<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 Colistin and can you explain it in depth? [/INST] Colistin, also known as polymyxin E, is an antibiotic medication used as a last-resort treatment for multidrug-resistant Gram-negative infections including pneumonia. These may involve bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter. It comes in two forms: colistimethate sodium can be injected into a vein, injected into a muscle, or inhaled, and colistin sulfate is mainly applied to the skin or taken by mouth.  Colistimethate sodium is a prodrug; it is produced by the reaction of colistin with formaldehyde and sodium bisulfite, which leads to the addition of a sulfomethyl group to the primary amines of colistin. Colistimethate sodium is less toxic than colistin when administered parenterally. In aqueous solutions it undergoes hydrolysis to form a complex mixture of partially sulfomethylated derivatives, as well as  colistin. Resistance to colistin began to appear as of 2015.Common side effects of the injectable form include kidney problems and neurological problems. Other serious side effects may include anaphylaxis, muscle weakness, and Clostridium difficile-associated diarrhea. The inhaled form may result in constriction of the bronchioles. It is unclear if use during pregnancy is safe for the fetus. Colistin is in the polymyxin class of medications. It works by breaking down the cytoplasmic membrane, which generally results in bacterial cell death.Colistin was discovered in 1947 and colistimethate sodium was approved for medical use in the United States in 1970. It is on the World Health Organizations List of Essential Medicines. The World Health Organization classifies colistin as critically important for human medicine. It is available as a generic medication. It is derived from bacteria of the genus Paenibacillus.

Medical uses
Antibacterial spectrum
Colistin has been effective in treating infections caused by Pseudomonas, Escherichia, and Klebsiella species. The following represents minimum inhibitory concentration (MIC) susceptibility data for a few medically significant microorganisms:
Escherichia coli: 0.12–128 μg/mL
Klebsiella pneumoniae: 0.25–128 μg/mL
Pseudomonas aeruginosa: ≤0.06–16 μg/mLFor example, colistin in combination with other drugs is used to attack P. aeruginosa biofilm infection in lungs of patients with cystic fibrosis.  Biofilms have a low-oxygen environment below the surface where bacteria are metabolically inactive, and colistin is highly effective in this environment. However, P. aeruginosa reside in the top layers of the biofilm, where they remain metabolically active.  This is because surviving tolerant cells migrate to the top of the biofilm via pili and form new aggregates via quorum sensing.

Administration and dosage
Forms
Two forms of colistin are available commercially: colistin sulfate and colistimethate sodium (colistin methanesulfonate sodium, colistin sulfomethate sodium).  Colistin sulfate is cationic; colistimethate sodium is anionic. Colistin sulfate is stable, whereas colistimethate sodium is readily hydrolysed to a variety of methanesulfonated derivatives.  Colistin sulfate and colistimethate sodium are eliminated from the body by different routes.  With respect to Pseudomonas aeruginosa, colistimethate is the inactive prodrug of colistin. The two drugs are not interchangeable.

Colistimethate sodium may be used to treat Pseudomonas aeruginosa infections in patients with cystic fibrosis, and it has come into recent use for treating multidrug-resistant Acinetobacter infection, although resistant forms have been reported. Colistimethate sodium has also been given intrathecally and intraventricularly in Acinetobacter baumannii and Pseudomonas aeruginosa meningitis and ventriculitis Some studies have indicated that colistin may be useful for treating infections caused by carbapenem-resistant isolates of Acinetobacter baumannii.
Colistin sulfate may be used to treat intestinal infections, or to suppress colonic flora.  Colistin sulfate is also used in topical creams, powders, and otic solutions.
Colistin A (polymyxin E1) and colistin B (polymyxin E2) can be purified individually to research and study their effects and potencies as separate compounds.

Dosage
Colistin sulfate and colistimethate sodium may both be given intravenously, but the dosing is complicated.  The different labeling of the parenteral products of colistin methanesulfonate in different parts of the world was noted by Li et al. Colistimethate sodium manufactured by Xellia (Colomycin injection) is prescribed in international units, whereas colistimethate sodium manufactured by Parkdale Pharmaceuticals (Coly-Mycin M Parenteral) is prescribed in milligrams of colistin base:

Colomycin 1,000,000 units is 80 mg colistimethate;
Coly-mycin M 150 mg colistin base is 360 mg colistimethate or 4,500,000 units.Because colistin was introduced into clinical practice over 50 years ago, it was never subject to the regulations that modern drugs are subject to, and therefore there is no standardised dosing of colistin and no detailed trials on pharmacology or pharmacokinetics. The optimal dosing of colistin for most infections is therefore unknown.  Colomycin has a recommended intravenous dose of 1 to 2 million units three times daily for patients weighing 60 kg or more with normal renal function. Coly-Mycin has a recommended dose of 2.5 to 5 mg/kg colistin base a day, which is equivalent to 6 to 12 mg/kg colistimethate sodium per day.  For a 60 kg man, therefore, the recommended dose for Colomycin is 240 to 480 mg of colistimethate sodium, yet the recommended dose for Coly-Mycin is 360 to 720 mg of colistimethate sodium.  Likewise, the recommended "maximum" dose for each preparation is different (480 mg for Colomycin and 720 mg for Coly-Mycin).  Each country has different generic preparations of colistin, and the recommended dose depends on the manufacturer.  This complete absence of any regulation or standardisation of dose makes intravenous colistin dosing difficult for the physician.Colistin has been used in combination with rifampicin; evidence of in vitro synergy exists, and the combination has been used successfully in patients. There is also in vitro evidence of synergy for colistimethate sodium used in combination with other antipseudomonal antibiotics.Colistimethate sodium aerosol (Promixin; Colomycin Injection) is used to treat pulmonary infections, especially in cystic fibrosis. In the UK, the recommended adult dose is 1–2 million units (80–160 mg) nebulised colistimethate twice daily. Nebulized colistin has also been used to decrease severe exacerbations in patients with chronic obstructive pulmonary disease and infection with Pseudomonas aeruginosa.

Resistance
Resistance to colistin is rare, but has been described. As of 2017, no agreement exists about how to define colistin resistance.  The Société Française de Microbiologie uses a MIC cut-off of 2 mg/L, whereas the British Society for Antimicrobial Chemotherapy sets a MIC cutoff of 4 mg/L or less as sensitive, and 8 mg/L or more as resistant.  No standards for describing colistin sensitivity are given in the United States.
The first known colistin-resistance gene in a plasmid which can be transferred between bacterial strains is mcr-1. It was found in 2011 in China on a pig farm where colistin is routinely used and became publicly known in November 2015. The presence of this plasmid-borne gene was confirmed starting December 2015 in South-East Asia, several European countries, and the United States. It is found in certain strains of the bacteria Paenibacillus polymyxa.India reported the first detailed colistin-resistance study, which mapped 13 colistin-resistant infections recorded over 18 months. It concluded that pan-drug-resistant infections, particularly those in the bloodstream, have a higher mortality. Multiple other cases were reported from other Indian hospitals. Although resistance to polymyxins is generally less than 10%, it is more frequent in the Mediterranean and South-East Asia (Korea and Singapore), where colistin resistance rates are increasing. Colistin-resistant E. coli was identified in the United States in May 2016.A recent review from 2016 to 2021 fount that E. coli is the dominant species harbouring mcr genes. Plasmid - mediated colistin resistance is also conferred upon other species that carry different genes resistant to antibiotics. The emergence of the mcr-9 gene is quite remarkable.Use of colistin to treat Acinetobacter baumannii infections has led to the development of resistant bacterial strains. They have also developed resistance to the antimicrobial compounds LL-37 and lysozyme, produced by the human immune system. This cross-resistance is caused by gain-of-function mutations to the pmrB gene, a phosphoethanolamine transferase (similar to mcr-1) located on the bacterial chromosome.Not all resistance to colistin and some other antibiotics is due to the presence of resistance genes. Heteroresistance, the phenomenon wherein apparently genetically identical microbes exhibit a range of resistance to an antibiotic, has been observed in some species of Enterobacter since at least 2016 and was observed in some strains of Klebsiella pneumoniae in 2017–2018. In some cases this phenomenon has significant clinical consequences.

Inherently resistant
Variable resistance
Aeromonas
Vibrio
Prevotella
Fusobacterium
Escherichia coli

Adverse reactions
The main toxicities described with intravenous treatment are nephrotoxicity (damage to the kidneys) and neurotoxicity (damage to the nerves), but this may reflect the very high doses given, which are much higher than the doses currently recommended by any manufacturer and for which no adjustment was made for pre-existing renal disease. Neuro- and nephrotoxic effects appear to be transient and subside on discontinuation of therapy or reduction in dose.At a dose of 160 mg colistimethate IV every eight hours, very little nephrotoxicity is seen.  Indeed, colistin appears to have less toxicity than the aminoglycosides that subsequently replaced it, and it has been used for extended periods up to six months with no ill effects. Colistin-induced nephrotoxicity is particularly likely in patients with hypoalbuminemia.The main toxicity described with aerosolised treatment is bronchospasm,  which can be treated or prevented with the use of β2-adrenergic receptor agonists such as salbutamol or following a desensitisation protocol.

Mechanism of action
Colistin is a polycationic peptide and has both hydrophilic and lipophilic moieties. These cationic regions interact with the bacterial outer membrane by displacing magnesium and calcium bacterial counter ions in the lipopolysaccharide. The hydrophobic and hydrophilic regions interact with the cytoplasmic membrane just like a detergent, solubilizing the membrane in an aqueous environment. This effect is bactericidal even in an isosmolar environment.Colistin binds to lipopolysaccharides and phospholipids in the outer cell membrane of Gram-negative bacteria. It competitively displaces divalent cations (Ca2+ and Mg2+) from the phosphate groups of membrane lipids, which leads to disruption of the outer cell membrane, leakage of intracellular contents and bacterial death.

