<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 Naratriptan and can you explain it in depth? [/INST] Naratriptan (trade names include Amerge) is a triptan drug marketed by GlaxoSmithKline and is used for the treatment of migraine headaches. It is a selective 5-HT1 receptor subtype agonist.
It was patented in 1987 and approved for medical use in 1997.

Medical uses
Naratriptan is used for the treatment of the acute migraine attacks and the symptoms of migraine, including severe, throbbing headaches that sometimes are accompanied by nausea and sensitivity to sound or light.

Efficacy
A meta-analysis of 53 clinical trials has shown that all triptans are effective for treating migraine at marketed doses and that naratriptan, although less effective than sumatriptan and rizatriptan was more effective than placebo in reducing migraine symptoms at two hours and efficacy was demonstrated in almost two thirds of subjects after four hours of treatment.

Side effects
Side effects include: dizziness, drowsiness, tingling of the hands or feet, nausea, dry mouth and unsteadiness </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 Arsenic trioxide and can you explain it in depth? [/INST] Arsenic trioxide, sold under the brand name Trisenox among others, is an inorganic compound and medication. As an industrial chemical, whose major uses include in the manufacture of wood preservatives, pesticides, and glass. As a medication, it is used to treat a type of cancer known as acute promyelocytic leukemia. For this use it is given by injection into a vein.Common side effects include vomiting, diarrhea, swelling, shortness of breath, and headaches. Severe side effects may include APL differentiation syndrome and heart problems. Use during pregnancy or breastfeeding may harm the baby. Arsenic trioxide has the formula As2O3. Its mechanism in treating cancer is not entirely clear.Arsenic trioxide was approved for medical use in the United States in 2000. It is on the World Health Organizations List of Essential Medicines. Approximately 50,000 tonnes are produced a year. Due to its toxicity, a number of countries have regulations around its manufacture and sale.

Uses
Medical
Arsenic trioxide is used to treat a type of cancer known as acute promyelocytic leukemia (APL). It may be used both in cases that are unresponsive to other agents, such as all-trans retinoic acid (ATRA) or as part of the initial treatment of newly diagnosed cases. This initial treatment may include combination therapy of arsenic trioxide with all-trans retinoic acid (ATRA).Effectiveness appears similar to Realgar/Indigo naturalis, which can be taken by mouth and is less expensive but is less available.In the 1970s, Chinese researcher Zhang Tingdong and colleagues discovered this use. It was approved for leukemia treatment in the United States in 2000. University of Hong Kong developed a liquid form of arsenic trioxide that can be given by mouth. Organoarsenic compounds, such as feed additives (roxarsone) and medication (neosalvarsan), are derived from arsenic trioxide.

Manufacturing
Industrial uses include usage as a precursor to forestry products, in colorless glass production, and in electronics. Being the main compound of arsenic, the trioxide is the precursor to elemental arsenic, arsenic alloys, and arsenide semiconductors. Bulk arsenic-based compounds sodium arsenite and sodium cacodylate are derived from the trioxide.A variety of applications exploit arsenics toxicity, including the use of the oxide as a wood preservative. Copper arsenates, which are derived from arsenic trioxide, are used on a large scale as a wood preservative in the U.S. and Malaysia, but such materials are banned in many parts of the world. This practice remains controversial. In combination with copper(II) acetate, arsenic trioxide gives the vibrant pigment known as Paris green used in paints and as a rodenticide. This application has been discontinued.

Alternative medicine
Despite the well known toxicity of arsenic, arsenic trioxide was used in traditional Chinese medicine, where it is known as pi-shuang (Chinese: 砒霜; pinyin: pīshuāng; lit. arsenic frost). In homeopathy, it is called arsenicum album. Some discredited patent medicines, e.g., Fowlers solution, contained derivatives of arsenic oxide.

Toxicology
Arsenic trioxide is readily absorbed by the digestive system: toxic effects are also well-known upon inhalation or upon skin contact. Elimination is rapid at first (half-life of 1–2 days), by methylation to monomethylarsonic acid and dimethylarsinic acid, and excretion in the urine, but a certain amount (30–40% in the case of repeated exposure) is incorporated into the bones, the muscles, the skin, the hair and
the nails (all tissues rich in keratin) and eliminated over a period of weeks or months.
The first symptoms of acute arsenic poisoning by ingestion are digestive problems: vomiting, abdominal pains, diarrhea often accompanied by bleeding. Sub-lethal doses can lead to convulsions, cardiovascular problems, inflammation of the liver and kidneys and abnormalities in the coagulation of the blood. These are followed by the appearance of characteristic white lines (Mees lines) on the nails and by hair loss. Lower doses lead to liver and kidney problems and to changes in the pigmentation of the skin. Even dilute solutions of arsenic trioxide are dangerous on contact with the eyes.
The poisonous properties are well known and the subject of an extensive literature.Chronic arsenic poisoning is known as arsenicosis. This disorder affects workers in smelters, in populations whose drinking water contains high levels of arsenic (0.3–0.4 ppm), and in patients treated for long periods with arsenic-based pharmaceuticals. Similarly, studies on workers exposed in copper foundries in the U.S., Japan and Sweden indicate a risk of lung cancer 6–10 times higher for the most exposed workers compared with the general population. Long-term ingestion of arsenic trioxide either in drinking water or as a medical treatment can lead to skin cancer. Reproductive problems (high incidences of miscarriage, low birth weight, congenital deformations) have also been indicated in one study of women exposed to arsenic trioxide dust as employees or neighbours of a copper foundry.
In Austria, there lived the so-called "arsenic eaters of Styria", who ingested doses far beyond the lethal dose of arsenic trioxide without any apparent harm. Arsenic is thought to enable strenuous work at high altitudes, e.g. in the Alps.In the U.S., the OSHA 1910.1018 occupational permissible exposure limit for inorganic arsenic compounds in breathing zone air is 0.010 mg/m3.

Production and occurrence
Arsenic trioxide can be generated via routine processing of arsenic compounds including the oxidation (combustion) of arsenic and arsenic-containing minerals in air. Illustrative is the roasting of orpiment, a typical arsenic sulfide ore.

2 As2S3 + 9 O2 → 2 As2O3 + 6 SO2Most arsenic oxide is, however, obtained as a volatile by-product of the processing of other ores. For example, arsenopyrite, a common impurity in gold- and copper-containing ores, liberates arsenic trioxide upon heating in air. The processing of such minerals has led to numerous cases of poisonings. Only in China are arsenic ores intentionally mined.In the laboratory, it is prepared by hydrolysis of arsenic trichloride:
2 AsCl3 + 3 H2O → As2O3 + 6 HClAs2O3 occurs naturally as two minerals, arsenolite (cubic) and claudetite (monoclinic). Both are relatively rare secondary minerals found in oxidation zones of As-rich ore deposits. Sheets of As2O3 stand for part of structures of the recently discovered minerals lucabindiite, (K,NH4)As4O6(Cl,Br), and its sodium-analogue torrecillasite.

Properties and reactions
Arsenic trioxide is an amphoteric oxide, and its aqueous solutions are weakly acidic. Thus, it dissolves readily in alkaline solutions to give arsenites. It is less soluble in acids, although it will dissolve in hydrochloric acid.With anhydrous HF and HCl, it gives AsF3 and the trichloride:
As2O3 + 6 HX → 2 AsX3 + 3 H2O (X = F, Cl)Only with strong oxidizing agents such as ozone, hydrogen peroxide, and nitric acid does it yield arsenic pentoxide, As2O5 or its corresponding acid:
2 HNO3 + As2O3 + 2 H2O → 2 H3AsO4 + N2O3In terms of its resistance to oxidation, arsenic trioxide differs from phosphorus trioxide, which readily combusts to phosphorus pentoxide.
Reduction gives elemental arsenic or arsine (AsH3) depending on conditions:
As2O3 + 6 Zn + 12 HNO3 → 2 AsH3 + 6 Zn(NO3)2 + 3 H2OThis reaction is used in the Marsh test.

Structure
In the liquid and gas phase below 800 °C, arsenic trioxide has the formula As4O6 and is isostructural with P4O6. Above 800 °C As4O6 significantly dissociates into molecular As2O3, which adopts the same structure as N2O3. Three forms (polymorphs) are known in the solid state:  a high temperature ( > 110 °C) cubic As4O6, containing molecular As4O6, and two related polymeric forms. The polymers, which both crystallize as monoclinic crystals, feature sheets of pyramidal AsO3 units that share O atoms.

Society and culture
Environmental effects
Smelting and related ore processing often generate arsenic trioxide, which poses a risk to the environment </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 Asparaginase and can you explain it in depth? [/INST] Asparaginase is an enzyme that is used as a medication and in food manufacturing. As a medication, L-asparaginase is used to treat acute lymphoblastic leukemia (ALL). It is given by injection into a vein, muscle, or under the skin. A pegylated version is also available. In food manufacturing it is used to decrease acrylamide.Common side effects when used by injection include allergic reactions, pancreatitis, blood clotting problems, high blood sugar, kidney problems, and liver dysfunction. Use in pregnancy may harm the baby. As a food it is generally recognized as safe. Asparaginase works by breaking down the amino acid known as asparagine without which the cancer cells cannot make protein.The most common adverse reactions of asparaginase erwinia chrysanthemi (recombinant)-rywn include abnormal liver tests, nausea, musculoskeletal pain, fatigue, infection, headache, pyrexia, drug hypersensitivity, febrile neutropenia, decreased appetite, stomatitis, bleeding, and hyperglycemia.Asparaginase was approved for medical use in the United States in 1978. It is on the World Health Organizations List of Essential Medicines. It is often made from Escherichia coli (E. coli) or Erwinia chrysanthemi.

Uses
Asparaginases can be used for different industrial and pharmaceutical purposes.

