<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 Triptorelin and can you explain it in depth? [/INST] Triptorelin, sold under the brand name Decapeptyl among others, is a medication that acts as an agonist analog of gonadotropin-releasing hormone, repressing expression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).It is a decapeptide (pGlu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2) and a gonadotropin-releasing hormone agonist (GnRH agonist) used as the acetate or pamoate salts.
Primary indications include endometriosis, for the reduction of uterine fibroids, to treat prostate cancer, and to treat male hypersexuality with severe sexual deviation. The drug has also been used off label to delay puberty in patients with gender dysphoria.It was patented in 1975 and approved for medical use in 1986. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Triptorelin is used to treat prostate cancer as part of androgen deprivation therapy.Another common use in the United Kingdom is for hormone replacement therapy to suppress testosterone or estrogen levels in transgender people (in conjunction with estradiol valerate for trans women or testosterone for trans men). Spironolactone and cyproterone acetate are other drugs used by trans people to suppress sex hormones, but these drugs have a completely different mechanism of action. It can also be used as a puberty blocker.Triptorelin has been used as a chemical castration agent for reducing sexual urges in sex offenders.

Drug action
Triptorelin is a gonadorelin analogue, also known as luteinizing hormone releasing analogue (GnRH analogue, LHRH analogue). The drug binds to receptors in the pituitary gland and stimulates secretion of gonadotropins (namely luteinizing hormone LH and follicle-stimulating hormone FSH). This causes an initial phase of LH and FSH stimulation, prior to down-regulation of the gonadotrophin-releasing hormone receptors, thereby reducing the release of gonadotropins in the long term, which in turn leads to the inhibition of androgen and estrogen production.

Side-effects
General side effects can include:
Anaphylaxis
Arthralgia
Asthenia
Asthma
Breast tenderness (males and females)
Changes in blood pressure
Changes in breast size
Depression
Ovarian cysts
Mood changes
Skin rashes
Hot flushes
Weight changes

Society and culture
Brand names
Triptorelin is marketed under the brand names Decapeptyl (Ipsen) and Diphereline and Gonapeptyl (Ferring Pharmaceuticals). In the United States, it is sold by Watson Pharmaceuticals as Trelstar and by Arbor Pharmaceuticals as Triptodur (an extended-release 6-month depot injection). In Iran, triptorelin is marketed under the brand name Variopeptyl. In the UK and Germany, it is sold as Salvacyl.

Research
Triptorelin and other antiandrogens may be effective in the treatment of obsessive–compulsive disorder.

References
Further reading
Lahlou N, Carel JC, Chaussain JL, Roger M (July 2000). "Pharmacokinetics and pharmacodynamics of GnRH agonists: clinical implications in pediatrics". J Pediatr Endocrinol Metab. 13 Suppl 1: 723–37. doi:10.1515/jpem.2000.13.s1.723 </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 Fosinopril and can you explain it in depth? [/INST] Fosinopril is an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of chronic heart failure. Fosinopril is the only phosphonate-containing ACE inhibitor marketed, by Bristol-Myers Squibb under the trade name Monopril. Fosinopril is a cascading pro-drug. The special niche for the medication that differentiates it from the other members of the ACE Inhibitor drug class is that was specifically developed for the use for patients with renal impairment. This was through manipulation of the metabolism and excretion, and is seen that fifty percent of the drug is hepatobiliary cleared, which can compensate for diminished renal clearance. The remaining fifty percent is excreted in urine. It does not need dose adjustment.
It was patented in 1980 and approved for medical use in 1991.

Medical uses
In congestive heart failure, the ability of the heart to pump enough blood to satisfy the physiological needs of the body is reduced </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 Pyrimethamine and can you explain it in depth? [/INST] Pyrimethamine, sold under the brand name Daraprim among others, is a medication used with leucovorin (leucovorin is used to decrease side effects of pyrimethamine; it does not have intrinsic anti-parasitic activity) to treat the parasitic diseases toxoplasmosis and cystoisosporiasis. It is also used with dapsone as a second-line option to prevent Pneumocystis jiroveci pneumonia  in people with HIV/AIDS. It was previously used for malaria but is no longer recommended due to resistance. Pyrimethamine is taken by mouth.Common side effects include gastrointestinal upset, severe allergic reactions, and bone marrow suppression. It should not be used by people with folate deficiency that has resulted in anemia. There is concern that it may increase the risk of cancer. While occasionally used in pregnancy it is unclear if pyrimethamine is safe for the baby. Pyrimethamine is classified as a folic acid antagonist. It works by inhibiting folic acid metabolism and therefore the making of DNA.Pyrimethamine was discovered in 1952 and came into medical use in 1953. It is on the World Health Organizations List of Essential Medicines. It was approved as a generic in the United States in February 2020.