Pharmacokinetics
No clinically useful absorption of colistin occurs in the gastrointestinal tract.  For systemic infection, colistin must therefore be given by injection.
Colistimethate is eliminated by the kidneys, but colistin is eliminated by non-renal mechanism(s) that are as of yet not characterised.

History
Colistin was first isolated in Japan in 1949 by Y. Koyama, from a flask of fermenting Bacillus polymyxa var. colistinus, and became available for clinical use in 1959.Colistimethate sodium, a less toxic prodrug, became available for injection in 1959. In the 1980s, polymyxin use was widely discontinued because of nephro- and neurotoxicity. As multi-drug resistant bacteria became more prevalent in the 1990s, colistin started to get a second look as an emergency solution, in spite of toxicity.Colistin has also been used in agriculture, particularly in China from the 1980s onwards. Chinese production for agriculture exceeded 2700 tons in 2015. China banned colistin use for livestock growth promotion in 2016.

Biosynthesis
The biosynthesis of colistin requires the use of three amino acids: threonine, leucine, and 2,4-diaminobutryic acid. The linear form of colistin is synthesized before cycliziation. Non-ribosomal peptide biosynthesis begins with a loading module and then the addition of each subsequent amino acid. The subsequent amino acids are added with the help of an adenylation domain (A), a peptidyl carrier protein domain (PCP), an epimerization domain (E), and a condensation domain (C). Cyclization is accomplished by a thioesterase. The first step is to have a loading domain, 6-methylheptanoic acid, associate with the A and PCP domains. Now with a C, A, and PCP domain that is associated with 2,4-diaminobutryic acid. This continues with each amino acid until the linear peptide chain is completed. The last module will have a thioesterase to complete the cyclization and form the product colistin.

References
Further reading
Reardon S (December 2015) </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 Oxycodone/ibuprofen 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 Onasemnogene abeparvovec and can you explain it in depth? [/INST] Onasemnogene abeparvovec, sold under the brand name Zolgensma, is a gene therapy medication used to treat spinal muscular atrophy (SMA). It is used as a one-time infusion into a vein.Onasemnogene abeparvovec works by providing a new copy of the gene that makes the human SMN protein.The treatment must be accompanied by a course of corticosteroids of at least two months. Common side effects include vomiting and increased liver enzymes.Onasemnogene abeparvovec was first approved for medical use in the United States in 2019 as a treatment for children less than two years old. It was later approved in other jurisdictions with similar scope. The approval scope in certain jurisdictions, including the European Union and Canada, is somewhat different.

Medical uses
Onasemnogene abeparvovec has been developed to treat spinal muscular atrophy, a disease linked to a mutation in the SMN1 gene on chromosome 5q and diagnosed predominantly in young children that causes progressive loss of muscle function and frequently death. The medication is administered as an intravenous infusion.The treatment is approved in the United States and certain other countries for use in children with spinal muscular atrophy up to the age of two, including at the presymptomatic stage of the disease. In the European Union and Canada, it is indicated for the treatment of patients with spinal muscular atrophy who either have a clinical diagnosis of spinal muscular atrophy type 1 or have up to three copies of the SMN2 gene.The medication is used with corticosteroids in an effort to protect the liver.

Adverse effects
Common adverse reactions may include nausea and elevated liver enzymes. Serious adverse reactions may include liver problems and low platelets. Transient elevated levels of cardiac troponin‑I were observed in clinical trials; the clinical importance of these findings is not known. However, cardiac toxicity was seen in studies of other animals.As the medication may reduce the platelet count, platelets may need to be checked before the medication is started, then weekly for the first month and every two weeks for the next two months until the level is back to baseline. Liver function should be monitored for three months after administration.

Mechanism of action
SMA is a neuromuscular disorder caused by a mutation in the SMN1 gene, which leads to a decrease in SMN protein, a protein necessary for survival of motor neurons. Onasemnogene abeparvovec is a biologic drug consisting of AAV9 virus capsids that contains a SMN1 transgene along with synthetic promoters. Upon administration, the AAV9 viral vector delivers the SMN1 transgene to the affected motor neurons, where it leads to an increase in SMN protein.

History
Onasemnogene abeparvovec was developed by the US biotechnology startup AveXis, which was acquired by Novartis in 2018, based on the work at the Institut de Myologie in France.The U.S. Food and Drug Administration (FDA) granted the application for onasemnogene abeparvovec-xioi fast track, breakthrough therapy, priority review, and orphan drug designations. The FDA also awarded the manufacturer a rare pediatric disease priority review voucher, and granted the approval of Zolgensma to AveXis Inc.In June 2015, the European Commission granted orphan designation for the drug. In July 2019, the drug was removed from the Committee for Medicinal Products for Human Use (CHMP) accelerated assessment program.In May 2019, onasemnogene abeparvovec received US FDA approval as a treatment for children less than two years old. Since 2019, the treatment has been reimbursed in Israel and Qatar. In March 2020, onasemnogene abeparvovec was granted regulatory approval in Japan with the label identical to the US one. Also in March 2020, the European Medicines Agency recommended a conditional marketing authorization for use in people with SMA type 1 or with any SMA type and having no more than three copies of the SMN2 gene. In May 2020, Onasemnogene abeparvovec was conditionally approved in Europe.In August 2020, onasemnogene abeparvovec was granted regulatory approval in Brazil by the Brazilian Health Regulatory Agency (ANVISA).In December 2020, onasemnogene abeparvovec was approved for medical use in Canada.Onasemnogene abeparvovec was approved for medical use in Australia in February 2021.An official approval in Russia was granted in December 2021.

Society and culture
Economics
The drug carries a list price of US$2.125 million per treatment, making it the most expensive medication in the world as of 2019. In its first full quarter of sales US$160 million of medication was sold.In Japan, the drug was made available through the public health care system on 20 May 2020, making it the most expensive drug covered by the Japanese public health care system. The Central Social Insurance Medical Council, responsible for approving the universal drug fee schedule in Japan, has negotiated the price down to ¥167,077,222 (approx </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 Acebutolol and can you explain it in depth? [/INST] Acebutolol, sold under the brand names Sectral among others, is a beta blocker for the treatment of hypertension and arrhythmias. Acebutolol is a cardioselective beta-1 blocker and has intrinsic sympathetic activity. It is commonly used in the treatment of angina.
It was patented in 1967 and approved for medical use in 1973.

Medical uses
Hypertension
Ventricular and atrial cardiac arrhythmia
Acute myocardial infarction in high-risk patients
Smith–Magenis syndrome

Contraindications
Stable or unstable angina (due to its partial agonist or ISA activity)

Side effects
The development of anti-nuclear antibodies (ANA) has been found in 10 to 30% of patients under treatment with acebutolol. A systemic disease with arthralgic pain and myalgias has been observed in 1%. A lupus erythematosus-like syndrome with skin rash and multiforme organ involvement is even less frequent. The incidence of both ANA and symptomatic disease under acebutolol is higher than under propranolol. Female patients are more likely to develop these symptoms than male patients. Some few cases of hepatotoxicity with increased liver enzymes (ALT, AST) have been seen. Altogether, 5 to 6% of all patients treated have to discontinue acebutolol due to intolerable side effects. When possible, the treatment should be discontinued gradually in order to avoid a withdrawal syndrome with increased frequency of angina and even precipitation of myocardial infarction.

Pharmacology
Acebutolol is a cardioselective beta-1 blocker which also considered a partial agonist due to its intrinsic sympathomimetic activity (ISA). This means it provides low-grade beta stimulation at rest but acting as typical beta-blockers when sympathetic activity is high. Among other drugs in the beta-blocker class, Acebutolol will provide beta-blockade effects to a lesser extent. Due to its cardioselectivity, Acebutolol is more suitable than non-cardioselective beta-blockers, in a patient with asthma or chronic obstructive pulmonary disease (COPD) who needs treatment with a beta-blocker. This cardio-specificity will minimize the anti-hypertensive effects as seen with non-specific beta blockers such as Propanalol and Nadolol.  (For these reasons, it may be a beta-blocker of choice in inclusion in Polypill strategies).  In doses lower than 800 mg daily its constricting effects on the bronchial system and smooth muscle vessels are only 10% to 30% of those observed under propranolol treatment, but there is experimental evidence that the cardioselective properties diminish at doses of 800 mg/day or more.
The drug has lipophilic properties and therefore crosses the blood–brain barrier. Acebutolol has no negative impact on serum lipids (cholesterol and triglycerides) </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 Sodium nitrite and can you explain it in depth? [/INST] Sodium nitrite is an inorganic compound with the chemical formula NaNO2. It is a white to slightly yellowish crystalline powder that is very soluble in water and is hygroscopic. From an industrial perspective, it is the most important nitrite salt. It is a precursor to a variety of organic compounds, such as pharmaceuticals, dyes, and pesticides, but it is probably best known as a food additive used in processed meats and (in some countries) in fish products.

Uses
Industrial chemistry
The main use of sodium nitrite is for the industrial production of organonitrogen compounds. It is a reagent for conversion of amines into diazo compounds, which are key precursors to many dyes, such as diazo dyes. Nitroso compounds are produced from nitrites. These are used in the rubber industry.It is used in a variety of metallurgical applications, for phosphatizing and detinning.Sodium nitrite is an effective corrosion inhibitor and is used as an additive in industrial greases, as an aqueous solution in closed loop cooling systems, and in a molten state as a heat transfer medium.