Medical
E. coli strains are the main source of medical asparaginase. Branded formulations (with different chemical and pharmacological properties) available in 1998 include Asparaginase Medac, Ciderolase, and Oncaspar.: 5  (Crasnitin has been discontinued.) Spectrila is a recombinant E. coli asparaginase.Asparaginase produced by Dickeya dadantii (formerly called Erwinia chrysanthemi) instead is known as crisantaspase (BAN), and is available in the United Kingdom under the brand name Erwinase.One of the E. coli asparaginases marketed under the brand name Elspar for the treatment of acute lymphoblastic leukemia (ALL) is also used in some mast cell tumor protocols.On 30 June 2021, the U.S. Food and Drug Administration (FDA) approved asparaginase erwinia chrysanthemi (recombinant)-rywn) as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in people aged one month or older who have developed hypersensitivity to E. coli-derived asparaginase. The FDA granted the application for asparaginase erwinia chrysanthemi (recombinant)-rywn fast track and orphan drug designations.

Food manufacturing
The most common use of asparaginases is as a processing aid in the manufacture of food.  Asparaginases are used as a food processing aid to reduce the formation of acrylamide, a suspected carcinogen, in starchy food products such as snacks, biscuits and fried potato.

Side effects
The main side effect is an allergic or hypersensitivity reaction; anaphylaxis is a possibility. Additionally, it can also be associated with a coagulopathy as it decreases protein synthesis, including synthesis of coagulation factors (e.g. progressive isolated decrease of fibrinogen) and anticoagulant factor (generally antithrombin III; sometimes protein C & S as well), leading to bleeding or thrombotic events such as stroke. Bone marrow suppression is common but only mild to moderate, rarely reaches clinical significance and therapeutic consequences are rarely required.Other common side effects include pancreatitis. These side effects mainly attributes to the dual activity of L.Asparaginase as it can also hydrolysis L.Glutamine to Glutamic acid and ammonia.

Mechanism of action
As a food processing aid
Acrylamide is often formed in the cooking of starchy foods. During heating the amino acid asparagine, naturally present in starchy foods, undergoes a process called the Maillard reaction, which is responsible for giving baked or fried foods their brown color, crust, and toasted flavor. Suspected carcinogens such as acrylamide and some heterocyclic amines are also generated in the Maillard reaction. By adding asparaginase before baking or frying the food, asparagine is converted into another common amino acid, aspartic acid, and ammonium. As a result, asparagine cannot take part in the Maillard reaction, and therefore the formation of acrylamide is significantly reduced. Complete acrylamide removal is probably not possible due to other, minor asparagine-independent formation pathways.As a food processing aid, asparaginases can effectively reduce the level of acrylamide in a range of starchy foods without changing the taste and appearance of the end product.

As a drug
The rationale behind asparaginase is that it takes advantage of the fact that acute lymphoblastic leukemia cells and some other suspected tumor cells are unable to synthesize the non-essential amino acid asparagine, whereas normal cells are able to make their own asparagine; thus leukemic cells require high amount of asparagine. These leukemic cells depend on circulating asparagine. Asparaginase, however, catalyzes the conversion of L-asparagine to aspartic acid and ammonia. This deprives the leukemic cell of circulating asparagine, which leads to cell death.

Enzyme regulation
Type I L-asparaginase protein may use the morpheein model of allosteric regulation.

Cost
Normal asparaginase costs less than its pegylated version, pegaspargase.  However, because it doesnt stay as long in the body, the injections need to be more frequent, with the result that total cost of treatment may be lower for the pegylated version.

History
The discovery and development of asparaginase as an anti-cancer drug began in 1953, when scientists first observed that lymphomas in rat and mice regressed after treatment with guinea pig serum. Later it was found out that it is not the serum itself which provoke the tumour regression, but rather the enzyme asparaginase.After researchers comparing different kinds of asparaginases, the one derived from Escherichia coli and Erwinia chrysanthemi turned out to have the best anti-cancer ability </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 Daridorexant and can you explain it in depth? [/INST] Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia. Daridorexant is taken by mouth.Side effects of daridorexant include headache, somnolence, and fatigue. The medication is a dual orexin receptor antagonist (DORA). It acts as a selective dual antagonist of the orexin receptors OX1 and OX2. Daridorexant has a relatively short elimination half-life of 8 hours and a time to peak of about 1 to 2 hours. It is not a benzodiazepine or Z-drug and does not interact with GABA receptors, instead having a distinct mechanism of action.Daridorexant was approved for medical use in the United States in January 2022 and became available in May 2022. It was approved in the European Union in April 2022, and is the first orexin receptor antagonist to become available in European Union. The medication is a schedule IV controlled substance in the United States and may have a modest potential for misuse.

Medical uses
Daridorexant is indicated for the treatment of adults with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. The medication has been found to significantly improve latency to persistent sleep (LPS), wake after sleep onset (WASO), and subjective total sleep time (TST) in regulatory clinical trials. At doses of 25 to 50 mg and in terms of treatment–placebo difference, it reduces LPS by 6 to 12 minutes, reduces WASO by 10 to 23 minutes, and increases subjective TST by 10 to 22 minutes. Daridorexant has also been found to improve daytime functioning at a dose of 50 mg but not at 25 mg. It is the first insomnia medication to have been evaluated and shown effectiveness in improving not only nighttime symptoms but also daytime functioning.Network meta-analyses have assessed the sleep-promoting effects of orexin receptor antagonists and have compared them between one another as well as to other sleep aids including benzodiazepines, Z-drugs, antihistamines, sedative antidepressants (e.g., trazodone, doxepin, amitriptyline, mirtazapine), and melatonin receptor agonists. A major systematic review and network meta-analysis of insomnia medications published in 2022 found that daridorexant had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4 weeks of 0.23 (95% CI –0.01 to 0.48). This was similar to but numerically lower than the effect sizes at 4 weeks for suvorexant (SMD 0.31, 95% CI 0.01 to 0.62) and lemborexant (SMD 0.36, 95% CI 0.08 to 0.63). Benzodiazepines and Z-drugs generally showed larger effect sizes than orexin receptor antagonists (e.g., SMDs of 0.45 to 0.83). The review concluded on the basis of daridorexants small effect size that it did not show an overall material benefit in the treatment of insomnia. Conversely, it concluded that lemborexant—as well as the Z-drug eszopiclone—had the best profiles overall in terms of efficacy, tolerability, and acceptability among all of the assessed insomnia medications.Orexin receptor antagonists are not used as first-line treatments for insomnia due to their costs and concerns about possible misuse liability.

Available forms
Daridorexant is available in the form of 25 and 50 mg oral tablets. It is provided as the salt daridorexant hydrochloride, with each tablet containing 27 or 54 mg of this substance (equivalent to 25 or 50 mg daridorexant).

Contraindications
Daridorexant is contraindicated in people with narcolepsy. It is not recommended in people with severe hepatic impairment, whereas a lower maximum dose is recommended in people with moderate hepatic impairment. Concomitant use of daridorexant with strong CYP3A4 inhibitors and moderate to strong CYP3A4 inducers is not recommended and should be avoided due to unfavorable modification of daridorexant exposure.

Side effects
Side effects of daridorexant include headache (6% at 25 mg vs. 7% at 50 mg vs. 5% for placebo), somnolence or fatigue (includes somnolence, sedation, fatigue, hypersomnia, and lethargy) (6% at 25 mg vs. 5% at 50 mg vs. 4% for placebo), dizziness (2% at 25 mg vs. 3% at 50 mg vs. 2% for placebo), and nausea (0% at 25 mg vs. 3% at 50 mg vs. 2% for placebo). No residual effects have been found after administration of 25 mg daridorexant in the evening to either young or elderly individuals. However, daridorexant may cause next-morning driving impairment at the start of treatment or in some individuals. Orexin receptor antagonists like daridorexant may have less or no propensity for causing tolerance compared to other sedatives and hypnotics based on animal studies. Daridorexant did not produce signs of withdrawal or dependence upon discontinuation in animal studies and clinical trials, and orexin receptor antagonists are not associated with rebound insomnia. Loss of sleep-promoting effectiveness occurs rapidly upon discontinuation of daridorexant. Preclinical research has suggested that orexin antagonists may reduce appetite, but daridorexant and other orexin antagonists have not been associated with weight loss in rigorous clinical trials.Orexin receptor antagonists can affect the reward system and produce drug-liking responses in humans. Daridorexant at a dose of 50 mg (the maximum recommended dose) showed significantly greater drug liking than placebo but significantly less drug liking than zolpidem (30 mg) and suvorexant (150 mg) in recreational sedative drug users. At higher doses of 100 and 150 mg (greater than the recommended maximum dose), drug liking with daridorexant was similar to that with zolpidem (30 mg) and suvorexant (150 mg). In other studies, suvorexant showed similar drug liking compared to zolpidem but lower misuse potential on other measures (e.g., overall rate of misuse potential adverse events of 58% for zolpidem and 31% for suvorexant in recreational drug users). No reports indicative of misuse liability were observed in large clinical trials with daridorexant, although these studies excluded participants with history of drug or alcohol misuse.

Overdose
There is limited clinical experience with overdose of daridorexant. Overdose of the medication at a dose of up to four times the maximum recommended dose may result in adverse effects including somnolence, muscle weakness, catalepsy-like symptoms, sleep paralysis, attention disturbances, fatigue, headache, and constipation. There is no specific antidote to overdose of daridorexant.