Medical uses
Pyrimethamine is typically given with a sulfonamide and folinic acid.It is used for the treatment of toxoplasmosis, actinomycosis, and isosporiasis, and for the treatment and prevention of Pneumocystis jirovecii pneumonia.

Toxoplasmosis
Pyrimethamine is also used in combination with sulfadiazine to treat active toxoplasmosis. The two drugs bind the same enzymatic targets as the drugs trimethoprim and sulfamethoxazole - dihydrofolate reductase and dihydropteroate synthase, respectively.Pyrimethamine has also been used in several trials to treat retinochoroiditis.

Pregnancy consideration
Pyrimethamine is labeled as pregnancy category C in the United States. To date,  not enough evidence on its risks in pregnancy or its effects on the fetus is available.

Malaria
It is primarily active against Plasmodium falciparum, but also against Plasmodium vivax. Due to the emergence of pyrimethamine-resistant strains of P. falciparum, pyrimethamine alone is seldom used now. In combination with a long-acting sulfonamide such as sulfadiazine, it was widely used, such as in Fansidar, though resistance to this combination is increasing.

Contraindications
Pyrimethamine is contraindicated in people with folate-deficiency anaemia.

Side effects
When higher doses are used, as in the treatment of toxoplasmosis, pyrimethamine can cause gastrointestinal symptoms such as nausea, vomiting, glossitis, anorexia, and diarrhea. A rash, which can be indicative of a hypersensitivity reaction, is also seen, particularly in combination with sulfonamides. Central nervous system effects include ataxia, tremors, and seizures. Hematologic side effects such as thrombocytopenia, leukopenia, and anemia can also occur.

Interactions
Other antifolate agents such as methotrexate and trimethoprim may potentiate the antifolate actions of pyrimethamine, leading to potential folate deficiency, anaemia, and other blood dyscrasias.

Mechanism of action
Pyrimethamine interferes with the regeneration of tetrahydrofolic acid from dihydrofolate by competitively inhibiting the enzyme dihydrofolate reductase. Tetrahydrofolic acid is essential for DNA and RNA synthesis in many species, including protozoa. It has also been found to reduce the expression of SOD1, a key protein involved in amyotrophic lateral sclerosis.

Other medications
Pyrimethamine is typically given with folinic acid and sulfadiazine.
Sulfonamides (e.g. sulfadiazine) inhibit dihydropteroate synthetase, an enzyme that participates in folic acid synthesis from para-aminobenzoic acid.  Hence, sulfonamides work synergistically with pyrimethamine by blocking a different enzyme needed for folic acid synthesis.
Folinic acid (leucovorin) is a folic acid derivative converted to tetrahydrofolate, the primary active form of folic acid, in vivo, without relying on dihydrofolate reductase. Folinic acid reduces side effects related to folate deficiency in the patient.

Mechanism of resistance
Resistance to pyrimethamine is widespread.  Mutations in the malarial gene for dihydrofolate reductase may reduce its effectiveness.  These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of hydrogen bonds and steric interactions.

History
Nobel Prize-winning American scientist Gertrude Elion developed the drug at Burroughs-Wellcome (now part of GlaxoSmithKline) to combat malaria. Pyrimethamine has been available since 1953. In 2010, GlaxoSmithKline sold the marketing rights for Daraprim to CorePharma. Impax Laboratories sought to buy CorePharma in 2014, and completed the acquisition, including Daraprim, in March 2015. In August 2015, the rights were bought by Turing Pharmaceuticals. Turing subsequently became infamous for a price hike controversy when it raised the price of a dose of the drug in the U.S. market from US$13.50 to US$750, a 5,500% increase.