Food additive and preservative
Sodium nitrite is used to speed up the curing of meat and also impart an attractive pink color. Nitrite reacts with the meat myoglobin to cause color changes, first converting to nitrosomyoglobin (bright red), then, on heating, to nitrosohemochrome (a pink pigment).Historically, salt has been used for the preservation of meat. The salt-preserved meatproduct was usually brownish-gray in color. When sodium nitrite is added with the salt, the meat develops a red, then pink color, which is associated with cured meats such as ham, bacon, hot dogs, and bologna.In the early 1900s, irregular curing was commonplace. This led to further research surrounding the use of sodium nitrite as an additive in food, standardizing the amount present in foods to minimize the amount needed while maximizing its food additive role. Through this research, sodium nitrite has been found to give taste and color to the meat and inhibit lipid oxidation that leads to rancidity, with varying degrees of effectiveness for controlling growth of disease-causing microorganisms. The ability of sodium nitrite to address the above-mentioned issues has led to production of meat with extended storage life and has improved desirable color and taste. According to scientists working for the meat industry, nitrite has improved food safety. This view is disputed in the light of its ineffectiveness against botulism and the possible carcinogenic effects caused by adding nitrites to meat.Nitrite has the E number E250. Potassium nitrite (E249) is used in the same way. It is approved for usage in the EU, USA and Australia and New Zealand.In meat-processing, sodium nitrite is never used in a pure state but always mixed with common salt. This mixture is known as nitrited salt, curing salt or nitrited curing salt. In Europe, nitrited curing salt contains between 99.1% and 99.5% common
salt and between 0.5% and 0.9% nitrite. In the US, nitrited curing salt is dosed at 6% and must be remixed with salt before use.

Color and taste
The appearance and taste of meat is an important component of consumer acceptance. Sodium nitrite is responsible for the desirable red color (or shaded pink) of meat. Very little nitrite is needed to induce this change. It has been reported that as little as 2 to 14 parts per million (ppm) is needed to induce this desirable color change. However, to extend the lifespan of this color change, significantly higher levels are needed. The mechanism responsible for this color change is the formation of nitrosylating agents by nitrite, which has the ability to transfer nitric oxide that subsequently reacts with myoglobin to produce the cured meat color. The unique taste associated with cured meat is also affected by the addition of sodium nitrite. However, the mechanism underlying this change in taste is still not fully understood.

Inhibition of microbial growth
A 2018 study by the British Meat Producers Association determined that legally permitted levels of nitrite have no effect on the growth of the Clostridium botulinum bacteria which causes botulism, in line with the UKs Advisory Committee on the Microbiological Safety of Food opinion that nitrites are not required to prevent C. botulinum growth and extend shelf life.  In some countries, cured-meat products are manufactured without nitrites. For example, Parma ham, which has been produced without nitrite since 1993, was reported in 2018 to have caused no cases of botulism.Sodium nitrite has shown varying degrees of effectiveness for controlling growth of other spoilage or disease causing microorganisms. Although the inhibitory mechanisms are not well known, its effectiveness depends on several factors including residual nitrite level, pH, salt concentration, reductants present and iron content. The type of bacteria also affects sodium nitrites effectiveness. It is generally agreed that sodium nitrite is not effective for controlling Gram-negative enteric pathogens such as Salmonella and Escherichia coli.Other food additives (such as lactate and sorbate) provide similar protection against bacteria, but do not provide the desired pink color.

Inhibition of lipid peroxidation
Sodium nitrite is also able to effectively delay the development of oxidative rancidity. Lipid peroxidation is considered to be a major reason for the deterioration of quality of meat products (rancidity and unappetizing flavors). Sodium nitrite acts as an antioxidant in a mechanism similar to the one responsible for the coloring effect. Nitrite reacts with heme proteins and metal ions, neutralizing free radicals by nitric oxide (one of its byproducts). Neutralization of these free radicals terminates the cycle of lipid oxidation that leads to rancidity.

Medication
Sodium nitrite is used as a medication together with sodium thiosulfate to treat cyanide poisoning. It is recommended only in severe cases of cyanide poisoning. In those who have both cyanide poisoning and carbon monoxide poisoning sodium thiosulfate by itself is usually recommended. It is given by slow injection into a vein.Side effects can include low blood pressure, headache, shortness of breath, loss of consciousness, and vomiting. Greater care should be taken in people with underlying heart disease. The patients levels of methemoglobin should be regularly checked during treatment. While not well studied during pregnancy, there is some evidence of potential harm to the baby. Sodium nitrite is believed to work by creating methemoglobin that then binds with cyanide and thus removes it from the mitochondria.Sodium nitrite came into medical use in the 1920s and 1930s. It is on the World Health Organizations List of Essential Medicines.

Suicide
Several academic publications in 2020 and 2021 have discussed the toxicity of sodium nitrite, and an apparent recent increase in suicides from using sodium nitrite which had been ordered online. The usage of sodium nitrite as a suicide method has been heavily discussed on suicide forums. Sodium nitrite was also the culprit of the McCarthy et al v Amazon lawsuit alleging that Amazon knowingly assisted in the deaths of healthy children by selling them "suicide kits" as Amazons "frequently bought together" feature recommended buying sodium nitrate, an antiemetic and a suicide instruction book together.

Toxicity
Sodium nitrite is toxic. The LD50 in rats is 180 mg/kg and in human LDLo is 71 mg/kg. Yet, death by sodium nitrite ingestion can happen at lower dose. Sodium nitrite is sometimes used for homicide. The online marketplace eBay has globally prohibited the sale of sodium nitrite since 2019. To prevent accidental intoxication, sodium nitrite (blended with salt) sold as a food additive in the US is dyed bright pink to avoid mistaking it for plain salt or sugar. In other countries, nitrited curing salt is not dyed but is strictly regulated.

Occurrence in vegetables
Nitrites are not naturally occurring in vegetables in significant quantities. Boiling vegetables does not affect nitrite levels.The presence of nitrite in animal tissue is a consequence of metabolism of nitric oxide, an important neurotransmitter. Nitric oxide can be created de novo from nitric oxide synthase utilizing arginine or from ingested nitrite.

Pigs
Because of sodium nitrites high level of toxicity to swine (Sus scrofa) it is now being developed in Australia to control feral pigs and wild boar. The sodium nitrite induces methemoglobinemia in swine, i.e. it reduces the amount of oxygen that is released from hemoglobin, so the animal will feel faint and pass out, and then die in a humane manner after first being rendered unconscious. The Texas Parks and Wildlife Department operates a research facility at Kerr Wildlife Management Area, where they examine feral pig feeding preferences and bait tactics to administer sodium nitrite.

Cancer
Carcinogenicity is the ability or tendency of a chemical to induce tumors, increase their incidence or malignancy, or shorten the time of tumor occurrence.Adding nitrites to meat has been shown to generate known carcinogens such as nitrosamines; the World Health Organization (WHO) advises that each 50 g (1.8 oz) of "processed meats" eaten a day would raise the risk of getting bowel cancer by 18% over a lifetime. The World Health Organizations review of more than 400 studies concluded, in 2015, that there was sufficient evidence that "processed meats" caused cancer, particularly colon cancer; the WHOs International Agency for Research on Cancer (IARC) classified "processed meats" as carcinogenic to humans (Group 1); "processed meat" meaning meat that has been transformed through salting, curing, fermentation, smoking, or other processes to enhance flavour or improve preservation.).Nitrosamines can be formed during the curing process used to preserve meats, when sodium nitrite-treated meat is cooked, and also from the reaction of nitrite with secondary amines under acidic conditions (such as occurs in the human stomach). Dietary sources of nitrosamines include US cured meats preserved with sodium nitrite as well as the dried salted fish eaten in Japan. In the 1920s, a significant change in US meat curing practices resulted in a 69% decrease in average nitrite content. This event preceded the beginning of a dramatic decline in gastric cancer mortality. Around 1970, it was found that ascorbic acid (vitamin C), an antioxidant, inhibits nitrosamine formation. Consequently, the addition of at least 550 ppm of ascorbic acid is required in meats manufactured in the United States </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 Nilutamide and can you explain it in depth? [/INST] Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer. It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women. It is taken by mouth.Side effects in men include breast tenderness and enlargement, feminization, sexual dysfunction, and hot flashes. Nausea, vomiting, visual disturbances, alcohol intolerance, elevated liver enzymes, and lung disease can occur in both sexes. Rarely, nilutamide can cause respiratory failure and liver damage. These unfavorable side effects, along with a number of associated cases of death, have limited the use of nilutamide.Nilutamide acts as a selective antagonist of the androgen receptor (AR), preventing the effects of androgens like testosterone and dihydrotestosterone (DHT) in the body. Because most prostate cancer cells rely on these hormones for growth and survival, nilutamide can slow the progression of prostate cancer and extend life in men with the disease.Nilutamide was discovered in 1977 and was first introduced for medical use in 1987. It became available in the United States in 1996. The drug has largely been replaced by newer and improved NSAAs, namely bicalutamide and enzalutamide, due to their better efficacy, tolerability, and safety, and is now rarely used.It is on the World Health Organizations List of Essential Medicines.

Medical uses
Prostate cancer
Nilutamide is used in prostate cancer in combination with a gonadotropin-releasing hormone (GnRH) analogue at a dosage of 300 mg/day (150 mg twice daily) for the first 4 weeks of treatment, and 150 mg/day thereafter. It is not indicated as a monotherapy in prostate cancer. Only one small non-comparative study has assessed nilutamide as a monotherapy in prostate cancer.Nilutamide has been used to prevent the effects of the testosterone flare at the start of GnRH agonist therapy in men with prostate cancer.