Interactions
CYP3A4 inhibitors like ranitidine and diltiazem and CYP3A4 inducers like efavirenz can increase and decrease exposure to daridorexant, respectively. Concomitant use of daridorexant with strong CYP3A4 inhibitors or moderate or strong CYP3A4 inducers should be avoided, while it is recommended that the maximum dose of daridorexant be limited with moderate CYP3A4 inhibitors. Gastric pH modifiers like famotidine can decrease peak levels of daridorexant without affecting total exposure. Alcohol and selective serotonin reuptake inhibitors (SSRIs) like citalopram have not shown significant pharmacokinetic interactions with daridorexant. Coadministration of daridorexant with other sedatives like benzodiazepines, opioids, tricyclic antidepressants, and alcohol may increase the risk of central nervous system depression and daytime impairment. Daridorexant has not been found to significantly influence the pharmacokinetics of other drugs including midazolam (CYP3A4 substrate), rosuvastatin (BCRP substrate), and the SSRI citalopram.

Pharmacology
Pharmacodynamics
Daridorexant acts as a selective dual antagonist of the orexin (hypocretin) receptors OX1 and OX2. The affinities (Ki) of daridorexant for the orexin receptors are 0.47 nM for the OX1 receptor and 0.93 nM for the OX2 receptor. Its Kb values for the human orexin receptors have been reported to be 0.5 nM for the OX1 receptor and 0.8 nM for the OX2 receptor. Hence, daridorexant is approximately equipotent in its antagonism of the orexin receptors. Daridorexant is selective for the orexin receptors over many other targets. In contrast to certain other sedatives and hypnotics, daridorexant is not a benzodiazepine or Z-drug and does not interact with GABA receptors.

Mechanism of action
The endogenous orexin neuropeptides, orexin A and orexin B, are involved in the regulation of sleep–wake cycles and act to promote wakefulness. Deficiency of orexin signaling is thought to be the primary cause of the sleep disorder narcolepsy. Disturbances in orexin signaling may also be involved in insomnia. Research suggests that orexin signaling may change with age, and this has been implicated in age-related sleep disturbances. By blocking the actions of orexins and modulating sleep–wake cycles, orexin receptor antagonists like daridorexant reduce wakefulness and improve sleep. The sleep-promoting effects of dual orexin receptor antagonists are thought to be mediated specifically by blockade of the OX2 receptor in the lateral hypothalamus. Although narcoleptic symptoms were a theoretical concern during the development of orexin receptor antagonists, this has not been observed in clinical trials of these agents.

Pharmacokinetics
Absorption
The absolute bioavailability of daridorexant is 62%. It reaches peak concentrations within 1 to 2 hours following a dose. Food prolonged the time to peak by 1.3 hours and decreased the peak concentrations by 16%, but did not affect area-under-the-curve concentrations.

Distribution
The volume of distribution of daridorexant is 31 L. Its plasma protein binding is 99.7%. The plasma-to-blood ratio of daridorexant is 0.64. Daridorexant effectively crosses the blood–brain barrier in animals.

Metabolism
Daridorexant is extensively metabolized primarily by CYP3A4 (89%). Other cytochrome P450 enzymes contribute individually to less than 3% of the clearance of daridorexant.

Elimination
Daridorexant is eliminated primarily by feces (57%) then by urine (28%). It is excreted mainly in the form of metabolites, with only trace amounts of the parent compound identified.The medication has an elimination half-life of about 8 hours or of 6 to 10 hours. Its half-life is shorter than that of other orexin receptor antagonists such as suvorexant (12 hours) and lemborexant (~18–55 hours). The relatively short half-life of daridorexant may allow for reduced daytime sedation. The duration of action of daridorexant in terms of sedative effects is approximately 8 hours with a 50 mg dose.

Chemistry
Daridorexant is a small-molecule compound. The chemical name of daridorexant is (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone. Its molecular formula is C23H23N6O2Cl and its molecular weight is 450.93 g/mol (or 487.38 g/mol for the hydrochloride). Daridorexant hydrochloride is a white to light yellowish powder and is very slightly soluble in water.

History
Daridorexant was patented in 2013 and was first described in the scientific literature in 2017. It was approved for medical use in the United States in January 2022 and became available in this country in May 2022. On 24 February 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Quviviq, intended for the treatment of insomnia. On 29 April 2022, daridorexant was authorized for use in the European Union. It was the first orexin receptor antagonist to become available for use in the European Union. (The earlier orexin receptor antagonists suvorexant and lemborexant are not available in the European Union.) Regulatory review is also ongoing in Canada and Switzerland and is planned for the United Kingdom. Daridorexant was originated by Actelion Pharmaceuticals and was further developed by Idorsia.

Society and culture
Legal status
Daridorexant is a schedule IV controlled substance under the Controlled Substances Act in the United States.Daridorexant (Quviviq) was approved for medical use in the European Union in April 2022.

References
Further reading
"Application Number: 214985Orig1s000. Integrated Review. Daridorexant (Quviviq) for Insomnia" (PDF) </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 Japanese encephalitis vaccine and can you explain it in depth? [/INST] Japanese encephalitis vaccine is a vaccine that protects against Japanese encephalitis. The vaccines are more than 90% effective. The duration of protection with the vaccine is not clear but its effectiveness appears to decrease over time. Doses are given either by injection into a muscle or just under the skin.It is recommended as part of routine immunizations in countries where the disease is a problem. One or two doses are given depending on the version of the vaccine. Extra doses are not typically needed in areas where the disease is common. In those with HIV/AIDS or those who are pregnant an inactivated vaccine should be used. Immunization of travellers who plan to spend time outdoors in areas where the disease is common is recommended.The vaccines are relatively safe. Pain and redness may occur at the site of injection. As of 2015, 15 different vaccines are available: some are based on recombinant DNA techniques, others weakened virus, and others inactivated virus.The Japanese encephalitis vaccines first became available in the 1930s. It is on the World Health Organizations List of Essential Medicines.

Efficacy
Randomized control trials on JE-VAX have shown that a two-dose schedule provides protection for one year.

History
Japanese encephalitis vaccines first became available in the 1930s. One of them was an inactivated mouse brain-derived vaccine (the Nakayama and/or Beijing-1 strain), made by BIKEN and marketed by Sanofi Pasteur as JE-VAX, until production ceased in 2005 </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 Testosterone (medication) and can you explain it in depth? [/INST] Testosterone (T) is a medication and naturally occurring steroid hormone. It is used to treat male hypogonadism, gender dysphoria, and certain types of breast cancer. It may also be used to increase athletic ability in the form of doping. It is unclear if the use of testosterone for low levels due to aging is beneficial or harmful. Testosterone can be used as a gel or patch that is applied to the skin, injection into a muscle, tablet that is placed in the cheek, or tablet that is taken by mouth.Common side effects of testosterone include acne, swelling, and breast enlargement in men. Serious side effects may include liver toxicity, heart disease, and behavioral changes. Women and children who are exposed may develop masculinization. It is recommended that individuals with prostate cancer not use the medication. It can cause harm to the baby if used during pregnancy or breastfeeding. Testosterone is in the androgen family of medications.Testosterone was first isolated in 1935, and approved for medical use in 1939. Rates of use have increased three times in the United States between 2001 and 2011. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 126th most commonly prescribed medication in the United States, with more than 5 million prescriptions.

Medical uses
The primary use of testosterone is the treatment of males with too little or no natural testosterone production, also termed hypogonadism or hypoandrogenism (androgen deficiency). This treatment is referred to as hormone replacement therapy (HRT), or alternatively, and more specifically, as testosterone replacement therapy (TRT) or androgen replacement therapy (ART). It is used to maintain serum testosterone levels in the normal male range. Decline of testosterone production with age has led to interest in testosterone supplementation.A 2020 guidelines from the American College of Physicians support the discussion of testosterone in adult men with age-related low levels of testosterone who have sexual dysfunction. They recommend yearly evaluation regarding possible improvement and, if none, to discontinue testosterone; physicians should consider intramuscular treatments, rather than transdermal treatments, due to costs and since the effectiveness and harm of either method is similar. Testosterone treatment for reasons other than possible improvement of sexual dysfunction may not be recommended.

Deficiency
Testosterone deficiency (also termed hypotestosteronism or hypotestosteronemia) is an abnormally low testosterone production. It may occur because of testicular dysfunction (primary hypogonadism) or hypothalamic–pituitary dysfunction (secondary hypogonadism) and may be congenital or acquired.

Low levels due to aging
Testosterone levels may decline gradually with age. The United States Food and Drug Administration (FDA) stated in 2015 that neither the benefits nor the safety of testosterone supplement have been established for low testosterone levels due to aging. The FDA has required that labels on testosterone include warnings about increased risk of heart attacks and stroke.

Transgender men
To take advantage of its virilizing effects, testosterone is administered to transgender men and other transmasculine individuals as part of masculinizing hormone therapy, titrated to clinical effect with a "target level" of the average males testosterone level.