Society and culture
Economics
In the United States in 2015, Turing Pharmaceuticals was criticized for increasing the price 50-fold, from US$13.50 to $750 a tablet, leading to a cost of $75,000 for a course of treatment reported at one hospital.

United States
In the United States, in 2015, with Turing Pharmaceuticals acquisition of the US marketing rights for Daraprim tablets, Daraprim became a single-source and specialty pharmacy item, and the price was increased. The cost of a monthly course for a person on 75 mg dose rose to about $75,000/month at one hospital, or $750 per tablet while it was previously priced at 13.50.Outpatients could no longer obtain the medication from a community pharmacy, but only through a single dispensing pharmacy, Walgreens Specialty Pharmacy, and institutions could no longer order from their general wholesaler, but had to set up an account with the Daraprim Direct program.  Presentations from Retrophin, a company formerly headed by Martin Shkreli, CEO of Turing, from which Turing acquired the rights to Daraprim, suggested that a closed distribution system could prevent generic competitors from legally obtaining the drugs for the bioequivalence studies required for FDA approval of a generic drug.Shkreli defended the price hike by saying, "If there was a company that was selling an Aston Martin at the price of a bicycle, and we buy that company and we ask to charge Toyota prices, I dont think that that should be a crime."  As a result of the backlash, Shkreli hired a crisis public relations firm to help explain his funds move. Turing Pharmaceuticals announced on 24 November 2015, "that it would not reduce the list price of that drug after all", but they would offer patient assistance programs. New York Times journalist Andrew Pollack noted that these programs "are standard for companies selling extremely high-priced drugs. They enable the patients to get the drug while pushing most of the costs onto insurance companies and taxpayers."The price increase was criticized by physician groups such as HIV Medicine Associates and Infectious Diseases Society of America.In 2016, a group of high school students from Sydney Grammar supported by the University of Sydney prepared pyrimethamine as an illustration that the synthesis is comparatively easy and the price-hike unjustifiable. His team produced 3.7 g for US$20, which would have been worth between US$35,000 and US$110,000 in the United States at the time </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 Valproate and can you explain it in depth? [/INST] Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.Common side effects of valproate include nausea, vomiting, somnolence, and dry mouth. Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended. Other serious risks include pancreatitis and an increased suicide risk. Valproate is known to cause serious abnormalities in fetuses if taken during pregnancy, and is contra-indicated for women of childbearing age unless the drug is essential to their medical condition. As of 2022 the drug was still prescribed in the UK to potentially pregnant women, but use declined by 51% from 2018–19 to 2020–21.Valproates precise mechanism of action is unclear. Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, and inhibiting histone deacetylases. Valproic acid is a branched short-chain fatty acid (SCFA) made from valeric acid.Valproate was first made in 1881 and came into medical use in 1962. It is on the World Health Organizations List of Essential Medicines and is available as a generic medication. In 2019, it was the 114th most commonly prescribed medication in the United States, with more than 5 million prescriptions.

Terminology
Valproic acid (VPA) is an organic weak acid. The conjugate base is valproate. The sodium salt of the acid is sodium valproate and a coordination complex of the two is known as valproate semisodium.

Medical uses
It is used primarily to treat epilepsy and bipolar disorder. It is also used to prevent migraine headaches.

Epilepsy
Valproate has a broad spectrum of anticonvulsant activity, although it is primarily used as a first-line treatment for tonic–clonic seizures, absence seizures and myoclonic seizures and as a second-line treatment for partial seizures and infantile spasms. It has also been successfully given intravenously to treat status epilepticus.

Mental illness
Bipolar disorder
Valproate products are also used to treat manic or mixed episodes of bipolar disorder.

Schizophrenia
A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:

Dopamine dysregulation syndrome
Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of the dopamine dysregulation syndrome that arise from the treatment of Parkinsons disease with levodopa.

Migraines
Valproate is also used to prevent migraine headaches.

Other
The medication has been tested in the treatment of AIDS and cancer, owing to its histone-deacetylase-inhibiting effects.