Transgender hormone therapy
Nilutamide has been studied for use as a component of feminizing hormone therapy for transgender women. It has been assessed in at least five small clinical studies for this purpose in treatment-naive subjects. In these studies, nilutamide monotherapy at a dosage of 300 mg/day, induced observable signs of clinical feminization in young transgender women (age range 19–33 years) within 8 weeks, including breast development, decreased body hair (though not facial hair), decreased morning erections and sex drive, and positive psychological and emotional changes. Signs of breast development occurred in all subjects within 6 weeks and were associated with increased nipple sensitivity, and along with decreased hair growth, were the earliest sign of feminization.Nilutamide did not change the size of the prostate gland (which is the same as with high-dosage cyproterone acetate and ethinylestradiol treatment for as long as 18 months), but was found to alter its histology, including increased stromal tissue with a significant reduction in acini and atrophic epithelial cells, indicating glandular atrophy. In addition, readily apparent histological changes were observed in the testes, including a reduction in tubular and interstitial cells.Nilutamide was found to more than double luteinizing hormone (LH) and testosterone levels and to triple estradiol levels. In contrast, follicle-stimulating hormone levels remained unchanged. A slight but significant increase in prolactin levels was observed, and levels of sex hormone-binding globulin increased as well. The addition of ethinylestradiol to nilutamide therapy after 8 weeks abolished the increase in LH, testosterone, and estradiol levels and dramatically suppressed testosterone levels, into the castrate range. Both nilutamide alone and the combination of nilutamide and estrogen were regarded as resulting in effective and favorable antiandrogen action and feminization in transgender women.

Skin conditions
Nilutamide has been assessed in the treatment of acne and seborrhea in women in at least one small clinical study. The dosage used was 200 mg/day, and in the study, "seborrhea and acne decreased markedly within the first month and practically disappeared after 2 months of [nilutamide] treatment."

Available forms
Nilutamide is available in the form of 50 and 150 mg oral tablets.

Side effects
General side effects of NSAAs, including nilutamide, include gynecomastia, breast pain/tenderness, hot flashes (67%), depression, fatigue, sexual dysfunction (including loss of libido and erectile dysfunction), decreased muscle mass, and decreased bone mass with an associated increase in fractures. Also, nausea (24–27%), vomiting, constipation (20%), and insomnia (16%) may occur with nilutamide. Nilutamide monotherapy is known to eventually induce gynecomastia in 40 to 80% of men treated with it for prostate cancer, usually within 6 to 9 months of treatment initiation.Relative to other NSAAs, nilutamide has been uniquely associated with mild and reversible visual disturbances (31–58%) including delayed ocular adaptation to darkness and impaired color vision, a disulfiram-like alcohol intolerance (19%), interstitial pneumonitis (0.77–2.4%) (which can result in dyspnea (1%) as a secondary effect and can progress to pulmonary fibrosis), and hepatitis (1%), and has a higher incidence of nausea and vomiting compared to other NSAAs. The incidence of interstitial pneumonitis with nilutamide has been found to be much higher in Japanese patients (12.6%), warranting particular caution in Asian individuals. There is a case report of simultaneous liver and lung toxicity in a nilutamide-treated patient.There is also a risk of hepatotoxicity with nilutamide, though occurrence is very rare and the risk is significantly less than with flutamide. The incidence of abnormal liver function tests (e.g., elevated liver enzymes) has been variously reported as 2 to 33% with nilutamide. For comparison, the risk of elevated liver enzymes has been reported as 4 to 62% in the case of flutamide. The risk of hepatotoxicity with nilutamide has been described as far less than with flutamide. Fulminant hepatic failure has been reported for nilutamide, with fatal outcome. Between 1986 and 2003, the numbers of published cases of hepatotoxicity for antiandrogens totaled 46 for flutamide, 21 for cyproterone acetate, 4 for nilutamide, and 1 for bicalutamide. Similarly to flutamide, nilutamide exhibits mitochondrial toxicity in hepatocytes by inhibiting respiratory complex I (NADH ubiquinone oxidoreductase) (though not respiratory complexes II, III, or IV) in the electron transport chain, resulting in reduced ATP and glutathione production and thus decreased hepatocyte survival. The nitro group of nilutamide has been theorized to be involved in both its hepatotoxicity and its pulmonary toxicity.

Pharmacology
Pharmacodynamics
Antiandrogenic activity
Nilutamide acts as a selective competitive silent antagonist of the AR (IC50 = 412 nM), which prevents androgens like testosterone and DHT from activating the receptor. The affinity of nilutamide for the AR is about 1 to 4% of that of testosterone and is similar to that of bicalutamide and 2-hydroxyflutamide. Similarly to 2-hydroxyflutamide, but unlike bicalutamide, nilutamide is able to weakly activate the AR at high concentrations. It does not inhibit 5α-reductase.Like other NSAAs such as flutamide and bicalutamide, nilutamide, without concomitant GnRH analogue therapy, increases serum androgen (by two-fold in the case of testosterone), estrogen, and prolactin levels due to inhibition of AR-mediated suppression of steroidogenesis via negative feedback on the hypothalamic–pituitary–gonadal axis. As such, though nilutamide is still effective as an antiandrogen as a monotherapy, it is given in combination with a GnRH analogue such as leuprorelin in prostate cancer to suppress androgen concentrations to castrate levels in order to attain maximal androgen blockade (MAB).Like flutamide and bicalutamide, nilutamide is able to cross the blood–brain barrier and has central antiandrogen actions.

Cytochrome P450 inhibition
Nilutamide is known to inhibit several cytochrome P450 enzymes, including CYP1A2, CYP2C9, and CYP3A4, and can result in increased levels of medications that are metabolized by these enzymes. It has also been found to inhibit the enzyme CYP17A1 (17α-hydroxylase/17,20-lyase) in vitro and thus the biosynthesis of androgens. However, nilutamide monotherapy significantly increases testosterone levels in vivo, so the clinical significance of this finding is uncertain.

Pharmacokinetics
Nilutamide has an elimination half-life of 23 to 87 hours, with a mean of 56 hours, or about two days; this allows for once-daily administration. Steady state (plateau) levels of the drug are attained after two weeks of administration with a dosage of 150 mg twice daily (300 mg/day total). It is metabolized by CYP2C19, with at least five metabolites. Virtually all of the antiandrogenic activity of nilutamide comes from the parent drug (as opposed to metabolites).

Chemistry
Nilutamide is structurally related to the first-generation NSAAs flutamide and bicalutamide as well as to the second-generation NSAAs enzalutamide and apalutamide.

History
Nilutamide was developed by Roussel and was first described in 1977. It was first introduced for medical use in 1987 in France and was the second NSAA to be marketed, with flutamide preceding it and bicalutamide following it in 1995. It was not introduced until 1996 in the United States.

Society and culture
Generic names
Nilutamide is the generic name of the drug and its INN, USAN, BAN, and DCF.

Brand names
Nilutamide is marketed under the brand name Nilandron in the United States and under the brand name Anandron elsewhere in the world such as in Australia, Canada, Europe, and Latin America.

Availability
Nilutamide is or has been available in the United States, Canada, Australia, Europe, Latin America, Egypt, and Lebanon. In Europe, it is or has been available in Belgium, Croatia, the Czech Republic, Finland, France, the Netherlands, Norway, Poland, Portugal, Serbia, Sweden, Switzerland, and Yugoslavia. in Latin America, it is or has been available in Argentina, Brazil, and Mexico.

Research
The combination of an estrogen and nilutamide as a form of combined androgen blockade for the treatment of prostate cancer has been studied in animals.Nilutamide has been studied in the treatment of advanced breast cancer.

References
Further reading
Raynaud JP, Bonne C, Moguilewsky M, Lefebvre FA, Bélanger A, Labrie F (1984). "The pure antiandrogen RU 23908 (Anandron), a candidate of choice for the combined antihormonal treatment of prostatic cancer: a review". Prostate. 5 (3): 299–311. doi:10.1002/pros.2990050307. PMID 6374639. S2CID 85417869.
Moguilewsky M, Bertagna C, Hucher M (1987). "Pharmacological and clinical studies of the antiandrogen Anandron". J. Steroid Biochem. 27 (4–6): 871–5. doi:10.1016/0022-4731(87)90162-2. PMID 3320565.
Du Plessis DJ (1991). "Castration plus nilutamide vs castration plus placebo in advanced prostate cancer. A review". Urology. 37 (2 Suppl): 20–4. doi:10.1016/0090-4295(91)80097-q. PMID 1992599.
Creaven PJ, Pendyala L, Tremblay D (1991). "Pharmacokinetics and metabolism of nilutamide". Urology. 37 (2 Suppl): 13–9. doi:10.1016/0090-4295(91)80096-p. PMID 1992598.
Harris MG, Coleman SG, Faulds D, Chrisp P (1993). "Nilutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer". Drugs Aging. 3 (1): 9–25. doi:10.2165/00002512-199303010-00002. PMID 8453188.
Dole EJ, Holdsworth MT (1997). "Nilutamide: an antiandrogen for the treatment of prostate cancer". Ann Pharmacother </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 Lodine 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 Ganirelix and can you explain it in depth? [/INST] Ganirelix acetate (or diacetate), sold under the brand names Orgalutran and Antagon  among others, is an injectable competitive gonadotropin-releasing hormone antagonist (GnRH antagonist). It is primarily used in assisted reproduction to control ovulation. The drug works by blocking the action of GnRH upon the pituitary, thus rapidly suppressing the production and action of LH and FSH. Ganirelix is used in fertility treatment to prevent premature ovulation that could result in the harvesting of eggs that are too immature to be used in procedures such as in vitro fertilization.GnRH agonists are also sometimes used in reproductive therapy, as well as to treat disorders involving sex-steroid hormones, such as endometriosis. One advantage of using GnRH antagonists is that repeated administration of GnRH agonists results in decreased levels of gonadotropins and sex steroids due to desensitization of the pituitary. This is avoided when using GnRH antagonists such as ganirelix. The success of ganirelix in reproductive therapy has been shown to be comparable to that when using GnRH agonists.

