human pregnancy have been conducted. Whether it can be passed by breastfeeding is unknown.

Adverse effects
Mebendazole sometimes causes diarrhea, abdominal pain, and elevated liver enzymes. In rare cases, it has been associated with a dangerously low white blood cell count, low platelet count, and hair loss, with a risk of agranulocytosis in rare cases.

Drug interactions
Carbamazepine and phenytoin lower serum levels of mebendazole. Cimetidine does not appreciably raise serum mebendazole (in contrast to the similar drug albendazole), consistent with its poor systemic absorption.Stevens–Johnson syndrome and the more severe toxic epidermal necrolysis can occur when mebendazole is combined with high doses of metronidazole.

Mechanism
Mebendazole works by selectively inhibiting the synthesis of microtubules via binding to the colchicine binding site of β-tubulin, thereby blocking polymerisation of tubulin dimers in intestinal cells of parasites </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Rifampicin/isoniazid/pyrazinamide and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Quinine and can you explain it in depth? [/INST] Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to Plasmodium falciparum that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg cramps, quinine is not recommended for this purpose due to the risk of serious side effects. It can be taken by mouth or intravenously. Malaria resistance to quinine occurs in certain areas of the world. Quinine is also used as an ingredient in tonic water to impart a bitter taste.Common side effects include headache, ringing in the ears, vision issues, and sweating. More severe side effects include deafness, low blood platelets, and an irregular heartbeat. Use can make one more prone to sunburn. While it is unclear if use during pregnancy causes harm to the baby, treating malaria during pregnancy with quinine when appropriate is still recommended. Quinine is an alkaloid, a naturally occurring chemical compound. How it works as a medicine is not entirely clear.Quinine was first isolated in 1820 from the bark of a cinchona tree, which is native to Peru, and its molecular formula was determined by Strecker in 1854. The class of chemical compounds to which it belongs is thus called the cinchona alkaloids. Bark extracts had been used to treat malaria since at least 1632 and it was introduced to Spain as early as 1636 by Jesuit missionaries returning from the New World. It is on the World Health Organizations List of Essential Medicines. Treatment of malaria with quinine marks the first known use of a chemical compound to treat an infectious disease.

Uses
Medical
As of 2006, quinine is no longer recommended by the World Health Organization (WHO) as a first-line treatment for malaria, because there are other substances that are equally effective with fewer side effects. They recommend that it be used only when artemisinins are not available. Quinine is also used to treat lupus and arthritis.
Quinine was frequently prescribed as an off-label treatment for leg cramps at night, but this has become less common due to a warning from the US Food and Drug Administration (FDA) that such practice is associated with life-threatening side effects. Quinine can also act as a competitive inhibitor of monoamine oxidase (MAO), an enzyme that removes neurotransmitters from the brain. As an MAO inhibitor, it has potential to serve as a treatment for individuals with psychological disorders similar to antidepressants that inhibit MAO.

Available forms
Quinine is a basic amine and is usually provided as a salt. Various existing preparations include the hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate. In the United States, quinine sulfate is commercially available in 324-mg tablets under the brand name Qualaquin.
All quinine salts may be given orally or intravenously (IV); quinine gluconate may also be given intramuscularly (IM) or rectally (PR). The main problem with the rectal route is that the dose can be expelled before it is completely absorbed; in practice, this is corrected by giving a further half dose. No injectable preparation of quinine is licensed in the US; quinidine is used instead.

Beverages
Quinine is a flavor component of tonic water and bitter lemon drink mixers. On the soda gun behind many bars, tonic water is designated by the letter "Q" representing quinine.Tonic water was initially marketed as a means of delivering quinine to consumers in order to offer anti-malarial protection. According to tradition, because of the bitter taste of anti-malarial quinine tonic, British colonials in India mixed it with gin to make it more palatable, thus creating the gin and tonic cocktail, which is still popular today. While it is possible to drink enough tonic water to temporarily achieve quinine levels that offer anti-malarial protection, this is not a sustainable long-term means of protection.In France, quinine is an ingredient of an apéritif known as quinquina, or "Cap Corse," and the wine-based apéritif Dubonnet. In Spain, quinine (also known as "Peruvian bark" for its origin from the native cinchona tree) is sometimes blended into sweet Malaga wine, which is then called "Malaga Quina". In Italy, the traditional flavoured wine Barolo Chinato is infused with quinine and local herbs, and is served as a digestif. In Scotland, the company A.G. Barr uses quinine as an ingredient in the carbonated and caffeinated beverage Irn-Bru. In Uruguay and Argentina, quinine is an ingredient of a PepsiCo tonic water named Paso de los Toros. In Denmark, it is used as an ingredient in the carbonated sports drink Faxe Kondi made by Royal Unibrew.
As a flavouring agent in drinks, quinine is limited to less than 83 parts per million in the United States, and 100 mg⁄l in the European Union.

Scientific
Quinine (and quinidine) are used as the chiral moiety for the ligands used in Sharpless asymmetric dihydroxylation as well as for numerous other chiral catalyst backbones. Because of its relatively constant and well-known fluorescence quantum yield, quinine is used in photochemistry as a common fluorescence standard.

Contraindications
Because of the narrow difference between its therapeutic and toxic effects, quinine is a common cause of drug-induced disorders, including thrombocytopenia and thrombotic microangiopathy. Even from minor levels occurring in common beverages, quinine can have severe adverse effects involving multiple organ systems, among which are immune system effects and fever, hypotension, hemolytic anemia, acute kidney injury, liver toxicity, and blindness. In people with atrial fibrillation, conduction defects, or heart block, quinine can cause heart arrhythmias, and should be avoided.Quinine can cause hemolysis in G6PD deficiency (an inherited deficiency), but this risk is small and the physician should not hesitate to use quinine in people with G6PD deficiency when there is no alternative.