Women
Testosterone therapy is effective in the short-term for the treatment of hypoactive sexual desire disorder (HSDD) in women. However, its long-term safety is unclear. Because of a lack data to support its efficacy and safety, the Endocrine Society recommends against the routine use of testosterone in women to treat low androgen levels due to hypopituitarism, adrenal insufficiency, surgical removal of the ovaries, high-dose corticosteroid therapy, or other causes. Similarly, because of a lack of data to support its efficacy and safety, the Endocrine Society recommends against the use of testosterone in women to improve general well-being, to treat infertility, sexual dysfunction due to causes other than HSDD, or to improve cognitive, cardiovascular, metabolic, and/or bone health.A 2014 systematic review and meta-analysis of 35 studies consisting of over 5,000 postmenopausal women with normal adrenal gland function found that testosterone therapy was associated with significant improvement in a variety of domains of sexual function. These domains included frequency of sexual activity, orgasm, arousal, and sexual satisfaction, among others. Women who were menopausal due to ovariectomy showed significantly greater improvement in sexual function with testosterone relative to those who had normal menopause. In addition to beneficial effects on sexual function, testosterone was associated with unfavorable changes in blood lipids. These included decreased levels of total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol, and increased levels of low-density lipoprotein (LDL) cholesterol. However, the changes were small in magnitude, and the long-term significance in relation to cardiovascular outcomes is uncertain. The changes were more pronounced with oral testosterone undecanoate than with parenteral routes, such as transdermal testosterone. Testosterone showed no significant effect on depressed mood anxiety, bone mineral density (BMD), or anthropomorphic measures like body weight or body mass index. Conversely, it was associated with a significant incidence of androgenic side effects, including acne and hirsutism (excessive facial/body hair growth). Other androgenic side effects, such as weight gain, pattern hair loss, and voice deepening, were also reported in some trials, but were excluded from analyses due to insufficient data. The overall quality of the evidence was rated as low and was considered to be inconclusive in certain areas, for instance on long-term safety.A subsequent 2017 systematic review and meta-analysis of studies including over 3,000 postmenopausal women with HSDD similarly found that short-term transdermal testosterone therapy was effective in improving multiple domains of sexual function. Androgenic adverse effects such as acne and hirsutism were significantly greater in incidence with testosterone therapy, whereas no significant differences in "increase in facial hair, alopecia, voice deepening, urinary symptoms, breast pain, headache, site reaction to the patch, total adverse events, serious adverse events, reasons for withdrawal from the study, and the number of women who completed the study" were seen relative to controls.Although testosterone has been found to be effective at improving sexual function in postmenopausal women, the doses employed have been supraphysiological. In contrast to these high doses, there is little support for the notion that testosterone is a critical hormone for sexual desire and function in women under normal physiological circumstances. Low doses of testosterone resulting in physiological levels of testosterone (<50 ng/dL) have not been found to significantly increase sexual desire or function in women in most studies. Similarly, there appears to be little or no relationship between total or free testosterone levels in the normal physiological range and sexual desire in premenopausal women. Only high doses of testosterone resulting in supraphysiological levels of testosterone (>50 ng/dL) significantly increase sexual desire in women, with levels of testosterone of 80 to 150 ng/dL "slightly" increasing sex drive. In accordance, men experience sexual dysfunction at testosterone levels of below 300 ng/dL, and men that have levels of testosterone of approximately 200 ng/dL frequently experience such problems. The high doses of testosterone required to increase sexual desire in women may have a significant risk of masculinization with long-term therapy. For this reason, and due to the unknown health effects and safety of testosterone therapy, its use may be inappropriate. In 2003, the FDA rejected Intrinsa, a 300 µg/day testosterone patch for the treatment of sexual dysfunction in postmenopausal women. The reasons cited were limited efficacy (about one additional sexually satisfying event per month), concerns about safety and potential adverse effects with long-term therapy, and concerns about inappropriate off-label use. It appears that in women, rather than testosterone, estradiol may be the most important hormone involved in sexual desire, although data on the clinical use of estradiol to increase sexual desire in women is limited.There are no testosterone products approved for use in women in the United States and many other countries. There are approved testosterone products for women in Australia (where it is considered a drug of dependence, medicines that are subject to misuse and trafficking.) and some European countries. Testosterone pellet implants are approved for use in postmenopausal women in the United Kingdom. Testosterone products for men can be used off-label in women in the United States. Alternatively, testosterone products for women are available from compounding pharmacies in the United States, although such products are unregulated and manufacturing quality is not ensured.

Available forms
Testosterone has been marketed for use by oral, sublingual, buccal, intranasal, transdermal (patches), topical (gels), intramuscular (injection), and subcutaneous (implant administration. It is provided unmodified and as a testosterone ester such as testosterone cypionate, testosterone enanthate, testosterone propionate, or testosterone undecanoate, which act as prodrugs of testosterone. The most common route of administration for testosterone is by intramuscular injection. However, it has been reported that AndroGel, a transdermal gel formulation of testosterone, has become the most popular form of testosterone in androgen replacement therapy for hypogonadism in the United States.

Non-medical use
Athletics
Testosterone is used as a form of doping among athletes in order to improve performance. Testosterone is classified as an anabolic agent and is on the World Anti-Doping Agency (WADA) List of Prohibited Substances and Methods. Hormone supplements cause the endocrine system to adjust its production and lower the natural production of the hormone, so when supplements are discontinued, natural hormone production is lower than it was originally.Anabolic–androgenic steroids (AAS), including testosterone and its esters, have also been taken to enhance muscle development, strength, or endurance. They do so directly by increasing the muscles protein synthesis. As a result, muscle fibers become larger and repair faster than the average persons.After a series of scandals and publicity in the 1980s (such as Ben Johnsons improved performance at the 1988 Summer Olympics), prohibitions of AAS use were renewed or strengthened by many sports organizations. Testosterone and other AAS were designated a "controlled substance" by the United States Congress in 1990, with the Anabolic Steroid Control Act. Their use is seen as an issue in modern sport, particularly given the lengths to which athletes and professional laboratories go to in trying to conceal such use from sports regulators. Steroid use once again came into the spotlight as a result of Canadian professional wrestler Chris Benoits double murder-suicide in 2007; however, there is no evidence implicating steroid use as a factor in the incident.Some female athletes may have naturally higher levels of testosterone than others, and may be asked to consent to sex verification and either surgery or drugs to decrease testosterone levels. This has proven contentious, with the Court of Arbitration for Sport suspending the IAAF policy due to insufficient evidence of a link between high androgen levels and improved athletic performance.

Detection of abuse
A number of methods for detecting testosterone use by athletes have been employed, most based on a urine test. These include the testosterone/epitestosterone ratio (normally less than 6), the testosterone/luteinizing hormone ratio and the carbon-13/carbon-12 ratio (pharmaceutical testosterone contains less carbon-13 than endogenous testosterone). In some testing programs, an individuals own historical results may serve as a reference interval for interpretation of a suspicious finding. Another approach being investigated is the detection of the administered form of testosterone, usually an ester, in hair.

Contraindications
Absolute contraindications of testosterone include prostate cancer, elevated hematocrit (>54%), uncontrolled congestive heart failure, various other cardiovascular diseases, and uncontrolled obstructive sleep apnea. Breast cancer is said by some sources to be an absolute contraindication of testosterone therapy, but androgens including testosterone have also actually been used to treat breast cancer. Relative contraindications of testosterone include elevated prostate-specific antigen (PSA) in men with a high risk of prostate cancer due to ethnicity or family history, severe lower urinary tract symptoms, and elevated hematocrit (>50%).

Side effects
Adverse effects may also include minor side effects such as oily skin, acne, and seborrhea, as well as loss of scalp hair, which may be prevented or reduced with 5α-reductase inhibitors. In women, testosterone can produce hirsutism (excessive facial/body hair growth), deepening of the voice, and other signs of virilization. Exogenous testosterone may cause suppression of spermatogenesis in men, leading to, in some cases, reversible infertility. Gynecomastia and breast tenderness may occur with high dosages of testosterone due to peripheral conversion of testosterone by aromatase into excessive amounts of the estrogen estradiol. Testosterone treatment, particularly in high dosages, can also be associated with mood changes, increased aggression, increased sex drive, spontaneous erections, and nocturnal emissions.Other side effects include increased hematocrit, which can require venipuncture in order to treat, and exacerbation of sleep apnea.The FDA stated in 2015 that neither the benefits nor the safety of testosterone have been established for low testosterone levels due to aging. The FDA has required that testosterone pharmaceutical labels include warning information about the possibility of an increased risk of heart attacks and stroke. They have also required the label include concerns about abuse and dependence.Injectable forms of testosterone can cause a lung problem called pulmonary oil microembolism (POME).  Symptoms of POME include cough, shortness of breath, tightening of the throat, chest pain, sweating, dizziness, and fainting. A postmarketing analysis by the manufacturer of Aveed (testosterone undeconate injection) found that POME occurred at a rate of less than 1% per injection per year for Aveed.

Long-term adverse effects
Cardiovascular disease
Adverse effects of testosterone supplementation may include increased cardiovascular events (including strokes and heart attacks) and deaths based on three peer-reviewed studies involving men taking testosterone replacement. In addition, an increase of 30% in deaths and heart attacks in older men has been reported. Due to an increased incidence of adverse cardiovascular events compared to a placebo group, a Testosterone in Older Men with Mobility Limitations (TOM) trial (a National Institute of Aging randomized trial) was halted early by the Data Safety and Monitoring Committee. On January 31, 2014, reports of strokes, heart attacks, and deaths in men taking FDA-approved testosterone-replacement led the FDA to announce that it would be investigating the issue. Later, in September 2014, the FDA announced, as a result of the "potential for adverse cardiovascular outcomes", a review of the appropriateness and safety of Testosterone Replacement Therapy (TRT). The FDA now requires warnings in the drug labeling of all approved testosterone products regarding deep vein thrombosis and pulmonary embolism.Up to the year 2010, studies had not shown any effect on the risk of death, prostate cancer or cardiovascular disease; more recent studies, however, do raise concerns. A 2013 study, published in the Journal of the American Medical Association, reported "the use of testosterone therapy was significantly associated with increased risk of adverse outcomes." The study began after a previous, randomized, clinical trial of testosterone therapy in men was stopped prematurely "due to adverse cardiovascular events raising concerns about testosterone therapy safety."

Prostate cancer
Testosterone in the presence of a slow-growing prostate cancer is assumed to increase its growth rate. However, the association between testosterone supplementation and the development of prostate cancer is unproven. Nevertheless, physicians are cautioned about the cancer risk associated with testosterone supplementation.Testosterone may accelerate pre-existing prostate cancer growth in individuals who have undergone androgen deprivation. It is recommended that physicians screen for prostate cancer with a digital rectal exam and prostate-specific antigen (PSA) level before starting therapy, and monitor PSA and hematocrit levels closely during therapy.Ethnic groups have different rates of prostate cancer. Differences in sex hormones, including testosterone, have been suggested as an explanation for these differences. This apparent paradox can be resolved by noting that prostate cancer is very common. In autopsies, 80% of 80-year-old men have prostate cancer.