Medical uses
Ganirelix is used as a fertility treatment drug for women. Specifically, it is used to prevent premature ovulation in people with ovaries undergoing fertility treatment involving ovarian hyperstimulation that causes the ovaries to produce multiple eggs. When such premature ovulation occurs, the eggs released by the ovaries may be too immature to be used in in-vitro fertilization. Ganirelix prevents ovulation until it is triggered by injecting human chorionic gonadotrophin (hCG).Ganirelix is administered by a subcutaneous injection of 250 µg once per day during the mid to late follicular phase of a patients menstrual cycle. Treatment should start on the 5th or 6th day after the start of ovarian stimulation, and the mean duration for its use is five days. Preferably, the subcutaneous injections are delivered in the upper leg, and the patient can be trained to do this themself. Continued use of the drug should take place until the administration of hCG begins. hCG administration is begun when a sufficient number of follicles have developed due to the effects of endogenous and or exogenously administered follicle stimulating hormone.

Contraindications
Ganirelix should not be used in women who are already pregnant, and because of this the onset of pregnancy must be ruled out before it is administered. Women using ganirelix should not breast feed, as it is not known whether ganirelix is excreted in breast milk.

Side effects
Clinical studies have shown that the most common side effect is a slight reaction at the site of injection in the form of redness, and sometimes swelling. Clinical studies have shown that, one hour after injection, the incidence of at least one moderate or severe local skin reaction per treatment cycle was 12% in 4 patients treated with ganirelix and 25% in patients treated subcutaneously with a GnRH agonist. The local reactions generally disappear within 4 hours after administration.
Other reported side effects are some that are known to be associated with ovarian hyperstimulation, including gynecological abdominal pain, headache, vaginal bleeding, nausea, and gastrointestinal abdominal pain. In some rare cases, less than 1 user in 10,000, hypersensitivity to ganirelix can cause anaphylactoid reactions, most likely due to allergy.

Birth defects
A follow-up analysis for ganirelix done by the Marketing Authorisation Holder compared the number of congenital malformations between individuals whose mothers were treated with ganirelix compared with individuals whose mothers were treated with a GnRH agonist. The total number of congenital malformations was higher in the ganirelix group than in the GnRH agonist group (7.6% vs. 5.5%). This falls within the range for the normal incidence of congenital malformations, and current data do not suggest that ganirelix increases the incidence of congenital malformations or anomalies. No important differences in the frequency of ectopic pregnancies and miscarriage were noted with the use of ganirelix.

Interactions
Currently, no studies have been done to assess the possible drug-drug interactions between ganirelix and other drugs.

Pharmacology
Pharmacodynamics
Ganierlix is a synthetic peptide that works as an antagonist against gonadotropin-releasing hormone (GnRH) ("Ganirelix acetate injection," 2009). Ganirelix competitively blocks GnRH receptors on the pituitary gonadotroph, quickly resulting in the suppression of gonadotropin secretion. This suppression is easily reversed by discontinuation of ganirelix administration </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 Ceftazidime/avibactam and can you explain it in depth? [/INST] Ceftazidime/avibactam, sold under the brand name Avycaz among others, is a fixed-dose combination medication composed of ceftazidime, a cephalosporin antibiotic, and avibactam, a β-lactamase inhibitor. It is used to treat complicated intra-abdominal infections, urinary tract infections, and pneumonia. It is only recommended when other options are not appropriate. It is given by injection into a vein.Common side effect include nausea, fever, liver problems, headache, trouble sleeping, and pain at the site of injection. Severe side effects may include anaphylaxis, seizures, and Clostridioides difficile-associated diarrhea. While use appears to be safe in pregnancy the medication has not been well studied in this group. Doses should be adjusted in those with kidney problems. Ceftazidime works by interfering with the building of the bacterial cell wall while avibactam works by preventing ceftazidimes breakdown.The combination was approved for medical use in the United States and the European Union in 2015. It is on the World Health Organizations List of Essential Medicines. Resistances are increasingly been reported with United States, Greece and Italy accounting for 80% of cases.

Medical use
Ceftazidime/avibactam is used to treat certain multidrug-resistant gram-negative infections.Ceftazidime/avibactam is used for the treatment of:

complicated intra-abdominal infections. In these cases it is often used in combination with metronidazole, which provides coverage for anaerobic pathogens.
complicated urinary tract infections, including acute pyelonephritis, in adults.
hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia.

Bacterial activity
For many bacterial infections, it offers little or no advantage over ceftazidime monotherapy, due to the widespread expression of resistance mechanisms other than β-lactamase production. These include Haemophilus, Moraxella and Neisseria pathogens, and infections caused by Acinectobacter baumannii.The antibacterial spectrum of ceftazidime/avibactam includes nearly all Enterobacteriaceae, including ceftazidime-resistant strains. The activity of ceftazidime/avibactam against the important hospital pathogen Pseudomonas aeruginosa is variable, due to the potential presence of other resistance mechanisms in addition to β-lactamase production. Synergy was observed for avibactam with ceftazidime in the Burkholderia cepacia complex.

Adverse events
When used to treat life-threatening infections, ceftazidime/avibactam is more likely than carbapenem antibiotics to cause serious adverse events, including worsening kidney function and gastrointestinal adverse effects.

Mechanism of action
Bacterial resistance to cephalosporins is often due to bacterial production of β-lactamase enzymes that deactivate these antibiotics </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 Cefotetan 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 Sodium ferric gluconate complex 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 Hydralazine and can you explain it in depth? [/INST] Hydralazine, sold under the brand name Apresoline among others, is a medication used to treat high blood pressure and heart failure. This includes high blood pressure in pregnancy and very high blood pressure resulting in symptoms. It has been found to be particularly useful in heart failure, together with isosorbide dinitrate, for treatment of people of African descent. It is given by mouth or by injection into a vein. Effects usually begin around 15 minutes and last up to six hours.Common side effects include headache and fast heart rate. It is not recommended in people with coronary artery disease or in those with rheumatic heart disease that affects the mitral valve. In those with kidney disease a low dose is recommended. Hydralazine is in the vasodilator family of medications, so it is believed to work by causing the dilation of blood vessels.Hydralazine was discovered while scientists at Ciba were looking for a treatment for malaria. It was patented in 1949. It is on the World Health Organizations List of Essential Medicines.  In 2019, it was the 99th most commonly prescribed medication in the United States, with more than 6 million prescriptions. Hydralazine has an adverse drug event of inducing drug-induced lupus and this drugs use is declining with more prescribers prescribing calcium channel blockers.

Medical use
Hydralazine is not used as a primary drug for treating hypertension because it elicits a reflex sympathetic stimulation of the heart (the baroreceptor reflex). The sympathetic stimulation may increase heart rate and cardiac output, and in people with coronary artery disease may cause angina pectoris or myocardial infarction. Hydralazine may also increase plasma renin concentration, resulting in fluid retention. To prevent these undesirable side effects, hydralazine is usually prescribed in combination with a beta blocker (e.g., propranolol) and a diuretic. Beta-blockers licensed to treat heart failure in the UK include bisoprolol, carvedilol, and nebivolol.Hydralazine is used to treat severe hypertension, but is not a first-line therapy for essential hypertension. Hydralazine is often used to treat hypertension in pregnancy, though, with either labetalol and/or methyldopa.Hydralazine is commonly used in combination with isosorbide dinitrate for the treatment of congestive heart failure in self-identified African-American populations. This preparation, isosorbide dinitrate/hydralazine, was the first race-based prescription drug.It should not be used in people who have tachycardia, heart failure, constrictive pericarditis, lupus, a dissecting aortic aneurysm, or porphyria.

Adverse effects
Prolonged treatment may cause a syndrome similar to lupus, which can become fatal if the symptoms are not noticed and drug treatment stopped </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 Saquinavir and can you explain it in depth? [/INST] Saquinavir (SQV), sold under the brand names Invirase and Fortovase, is an antiretroviral drug used together with other medications to treat or prevent HIV/AIDS. Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect. It is taken by mouth.Common side effects include nausea, vomiting, diarrhea, and feeling tired. More serious side effects include problems with QT prolongation, heart block, high blood lipids, and liver problems. It appears to be safe in pregnancy. It is in the protease inhibitor class and works by blocking the HIV protease.Saquinavir was patented in 1988 and first sold in 1995.

Medical uses
Saquinavir is used together with other medications to treat or prevent HIV/AIDS. Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect.

Side effects
The most frequent adverse events with saquinavir in either formulation are mild  gastrointestinal symptoms, including diarrhoea, nausea, loose stools and abdominal discomfort. Invirase is better tolerated than Fortovase.

Bioavailability and drug interactions
Saquinavir, in the Invirase formulation, has a low and variable oral bioavailability, when given alone. The Fortovase formulation at the standard dosage delivers approximately eightfold more active drug than Invirase, also at the standard dosage.In the clinic, it was found that the oral bioavailability of saquinavir in both formulations significantly increases when patients also receive the PI ritonavir. For patients, this has the major benefit that they can take less saquinavir, while maintaining sufficient saquinavir blood plasma levels to efficiently suppress the replication of HIV.The mechanism behind this welcome observation was not directly known, but later it was determined that ritonavir inhibits the cytochrome P450 3A4 isozyme. Normally, this enzyme metabolizes saquinavir to an inactive form, but with the ritonavir inhibiting this enzyme, the saquinavir blood plasma levels increased considerably. Additionally, ritonavir also inhibits multidrug transporters, although to a much lower extent.Unlike other protease inhibitors, the absorption of saquinavir seems to be improved by omeprazole.