Adverse effects
Quinine can cause unpredictable serious and life-threatening blood and cardiovascular reactions including low platelet count and hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), long QT syndrome and other serious cardiac arrhythmias including torsades de pointes, blackwater fever, disseminated intravascular coagulation, leukopenia, and neutropenia. Some people who have developed TTP due to quinine have gone on to develop kidney failure. It can also cause serious hypersensitivity reactions including anaphylactic shock, urticaria, serious skin rashes, including Stevens–Johnson syndrome and toxic epidermal necrolysis, angioedema, facial edema, bronchospasm, granulomatous hepatitis, and itchiness.The most common adverse effects involve a group of symptoms called cinchonism, which can include headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, and disturbance in color perception. More severe cinchonism includes vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in heart rhythms. Cinchonism is much less common when quinine is given by mouth, but oral quinine is not well tolerated (quinine is exceedingly bitter and many people will vomit after ingesting quinine tablets). Other drugs, such as Fansidar (sulfadoxine with pyrimethamine) or Malarone (proguanil with atovaquone), are often used when oral therapy is required. Quinine ethyl carbonate is tasteless and odourless, but is available commercially only in Japan. Blood glucose, electrolyte and cardiac monitoring are not necessary when quinine is given by mouth.
Quinine has diverse unwanted interactions with numerous prescription drugs, such as potentiating the anticoagulant effects of warfarin.

Mechanism of action
Quinine is used for its toxicity to the malarial pathogen, Plasmodium falciparum, by interfering with its ability to dissolve and metabolize hemoglobin. As with other quinoline antimalarial drugs, the precise mechanism of action of quinine has not been fully resolved, although in vitro studies indicate it inhibits nucleic acid and protein synthesis, and inhibits glycolysis in P. falciparum. The most widely accepted hypothesis of its action is based on the well-studied and closely related quinoline drug, chloroquine. This model involves the inhibition of hemozoin biocrystallization in the heme detoxification pathway, which facilitates the aggregation of cytotoxic heme. Free cytotoxic heme accumulates in the parasites, causing their deaths. Quinine may target the malaria purine nucleoside phosphorylase enzyme.

Chemistry
The UV absorption of quinine peaks around 350 nm (in UVA). Fluorescent emission peaks at around 460 nm (bright blue/cyan hue). Quinine is highly fluorescent (quantum yield ~0.58) in 0.1 M sulfuric acid solution.

Synthesis
Cinchona trees remain the only economically practical source of quinine. However, under wartime pressure during World War II, research towards its synthetic production was undertaken. A formal chemical synthesis was accomplished in 1944 by American chemists R.B. Woodward and W.E. Doering. Since then, several more efficient quinine total syntheses have been achieved, but none of them can compete in economic terms with isolation of the alkaloid from natural sources. The first synthetic organic dye, mauveine, was discovered by William Henry Perkin in 1856 while he was attempting to synthesize quinine.

Biosynthesis
In the first step of quinine biosynthesis, the enzyme strictosidine synthase catalyzes a stereoselective Pictet–Spengler reaction between tryptamine and secologanin to yield strictosidine. Suitable modification of strictosidine leads to an aldehyde. Hydrolysis and decarboxylation would initially remove one carbon from the iridoid portion and produce corynantheal. Then the tryptamine side-chain were cleaved adjacent to the nitrogen, and this nitrogen was then bonded to the acetaldehyde function to yield cinchonaminal. Ring opening in the indole heterocyclic ring could generate new amine and keto functions. The new quinoline heterocycle would then be formed by combining this amine with the aldehyde produced in the tryptamine side-chain cleavage, giving cinchonidinone. For the last step, hydroxylation and methylation gives quinine.

Catalysis
Quinine and other Cinchona alkaloids can be used as catalysts for stereoselective reactions in organic synthesis.: Table 3B Plate 560  For example, the quinine-catalyzed Michael addition of a malononitrile to α,β-enones gives a high degree of sterechemical control.