Pregnancy and breastfeeding
Testosterone is contraindicated in pregnancy and not recommended during breastfeeding. Androgens like testosterone are teratogens and are known to cause fetal harm, such as producing virilization and ambiguous genitalia.

Interactions
5α-Reductase inhibitors
5α-Reductase inhibitors like finasteride and dutasteride can slightly increase circulating levels of testosterone by inhibiting its metabolism. However, these drugs do this via prevention of the conversion of testosterone into its more potent metabolite dihydrotestosterone (DHT), and this results in dramatically reduced circulating levels of DHT (which circulates at much lower relative concentrations). In addition, local levels of DHT in so-called androgenic (5α-reductase-expressing) tissues are also markedly reduced, and this can have a strong impact on certain effects of testosterone. For instance, growth of body and facial hair and penile growth induced by testosterone may be inhibited by 5α-reductase inhibitors, and this could be considered undesirable in the context of, for instance, puberty induction. On the other hand, 5α-reductase inhibitors may prevent or reduce adverse androgenic side effects of testosterone like scalp hair loss, oily skin, acne, and seborrhea. In addition to the prevention of testosterone conversion into DHT, 5α-reductase inhibitors also prevent the formation of neurosteroids like 3α-androstanediol from testosterone, and this may have neuropsychiatric consequences in some men.

Aromatase inhibitors
Aromatase inhibitors like anastrozole prevent the conversion of testosterone into estradiol by aromatase. As only a very small fraction of testosterone is converted into estradiol, this does not affect testosterone levels, but it can prevent estrogenic side effects like gynecomastia that can occur when testosterone is administered at relatively high dosages. However, estradiol exerts negative feedback on the hypothalamic–pituitary–gonadal axis and, for this reason, prevention of its formation can reduce this feedback and disinhibit gonadal production of testosterone, which in turn can increase levels of endogenous testosterone. Testosterone therapy is sometimes combined with an aromatase inhibitor for men with secondary hypogonadism who wish to conceive children with their partners.

Cytochrome P450 inhibitors
Inhibitors and inducers of cytochrome P450 enzymes like CYP3A4 have been associated with little or no effect on circulating testosterone levels.

Antiandrogens and estrogens
Antiandrogens like cyproterone acetate, spironolactone, and bicalutamide can block the androgenic and anabolic effects of testosterone. Estrogens can reduce the effects of testosterone by increasing the hepatic production and in turn circulating levels of sex hormone-binding globulin (SHBG), a carrier protein that binds to and occupies androgens like testosterone and DHT, and thereby reducing free concentrations of these androgens.

Pharmacology
Pharmacodynamics
Testosterone is a high affinity ligand for and agonist of the nuclear androgen receptor (AR). In addition, testosterone binds to and activates membrane androgen receptors (mARs) such as GPRC6A and ZIP9. Testosterone is also potentiated via transformation by 5α-reductase into the more potent androgen DHT in so-called androgenic tissues such as the prostate gland, seminal vesicles, skin, and hair follicles. In contrast to the case of testosterone, such potentiation occurs to a reduced extent or not at all with most synthetic AAS (as well as with DHT), and this is primarily responsible for the dissociation of anabolic and androgenic effects with these agents. In addition to DHT, testosterone is converted at a rate of approximately 0.3% into the estrogen estradiol via aromatase. This occurs in many tissues, especially adipose tissue, the liver, and the brain, but primarily in adipose tissue. Testosterone, after conversion into DHT, is also metabolized into 3α-androstanediol, a neurosteroid and potent positive allosteric modulator of the GABAA receptor, and 3β-androstanediol, a potent and preferential agonist of the ERβ. These metabolites, along with estradiol, may be involved in a number of the effects of testosterone in the brain, including its antidepressant, anxiolytic, stress-relieving, rewarding, and pro-sexual effects.

Effects in the body and brain
The ARs are expressed widely throughout the body, including in the penis, testicles, epididymides, prostate gland, seminal vesicles, fat, skin, bone, bone marrow, muscle, larynx, heart, liver, kidneys, pituitary gland, hypothalamus, and elsewhere throughout the brain. Through activation of the ARs (as well as the mARs), testosterone has many effects, including the following:
Promotes growth, function, and maintenance of the prostate gland, seminal vesicles, and penis during puberty and thereafter
Promotes growth and maintenance of muscles, particularly of the upper body
Causes subcutaneous fat to be deposited in a masculine pattern and decreases overall body fat
Suppresses breast development induced by estrogens, but can also still produce gynecomastia via excessive conversion into estradiol if levels are too high
Maintains skin health, integrity, appearance, and hydration and slows the rate of aging of the skin, but can also cause oily skin, acne, and seborrhea
Promotes the growth of facial and body hair, but can also cause scalp hair loss and hirsutism
Contributes to bone growth and causes broadening of the shoulders at puberty
Modulates liver protein synthesis, such as the production of sex hormone-binding globulin and many other proteins
Increases production of erythropoietin in the kidneys and thereby stimulates red blood cell production in bone marrow and elevates hematocrit
Exerts negative feedback on the hypothalamic–pituitary–gonadal axis by suppressing the secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland, thereby inhibiting gonadal sex hormone production as well as spermatogenesis and fertility
Regulates the vasomotor system and body temperature via the hypothalamus, thereby preventing hot flashes
Modulates brain function, with effects on mood, emotionality, aggression, and sexuality, as well as cognition and memory
Increases sex drive and erectile capacity and causes spontaneous erections and nocturnal emissions
Increases the risk of benign prostatic hyperplasia and prostate cancer and accelerates the progression of prostate cancer
Decreases breast proliferation and the risk of breast cancer

Pharmacokinetics
Testosterone can be taken by a variety of different routes of administration. These include oral, buccal, sublingual, intranasal, transdermal (gels, creams, patches), rectal suppositories), by intramuscular or subcutaneous injection (in oil or aqueous), and as a subcutaneous implant. The pharmacokinetics of testosterone, including its bioavailability, circulating testosterone levels, metabolism, biological half-life, and other parameters, differ by route of administration.

Chemistry
Testosterone is a naturally occurring androstane steroid and is also known by the chemical name androst-4-en-17β-ol-3-one. It has a double bond between the C4 and C5 positions (making it an androstene), a ketone group at the C3 position, and a hydroxyl (alcohol) group at the C17β position.

Derivatives
Testosterone esters are substituted at the C17β position with a lipophilic fatty acid ester moiety of varying chain length. Major testosterone esters include testosterone cypionate, testosterone enanthate, testosterone propionate, and testosterone undecanoate. A C17β ether prodrug of testosterone, cloxotestosterone acetate, has also been marketed, although it is little known and is used very rarely or no longer. Another C17β ether prodrug of testosterone, silandrone, also exists but was never marketed, and is notable in that it is orally active. In addition to ester and ether prodrugs, androgen prohormones or precursors of testosterone, such as dehydroepiandrosterone (DHEA), androstenediol, and androstenedione, exist as well, and convert into testosterone to variable extents upon oral ingestion. Unlike testosterone ester and ether prodrugs however, these prohormones are only weakly androgenic/anabolic.All synthetic AAS are derivatives of testosterone. Prominent examples include nandrolone (19-nortestosterone), metandienone (17α-methyl-δ1-testosterone), and stanozolol (a 17α-alkylated derivative of DHT). Unlike testosterone, AAS that are 17α-alkylated, like metandienone and stanozolol, are orally active. This is due to steric hindrance of C17β-position metabolism during the first-pass through the liver. In contrast, most AAS that are not 17α-alkylated, like nandrolone, are not active orally, and must instead be administered via intramuscular injection. This is almost always in ester form; for instance, in the case of nandrolone, as nandrolone decanoate or nandrolone phenylpropionate.

History
Testosterone was first isolated and synthesized in 1935. Shortly thereafter, in 1937, testosterone first became commercially available as a pharmaceutical drug in the form of pellets and then in ester form for intramuscular injection as the relatively short-acting testosterone propionate. Methyltestosterone, one of the first synthetic AAS and orally active androgens, was introduced in 1935, but was associated with hepatotoxicity and eventually became largely medically obsolete. In the mid-1950s, the longer-acting testosterone esters testosterone enanthate and testosterone cypionate were introduced. They largely superseded testosterone propionate and became the major testosterone esters used medically for over half a century. In the 1970s, testosterone undecanoate was introduced for oral use in Europe, although intramuscular testosterone undecanoate had already been in use in China for several years. Intramuscular testosterone undecanoate was not introduced in Europe and the United States until much later (in the early to mid 2000s and 2014, respectively).The history of testosterone as a medication has been reviewed.

Society and culture
Usage
In the US in the 2000s, companies and figures in the popular media have heavily marketed notions of "andropause" as something parallel to menopause; these notions have been rejected by the medical community. Additionally, advertising from drug companies selling testosterone and human growth hormone, as well as dietary supplement companies selling all kinds of "boosters" for aging men, have emphasized the "need" of middle-aged or ageing men for testosterone. There is a medical condition called late-onset hypogonadism; according to Thomas Perls and David J. Handelsman, writing in a 2015 editorial in the Journal of the American Geriatrics Society, it appears that this condition is overdiagnosed and overtreated. Perls and Handelsman note that in the US, "sales of testosterone increased from $324 million in 2002 to $2 billion in 2012, and the number of testosterone doses prescribed climbed from 100 million in 2007 to half a billion in 2012, not including the additional contributions from compounding pharmacies, Internet, and direct-to-patient clinic sales."