Mechanism of action
Saquinavir is a protease inhibitor. Proteases are enzymes that cleave protein molecules into smaller fragments. HIV protease is vital for both viral replication within the cell and release of mature viral particles from an infected cell </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 Cilostazol and can you explain it in depth? [/INST] Cilostazol, sold under the brand name Pletal among others, is a medication used to help the symptoms of intermittent claudication in peripheral vascular disease. If no improvement is seen after 3 months, stopping the medication is reasonable. It may also be used to prevent stroke. It is taken by mouth.Common side effects include headache, diarrhea, dizziness, and cough. Serious side effects may include decreased survival in those with heart failure, low platelets, and low white blood cells. Cilostazol is a phosphodiesterase 3 inhibitor which works by inhibiting platelet aggregation and dilating arteries.Cilostazol was approved for medical use in the United States in 1999. It is available as a generic medication. In 2017, it was the 301st most commonly prescribed medication in the United States, with more than one million prescriptions.

Medical uses
Cilostazol is approved for the treatment of intermittent claudication in the United States and United Kingdom.Cilostazol is also used for secondary stroke prevention, though to date no regulatory body has approved it specifically for that indication.

Heart failure
Cilostazol is dangerous for people with severe heart failure. Cilostazol has been studied in people without heart failure, without evidence of harm, but much more data would be needed to determine no risk exists </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 Dutasteride/tamsulosin 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 Celecoxib and can you explain it in depth? [/INST] Celecoxib, sold under the brand name Celebrex among others, is a COX-2 inhibitor and nonsteroidal anti-inflammatory drug (NSAID). It is used to treat the pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis, ankylosing spondylitis, painful menstruation, and juvenile rheumatoid arthritis. It may also be used to decrease the risk of colorectal adenomas in people with familial adenomatous polyposis. It is taken by mouth. Benefits are typically seen within an hour.Common side effects include abdominal pain, nausea, and diarrhea. Serious side effects may include heart attacks, strokes, gastrointestinal perforation, gastrointestinal bleeding, kidney failure, and anaphylaxis. Use is not recommended in people at high risk for heart disease. The risks are similar to other NSAIDs, such as ibuprofen and naproxen. Use in the later part of pregnancy or during breastfeeding is not recommended.Celecoxib was patented in 1993 and came into medical use in 1999. It is available as a generic medication. In 2019, it was the 102nd most commonly prescribed medication in the United States, with more than 6 million prescriptions.

Medical uses
Celecoxib is indicated for the treatment of osteoarthritis, rheumatoid arthritis, acute pain, musculoskeletal pain, painful menstruation, ankylosing spondylitis, juvenile rheumatoid arthritis, and to reduce the number of colon and rectal polyps in people with familial adenomatous polyposis. It may be used in children with juvenile rheumatoid arthritis who are older than two years of age and weigh more than 10 kg (22 lb).For postoperative pain, it is more or less equal to ibuprofen. For pain relief, it is similar to paracetamol (acetaminophen), which is the first line treatment for osteoarthritis.Evidence of effects are not clear as a number of studies done by the manufacturer have not been released for independent analysis.

Familial adenomatous polyposis
It has been used to reduce colon and rectal polyps in people with familial adenomatous polyposis, but it is not known if it decreases rates of cancer, so it is not a good choice for this reason.

Adverse effects
Cardiovascular events:  NSAIDs are associated with an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including myocardial infarction and stroke. Risk may be increased with duration of use or pre-existing cardiovascular risk factors or disease. Individual cardiovascular risk profiles should be evaluated prior to prescribing. New-onset hypertension or exacerbation of hypertension may occur (NSAIDs may impair response to thiazide or loop diuretics), and may contribute to cardiovascular events; monitor blood pressure and use with caution in patients with hypertension. May cause sodium and fluid retention, use with caution in patients with edema or heart failure. Long-term cardiovascular risk in children has not been evaluated. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternative therapies should be considered for patients at high risk. The increased risk is about 37%.
Gastrointestinal events:  NSAIDs may increase risk of serious gastrointestinal (GI) ulceration, bleeding, and perforation (may be fatal). These events may occur at any time during therapy and without warning. Use caution with a history of GI disease (bleeding or ulcers), concurrent therapy with aspirin, anticoagulants and/or corticosteroids, smoking, use of alcohol, the elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with ≤325 mg of aspirin, a substantial increase in the risk of gastrointestinal complications (e.g., ulcer) occurs; concomitant gastroprotective therapy (e.g., proton pump inhibitors) is recommended. The increased risk is about 81%.
Hematologic effects: Anemia may occur; monitor hemoglobin or hematocrit in people on long-term treatment. Celecoxib does not usually affect prothrombin time, partial thromboplastin time or platelet counts; it does not inhibit platelet aggregation at approved doses.People with prior history of ulcer disease or GI bleeding require special precaution. Moderate to severe liver impairment or GI toxicity can occur with or without warning symptoms in people treated with NSAIDs.
In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.

Allergy
Celecoxib contains a sulfonamide moiety and may cause allergic reactions in those allergic to other sulfonamide-containing drugs. This is in addition to the contraindication in people with severe allergies to other NSAIDs. However, it has a low (reportedly 4%) chance of inducing cutaneous reactions among persons who have a history of such reactions to aspirin or nonselective NSAIDs. NSAIDs may cause serious skin adverse events, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis; events may occur without warning and in patients without prior known sulfa allergy. Use should be discontinued at first sign of rash (or any other hypersensitivity).

Heart attack and stroke
A 2013 meta-analysis of hundreds of clinical trials found that coxibs (the class of drugs that includes celecoxib) increase the risk of major cardiovascular problems by about 37% over placebo. In 2016, a randomized trial provided strong evidence that treatment with celecoxib is not more likely to result in poor cardiovascular outcomes than treatment with naproxen or ibuprofen. As a result, in 2018 an FDA advisory panel concluded that celecoxib poses no greater risk for causing heart attacks and strokes than the commonly-used NSAIDs ibuprofen or naproxen and recommended that the FDA consider changing its advice to physicians regarding celecoxibs safety.The COX-2 inhibitor rofecoxib (Vioxx) was removed from the market in 2004 due to its risk. Like all NSAIDs on the US market, celecoxib carries an FDA-mandated "black box warning" for cardiovascular and gastrointestinal risk. In February 2007, the American Heart Association warned that with respect to "patients with a prior history of or at high risk for cardiovascular disease... use of COX-2 inhibitors for pain relief should be limited to patients for whom there are no appropriate alternatives, and then, only in the lowest dose and for the shortest duration necessary."In 2005, a study published in the Annals of Internal Medicine found that cardiovascular effects of COX-2 inhibitors differ, depending on the drug. Other COX-2-selective inhibitors, such as rofecoxib, have significantly higher myocardial infarction rates than celecoxib. In April 2005, after an extensive review of data, the FDA concluded it was likely "that there is a class effect for increased CV risk for all NSAIDs". In a 2006 meta-analysis of randomized control studies, the cerebrovascular events associated with COX-2 inhibitors were examined, but no significant risks were found when compared to nonselective NSAIDs or placebos.

Drug interactions
Celecoxib is predominantly metabolized by cytochrome P450 2C9. Caution must be exercised with concomitant use of 2C9 inhibitors, such as fluconazole, which can greatly elevate celecoxib serum levels. If used concomitantly with lithium, celecoxib increases lithium plasma levels. If used concomitantly with warfarin, celecoxib may result in increased risk of bleeding complications. The risk of bleeding and gastric ulcers also increase further when SSRIs are used in combination with celecoxib. The drug may increase the risk of kidney failure with angiotensin-converting enzyme-inhibitors, such as lisinopril, and diuretics, such as hydrochlorothiazide.

Pregnancy
In the US FDAs pregnancy categories, the drug is category C prior to 30 weeks gestation, and category D starting at 30 weeks gestation.

Mechanism of action
Anti-inflammatory
A highly selective reversible inhibitor of the COX-2 isoform of cyclooxygenase, celecoxib inhibits the transformation of arachidonic acid to prostaglandin precursors. Therefore, it has analgesic and anti-inflammatory properties.  Nonselective NSAIDs (such as aspirin, naproxen, and ibuprofen) inhibit both COX-1 and COX-2. Inhibition of COX-1 (which celecoxib does not inhibit at therapeutic concentrations) inhibits the production of prostaglandins and the production of thromboxane A2, a platelet activator. COX-1 is traditionally defined as a constitutively expressed "housekeeping" enzyme and plays a role in the protection of the gastrointestinal mucosa, kidney hemodynamics, and platelet thrombogenesis. COX-2, on the contrary, is extensively expressed in cells involved in inflammation and is upregulated by bacterial lipopolysaccharides, cytokines, growth factors, and tumor promoters. Celecoxib is approximately 10-20 times more selective for COX-2 inhibition over COX-1. It binds with its polar sulfonamide side chain to a hydrophilic side pocket region close to the active COX-2 binding site. In theory, this selectivity allows celecoxib and other COX-2 inhibitors to reduce inflammation (and pain) while minimizing gastrointestinal adverse drug reactions (e.g. stomach ulcers) that are common with nonselective NSAIDs.

Anti-cancer
For its use in reducing colon polyps, celecoxib affects genes and pathways involved in inflammation and malignant transformation in tumors, but not normal tissues.Celecoxib binds to Cadherin-11 (which may explain the reduction in cancer progression).