History
Quinine was used as a muscle relaxant by the Quechua people, who are indigenous to Peru, Bolivia and Ecuador, to halt shivering. The Quechua would mix the ground bark of cinchona trees with sweetened water to offset the barks bitter taste, thus producing something similar to tonic water.Spanish Jesuit missionaries were the first to bring cinchona to Europe.  The Spanish had observed the Quechuas use of cinchona and were aware of the medicinal properties of cinchona bark by the 1570s or earlier:  Nicolás Monardes (1571) and Juan Fragoso (1572) both described a tree, which was subsequently identified as the cinchona tree, whose bark was used to produce a drink to treat diarrhea. Quinine has been used in unextracted form by Europeans since at least the early 17th century.A popular story of how it was brought to Europe by the Countess of Chinchon was debunked by medical historian Alec Haggis around 1941. During the 17th century, malaria was endemic to the swamps and marshes surrounding the city of Rome. It had caused the deaths of several popes, many cardinals and countless common Roman citizens. Most of the Catholic priests trained in Rome had seen malaria patients and were familiar with the shivering brought on by the febrile phase of the disease.
The Jesuit Agostino Salumbrino (1564–1642), an apothecary by training who lived in Lima (now in present-day Peru), observed the Quechua using the bark of the cinchona tree to treat such shivering. While its effect in treating malaria (and malaria-induced shivering) was unrelated to its effect in controlling shivering from rigors, it was a successful medicine against malaria. At the first opportunity, Salumbrino sent a small quantity to Rome for testing as a malaria treatment. In the years that followed, cinchona bark, known as Jesuits bark or Peruvian bark, became one of the most valuable commodities shipped from Peru to Europe. When King Charles II was cured of malaria at the end of the 17th Century with quinine, it became popular in London. It remained the antimalarial drug of choice until the 1940s, when other drugs took over.The form of quinine most effective in treating malaria was found by Charles Marie de La Condamine in 1737. In 1820, French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou first isolated quinine from the bark of a tree in the genus Cinchona – probably Cinchona pubescens – and subsequently named the substance. The name was derived from the original Quechua (Inca) word for the cinchona tree bark, quina or quina-quina, which means "bark of bark" or "holy bark". Prior to 1820, the bark was dried, ground to a fine powder, and mixed into a liquid (commonly wine) in order to be drunk. Large-scale use of quinine as a malaria prophylaxis started around 1850. In 1853 Paul Briquet published a brief history and discussion of the literature on "quinquina".Quinine played a significant role in the colonization of Africa by Europeans. The availability of quinine for treatment had been said to be the prime reason Africa ceased to be known as the "white mans grave". A historian said, "it was quinines efficacy that gave colonists fresh opportunities to swarm into the Gold Coast, Nigeria and other parts of west Africa".To maintain their monopoly on cinchona bark, Peru and surrounding countries began outlawing the export of cinchona seeds and saplings in the early 19th century. In 1865, Manuel Incra Mamani collected seeds from a plant particularly high in quinine and provided them to Charles Ledger. Ledger sent them to his brother, who sold them to the Dutch government. Mamani was arrested on a seed collecting trip in 1871, and beaten so severely, likely because of providing the seeds to foreigners, that he died soon afterwards.By the late 19th century the Dutch grew the plants in Indonesian plantations. Soon they became the main suppliers of the tree. In 1913 they set up the Kina Bureau, a cartel of cinchona producers charged with controlling price and production. By the 1930s Dutch plantations in Java were producing 22 million pounds of cinchona bark, or 97% of the worlds quinine production. U.S. attempts to prosecute the Kina Bureau proved unsuccessful.During World War II, Allied powers were cut off from their supply of quinine when Germany conquered the Netherlands, and Japan controlled the Philippines and Indonesia. The US had obtained four million cinchona seeds from the Philippines and began operating cinchona plantations in Costa Rica. Additionally, they began harvesting wild cinchona bark during the Cinchona Missions. Such supplies came too late. Tens of thousands of US troops in Africa and the South Pacific died of malaria due to the lack of quinine. Despite controlling the supply, the Japanese did not make effective use of quinine, and thousands of Japanese troops in the southwest Pacific died as a result.Quinine remained the antimalarial drug of choice until after World War II. Since then, other drugs that have fewer side effects, such as chloroquine, have largely replaced it.Bromo Quinine were brand name cold tablets containing quinine, manufactured by Grove Laboratories. They were first marketed in 1889 and available until at least the 1960s.Conducting research in central Missouri, Dr. John S. Sappington independently developed an anti-malaria pill from quinine. Sappington began importing cinchona bark from Peru in 1820. In 1832, using quinine derived from the cinchona bark, Sappington developed a pill to treat a variety of fevers, such as scarlet fever, yellow fever, and influenza in addition to malaria. These illnesses were widespread in the Missouri and Mississippi valleys. He manufactured and sold "Dr. Sappingtons Anti-Fever Pills" across Missouri. Demand became so great that within three years, Dr. Sappington founded a company known as Sappington and Sons to sell his pills nationwide.

Society and culture
Natural occurrence
The bark of Remijia contains 0.5–2% of quinine. The bark is cheaper than bark of Cinchona. As it has an intense taste, it is used for making tonic water.

Regulation in the US
From 1969, to 1992, the US Food and Drug Administration (FDA) received 157 reports of health problems related to quinine use, including 23 which had resulted in death. In 1994, the FDA banned the marketing of over-the-counter quinine as a treatment for nocturnal leg cramps. Pfizer Pharmaceuticals had been selling the brand name Legatrin for this purpose. Also sold as a Softgel (by SmithKlineBeecham) as Q-vel. Doctors may still prescribe quinine, but the FDA has ordered firms to stop marketing unapproved drug products containing quinine. The FDA is also cautioning consumers about off-label use of quinine to treat leg cramps. Quinine is approved for treatment of malaria, but was also commonly prescribed to treat leg cramps and similar conditions. Because malaria is life-threatening, the risks associated with quinine use are considered acceptable when used to treat that condition.Though Legatrin was banned by the FDA for the treatment of leg cramps, the drug manufacturer URL Mutual has branded a quinine-containing drug named Qualaquin. It is marketed as a treatment for malaria and is sold in the United States only by prescription. In 2004, the CDC reported only 1,347 confirmed cases of malaria in the United States.

Cutting agent
Quinine is sometimes detected as a cutting agent in street drugs such as cocaine and heroin.

Other animals
Quinine is used as a treatment for Cryptocaryon irritans (commonly referred to as white spot, crypto or marine ich) infection of marine aquarium fish.

References
Further reading
Schroeder-Lein G (2008). The encyclopedia of Civil War medicine. Armonk, NY: Sharpe, Inc.
Hobhouse, Henry (2005) [1986]. Seeds of Change: Six Plants That Transformed Mankind. Berkeley, CA: Counterpoint. ISBN 978-1-59376-049-6.
Stockwell HR (1982). "Aeromedical considerations of malaria prophylaxis with mefloquine hydrochloride". Aviation, Space, and Environmental Medicine. 3 (10): 1011–13. PMID 6983345.
Wolff RS, Wirtschafter D, Adkinson C (June 1997). "Ocular quinine toxicity treated with hyperbaric oxygen". Undersea & Hyperbaric Medicine. 24 (2): 131–4. PMID 9171472. Archived from the original on 11 August 2011. Retrieved 13 August 2008.
Slater L (2009). War and disease : biomedical research on malaria in the twentieth century. New Brunswick, NJ: Rutgers University Press.
Lloyd, Henry D. (June 1884). "Lords of Industry". The North American Review </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Talc and can you explain it in depth? [/INST] Talc, or talcum, is a clay mineral, composed of hydrated magnesium silicate with the chemical formula Mg3Si4O10(OH)2. Talc in powdered form, often combined with corn starch, is used as baby powder. This mineral is used as a thickening agent and lubricant. It is an ingredient in ceramics, paints, and roofing material. It is a main ingredient in many cosmetics. It occurs as foliated to fibrous masses, and in an exceptionally rare crystal form. It has a perfect basal cleavage and an uneven flat fracture, and it is foliated with a two-dimensional platy form.
The Mohs scale of mineral hardness, based on scratch hardness comparison, defines value 1 as the hardness of talc, the softest mineral. When scraped on a streak plate, talc produces a white streak; though this indicator is of little importance, because most silicate minerals produce a white streak. Talc is translucent to opaque, with colors ranging from whitish grey to green with a vitreous and pearly luster. Talc is not soluble in water, and is slightly soluble in dilute mineral acids.Soapstone is a metamorphic rock composed predominantly of talc.