Contraindications
Contraindications include:

Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related.
Known hypersensitivity to valproate or any of the ingredients used in the preparation
Urea cycle disorders
Hepatic porphyria
Hepatotoxicity
Mitochondrial disease
Pancreatitis
Porphyria

Adverse effects
Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.It is worthy of mentioning that some adverse effects related to valproic acid may be dose-dependent such as pancytopenia.There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height. Valproic acid can also cause mydriasis, a dilation of the pupils. There is evidence that shows valproic acid may increase the chance of polycystic ovary syndrome (PCOS) in women with epilepsy or bipolar disorder. Studies have shown this risk of PCOS is higher in women with epilepsy compared to those with bipolar disorder. Weight gain is also possible.

Pregnancy
Valproate causes birth defects; exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida with the risks being related to the strength of medication used and use of more than one drug. More rarely, with several other defects, including a "valproate syndrome". Characteristics of this valproate syndrome include facial features that tend to evolve with age, including a triangle-shaped forehead, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth. While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.Children of mothers taking valproate during pregnancy are at risk for lower IQs. Maternal valproate use during pregnancy increased the probability of autism in the offspring compared to mothers not taking valproate from 1.5% to 4.4%. A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%. The normal incidence for autism in the general population is estimated at 1 in 44 (2.3%). A 2009 study found that the 3-year-old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.Sodium valproate has been associated with paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate. Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have worse outcomes for the fetus than exposure to valproate). Studies have shown that taking folic acid supplements can reduce the risk of congenital neural tube defects. The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the European Union, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.

Elderly
Valproate may cause increased somnolence in the elderly. In a trial of valproate in elderly patients with dementia, a significantly higher portion of valproate patients had somnolence compared to placebo. In approximately one-half of such patients, there was associated reduced nutritional intake and weight loss.

Overdose and toxicity
Excessive amounts of valproic acid can result in somnolence, tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/L during controlled therapy, but may reach 150–1500 mg/L following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography.
In contrast to other antiepileptic drugs, at present there is little favorable evidence for salivary therapeutic drug monitoring. Salivary levels of valproic acid correlate poorly with serum levels, partly due to valproates weak acid property (pKa of 4.9).In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body. Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored. Supplemental L-carnitine is indicated in patients having an acute overdose and also prophylactically in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly than L-carnitine.

Interactions
Valproate inhibits CYP2C9, glucuronyl transferase, and epoxide hydrolase and is highly protein bound and hence may interact with drugs that are substrates for any of these enzymes or are highly protein bound themselves. It may also potentiate the CNS depressant effects of alcohol. It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics (including carbamazepine, lamotrigine, phenytoin and phenobarbitone) and itself. It may also interact with:
Aspirin: may increase valproate concentrations. May also interfere with valproates metabolism.
Benzodiazepines: may cause CNS depression and there are possible pharmacokinetic interactions.
Carbapenem antibiotics: reduce valproate levels, potentially leading to seizures.
Cimetidine: inhibits valproates metabolism in the liver, leading to increased valproate concentrations.
Erythromycin: inhibits valproates metabolism in the liver, leading to increased valproate concentrations.
Ethosuximide: valproate may increase ethosuximide concentrations and lead to toxicity.
Felbamate: may increase plasma concentrations of valproate.
Mefloquine: may increase valproate metabolism combined with the direct epileptogenic effects of mefloquine.
Oral contraceptives: may reduce plasma concentrations of valproate.
Primidone: may accelerate metabolism of valproate, leading to a decline of serum levels and potential breakthrough seizure.
Rifampicin: increases the clearance of valproate, leading to decreased valproate concentrations
Warfarin: valproate may increase free warfarin concentration and prolong bleeding time.
Zidovudine: valproate may increase zidovudine serum concentration and lead to toxicity.

Pharmacology
Pharmacodynamics
Although the mechanism of action of valproate is not fully understood, traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA). The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate. In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells.Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism. Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.It also has histone-deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.

Endocrine actions
Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence as a nonsteroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels. In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations. These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.Valproic acid has been found to directly stimulate androgen biosynthesis in the gonads via inhibition of histone deacetylases and has been associated with hyperandrogenism in women and increased 4-androstenedione levels in men. High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.