Structure-activity relationship
The Searle research group found the two appropriately substituted aromatic rings must reside on adjacent positions about the central ring for adequate COX-2 inhibition. Various modifications can be made to the 1,5-diarylpyrazole moiety to deduce the structure-activity relationship of celecoxib. A para-sulfamoylphenyl at position 1 of the pyrazole was found to have a higher potency for COX-2 selective inhibition than a para-methoxyphenyl (see structures 1 and 2, below). In addition, a 4-(methylsulfonyl)phenyl or 4-sulfamoylphenyl is known to be necessary for COX-2 inhibition. For instance, replacing either of these entities with a –SO2NHCH3 substituent diminishes COX-2 inhibitory activity as noted with a very high inhibitory concentration-50 (see structures 3 – 5). At the 3-position of the pyrazole, a trifluoromethyl or difluoromethyl provides superior selectivity and potency compared to a fluoromethyl or methyl substitution (see structures 6 – 9).Celecoxib is compound 22; the 4-sulfamoylphenyl on the 1-pyrazol substituent is required for COX-2 inhibition and the 4-methyl on the 5-pyrazol system has low steric hindrance to maximize potency, while the 3-trifluoromethyl group provides superior selectivity and potency. To explain the selectivity of celecoxib, it is necessary to analyze the free energy of binding difference between the drug molecule and COX-1 compared to COX-2 enzymes. The structural modifications highlight the importance of binding to residue 523 in the side binding pocket of the cyclooxygenase enzyme, which is an isoleucine in COX-1 and a valine in COX-2. This mutation appears to contribute to COX-2 selectivity by creating steric hindrance between the sulfonamide oxygen and the methyl group of Ile523 that effectively destabilizes the celecoxib-COX-1 complex.

History
It was initially marketed by Pfizer for arthritis. Celecoxib and other COX-2 selective inhibitors, valdecoxib, parecoxib, and mavacoxib, were discovered by a team at the Searle division of Monsanto led by John Talley.Two lawsuits arose over discovery of celecoxib. Daniel L. Simmons of Brigham Young University (BYU) discovered the COX-2 enzyme in 1988, and in 1991, BYU entered into a collaboration with Monsanto to develop drugs to inhibit it. Monsantos pharmaceutical division was later purchased by Pfizer, and in 2006, BYU sued Pfizer for breach of contract, claiming Pfizer did not properly pay contractual royalties back to BYU. A settlement was reached in April 2012, in which Pfizer agreed to pay $450 million. Other important discoveries in COX-2 were made at University of Rochester, which patented the discoveries. When the patent issued, the university sued Searle (later Pfizer) in a case called, University of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004). The court ruled in favor of Searle in 2004, holding in essence that the university had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2 and therefore the patent was invalid.According to the National Academy of Sciences, Philip Needleman, who was vice president of Monsanto in 1989 and president of Searle in 1993 oversaw research into COX-2 that led to the development of the anti-inflammatory drug celecoxib (Celebrex). He became senior executive vice president and chief scientist of Pharmacia from 2000 to 2003. Celecoxib was discovered and developed by G. D. Searle & Company and was approved by the FDA on 31 December 1998. It was co-promoted by Monsanto Company (parent company of Searle) and Pfizer under the brand name Celebrex. Monsanto merged with Pharmacia, from which the Medical Research Division was acquired by Pfizer, giving Pfizer ownership of Celebrex. The drug was at the core of a major patent dispute that was resolved in Searles favor (later Pfizer) in 2004. In University of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004), the University of Rochester claimed that United States Pat. No. 6,048,850 (which claimed a method of inhibiting COX-2 in humans using a compound, without actually disclosing what that compound might be) covered drugs such as celecoxib. The court ruled in favor of Searle, holding in essence that the university had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2 and therefore the patent was invalid.
After the withdrawal of rofecoxib from the market in September 2004, celecoxib enjoyed a robust increase in sales. However, the results of the APC trial in December of that year raised concerns that Celebrex might carry risks similar to those of rofecoxib, and Pfizer announced a moratorium on direct-to-consumer advertising of Celebrex soon afterwards. Sales reached $2 billion in 2006. Prior to its availability in generic form, it was one of Pfizers "best-selling drugs, amounting to more than $2.5 billion in sales [by 2012], and was prescribed to 2.4 million" people in 2011. By 2012, 33 million Americans had taken celecoxib.Pfizer resumed advertising Celebrex in magazines in 2006, and resumed television advertising in April 2007 with an unorthodox, 2+1⁄2-minute advertisement which extensively discussed the adverse effects of Celebrex in comparison with other anti-inflammatory drugs. The ad drew criticism from the consumer advocacy group Public Citizen, which called the ads comparisons misleading. Pfizer responded to Public Citizens concerns with assurances that they are truthfully advertising the risk and benefits of Celebrex as set forth by the FDA.

Society and culture
Fabricated efficacy studies
Pfizer and its partner, Pharmacia presented findings from their study that Celebrex was "better in protecting the stomach from serious complications than other drugs." This became Celebrexs main selling point. However, following federal investigations it was revealed that Pfizer and Pharmacia "only presented the results from the first six months of a year long study rather than the whole thing." These partial results were then published in The Journal of the American Medical Association. In 2001, the US Food and Drug Administration (FDA) released the full results of the Pfizer and Pharmacia study which showed that they had withheld crucial data. By 2012, a federal judge unsealed "thousands of pages of internal documents and depositions" in a "long-running securities fraud case against Pfizer."On 11 March 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Massachusetts, revealed that the data for 21 studies he had authored for the efficacy of the drug (along with others such as Vioxx) had been fabricated. The analgesic effects of the drugs had been exaggerated. Reuben was also a former paid spokesperson for Pfizer. Although from 2002 to 2007 Pfizer underwrote much of Dr. Reubens research and "many of his trials found that Celebrex and Lyrica, Pfizer drugs, were effective against postoperative pain," Pfizer was not aware of the fraudulent data. None of the retracted studies were submitted to either the US Food and Drug Administration or the European Unions regulatory agencies prior to the drugs approval. Although Pfizer issued a public statement declaring, "It is very disappointing to learn about Dr. Scott Reubens alleged actions. When we decided to support Dr. Reubens research, he worked for a credible academic medical center and appeared to be a reputable investigator", the documents unsealed in 2012, revealed that by February 2000, Pharmacia employees had devised a strategy to present the findings.

Availability
Pfizer markets celecoxib under the brand name Celebrex, and it is available as oral capsules containing 50, 100, 200 or 400 mg of celecoxib.It is legally available in many jurisdictions as a generic under several brand names. In the US, celecoxib was covered by three patents, two of which expired on 30 May 2014, and one of which (US RE44048) was due to expire 2 December 2015. On 13 March 2014, that patent was found to be invalid for double patenting. Upon the patent expiry on 30 May 2014, the FDA approved the first versions of generic celecoxib.

Research
Psychiatry
On the theory that inflammation plays a role in the pathogenesis of major mental disorders, celecoxib has been trialed for a number of psychiatric disorders, including major depression, bipolar disorder, and schizophrenia.

Bipolar disorder
A meta-analysis considering trials of celecoxib as an adjunctive treatment in bipolar disorder was inconclusive citing low evidence quality.

Familial adenomatous polyposis
It has been used to reduce colon and rectal polyps in people with familial adenomatous polyposis, but it is not known if it decreases rates of cancer, so it is not a good choice for this reason.

Cancer prevention
The use of celecoxib to reduce the risk of colorectal cancer has been investigated, but neither celecoxib nor any other drug is indicated for this use. Small-scale clinical trials in very high-risk people (belonging to FAP families) showed celecoxib can prevent polyp growth. Hence, large-scale randomized clinical trials were undertaken. Results show a 33 to 45% polyp recurrence reduction in people treated with celecoxib each day. However, serious cardiovascular events were significantly more frequent in the celecoxib-treated groups. Aspirin shows a similar (and possibly larger) protective effect, has demonstrated cardioprotective effects and is significantly cheaper, but no head-to-head clinical trials have compared the two drugs.

Cancer treatment
Different from cancer prevention, cancer treatment is focused on the therapy of tumors that have already formed and have established themselves inside the patient. Many studies are going on to determine whether celecoxib might be useful for this latter condition. However, during molecular studies in the laboratory, it became apparent that celecoxib could interact with other intracellular components besides its most famous target, COX-2. The discovery of these additional targets has generated much controversy, and the initial assumption that celecoxib reduces tumor growth primarily by the inhibition of COX-2 became contentious.Certainly, the inhibition of COX-2 is paramount for the anti-inflammatory and analgesic function of celecoxib. However, whether inhibition of COX-2 also plays a dominant role in this drugs anticancer effects is unclear. For example, a recent study with malignant tumor cells showed celecoxib could inhibit the growth of these cells in vitro, but COX-2 played no role in this outcome; even more strikingly, the anticancer effects of celecoxib were also obtained with the use of cancer cell types that do not even contain COX-2.  Karen Seibert and colleagues have published research showing antiangiogenic and antitumor activity of celecoxib in animal models.Additional support for the idea that other targets besides COX-2 are important for celecoxibs anticancer effects has come from studies with chemically modified versions of celecoxib. Several dozen analogs of celecoxib were generated with small alterations in their chemical structures. Some of these analogs retained COX-2 inhibitory activity, whereas many others did not. However, when the ability of all these compounds to kill tumor cells in cell culture was investigated, the antitumor potency did not at all depend on whether or not the respective compound could inhibit COX-2, showing the inhibition of COX-2 was not required for the anticancer effects. One of these compounds, 2,5-dimethyl-celecoxib, which entirely lacks the ability to inhibit COX-2, actually displayed stronger anticancer activity than celecoxib.