Etymology
The word "talc" derives from Medieval Latin talcum, which in turn originates from Arabic: طلق ṭalq which, derives from Persian: تالک tālk. In ancient times, the word was used for various related minerals, including talc, mica, and selenite.

Formation
Talc dominantly forms from the metamorphism of magnesian minerals such as serpentine, pyroxene, amphibole, and olivine, in the presence of carbon dioxide and water. This is known as "talc carbonation" or "steatization" and produces a suite of rocks known as talc carbonates.
Talc is primarily formed by hydration and carbonation by this reaction:

serpentine2 Mg3Si2O5(OH)4 + carbon dioxide3 CO2 → talcMg3Si4O10(OH)2 + magnesite3 MgCO3 + water3 H2OTalc can also be formed via a reaction between dolomite and silica, which is typical of skarnification of dolomites by silica-flooding in contact metamorphic aureoles:

dolomite3 CaMg(CO3)2 + silica4 SiO2 + waterH2O → talcMg3Si4O10(OH)2 + calcite3 CaCO3 + carbon dioxide3 CO2Talc can also be formed from magnesium chlorite and quartz in blueschist and eclogite metamorphism by the following metamorphic reaction:

chlorite + quartz → kyanite + talc + waterTalc is also found as a diagenetic mineral in sedimentary rocks where it can form from the transformation of metastable hydrated magnesium-clay precursors such as kerolite, sepiolite, or stevensite that can precipitate from marine and lake water in certain conditions.In this reaction, the ratio of talc and kyanite depends on aluminium content, with more aluminous rocks favoring production of kyanite. This is typically associated with high-pressure, low-temperature minerals such as phengite, garnet, and glaucophane within the lower blueschist facies. Such rocks are typically white, friable, and fibrous, and are known as
whiteschist.
Talc is a trioctahedral layered mineral; its structure is similar to pyrophyllite, but with magnesium in the octahedral sites of the composite layers. The crystal structure of talc is described as TOT, meaning that it is composed of parallel TOT layers weakly bonded to each other by weak van der Waals forces. The TOT layers in turn consist of two tetrahedral sheets (T) strongly bonded to the two faces of a single trioctahedral sheet (O). It is the weak bonding between TOT layers that gives talc its perfect basal cleavage and softness.The tetrahedral sheets consist of silica tetrahedra, which are silicon ions surrounded by four oxygen ions. The tetrahedra each share three of their four oxygen ions with neighboring tetrahedra to produce a hexagonal sheet. The remaining oxygen ion (the apical oxygen ion) is available to bond with the trioctahedral sheet.The trioctahedral sheet has the structure of a sheet of the mineral brucite. Apical oxygens take the place of some of the hydroxyl ions that would be present in a brucite sheet, bonding the tetrahedral sheets tightly to the trioctahedral sheet.Tetrahedral sheets have a negative charge, since their bulk composition is Si4O104-. The trioctahedral sheet has an equal positive charge, since its bulk composition is Mg3(OH)24+ The combined TOT layer thus is electrically neutral.Because the hexagons in the T and O sheets are slightly different in size, the sheets are slightly distorted when they bond into a TOT layer. This breaks the hexagonal symmetry and reduces it to monoclinic or triclinic symmetry. However, the original hexahedral symmetry is discernible in the pseudotrigonal character of talc crystals.

Occurrence
Talc is a common metamorphic mineral in metamorphic belts that contain ultramafic rocks, such as soapstone (a high-talc rock), and within whiteschist and blueschist metamorphic terranes. Prime examples of whiteschists include the Franciscan Metamorphic Belt of the western United States, the western European Alps especially in Italy, certain areas of the Musgrave Block, and some collisional orogens such as the Himalayas, which stretch along Pakistan, India, Nepal, and Bhutan.
Talc carbonate ultramafics are typical of many areas of the Archaean cratons, notably the komatiite belts of the Yilgarn Craton in Western Australia. Talc-carbonate ultramafics are also known from the Lachlan Fold Belt, eastern Australia, from Brazil, the Guiana Shield, and from the ophiolite belts of Turkey, Oman, and the Middle East.
China is the key world talc and steatite producing country with an output of about 2.2M tonnes(2016), which accounts for 30% of total global output. The other major producers are Brazil (12%), India (11%), the U.S. (9%), France (6%), Finland (4%), Italy, Russia, Canada, and Austria (2%, each).Notable economic talc occurrences include the Mount Seabrook talc mine, Western Australia, formed upon a polydeformed, layered ultramafic intrusion. The France-based Luzenac Group is the worlds largest supplier of mined talc. Its largest talc mine at Trimouns near Luzenac in southern France produces 400,000 tonnes of talc per year.

Conflict mineral
Extraction in disputed areas of Nangarhar province, Afghanistan, has led the international monitoring group Global Witness to declare talc a conflict resource, as the profits are used to fund armed confrontation between the Taliban and Islamic State.