Generic names
Testosterone is the generic name of testosterone in English and Italian and the INN, USAN, USP, BAN, and DCIT of the drug, while testostérone is its French name and the DCF. It is also referred to in Latin as testosteronum, in Spanish and Portuguese as testosterona, and in German, Dutch, and Russian and other Slavic languages as testosteron. The Cyrillic script of testosterone is тестостерон.

Brand names
Testosterone is marketed under a large number of brand names throughout the world. Major brand names of testosterone and/or its esters include Andriol, Androderm, AndroGel, Axiron, Delatestryl, Depo-Testosterone, Intrinsa, Nebido, Omnadren, Primoteston, Sustanon, Testim, TestoGel, TestoPatch, Testoviron, and Tostran.

Availability
United States
As of November 2016, unmodified (non-esterified) testosterone is available in the United States in the following formulations:
Topical gels: AndroGel, Fortesta, Testim, Testosterone (generic)
Topical solutions: Axiron, Testosterone (generic)
Transdermal patches: Androderm, Testoderm (discontinued), Testoderm TTS (discontinued), Testosterone (generic)
Intranasal gels: Natesto
Buccal tablets: Striant
Pellet implants: TestopelAnd the following ester prodrugs of testosterone are available in the United States in oil solutions for intramuscular injection:
Testosterone cypionate: Depo-Testosterone, Testosterone Cypionate (generic)
Testosterone enanthate: Delatestryl, Xyosted (auto-injector), Testosterone Enanthate (generic)
Testosterone propionate: Testosterone Propionate (generic)
Testosterone undecanoate: AveedUnmodified testosterone was also formerly available for intramuscular injection but was discontinued.Testosterone cypionate and testosterone enanthate were formerly available in combination with estradiol cypionate and estradiol valerate, respectively, under the brand names Depo-Testadiol and Ditate-DS, respectively, as oil solutions for intramuscular injection, but these formulations have been discontinued.Unlike in Europe, Canada, and much of the rest of the world, oral testosterone undecanoate is not available in the United States.

Canada
As of November 2016, testosterone is available in Canada in the form of topical gels (AndroGel, Testim), topical solutions (Axiron), transdermal patches (Androderm), and intranasal gels (Natesto). Testosterone cypionate (Depo-Testosterone, Testosterone Cypionate (generic)), testosterone enanthate (Delatestryl, PMS-Testosterone Enanthate), and testosterone propionate (Testosterone Propionate (generic)) are available as oil solutions for intramuscular injection and testosterone undecanoate (Andriol, PMS-Testosterone, Taro-Testosterone) is available in the form of oral capsules. Testosterone buccal tablets and pellet implants do not appear to be available in Canada.

Other countries
Testosterone and/or its esters are widely available in countries throughout the world in a variety of formulations.

Legal status
Testosterone and its esters, along with other AAS, are prescription-only controlled substances in many countries throughout the world. In the United States, they are Schedule III drugs under the Controlled Substances Act, in Canada, they are Schedule IV drugs under the Controlled Drugs and Substances Act, and in the United Kingdom, they are Class C drugs under the Misuse of Drugs Act.

Litigation
As of 2014, a number of lawsuits are underway against manufacturers of testosterone, alleging a significantly increased rate of stroke and heart attack in elderly men who use testosterone supplementation.

Doping in sports
There are many known cases of doping in sports with testosterone and its esters by professional athletes.

Research
Depression
Testosterone has been used to treat depression in men who are of middle age with low testosterone. However, a 2014 review showed no benefit on the mood of the men with normal levels of testosterone or on the mood of the older men with low testosterone. Conversely, a 2009 review found that testosterone had an antidepressant effect in men with depression, especially those with hypogonadism, HIV/AIDS, and in the elderly.

Heart failure
Testosterone replacement can significantly improve exercise capacity, muscle strength and reduce QT intervals in men with chronic heart failure (CHF). Over the 3 to 6-month course of the studies reviewed, testosterone therapy appeared safe and generally effective, and (ruling out prostate cancer) the authors found no justification to absolutely restrict its use in men with CHF. A similar 2012 review also found increased exercise capacity and reasoned the benefits generlizable to women. However, both reviews advocate larger, longer term, randomized controlled trials.

Male contraception
Testosterone, as esters such as testosterone undecanoate or testosterone buciclate, has been studied and promoted as a male contraceptive analogous to estrogen-based contraceptives in 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 Disopyramide and can you explain it in depth? [/INST] Disopyramide (INN, trade names Norpace and Rythmodan) is an antiarrhythmic medication used in the treatment of ventricular tachycardia. It is a sodium channel blocker and therefore classified as a Class 1a anti-arrhythmic agent. Disopyramide has a negative inotropic effect on the ventricular myocardium, significantly decreasing the contractility. Disopyramide also has an anticholinergic effect on the heart which accounts for many adverse side effects. Disopyramide is available in both oral and intravenous forms, and has a low degree of toxicity.

Mechanism of action
Disopyramides Class 1a activity is similar to that of quinidine in that it targets sodium channels to inhibit conduction. Disopyramide depresses the increase in sodium permeability of the cardiac myocyte during Phase 0 of the cardiac action potential, in turn decreasing the inward sodium current. This results in an increased threshold for excitation and a decreased upstroke velocity. Disopyramide prolongs the PR interval by lengthening both the QRS and P wave duration. This effect is particularly well suited in the treatment of ventricular tachycardia as it slows the action potential propagation through the atria to the ventricles. Disopyramide does not act as a blocking agent for beta or alpha adrenergic receptors, but does have a significant negative inotropic effect on the ventricular myocardium. As a result, the use of disopyramide may reduce contractile force up to 42% at low doses and up to 100% in higher doses compared to quinidine.Levites proposed a possible secondary mode of action for disopyramide, against reentrant arrhythmias after an ischemic insult. Disopyramide decreases the inhomogeneity between infarcted and normal myocardium refractory periods; in addition to lengthening the refractory period. This decreases the chance of re-entry depolarization, because signals are more likely to encounter tissue in a refractory state which cannot be excited. This provides a possible treatment for atrial and ventricular fibrillation, as it restores pacemaker control of the tissue to the SA and AV nodes.

Obstructive hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, occurring in 1:500 individuals in the general population. It is estimated that there are 600,000 individuals in the United States with hypertrophic cardiomyopathy. The most common variant of HCM presents with left ventricular (LV) intracavitary obstruction due to systolic anterior motion of the mitral valve, and mitral-septal contact, diagnosed readily with echocardiography. Pharmacologic treatment with negative inotropic drugs is first-line therapy. Beta-blockers are used first, and while they improve symptoms of shortness of breath, chest pain and exercise intolerance, they do not reduce resting LV intraventricular pressure gradients and often are inadequate to control symptoms. Many investigators and clinicians believe that disopyramide controlled release is the most potent agent available for reducing resting pressure gradients and improving symptoms. Disopyramide has been actively used for more than 30 years. Disopyramide administration for obstructive HCM has a IB recommendation in the 2020 American Heart Association/American College of Cardiology Foundation guidelines for treatment of obstructive HCM. A IB treatment recommendation indicates that a treatment is recommended, and may be useful, and beneficial.
Negative inotropes improve LV obstruction by decreasing LV ejection acceleration and hydrodynamic forces on the mitral valve. Disopyramides particular efficacy is due to its potent negative inotropic effects; in head-to-head comparison, it is more effective for gradient reduction than either beta-blocker or verapamil. Disopyramide is most often administered with beta-blockade. When used in patients resistant to beta-blockade, disopyramide is effective in 60% of cases, reducing symptoms and gradient to the extent that invasive procedures such as surgical septal myectomy are not required.Disopyramide, despite its efficacy, has one main side effect that has limited its use in the US, though it has seen wider application in Canada, UK and Japan. Vagal blockade predictably causes dry mouth, and in men with prostatism, may cause urinary retention. Teichman et al. showed that pyridostigmine used in combination with disopyramide substantially alleviates vagolytic side effects without compromising antiarrhythmic efficacy </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 Erythromycin and can you explain it in depth? [/INST] Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used during pregnancy to prevent Group B streptococcal infection in the newborn, as well as to improve delayed stomach emptying. It can be given intravenously and by mouth. An eye ointment is routinely recommended after delivery to prevent eye infections in the newborn.Common side effects include abdominal cramps, vomiting, and diarrhea. More serious side effects may include Clostridium difficile colitis, liver problems, prolonged QT, and allergic reactions. It is generally safe in those who are allergic to penicillin. Erythromycin also appears to be safe to use during pregnancy. While generally regarded as safe during breastfeeding, its use by the mother during the first two weeks of life may increase the risk of pyloric stenosis in the baby. This risk also applies if taken directly by the baby during this age. It is in the macrolide family of antibiotics and works by decreasing bacterial protein production.Erythromycin was first isolated in 1952 from the bacteria Saccharopolyspora erythraea. It is on the World Health Organizations List of Essential Medicines. In 2017, it was the 215th most commonly prescribed medication in the United States, with more than two million prescriptions.

Medical uses
Erythromycin can be used to treat bacteria responsible for causing infections of the skin and upper respiratory tract, including Streptococcus, Staphylococcus, Haemophilus and Corynebacterium genera. The following represents MIC susceptibility data for a few medically significant bacteria:
Haemophilus influenzae: 0.015 to 256 μg/ml
Staphylococcus aureus: 0.023 to 1024 μg/ml
Streptococcus pyogenes: 0.004 to 256 μg/ml
Corynebacterium minutissimum: 0.015 to 64 μg/mlIt may be useful in treating gastroparesis due to this promotility effect. It has been shown to improve feeding intolerances in those who are critically ill. Intravenous erythromycin may also be used in endoscopy to help clear stomach contents.