References
Further reading
Dean L (2016). "Celecoxib Therapy and CYP2C9 Genotype".  In Pratt VM, McLeod HL, Rubinstein WS,  et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520369. Bookshelf ID: NBK379478.
Zhang J, Ding EL, Song Y (October 2006). "Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials". JAMA. 296 (13): 1619–32. doi:10.1001/jama.296.13.jrv60015 </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 Talimogene laherparepvec and can you explain it in depth? [/INST] Talimogene laherparepvec, sold under the brand name Imlygic, is a biopharmaceutical medication used to treat melanoma that cannot be operated on; it is injected directly into a subset of lesions which generates a systemic immune response against the recipients cancer.  The final four year analysis from the pivotal phase 3 study upon which TVEC was approved by the FDA showed a 31.5% response rate with a 16.9% complete response (CR) rate. There was also a substantial and statistically significant survival benefit in patients with earlier metastatic disease (stages IIIb-IVM1a) and in patients who hadnt received prior systemic treatment for melanoma. The earlier stage group had a reduction in the risk of death of approximately 50% with one in four patients appearing to have met, or be close to be reaching, the medical definition of cure. Real world use of talimogene laherparepvec have shown response rates of up to 88.5% with CR rates of up to 61.5%.Around half of people treated with talimogene laherparepvec in clinical trials experienced fatigue and chills; around 40% had fever, around 35% had nausea, and around 30% had flu-like symptoms as well as pain at the injection site.  The reactions were mild to moderate in severity; 2% of people had severe reactions and these were generally cellulitis.Talimogene laherparepvec is a genetically engineered herpes virus (an oncolytic herpes virus). Two genes were removed – one that shuts down an individual cells defenses, and another that helps the virus evade the immune system – and a gene for human GM-CSF was added.  The drug works by replicating in cancer cells, causing them to burst; it was also designed to stimulate an immune response against the patients cancer, which has been demonstrated by multiple pieces of data, including regression of tumors which have not been injected with talimogene laherparepvec.The drug was created and initially developed by BioVex, Inc. and was continued by Amgen, which acquired BioVex in 2011. It was one of the first oncolytic immunotherapy approved globally; it was approved in the US in October 2015 and approved in Europe in December 2015.

Medical uses
Talimogene laherparepvec is delivered by injecting it directly into tumors, thereby creating a systemic anti-tumor immune response.In the US, talimogene laherparepvec is FDA approved to treat Stage IIIb-IVM1c melanoma patients for whom surgical intervention is not appropriate and with tumors which can be directly injected; the EMA approved population in Europe is for Stage IIIb-IVM1a.Talimogene laherparepvec has been shown to extend survival in patients with Stage IIIb-IVM1a melanoma and patients who have not received prior systemic therapy for melanoma.

Adverse effects
Around half of people treated with talimogene laherparepvec in clinical trials experienced fatigue and chills; around 40% had fever, around 35% had nausea, and around 30% had flu-like symptoms as well as pain at the injection site.  The reactions were mild to moderate in severity; 2% of people had severe reactions and these were generally cellulitis.More than 10% of people had edema, headache, cough, vomiting, diarrhea, constipation, muscle pain, or joint pain.  Between 1% and 10% developed cold sores, pain or infection in the lesion, anemia, immune mediated events (like vasculitis, pneumonia, worsening psoriasis, glomerulonephritis and vitiligo ), dehydration, confusion, anxiety, depression, dizziness, insomnia, ear pain, fast heart beating, deep vein thrombosis, high blood pressure, flushing, shortness of breath when exercising, sore throat, symptoms of the common cold, stomach pain, back pain, groin pain, weight loss, or oozing from the injection site.

Pharmacology
Talimogene laherparepvec is taken up by normal cells and cancer cells like the wild type herpes simplex virus, it is cleared in the same way.

Mechanism
Talimogene laherparepvec directly destroys the cancer cells it infects, inducing a systemic immune response against the patients cancer.The virus invades both cancerous and healthy cells, but it cannot productively replicate in healthy tissue because it lacks Infected cell protein 34.5 (ICP34.5).  When cells are infected with a virus they shut down and die, but ICP34.5 blocks this stress response, allowing the virus to hijack the cells translation machinery to replicate itself. A herpesvirus lacking the gene coding for ICP34.5 cannot replicate in normal tissue. However, in many cancer cells the stress response is already disrupted, so a virus lacking ICP34.5 can still replicate in tumors.   After the virus has replicated many times, the cell swells and finally bursts, killing the cell and releasing the copies of the virus, which can then infect nearby cells.While talimogene laherparepvec is using the cells translation machinery to replicate, it also uses it to make the cell create GM-CSF.  GM-CSF  is secreted or released when the cancer cell bursts, attracting dendritic cells to the site, which pick up the tumor antigens, process them, and then present them on their surface to cytotoxic (killer) T cells which in turn sets off an immune response.

Composition
Talimogene laherparepvec is a biopharmaceutical drug; it is an oncolytic herpes virus that was created by genetically engineering a strain of herpes simplex virus 1 (HSV-1) taken from a person infected with the virus, rather than a laboratory strain.  Both copies of the viral gene coding for ICP34.5 were deleted and replaced with the gene coding for human GM-CSF, and the gene coding for ICP47 was removed.  In wild herpes virus, ICP47 suppresses the immune response to the virus; it was removed because the drug was designed with the intention of activating the immune system.

History
The first oncolytic virus to be approved by a regulatory agency was a genetically modified adenovirus named H101 by Shanghai Sunway Biotech. It gained regulatory approval in 2005 from Chinas State Food and Drug Administration (SFDA) for the treatment of head and neck cancer. Talimogene laherparepvec is the worlds first approved oncolytic immunotherapy, i.e </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 Lactic acid/citric acid/potassium bitartrate and can you explain it in depth? [/INST] Lactic acid/citric acid/potassium bitartrate, sold under the brand name Phexxi, is a non-hormonal combination medication used as a method of birth control. It contains lactic acid, citric acid, and potassium bitartrate </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 Olopatadine/mometasone 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 Fosfomycin and can you explain it in depth? [/INST] Fosfomycin, sold under the brand name Monurol among others, is an antibiotic primarily used to treat lower UTI. It is not indicated for kidney infections. Occasionally it is used for prostate infections. It is generally taken by mouth.Common side effects include diarrhea, nausea, headache, and vaginal yeast infections. Severe side effects may include anaphylaxis and Clostridium difficile-associated diarrhea. While use during pregnancy has not been found to be harmful, such use is not recommended. A single dose when breastfeeding appears safe. Fosfomycin works by interfering with the production of the bacterial cell wall.Fosfomycin was discovered in 1969 and approved for medical use in the United States in 1996. It is on the World Health Organizations List of Essential Medicines. The World Health Organization classifies fosfomycin as critically important for human medicine. It is available as a generic medication. It was originally produced by certain types of Streptomyces, although it is now made chemically.

Medical uses
Fosfomycin is used to treat bladder infections, where it is usually given as a single dose by mouth.Oral fosfomycin is not recommended for children under 12 years old.Additional uses have been proposed. The global problem of advancing antimicrobial resistance has led to a renewed interest in its use more recently.Fosfomycin can be used as an efficacious treatment for both UTIs and complicated UTIs including acute pyelonephritis. The standard regimen for complicated UTIs is an oral 3 g dose administered once every 48 or 72 hours for a total of 3 doses or a 6 g dose every 8 hours for 7–14 days when fosfomycin is given in IV form. Intravenous fosfomycin is being increasing used for treating infections caused by multidrug-resistant bacteria, mostly as partner drug in order to avoid the occurrence of resistances and to take advantage of its synergistic activity with several other antimicrobials. Daily adult dose usually ranges from 12 to 24 grams.

Bacterial sensitivity
The fosfomycin molecule has an epoxide or oxirane ring, which is highly strained and thus very reactive.
Fosfomycin has broad antibacterial activity against both Gram-positive and Gram-negative pathogens, with useful activity against E. faecalis, E. coli, and various Gram-negatives such as  Citrobacter and Proteus.  Given a greater activity in a low-pH milieu, and predominant excretion in active form into the urine, fosfomycin has found use for the prophylaxis and treatment of UTIs caused by these uropathogens.  Of note, activity against S. saprophyticus, Klebsiella, and Enterobacter is variable and should be confirmed by minimum inhibitory concentration testing.
Activity against extended-spectrum β-lactamase-producing pathogens, notably ESBL-producing E. coli, is good to excellent, because the drug is not affected by cross-resistance issues.
Existing clinical data support use in uncomplicated UTIs, caused by susceptible organisms.  However, susceptibility break-points of 64 mg/L should not be applied for systemic infections.

Resistance
Development of bacterial resistance under therapy is a frequent occurrence and makes fosfomycin unsuitable for sustained therapy of severe infections. Mutations that inactivate the nonessential glycerophosphate transporter render bacteria resistant to fosfomycin.Prescribing fosfomycin together with at least another active drug reduces the risk of developing bacterial resistance. Fosfomycin acts synergistically with many other antibiotics, including aminoglycosides, carbapenems, cephalosporins, daptomycin and oritavancin. Enzymes conferring resistance to fosfomycin have also been identified and are encoded both chromosomally and on plasmids.Three related fosfomycin resistance enzymes (named FosA, FosB, and FosX) are members of the glyoxalase superfamily. These enzymes function by nucleophilic attack on carbon 1 of fosfomycin, which opens the epoxide ring and renders the drug ineffective.
The enzymes differ by the identity of the nucleophile used in the reaction: glutathione for FosA, bacillithiol for FosB, and water for FosX.In general, FosA and FosX enzymes are produced by Gram-negative bacteria, whereas FosB is produced by Gram-positive bacteria.FosC uses ATP and adds a phosphate group to fosfomycin, thus altering its properties and making the drug ineffective.

Side effects
The drug is well tolerated and has a low incidence of harmful side effects.

Mechanism of action
Despite its name (ending in -omycin) Fosfomycin is not a macrolide, but a member of a novel class of phosphonic antibiotics.  Fosfomycin is bactericidal and inhibits bacterial cell wall biogenesis by inactivating the enzyme UDP-N-acetylglucosamine-3-enolpyruvyltransferase, also known as MurA. This enzyme catalyzes the committed step in peptidoglycan biosynthesis, namely the ligation of phosphoenolpyruvate (PEP) to the 3-hydroxyl group of UDP-N-acetylglucosamine </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 Fenoldopam and can you explain it in depth? [/INST] Fenoldopam mesylate (Corlopam) is a drug and synthetic benzazepine derivative which acts as a selective D1 receptor partial agonist </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 Arava and can you explain it in depth? [/INST]  </s>