Uses
Talc is used in many industries, including paper making, plastic, paint and coatings (e.g. for metal casting molds), rubber, food, electric cable, pharmaceuticals, cosmetics, and ceramics. A coarse grayish-green high-talc rock is soapstone or steatite, used for stoves, sinks, electrical switchboards, etc. It is often used for surfaces of laboratory table tops and electrical switchboards because of its resistance to heat, electricity, and acids.
In finely ground form, talc finds use as a cosmetic (talcum powder), as a lubricant, and as a filler in paper manufacture. It is used to coat the insides of inner tubes and rubber gloves during manufacture to keep the surfaces from sticking. Talcum powder, with heavy refinement, has been used in baby powder, an astringent powder used to prevent diaper rash (nappy rash). The American Academy of Pediatrics recommends that parents avoid using baby powder because it poses a risk of respiratory problems, including breathing trouble and serious lung damage if inhaled. The small size of the particles makes it difficult to keep them out of the air while applying the powder. Zinc oxide-based ointments are a much safer alternative.Soapstone (massive talc) is often used as a marker for welding or metalworking.Talc is also used as food additive or in pharmaceutical products as a glidant. In medicine, talc is used as a pleurodesis agent to prevent recurrent pleural effusion or pneumothorax. In the European Union, the additive number is E553b.
Talc may be used in the processing of white rice as a buffing agent in the polishing stage.
Due to its low shear strength, talc is one of the oldest known solid lubricants. Also, limited use is made of talc as a friction-reducing additive in lubricating oils.Talc is widely used in the ceramics industry in both bodies and glazes. In low-fire art-ware bodies, it imparts whiteness and increases thermal expansion to resist crazing. In stonewares, small percentages of talc are used to flux the body and therefore improve strength and vitrification. It is a source of MgO flux in high-temperature glazes (to control melting temperature). It is also employed as a matting agent in earthenware glazes and can be used to produce magnesia mattes at high temperatures.
ISO standard for quality (ISO 3262)

Patents are pending on the use of magnesium silicate as a cement substitute. Its production requirements are less energy-intensive than ordinary Portland cement (at a heating requirement of around 650 °C for talc compared to 1500 °C for limestone to produce Portland cement), while it absorbs far more carbon dioxide as it hardens. This results in a negative carbon footprint overall, as the cement substitute removes 0.6 tonnes of CO2 per tonne used. This contrasts with a positive carbon footprint of 0.4 tonnes per tonne of conventional cement.Talc is used in the production of the materials that are widely used in the building interiors such as base content paints in wall coatings. Other areas that use talc to a great extent are organic agriculture, the food industry, cosmetics, and hygiene products such as baby powder and detergent powder.
Talc is sometimes used as an adulterant to illegal heroin, to expand volume and weight and thereby increase its street value. With intravenous use, it may lead to pulmonary talcosis, a granulomatous inflammation in the lungs.

Sterile talc powder
Sterile talc powder (NDC 63256-200-05) is a sclerosing agent used in the procedure of pleurodesis. This can be helpful as a cancer treatment to prevent pleural effusions (an abnormal collection of fluid in the space between the lungs and the thoracic wall). It is inserted into the space via a chest tube, causing it to close up, so fluid cannot collect there. The product can be sterilized by dry heat, ethylene oxide, or gamma irradiation.

Safety
Suspicions have been raised that talc use contributes to certain types of disease, mainly cancers of the ovaries and lungs. According to the IARC, talc containing asbestos is classified as a group 1 agent (carcinogenic to humans), talc use in the perineum is classified as group 2B (possibly carcinogenic to humans), and talc not containing asbestos is classified as group 3 (unclassifiable as to carcinogenicity in humans). Reviews by Cancer Research UK and the American Cancer Society conclude that some studies have found a link, but other studies have not.The studies discuss pulmonary issues, lung cancer, and ovarian cancer. One of these, published in 1993, was a US National Toxicology Program report, which found that cosmetic grade talc containing no asbestos-like fibres was correlated with tumor formation in rats forced to inhale talc for 6 hours a day, five days a week over at least 113 weeks. A 1971 paper found particles of talc embedded in 75% of the ovarian tumors studied.
Research published in 1995 and 2000 concluded that it was plausible that talc could cause ovarian cancer, but no conclusive evidence was shown. The Cosmetic Ingredient Review Expert Panel concluded in 2015 that talc, in the concentrations currently used in cosmetics, is safe.  In 2018, Health Canada issued a warning, advising against inhaling talcum powder or using it in the female perineal area.

Industrial grade
In the United States, the Occupational Safety and Health Administration and National Institute for Occupational Safety and Health have set occupational exposure limits to respirable talc dusts at 2 mg/m3 over an eight-hour workday. At levels of 1000 mg/m3, inhalation of talc is considered immediately dangerous to life and health.

Food grade
The United States Food and Drug Administration considers talc (magnesium silicate) generally recognized as safe (GRAS) to use as an anticaking agent in table salt in concentrations smaller than 2%.

Association with asbestos
One particular issue with commercial use of talc is its frequent co-location in underground deposits with asbestos ore. Asbestos is a general term for different types of fibrous silicate minerals, desirable in construction for their heat resistant properties. There are six varieties of asbestos; the most common variety in manufacturing, white asbestos, is in the serpentine family. Serpentine minerals are sheet silicates; although not in the serpentine family, talc is also a sheet silicate, with two sheets connected by magnesium cations. The frequent co-location of talc deposits with asbestos may result in contamination of mined talc with white asbestos, which poses serious health risks when dispersed into the air and inhaled. Stringent quality control since 1976, including separating cosmetic- and food-grade talc from "industrial"-grade talc, has largely eliminated this issue, but it remains a potential hazard requiring mitigation in the mining and processing of talc. A 2010 US FDA survey failed to find asbestos in a variety of talc-containing products. A 2018 Reuters investigation asserted that pharmaceuticals company Johnson & Johnson knew for decades that there was asbestos in its baby powder, and in 2020 the company stopped selling its baby powder in the US and Canada. There were calls for Johnson & Johnsons largest shareholders to force the company to end global sales of baby powder, and hire an independent firm to conduct a racial justice audit as it had been marketed to African American and overweight women </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Compound and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Loncastuximab tesirine and can you explain it in depth? [/INST] Loncastuximab tesirine , sold under the brand name Zynlonta,  is a monoclonal antibody conjugate medication used to treat large B-cell lymphoma. It is an antibody-drug conjugate (ADC) composed of a humanized antibody targeting the protein CD19.Loncastuximab tesirine was approved for medical use in the United States in April 2021.

Medical uses
Loncastuximab tesirine is indicated for the treatment of adults with relapsed or refractory large B-cell lymphoma.