Available forms
Erythromycin is available in enteric-coated tablets, slow-release capsules, oral suspensions, ophthalmic solutions, ointments, gels, enteric-coated capsules, non enteric-coated tablets, non enteric-coated capsules, and injections.
The following erythromycin combinations are available for oral dosage:
erythromycin base (capsules, tablets)
erythromycin estolate (capsules, oral suspension, tablets),  contraindicated during pregnancy
erythromycin ethylsuccinate (oral suspension, tablets)
erythromycin stearate (oral suspension, tablets)For injection, the available combinations are:
erythromycin gluceptate
erythromycin lactobionateFor ophthalmic use:

erythromycin base (ointment)

Adverse effects
Gastrointestinal disturbances, such as diarrhea, nausea, abdominal pain, and vomiting, are very common because erythromycin is a motilin agonist. Because of this, erythromycin tends not to be prescribed as a first-line drug.
More serious side effects include arrhythmia with prolonged QT intervals, including torsades de pointes, and reversible deafness. Allergic reactions range from urticaria to anaphylaxis. Cholestasis, Stevens–Johnson syndrome, and toxic epidermal necrolysis are some other rare side effects that may occur.
Studies have shown evidence both for and against the association of pyloric stenosis and exposure to erythromycin prenatally and postnatally. Exposure to erythromycin (especially long courses at antimicrobial doses, and also through breastfeeding) has been linked to an increased probability of pyloric stenosis in young infants. Erythromycin used for feeding intolerance in young infants has not been associated with hypertrophic pyloric stenosis.Erythromycin estolate has been associated with reversible hepatotoxicity in pregnant women in the form of elevated serum glutamic-oxaloacetic transaminase and is not recommended during pregnancy. Some evidence suggests similar hepatotoxicity in other populations.It can also affect the central nervous system, causing psychotic reactions, nightmares, and night sweats.

Interactions
Erythromycin is metabolized by enzymes of the cytochrome P450 system, in particular, by isozymes of the CYP3A superfamily. The activity of the CYP3A enzymes can be induced or inhibited by certain drugs (e.g., dexamethasone), which can cause it to affect the metabolism of many different drugs, including erythromycin. If other CYP3A substrates — drugs that are broken down by CYP3A — such as simvastatin (Zocor), lovastatin (Mevacor), or atorvastatin (Lipitor)—are taken concomitantly with erythromycin, levels of the substrates increase, often causing adverse effects. A noted drug interaction involves erythromycin and simvastatin, resulting in increased simvastatin levels and the potential for rhabdomyolysis. Another group of CYP3A4 substrates are drugs used for migraine such as ergotamine and dihydroergotamine; their adverse effects may be more pronounced if erythromycin is associated.
Earlier case reports on sudden death prompted a study on a large cohort that confirmed a link between erythromycin, ventricular tachycardia, and sudden cardiac death in patients also taking drugs that prolong the metabolism of erythromycin (like verapamil or diltiazem) by interfering with CYP3A4. Hence, erythromycin should not be administered to people using these drugs, or drugs that also prolong the QT interval. Other examples include terfenadine (Seldane, Seldane-D), astemizole (Hismanal), cisapride (Propulsid, withdrawn in many countries for prolonging the QT time) and pimozide (Orap). Theophylline, which is used mostly in asthma, is also contraindicated.
Erythromycin and doxycycline can have a synergistic effect when combined and kill bacteria (E. coli) with a higher potency than the sum of the two drugs together. This synergistic relationship is only temporary. After approximately 72 hours, the relationship shifts to become antagonistic, whereby a 50/50 combination of the two drugs kills less bacteria than if the two drugs were administered separately.It may alter the effectiveness of combined oral contraceptive pills because of its effect on the gut flora. A review found that when erythromycin was given with certain oral contraceptives, there was an increase in the maximum serum concentrations and AUC of estradiol and dienogest.Erythromycin is an inhibitor of the cytochrome P450 system, which means it can have a rapid effect on levels of other drugs metabolised by this system, e.g., warfarin.

Pharmacology
Mechanism of action
Erythromycin displays bacteriostatic activity or inhibits growth of bacteria, especially at higher concentrations. By binding to the 50s subunit of the bacterial  rRNA complex, protein synthesis and subsequent structure and function processes critical for life or replication are inhibited. Erythromycin interferes with aminoacyl translocation, preventing the transfer of the tRNA bound at the A site of the rRNA complex to the P site of the rRNA complex. Without this translocation, the A site remains occupied, thus the addition of an incoming tRNA and its attached amino acid to the nascent polypeptide chain is inhibited. This interferes with the production of functionally useful proteins, which is the basis of this antimicrobial action.
Erythromycin increases gut motility by binding to Motillin receptor, thus it is a Motillin receptor agonist in addition to its antimicrobial properties.

Pharmacokinetics
Erythromycin is easily inactivated by gastric acid; therefore, all orally administered formulations are given as either enteric-coated or more-stable salts or esters, such as erythromycin ethylsuccinate. Erythromycin is very rapidly absorbed, and diffuses into most tissues and phagocytes. Due to the high concentration in phagocytes, erythromycin is actively transported to the site of infection, where, during active phagocytosis, large concentrations of erythromycin are released.

Metabolism
Most of erythromycin is metabolised by demethylation in the liver by the hepatic enzyme CYP3A4. Its main elimination route is in the bile with little renal excretion, 2%-15% unchanged drug. Erythromycins elimination half-life ranges between 1.5 and 2.0 hours and is between 5 and 6 hours in patients with end-stage renal disease.  Erythromycin levels peak in the serum 4 hours after dosing; ethylsuccinate peaks 0.5-2.5 hours after dosing, but can be delayed if digested with food.Erythromycin crosses the placenta and enters breast milk.  The American Association of Pediatrics determined erythromycin is safe to take while breastfeeding. Absorption in pregnant patients has been shown to be variable, frequently resulting in levels lower than in nonpregnant patients.

Chemistry
Composition
Standard-grade erythromycin is primarily composed of four related compounds known as erythromycins A, B, C, and D. Each of these compounds can be present in varying amounts and can differ by lot. Erythromycin A has been found to have the most antibacterial activity, followed by erythromycin B. Erythromycins C and D are about half as active as erythromycin A. Some of these related compounds have been purified and can be studied and researched individually.

Synthesis
Over the three decades after the discovery of erythromycin A and its activity as an antimicrobial, many attempts were  made to synthesize it in the laboratory. The presence of 10 stereogenic carbons and several points of distinct substitution has made the total synthesis of erythromycin A a formidable task. Complete syntheses of erythromycins’ related structures and precursors such as 6-deoxyerythronolide B have been accomplished, giving way to possible syntheses of different erythromycins and other macrolide antimicrobials. Woodward successfully completed the synthesis of erythromycin A.

Erythromycin related compounds
History
In 1949 Abelardo B. Aguilar, a Filipino scientist, sent some soil samples to his employer at Eli Lilly. Aguilar managed to isolate erythromycin from the metabolic products of a strain of Streptomyces erythreus (designation changed to Saccharopolyspora erythraea) found in the samples. Aguilar received no further credit or compensation for his discovery.
The scientist was allegedly promised a trip to the company’s manufacturing plant in Indianapolis, but it was never fulfilled. In a letter to the company’s president, Aguilar wrote: “A leave of absence is all I ask as I do not wish to sever my connection with a great company which has given me wonderful breaks in life.” The request was not granted.Aguilar reached out to Eli Lilly again in 1993, requesting royalties from sales of the drug over the years, intending to use them to put up a foundation for poor and sickly Filipinos. This request was also denied. He died in September of the same year.Lilly filed for patent protection on the compound which was granted in 1953. The product was launched commercially in 1952 under the brand name Ilosone (after the Philippine region of Iloilo where it was originally collected). Erythromycin was formerly also called Ilotycin.
The antibiotic clarithromycin was invented by scientists at the Japanese drug company Taisho Pharmaceutical in the 1970s as a result of their efforts to overcome the acid instability of erythromycin.
Scientists at Chugai Pharmaceuticals discovered an erythromycin-derived motilin agonist called mitemcinal that is believed to have strong prokinetic properties (similar to erythromycin) but lacking antibiotic properties. Erythromycin is commonly used off-label for gastric motility indications such as gastroparesis. If mitemcinal can be shown to be an effective prokinetic agent, it would represent a significant advance in the gastrointestinal field, as treatment with this drug would not carry the risk of unintentional selection for antibiotic-resistant bacteria.

Society and culture
Cost
It is available as a generic medication.In the United States in 2014 the price increased to seven dollars per tablet.The price of Erythromycin rose three times between 2010 and 2015, from 24 cents per tablet in 2010 to $8.96 in 2015. In 2017, a Kaiser Health News study found that the per-unit cost of dozens of generics doubled or even tripled from 2015 to 2016, increasing spending by the Medicaid program. Due to price increases by drug manufacturers, Medicaid paid on average $2,685,330 more for Erythromycin in 2016 compared to 2015 (not including rebates) </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 Pimecrolimus and can you explain it in depth? [/INST] Pimecrolimus is an immunomodulating agent of the calcineurin inhibitor class used in the treatment of atopic dermatitis (eczema). It is available as a topical cream, once marketed by Novartis (however, Galderma has been promoting the compound in Canada since early 2007) under the trade name Elidel.

Medical uses
It has been proven to be effective in various inflammatory skin diseases, e.g., seborrheic dermatitis,  cutaneous lupus erythematosus, oral lichen planus,  vitiligo, and psoriasis </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 DTaP-IPV/Hib vaccine 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 Fosphenytoin and can you explain it in depth? [/INST] Fosphenytoin, also known as fosphenytoin sodium, and sold under the brand name Cerebyx among others, is a water-soluble phenytoin prodrug that is administered intravenously to deliver phenytoin, potentially more safely than intravenous phenytoin. It is used in the acute treatment of convulsive status epilepticus.
Fosphenytoin was developed in 1996. On 18 November 2004, Sicor (a subsidiary of Teva) received a tentative approval letter from the United States Food and Drug Administration for a generic version of fosphenytoin.