Pharmacokinetics
Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut. When in the bloodstream, 80–90% of the substance are bound to plasma proteins, mainly albumin. Protein binding is saturable: it decreases with increasing valproate concentration, low albumin concentrations, the patients age, additional use of other drugs such as aspirin, as well as liver and kidney impairment. Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.The vast majority of valproate metabolism occurs in the liver. Valproate is known to be metabolized by the cytochrome P450 enzymes CYP2A6, CYP2B6, CYP2C9, and CYP3A5. It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15.  Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):
via glucuronidation (30–50%): valproic acid β-O-glucuronide
via beta oxidation (>40%): 2E-ene-valproic acid, 2Z-ene-valproic acid, 3-hydroxyvalproic acid, 3-oxovalproic acid
via omega oxidation: 5-hydroxyvalproic acid, 2-propyl-glutaric acid
some others: 3E-ene-valproic acid, 3Z-ene-valproic acid, 4-ene-valproic acid, 4-hydroxyvalproic acidAll in all, over 20 metabolites are known.In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as the glucuronide conjugate.  The other major pathway in the metabolism of valproate is mitochondrial beta oxidation, which typically accounts for over 40% of an administered dose. Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine. Only a small amount is excreted via the faeces. Elimination half-life is 16±3 hours and can decrease to 4–9 hours when combined with enzyme inducers.

Chemistry
Valproic acid is a branched short-chain fatty acid and the 2-n-propyl derivative of valeric acid.

History
Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian. Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented pentylenetetrazol-induced convulsions in laboratory rats. It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide. Valproic acid has also been used for migraine prophylaxis and bipolar disorder.

Society and culture
Valproate is available as a generic medication.

Approval status
Off-label uses
In 2012, pharmaceutical company Abbott paid $1.6 billion in fines to US federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents.Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.

Formulations
Valproate exists in two main molecular variants: sodium valproate and valproic acid without sodium (often implied by simply valproate). A mixture between these two is termed semisodium valproate. It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more mass of sodium valproate is needed than valproic acid without sodium to compensate for the sodium itself.

Brand names of valproic acid
Branded products include:

Brand names of sodium valproate
Portugal
Tablets – Diplexil-R by Bial.

United States
Intravenous injection – Depacon by Abbott Laboratories.
Syrup – Depakene by Abbott Laboratories. (Note Depakene capsules are valproic acid).
Depakote tablets are a mixture of sodium valproate and valproic acid.
Tablets – Eliaxim by Bial.

Australia
Epilim Crushable Tablets Sanofi
Epilim Sugar Free Liquid Sanofi
Epilim Syrup Sanofi
Epilim Tablets Sanofi
Sodium Valproate Sandoz Tablets Sanofi
Valpro Tablets Alphapharm
Valproate Winthrop Tablets Sanofi
Valprease tablets Sigma

New Zealand
Epilim by Sanofi-AventisAll the above formulations are Pharmac-subsidised.

UK
Depakote Tablets (as in USA)
Tablets – Orlept by Wockhardt and Epilim by Sanofi
Oral solution – Orlept Sugar Free by Wockhardt and Epilim by Sanofi
Syrup – Epilim by Sanofi-Aventis
Intravenous injection – Epilim Intravenous by Sanofi
Extended release tablets – Epilim Chrono by Sanofi is a combination of sodium valproate and valproic acid in a 2.3:1 ratio.
Enteric-coated tablets – Epilim EC200 by Sanofi is a 200-mg sodium valproate enteric-coated tablet.

UK only
Capsules – Episenta prolonged release by Beacon
Sachets – Episenta prolonged release by Beacon
Intravenous solution for injection – Episenta solution for injection by Beacon

Germany, Switzerland, Norway, Finland, Sweden
Tablets – Orfiril by Desitin Pharmaceuticals
Intravenous injection – Orfiril IV by Desitin Pharmaceuticals

South Africa
Syrup – Convulex by Byk Madaus
Tablets – Epilim by Sanofi-synthelabo

Malaysia
Tablets – Epilim by Sanofi-Aventis

Romania
Companies are SANOFI-AVENTIS FRANCE, GEROT PHARMAZEUTIKA GMBH and DESITIN ARZNEIMITTEL GMBH
Types are Syrup, Extended release mini tablets, Gastric resistant coated tablets, Gastric resistant soft capsules, Extended release capsules, Extended release tablets and Extended release coated tablets

Canada
Intravenous injection – Epival or Epiject by Abbott Laboratories.
Syrup – Depakene by Abbott Laboratories its generic formulations include Apo-Valproic and ratio-Valproic.