Technology
The humanized monoclonal antibody is stochastically conjugated via a valine-alanine cleavable, maleimide linker to a cytotoxic (anticancer) pyrrolobenzodiazepine (PBD) dimer. The antibody binds to CD19, a protein which is highly expressed on the surface of B-cell hematological tumors including certain forms of lymphomas and leukemias. After binding to the tumor cells the antibody is internalized, the cytotoxic drug PBD is released and the cancer cells are killed. PBD dimers are generated out of PBD monomers, a class of natural products produced by various actinomycetes. PBD dimers work by crosslinking specific sites of the DNA, blocking the cancer cells’ division that cause the cells to die. As a class of DNA-crosslinking agents they are significantly more potent than systemic chemotherapeutic drugs.

Clinical trials
Two phase I trials are evaluating the medication in people with relapsed or refractory B-cell non-Hodgkin’s lymphoma and relapsed or refractory B-cell acute lymphoblastic leukemia. At the 14th International Conference on Malignant Lymphoma interim results from a Phase I, open-label, dose-escalating study designed to evaluate the treatment of loncastuximab tesirine in relapsed or refractory non-Hodgkin’s lymphoma were presented </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Pyrazinamide and can you explain it in depth? [/INST] Pyrazinamide is a medication used to treat tuberculosis. For active tuberculosis, it is often used with rifampicin, isoniazid, and either streptomycin or ethambutol. It is not generally recommended for the treatment of latent tuberculosis. It is taken by mouth.Common side effects include nausea, loss of appetite, muscle and joint pains, and rash. More serious side effects include gout, liver toxicity, and sensitivity to sunlight. It is not recommended in those with significant liver disease or porphyria. It is unclear if use during pregnancy is safe but it is likely okay during breastfeeding. Pyrazinamide is in the antimycobacterial class of medications. How it works is not entirely clear.Pyrazinamide was first made in 1936, but did not come into wide use until 1972. It is on the World Health Organizations List of Essential Medicines. Pyrazinamide is available as a generic medication.

Medical uses
Pyrazinamide is only used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis and as directly observed therapy (DOT). It is never used on its own.  It has no other indicated medical uses. In particular, it is not used to treat other mycobacteria; Mycobacterium bovis and Mycobacterium leprae are innately resistant to pyrazinamide.
Pyrazinamide is used in the first 2 months of treatment to reduce the duration of treatment required. Regimens not containing pyrazinamide must be taken for 9 months or more.
Pyrazinamide is a potent antiuricosuric drug and consequently has an off-label use in the diagnosis of causes of hypouricemia and hyperuricosuria.  It acts on URAT1.

Adverse effects
The most common (roughly 1%) side effect of pyrazinamide is joint pains (arthralgia), but this is not usually so severe that patients need to stop taking it. Pyrazinamide can precipitate gout flares by decreasing renal excretion of uric acid.The most dangerous side effect of pyrazinamide is hepatotoxicity, which is dose-related.  The old dose for pyrazinamide was 40–70 mg/kg daily and the incidence of drug-induced hepatitis has fallen significantly since the recommended dose has been reduced to 12–30 mg/kg daily.  In the standard four-drug regimen (isoniazid, rifampicin, pyrazinamide, ethambutol), pyrazinamide is the most common cause of drug-induced hepatitis. It is not possible to clinically distinguish pyrazinamide-induced hepatitis from hepatitis caused by isoniazid or rifampicin; test dosing is required (this is discussed in detail in tuberculosis treatment)Other side effects include nausea and vomiting, anorexia, sideroblastic anemia, skin rash, urticaria, pruritus, dysuria, interstitial nephritis, malaise, rarely porphyria, and fever.

Pharmacokinetics
Pyrazinamide is well absorbed orally.  It crosses inflamed meninges and is an essential part of the treatment of tuberculous meningitis.  It is metabolised by the liver and the metabolic products are excreted by the kidneys.
Pyrazinamide is routinely used in pregnancy in the UK and the rest of the world;  the World Health Organization (WHO) recommends its use in pregnancy; and  extensive clinical experience shows that it is safe.  In the US, pyrazinamide is not used in pregnancy, citing insufficient evidence of safety.  Pyrazinamide is removed by haemodialysis, so doses should always be given at the end of a dialysis session.

Mechanism of action
Pyrazinamide is a prodrug that stops the growth of M. tuberculosis.
Pyrazinamide diffuses into the granuloma of M. tuberculosis, where the tuberculosis enzyme pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid.  Under acidic conditions of pH 5 to 6, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate.  The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH.Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesize fatty acids although this has been discounted. The accumulation of pyrazinoic acid  was also suggested to disrupt membrane potential and interfere with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. However, since an acidic environment is not essential for pyrazinamide susceptibility and pyrazinamide treatment does not lead to intrabacterial acidification nor rapid disruption of membrane potential, this model has also been discounted. Pyrazinoic acid was proposed to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation, but more detailed experiments have shown that it does not have this activity.The current hypothesis is that pyrazinoic acid blocks synthesis of coenzyme A. Pyrazinoic acid binds weakly to aspartate decarboxylase (PanD), triggering its degradation. This is an unusual mechanism of action in that pyrazinamide does not directly block the action of its target, but indirectly triggers its destruction.

Resistance
Mutations in the pncA gene of M. tuberculosis, which encodes a pyrazinamidase and converts pyrazinamide to its active form pyrazinoic acid, are responsible for the majority of pyrazinamide resistance in M. tuberculosis strains. A few pyrazinamide-resistant strains with mutations in the rpsA gene have also been identified. However, a direct association between these rpsA mutations and pyrazinamide resistance has not been established. The pyrazinamide-resistant M. tuberculosis strain DHMH444, which harbors a mutation in the carboxy terminal coding region of rpsA, is fully susceptible to pyrazinoic acid and pyrazinamide resistance of this strain was previously associated with decreased pyrazinamidase activity. Further, this strain was found to be susceptible to pyrazinamide in a mouse model of tuberculosis. Thus, current data indicate that rpsA mutations are not likely to be associated with pyrazinamide resistance </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Oxybutynin and can you explain it in depth? [/INST] Oxybutynin, sold as under the brand names Ditropan among others, is a medication used to treat overactive bladder. It works similar to tolterodine, Darifenacin, and Solifenacin. While used for bed wetting in children, evidence to support this use is poor. It is taken by mouth or applied to the skin.Common side effects include dry mouth, constipation, dizziness, trouble sleeping, and urinary tract infections. Serious side effects may include urinary retention and an increased risk of heat stroke. Use in pregnancy appears safe but has not been well studied while use in breastfeeding is of unclear safety. It is an antimuscarinic and works by blocking the effects of acetylcholine on smooth muscle.Oxybutynin was approved for medical use in the United States in 1975. It is available as a generic medication.  In 2019, it was the 112th most commonly prescribed medication in the United States, with more than 5 million prescriptions.