Medical uses
Fosphenytoin is approved in the United States for the short-term (five days or fewer) treatment of epilepsy when more widely used means of phenytoin administration are not possible or are ill-advised, such as endotracheal intubation, status epilepticus or some other type of repeated seizures; cluster seizure, vomiting, and/or the patient is unalert or not awake or both.

Other
In 2003, it was reported that even though anticonvulsants are often very effective in mania, and acute mania requires rapid treatment, fosphenytoin had no antimanic effect.

Metabolism
One millimole of phenytoin is produced for every millimole of fosphenytoin administered; the hydrolysis of fosphenytoin also yields phosphate and formaldehyde, the latter of which is subsequently metabolized to formate, which is in turn metabolized by a folate dependent mechanism.

Side effects
Side effects are similar to intravenous phenytoin and include hypotension, cardiac arrhythmias, CNS adverse events (nystagmus, dizziness, sedation/somnolence, ataxia and stupor), and local dermatological reactions </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 Amlodipine/celecoxib 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 Fludarabine and can you explain it in depth? [/INST] Fludarabine is a purine analogue and antineoplastic agent.   It is generally used as its 5-O-phosphorylated form known as fludarabine phosphate,
sold under the brand name Fludara among others.  It is a chemotherapy medication used in the treatment of leukemia and lymphoma. These include chronic lymphocytic leukemia, non-Hodgkins lymphoma, acute myeloid leukemia, and acute lymphocytic leukemia. It is given by injection into a vein or by mouth.Common side effects include nausea, diarrhea, fever, rash, shortness of breath, numbness, vision changes, and feeling tired. Severe side effects include brain dysfunction, low blood cell counts, and lung inflammation. Use in pregnancy will likely result in harm to the fetus. Fludarabine is in the purine analog family of medications and works by interfering with the duplication of DNA.Fludarabine was approved for medical use in the United States in 1991. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Fludarabine is highly effective in the treatment of chronic lymphocytic leukemia, producing higher response rates than alkylating agents such as chlorambucil alone.
Fludarabine is used in various combinations with cyclophosphamide, mitoxantrone, dexamethasone and rituximab in the treatment of indolent non-Hodgkins lymphomas.  As part of the FLAG or FLAMSA regimen, fludarabine is used together with cytarabine and granulocyte colony-stimulating factor in the treatment of acute myeloid leukaemia.  Because of its immunosuppressive effects, fludarabine is also used in some conditioning regimens prior to allogeneic stem cell transplant.

Side effects
Fludarabine is associated with profound lymphopenia, and as a consequence, increases the risk of opportunistic infections. People who have been treated with fludarabine will usually be asked to take co-trimoxazole or to use monthly nebulised pentamidine to prevent Pneumocystis jiroveci pneumonia </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 Sarecycline 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 Busulfan and can you explain it in depth? [/INST] Busulfan (Myleran, GlaxoSmithKline, Busulfex IV, Otsuka America Pharmaceutical, Inc.) is a chemotherapy drug in use since 1959. It is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates. Its chemical designation is 1,4-butanediol dimethanesulfonate.

History
Busulfan was approved by the US Food and Drug Administration (FDA) for treatment of chronic myeloid leukemia (CML) in 1999.  Busulfan was the mainstay of the chemotherapeutic treatment of chronic myeloid leukemia (CML) until it was displaced by the new gold standard, imatinib, though it is still in use to a degree as a result of the drugs relative low cost.

Indications
Busulfan is used in pediatrics and adults in combination with cyclophosphamide or fludarabine/clofarabine as a conditioning agent prior to bone marrow transplantation, especially in chronic myelogenous leukemia (CML) and other leukemias, lymphomas, and myeloproliferative disorders.  Busulfan can control tumor burden but cannot prevent transformation or correct cytogenic abnormalities.
The drug was recently used in a study to examine the role of platelet-transported serotonin in liver regeneration.

Availability
Myleran is supplied in white film coated tablets with 2 mg of busulfan per tablet. After 2002, a great interest has appeared for intravenous presentations of busulfan. Busulfex is supplied as an intravenous solution with 6 mg/ml busulfan.  Busulfex has proved equally effective as oral busulfan, with presumedly less toxic side effects. Pharmacokinetic and dynamic studies support this use, that has prompted its usage in transplantation regimes, particularly in frail patients. Fludarabine + busulfan is a typical example of this use.

Side effects
Toxicity may include interstitial pulmonary fibrosis ("busulfan lung"), hyperpigmentation, seizures, hepatic (veno-occlusive disease) (VOD) or sinusoidal obstruction syndrome (SOS), emesis, and wasting syndrome. Busulfan also induces thrombocytopenia, a condition of lowered blood platelet count and activity, and sometimes medullary aplasia.  Seizures and VOD are serious concerns with busulfan therapy and prophylaxis is often utilized to avoid these effects.  Hepatic VOD is a dose-limiting toxicity. Symptoms of VOD include weight gain, elevated bilirubin, painful hepatomegaly, and edema. The reason busulfan causes VOD is mostly unknown and can be deadly.  Ursodiol may be considered for prophylaxis of veno-occlusive disease.
Antiemetics are often administered prior to busulfan to prevent vomiting (emesis).
Phenytoin may be used concurrently to prevent the seizures. Levetiracetam, has shown efficacy for the prophylaxis against busulfan-induced seizures. Benzodiazepines can also be used for busulfan-induced seizures.Busulfan is listed by the IARC as a Group 1 carcinogen.

Dosing, administration, and pharmacokinetics
As an adjunct therapy with cyclophosphamide for conditioning prior to bone marrow transplantation in adults and children >12 kg, intravenous (IV) busulfan (Bulsulfex) is dosed at 0.8 mg/kg every six hours for 16 doses (four days).  IV busulfan is usually administered over two hours.  Both IV and oral formulations require prophylactic antiemetic agents administered prior to the busulfan dose and scheduled antiemetics administered thereafter. Oral bioavailability of busulfan shows a large interindividual variation. Taking busulfan on an empty stomach is recommended to reduce the risk of nausea and emesis.
Peak plasma concentrations are achieved within one hour of oral administration.  About 30% of the drug is bound to plasma proteins, such as albumin.
Busulfan therapeutic drug monitoring is completed based on trough (pre-dose) levels with a target six-hour area under the curve (AUC) of between 900 and 1500 micromolxmin.  AUCs (six-hour) >1500 micromolxmin are associated with hepatic VOD and subsequent dose reduction should be considered.  AUCs (six-hour) <900 micromolxmin are associated with incomplete bone marrow ablation and subsequent dose escalation should be considered.  Dose adjustments are performed using first order kinetics, such that the adjusted dose = current dose × (target AUC/actual AUC).

Drug interactions
Busulfan is metabolized via glutathione conjugation in the liver to inactive metabolites.  Itraconazole can decrease busulfan clearance by up to 25%, resulting in AUC levels >1500 micromolxmin and increased risk of hepatic VOD.  Concomitant use of acetaminophen within 72 hours of busulfan use can reduce busulfan clearance (resulting in increased busulfan AUC), as acetaminophen is also metabolized via glutathione and may deplete stores </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 Cetrorelix and can you explain it in depth? [/INST] Cetrorelix (INN, BAN), or cetrorelix acetate (USAN, JAN), sold under the brand name Cetrotide, is an injectable gonadotropin-releasing hormone (GnRH) antagonist. A synthetic decapeptide, it is used in assisted reproduction to inhibit premature luteinizing hormone surges The drug works by blocking the action of GnRH upon the pituitary, thus rapidly suppressing the production and action of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In addition, cetrorelix can be used to treat hormone-sensitive cancers of the prostate and breast (in pre-/perimenopausal women) and some benign gynaecological disorders (endometriosis, uterine fibroids and endometrial thinning). It is administered as either multiple 0.25 mg daily subcutaneous injections or as a single-dose 3 mg subcutaneous injection. The duration of the 3 mg single dose is four days; if human chorionic gonadotropin (hCG) is not administered within four days, a daily 0.25 mg dose is started and continued until hCG is administered.

Medical uses
Cetrorelix is marketed by Merck Serono for use in in-vitro fertilization in all countries except Japan, where it is marketed by Shionogi and Nippon Kayaku. Aeterna Zentaris receives royalties on these sales and retains rights to develop cetrorelix for other indications. In IVF use it is injected daily after follicle stimulation has been initiated and evidence of follicle maturation is approaching; given daily it prevents an endogenous LH surge that would trigger an untimely ovulation prior to the hCG administration by the treating physician. As an alternative to the GnRH antagonist, also a GnRH agonist could be given, but agonist have to be started earlier to overcome the agonistic effect. Cetrorelix can be mixed with follitropin alpha without compromising their reported safety and efficacy.

Contraindications
The use of cetrorelix is contraindicated in severe renal impairment. It is not intended for women aged 65 years or older. Use in women with severe allergic conditions is not recommended. Use with caution in women with active allergies or history of allergies.

Research
Cetrorelix was under development for the treatment of benign prostatic hyperplasia, premenopausal breast cancer, endometriosis, ovarian cancer, prostate cancer, and uterine fibroids, but development for these indications was discontinued.A study published in Nature Medicine found a link between hormonal imbalance in the womb and Polycystic ovary syndrome (PCOS), specifically prenatal exposure to anti-Müllerian hormone.  For the study, the researchers injected pregnant mice with AMH so that they had a higher than normal concentration of the hormone. Indeed, they gave birth to daughters who later developed PCOS-like tendencies. These included problems with fertility, delayed puberty, and erratic ovulation. To reverse it, the researchers dosed the polycystic mice with cetrorelix, which made the symptoms to go away </s>