Japan
Tablets – Depakene by Kyowa Hakko Kirin
Extended release tablets – Depakene-R by Kyowa Hakko Kogyo and Selenica-R by Kowa
Syrup – Depakene by Kyowa Hakko Kogyo

Europe
In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.

Taiwan
Tablets (white round tablet) – Depakine (Chinese: 帝拔癲; pinyin: di-ba-dian) by Sanofi Winthrop Industrie (France)

Iran
Tablets – Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo
Slow release tablets – Depakine Chrono by Sanofi Winthrop Industrie (France)

Israel
Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above </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 Viltolarsen and can you explain it in depth? [/INST] Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen is a Morpholino antisense oligonucleotide.The most common side effects include upper respiratory tract infection, injection site reaction, cough, and pyrexia (fever).Viltolarsen was approved for medical use in the United States in August 2020. After golodirsen was approved in December 2019, viltolarsen is the second approved targeted treatment for people with this type of mutation in the United States. Approximately 8% of people with DMD have a mutation that is amenable to exon 53 skipping.

Medical uses
Viltolarsen is indicated for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness. It is the most common type of muscular dystrophy. DMD is caused by mutations in the DMD gene that results in an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between three and five years of age and worsen over time. DMD occurs in approximately one out of every 3,600 male infants worldwide; in rare cases, it can affect females.

Adverse effects
The most common side effects include upper respiratory tract infection, injection site reaction, cough, and pyrexia (fever).Although kidney toxicity was not observed in the clinical studies, the clinical experience is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides.

History
Viltolarsen was developed by Nippon Shinyaku and the NCNP based on pre-clinical study conducted by Toshifumi Yokota and colleagues, and evaluated in two clinical studies with a total of 32 participants, all of whom were male and had genetically confirmed DMD. The increase in dystrophin production was established in one of those two studies, a study that included sixteen DMD participants, with eight participants receiving viltolarsen at the recommended dose. In the study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25. Trial 1 provided data for evaluation of the benefits of viltolarsen. The combined populations from both trials provided data for evaluation of the side effects of viltolarsen. Trial 1 was conducted at six sites in the United States and Canada and Trial 2 was conducted at five sites in Japan. All participants in both trials were on a stable dose of corticosteroids for at least three months before entering the trials.The U.S. Food and Drug Administration (FDA) concluded that the applicants data demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in people with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping. A clinical benefit of the drug has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.The application for viltolarsen was granted priority review designation and the FDA granted the approval to NS Pharma, Inc.

Society and culture
Economics
Viltolarsen costs around US$733,000 per year for a person that weighs 30 kilograms (66 lb).

References
Further reading
Dhillon S (July 2020). "Viltolarsen: First Approval". Drugs. 80 (10): 1027–1031. doi:10.1007/s40265-020-01339-3. PMID 32519222. S2CID 219542850.
Dzierlega K, Yokota T (June 2020). "Optimization of antisense-mediated exon skipping for Duchenne muscular dystrophy". Gene Ther. 27 (9): 407–416. doi:10.1038/s41434-020-0156-6. PMID 32483212. S2CID 219157034.
Hwang J, Yokota T (October 2019). "Recent advancements in exon-skipping therapies using antisense oligonucleotides and genome editing for the treatment of various muscular dystrophies". Expert Rev Mol Med. 21: e5. doi:10.1017/erm.2019.5. PMID 31576784 </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 Brinzolamide/brimonidine and can you explain it in depth? [/INST] Brinzolamide/brimonidine, sold under the brand name Simbrinza, is a fixed-dose combination medication used to reduce intra-ocular pressure (pressure inside the eye) in adults with ocular hypertension (high intra-ocular pressure) or in those with an eye condition known as open-angle glaucoma. It contains brinzolamide and brimonidine tartrate. It is used as an eye drop.The most common side effects include ocular hyperaemia (red eye), allergic reactions in the eye, and dysgeusia (taste disturbances).Open-angle glaucoma (a condition where the aqueous humour, the watery fluid inside the eyeball, cannot drain away properly) and other causes of high pressure in the eye increase the risk of damage to the retina and the optic nerve (the nerve that sends signals from the eye to the brain). This can result in serious vision loss and even blindness.The active substances, brinzolamide and brimonidine tartrate, help to reduce intra-ocular pressure by reducing the production of aqueous humour. Brinzolamide works by blocking an enzyme called carbonic anhydrase, which produces bicarbonate needed for the production of the aqueous humour, while brimonidine tartrate blocks another enzyme known as adenylate cyclase, which is also involved in the production of the aqueous humour. Brimonidine also increases the drainage of aqueous humour from the front of the eye.Brinzolamide/brimonidine was approved for medical use in the United States in April 2013, and in the European Union in July 2014.