Medical use
The immediate and slow release versions work equally.In people with overactive bladder, transdermal oxybutynin decreased the number of incontinence episodes and increased average voided volume. There was no difference between transdermal oxybutynin and extended-release oral tolterodine.Tentative evidence supports the use of oxybutynin in hyperhidrosis (excessive sweating).

Adverse effects
Common adverse effects that are associated with oxybutynin and other anticholinergics include: dry mouth, difficulty in urination, constipation, blurred vision, drowsiness, and dizziness. Anticholinergics have also been known to induce delirium.Oxybutynins tendency to reduce sweating can be dangerous. Reduced sweating increases the risk of heat exhaustion and heat stroke in apparently safe situations where normal sweating keeps others safe and comfortable. Adverse effects of elevated body temperature are more likely for the elderly and for those with health issues, especially multiple sclerosis.N-Desethyloxybutynin is an active metabolite of oxybutynin that is thought responsible for much of the adverse effects associated with the use of oxybutynin. N-Desethyloxybutynin plasma levels may reach as much as six times that of the parent drug after administration of the immediate-release oral formulation. Alternative dosage forms have been developed in an effort to reduce blood levels of N-desethyloxybutynin and achieve a steadier concentration of oxybutynin than is possible with the immediate release form. The long-acting formulations also allow once-daily administration instead of the twice-daily dosage required with the immediate-release form. The transdermal patch, in addition to the benefits of the extended-release oral formulations, bypasses the first-pass hepatic effect that the oral formulations are subject to.  In those with overflow incontinence because of diabetes or neurological diseases like multiple sclerosis or spinal cord trauma, oxybutynin can worsen overflow incontinence since the fundamental problem is that the bladder is not contracting.
A large study linked the development of dementia in those over 65 to the use of oxybutynin, due to its anticholinergic properties.

Contraindications
Oxybutynin chloride is contraindicated in patients with untreated narrow angle glaucoma, and in patients with untreated narrow anterior chamber angles—since anticholinergic drugs may aggravate these conditions. It is also contraindicated in partial or complete obstruction of the gastrointestinal tract, hiatal hernia, gastroesophageal reflux disease, paralytic ileus, intestinal atony of the elderly or debilitated patient, megacolon, toxic megacolon complicating ulcerative colitis, severe colitis, and myasthenia gravis. It is contraindicated in patients with obstructive uropathy and in patients with unstable cardiovascular status in acute hemorrhage. Oxybutynin chloride is contraindicated in patients who have demonstrated hypersensitivity to the product.

Pharmacology
Oxybutynin chloride exerts direct antispasmodic effect on smooth muscle and inhibits the muscarinic action of acetylcholine on smooth muscle. It exhibits one-fifth of the anticholinergic activity of atropine on the rabbit detrusor muscle, but four to ten times the antispasmodic activity. No blocking effects occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).
Sources say the drug is absorbed within one hour and has an elimination half-life of 2 to 5 hours </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Acarbose and can you explain it in depth? [/INST] Acarbose (INN) is an anti-diabetic drug used to treat diabetes mellitus type 2 and, in some countries, prediabetes. It is a generic sold in Europe and China as Glucobay (Bayer AG), in North America as Precose (Bayer Pharmaceuticals), and in Canada as Prandase (Bayer AG). It is cheap and popular in China, but not in the U.S. One physician explains the use in the U.S. is limited because it is not potent enough to justify the side effects of diarrhea and flatulence. However, a recent large study concludes "acarbose is effective, safe and well tolerated in a large cohort of Asian patients with type 2 diabetes." A possible explanation for the differing opinions is an observation that acarbose is significantly more effective in patients eating a relatively high carbohydrate Eastern diet.It is a starch blocker, and inhibits alpha glucosidase, an intestinal enzyme that releases glucose from larger carbohydrates. It is composed of an acarviosin moiety with a maltose at the reducing terminus. Acarbose is also degraded to maltose and acarviosin by the glucosidase cyclomaltodextrinase from gut bacteria Lactobacillus plantarum.

Natural distribution
In nature, acarbose is synthesized by soil bacteria Actinoplanes sp through its precursor valienamine. And acarbose is also degraded by gut bacteria Lactobacillus plantarum and soil bacteria Thermus sp by acarbose degrading glucosidases.

Mechanism of action
Acarbose inhibits enzymes (glycoside hydrolases) needed to digest carbohydrates, specifically, alpha-glucosidase enzymes in the brush border of the small intestines, and pancreatic alpha-amylase. It locks up the enzymes by mimicking the transisition state of the substrate with its amine linkage. However, bacterial alpha-amylases from gut microbiome are able to degrade acarbose.Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, whereas the membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the small intestine. Inhibition of these enzyme systems reduces the rate of digestion of complex carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules. In diabetic patients, the short-term effect of these drug therapies is to decrease current blood glucose levels; the long-term effect is a reduction in HbA1c level. This reduction averages an absolute decrease of 0.7%, which is a decrease of about 10% in typical HbA1c values in diabetes studies.

Combination therapy
The combination of acarbose with metformin results in greater reductions of HbA1c, fasting blood glucose and post-prandial glucose than either agent alone.

Dosing
Since acarbose prevents the digestion of complex carbohydrates, the drug should be taken at the start of main meals (taken with first bite of meal). Moreover, the amount of complex carbohydrates in the meal will determine the effectiveness of acarbose in decreasing postprandial hyperglycemia.  Adults may take doses of 25 mg 3 times daily, increasing to 100 mg 3 times a day. However the maximum dose per day is 600 mg.

Side-effects
Since acarbose prevents the degradation of complex carbohydrates into glucose, some carbohydrate will remain in the intestine and be delivered to the colon.  In the colon, bacteria digest the complex carbohydrates, causing gastrointestinal side-effects such as flatulence (78% of patients) and diarrhea (14% of patients). Since these effects are dose-related, in general it is advised to start with a low dose and gradually increase the dose to the desired amount. One study found that gastrointestinal side effects decreased significantly (from 50% to 15%) over 24 weeks, even on constant dosing.If a patient using acarbose has a bout of hypoglycemia, the patient must eat something containing monosaccharides, such as glucose tablets or gel (GlucoBurst, Insta-Glucose, Glutose, Level One) and a doctor should be called. Because acarbose blocks the breakdown of table sugar and other complex sugars, fruit juice or starchy foods will not effectively reverse a hypoglycemic episode in a patient taking acarbose.Hepatitis has been reported with acarbose use.  It usually goes away when the medicine is stopped. Therefore, liver enzymes should be checked before and during use of this medicine.

Life extension
In studies conducted by three independent laboratories by the US National Institute on Agings intervention testing programme, acarbose was shown to extend the lifespan of female mice by 5% and of male mice by 22%.

Metabolism
Acarbose degradation is the unique feature of glycoside hydrolases in gut microbiota, acarbose degrading glucosidase, which hydrolyze acarbose into an acarviosine-glucose and glucose. Human enzymes do transform acarbose: the pancreatic alpha-amylase is able to perform a rearrangement reaction, moving the glucose unit in the "tail" maltose to the "head" of the molecule. Analog drugs with the "tail" glucose removed or flipped to an α(1-6) linkage resist this transformation.It has been reported that the maltogenic alpha-amylase from Thermus sp </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Dronabinol and can you explain it in depth? [/INST] The International Nonproprietary Name Dronabinol, also known as delta-9-tetrahydrocannabinol, or under the trade names Marinol, Syndros, Reduvo and Adversa, is a generic name for the molecule of delta-9-tetrahydrocannabinol in the pharmaceutical context. It has indications as an appetite stimulant, antiemetic, and sleep apnea reliever and is approved by the FDA as safe and effective for HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting only.Dronabinol is the principal psychoactive constituent enantiomer form, (−)-trans-Δ9-tetrahydrocannabinol, found in cannabis. Dronabinol does not include any other tetrahydrocannabinol (THC) isomers or any cannabidiol.

Medical uses
Appetite stimulant and anti-emetic
Dronabinol is used to stimulate appetite and therefore weight gain in patients with HIV/AIDS and cancer. It is also used to treat chemotherapy-induced nausea and vomiting.

Analgesic
Dronabinol demonstrated analgesic efficacy in a majority of studies in chronic pain, the data in acute pain is less conclusive.

Cannabis addiction
Dronabinol may be useful in treating cannabis addiction as it has been shown to reduce cannabis withdrawal symptoms and the subjective effects of marijuana.

Sleep apnea
Dronabinol demonstrates significant improvement in sleep apnea scores. Phase 2B clinical trials were completed in 2017 for FDA approval for this indication.

Overdose
A mild overdose of dronabinol presents drowsiness, dry-mouth, euphoria, and tachycardia; whereas a severe overdose presents lethargy, slurred speech, decreased motor coordination, and postural hypotension.

History
While dronabinol was initially approved by the United States Food and Drug Administration on May 31, 1985, it was not until May 13, 1986, the Drug Enforcement Administration (DEA) issued a Final Rule and Statement of Policy authorizing the "rescheduling of synthetic dronabinol in sesame oil and encapsulated in soft gelatin capsules from Schedule I to Schedule II" (DEA 51 FR 17476-78). This permitted medical use of Marinol, albeit with the severe restrictions associated with Schedule II status. For instance, refills of Marinol prescriptions were not permitted.
On April 29, 1991, the Commission on Narcotic Drugs, in accordance with article 2, paragraphs 5 and 6, of the Convention on Psychotropic Substances of 1971, decided that Δ9-tetrahydrocannabinol (also referred to as Δ9-THC) and its stereochemical variants should be transferred from Schedule I to Schedule II of that Convention. This released Δ9-THC from many of the restrictions imposed by the Convention, facilitating the its marketing as medication.An article published in the April–June 1998 issue of the Journal of Psychoactive Drugs found that "Healthcare professionals have detected no indication of scrip-chasing or doctor-shopping among the patients for whom they have prescribed dronabinol". The authors state that Marinol has a low potential for abuse.In 1999, in the United States, Marinol was rescheduled from Schedule II to III of the Controlled Substances Act, reflecting a finding that THC had a potential for abuse less than that of cocaine and heroin. This rescheduling constituted part of the argument for a 2002 petition for removal of cannabis from Schedule I of the Controlled Substances Act, in which petitioner Jon Gettman noted, "Cannabis is a natural source of dronabinol (THC), the ingredient of Marinol, a Schedule III drug. There are no grounds to schedule cannabis in a more restrictive schedule than Marinol".In 2003, the World Health Organization Expert Committee on Drug Dependence recommended transferring THC to Schedule IV of the Convention, citing its medical uses and low abuse potential. In 2019, the Committee recommended transferring Δ9-THC to Schedule I of the Single Convention on Narcotic Drugs of 1961, but its recommendations were rejected by the United Nations Commission on Narcotic Drugs.

Society and culture
Brand names
Dronabinol is marketed as Marinol and Syndros, a registered trademark of Solvay Pharmaceuticals. Dronabinol is also marketed, sold, and distributed by PAR Pharmaceutical Companies under the terms of a license and distribution agreement with SVC pharma LP, an affiliate of Rhodes Technologies for Marinol and Insys Pharmaceuticals for Syndros.   Dronabinol is available as a prescription drug (under Marinol and Syndros ) in several countries including the United States, Germany, South Africa and Australia </s>