Medical uses
Brinzolamide/brimonidine is indicated to decrease of elevated intraocular pressure (IOP) in adults with open-angle glaucoma or ocular hypertension for whom monotherapy provides insufficient IOP reduction.

History
Brinzolamide/brimonidine was approved for medical use in the United States in April 2013, and in the European Union in July 2014.

References
Further reading
Li T, Lindsley K, Rouse B, Hong H, Shi Q, Friedman DS, Wormald R, Dickersin K (January 2016). "Comparative Effectiveness of First-Line Medications for Primary Open-Angle Glaucoma: A Systematic Review and Network Meta-analysis". Ophthalmology. 123 (1): 129–40. doi:10.1016/j.ophtha.2015.09.005. PMC 4695285. PMID 26526633.
Lusthaus JA, Goldberg I (September 2017). "Brimonidine and brinzolamide for treating glaucoma and ocular hypertension; a safety evaluation". Expert Opin Drug Saf. 16 (9): 1071–1078. doi:10.1080/14740338.2017.1346083. PMID 28656780 </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 Torasemide and can you explain it in depth? [/INST] Torasemide, also known as torsemide, is a diuretic medication used to treat fluid overload due to heart failure, kidney disease, and liver disease and high blood pressure. It is a less preferred treatment for high blood pressure. It is taken by mouth or by injection into a vein.Common side effects include headache, increased urination, diarrhea, cough, and dizziness. Other side effects may include hearing loss and low blood potassium. Torasemide is a sulfonamide and loop diuretic. Use is not recommended in pregnancy or breastfeeding. It works by decreasing the reabsorption of sodium by the kidneys.Torasemide was patented in 1974 and came into medical use in 1993. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication </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 Lincomycin and can you explain it in depth? [/INST] Lincomycin is a lincosamide antibiotic that comes from the actinomycete Streptomyces lincolnensis. A related compound, clindamycin, is derived from lincomycin by using thionyl chloride to replace the 7-hydroxy group with a chlorine atom with inversion of chirality. It was released for medical use in September 1964.

Uses
Although similar in antibacterial spectrum and mechanism of action to macrolides, lincomycin is also effective against other organisms including actinomycetes and some species of Mycoplasma and Plasmodium.However, because of its adverse effects and toxicity, it is rarely used today and reserved for patients allergic to penicillin or where bacteria have developed resistance.

Clinical pharmacology
Intramuscular administration of a single dose of 600 mg of Lincomycin produces average peak serum levels of 11.6 µg/mL at 60 min, and maintains therapeutic levels for 17 h to 20 h, for most susceptible gram-positive organisms.  Urinary excretion after this dose ranges from 1.8% to 24.8% (mean: 17.3%).
A two-hour intravenous infusion of 600 mg of Lincomycin achieves average peak serum levels of 15.9 µg/mL and yields therapeutic levels for 14 h for most susceptible gram-positive organisms.  Urinary excretion ranges from 4.9% to 30.3% (mean: 13.8%).
The biological half-life after IM or IV administration is 5.4 ± 1.0 h.  The serum half-life of lincomycin may be prolonged in patients with severe impairment of renal function, compared to patients with normal renal function.  In patients with abnormal hepatic function, serum half-life may be twofold longer than in patients with normal hepatic function.  Hemodialysis and peritoneal dialysis are not effective in removing lincomycin from the serum.
Tissue level studies indicate that bile is an important route of excretion.  Significant levels have been demonstrated in the majority of body tissues.  Although lincomycin appears to diffuse in the cerebrospinal fluid (CSF), levels of lincomycin in the CSF appear inadequate for the treatment of meningitis.

Biosynthesis
Lincomycin is an antibiotic classified as a member of the lincosamide class, which typically features a L-proline amino acid derivative linked through amide group with an eight-carbon aminothio sugar </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 Osilodrostat and can you explain it in depth? [/INST] Osilodrostat, sold under the brand name Isturisa, is a medication for the treatment of adults with Cushings disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. It is taken by mouth.The most common side effects are adrenal insufficiency, headache, vomiting, nausea, fatigue, and edema (swelling caused by fluid retention).Hypocortisolism (low cortisol levels), QTc prolongation (a heart rhythm condition) and elevations in adrenal hormone precursors (inactive substance converted into a hormone) and androgens (hormone that regulates male characteristics) may also occur in people taking osilodrostat.Osilodrostat was approved for medical use in the European Union in January 2020, and for medical use in the United States in March 2020. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.Osilodrostat is an orally active, nonsteroidal corticosteroid biosynthesis inhibitor which was developed by Novartis for the treatment of Cushings syndrome and pituitary ACTH hypersecretion (a specific subtype of Cushings syndrome). It specifically acts as a potent and selective inhibitor of aldosterone synthase (CYP11B2) and at higher dosages of 11β-hydroxylase (CYP11B1).

History
In October 2014, an orphan designation was granted by the European Commission for osilodrostat for the treatment of Cushings syndrome.Osilodrostat was approved for medical use in the European Union in January 2020, and for medical use in the United States in March 2020.Osilodrostats safety and effectiveness for treating Cushings disease among adults was evaluated in a study of 137 adult subjects (about three-quarters women) with a mean age of 41 years. The majority of subjects either had undergone pituitary surgery that did not cure Cushings disease or were not surgical candidates. In the 24-week, single-arm, open-label period, all subjects received a starting dose of 2 milligrams (mg) of osilodrostat twice a day that could be increased every two weeks up to 30 mg twice a day. At the end of this 24-week period, about half of subjects had cortisol levels within normal limits. After this point, 71 subjects who did not need further dose increases and tolerated the drug for the last 12 weeks entered an eight-week, double-blind, randomized withdrawal study where they either received osilodrostat or a placebo (inactive treatment). At the end of this withdrawal period, 86% of subjects receiving osilodrostat maintained cortisol levels within normal limits compared to 30% of subjects taking the placebo.The U.S. Food and Drug Administration (FDA) approved osilodrostat based on the evidence from one clinical trial (NCT02180217) of 137 subjects with Cushings disease. The trial was conducted at 66 sites across 19 countries (United States, Argentina, Austria, Bulgaria, Canada, China, Columbia, Germany, Spain, France, Great Britain, India, Italy, Japan, Korea, Netherlands, Russia, Thailand, and Turkey).There was one trial of 48 weeks duration that assessed the benefits and side effects of osilodrostat. The trial enrolled subjects with Cushings disease for whom pituitary gland surgery was not an option or did not work. The trial was divided in four periods. Subjects received osilodrostat two times a day in all four periods. After the first two periods (24 weeks), the benefit of osilodrostat was assessed by the percentage of subjects who had 24-hour urinary free cortisol levels within normal limits.In the third period (which lasted eight weeks), half of the subjects who had normal urinary free cortisol levels after 24 weeks of treatment continued taking osilodrostat and the other half was switched to placebo. Neither the subjects nor the healthcare providers know which treatment was given during this period. The benefit of osilodrostat was assessed on the percentage of subjects who had normal cortisol levels at the end of this period versus the subjects who received placebo.The FDA granted osilodrostat an orphan drug designation and granted the approval of Isturisa to Novartis.

See also
Levoketoconazole

References
Further reading
Turcu A, Smith JM, Auchus R,  et al. (October 2014). "Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions" </s>