<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Ofloxacin and explain in detail? [/INST] Ofloxacin is a quinolone antibiotic useful for the treatment of a number of bacterial infections. When taken by mouth or injection into a vein, these include pneumonia, cellulitis, urinary tract infections,
prostatitis, plague, and certain types of infectious diarrhea. Other uses, along with other medications, include treating multidrug resistant tuberculosis. An eye drop may be used for a superficial bacterial infection of the eye and an ear drop may be used for otitis media when a hole in the ear drum is present.When taken by mouth, common side effects include vomiting, diarrhea, headache, and rash. Other serious side effect include tendon rupture, numbness due to nerve damage, seizures, and psychosis. Use in pregnancy is typically not recommended. Ofloxacin is in the fluoroquinolone family of medications. It works by interfering with the bacteriums DNA.Ofloxacin was patented in 1980 and approved for medical use in 1985. It is on the World Health Organizations List of Essential Medicines. Ofloxacin is available as a generic medication. In 2017, it was the 278th most commonly prescribed medication in the United States, with more than one million prescriptions.

Medical uses
Ofloxacin is used in the treatment of bacterial infections such as:

Acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD)
Community-acquired pneumonia
Uncomplicated skin and skin structure infections
Nongonococcal urethritis and cervicitis
Epididymitis
Mixed Infections of the urethra and cervix
Acute pelvic inflammatory disease
Uncomplicated cystitis
Complicated urinary tract infections
Prostatitis
Acute, uncomplicated urethral and cervical gonorrheaOfloxacin has not been shown to be effective in the treatment of syphilis. Ofloxacin is no longer considered a first-line treatment for gonorrhea, because of bacterial resistance.

Susceptible bacteria
According to the product package insert, ofloxacin is effective against these microorganisms:Aerobic Gram-positive microorganisms:

Staphylococcus aureus (methicillin-susceptible strains)
Streptococcus pneumoniae (penicillin-susceptible strains)
Streptococcus pyogenesAerobic Gram-negative microorganisms

Citrobacter koseri (Citrobacter diversus)
Enterobacter aerogenes
Escherichia coli
Haemophilus influenzae
Klebsiella pneumoniae
Neisseria gonorrhoeae
Proteus mirabilis
Pseudomonas aeruginosaOther microorganisms:

Chlamydia trachomatis

Adverse effects
In general, fluoroquinolones are well tolerated, with most side effects being mild to moderate. On occasion, serious adverse effects occur. Common side effects include gastrointestinal effects such as nausea, vomiting, and diarrhea, as well as headache and insomnia.
The overall rate of adverse events in patients treated with fluoroquinolones is roughly similar to that seen in patients treated with other antibiotic classes. A U.S. Centers for Disease Control study found patients treated with fluoroquinolones experienced adverse events severe enough to lead to an emergency department visit more frequently than those treated with cephalosporins or macrolides, but less frequently than those treated with penicillins, clindamycin, sulfonamides, or vancomycin.Postmarketing surveillance has revealed a variety of relatively rare but serious adverse effects associated with all members of the fluoroquinolone antibacterial class. Among these, tendon problems and exacerbation of the symptoms of the neurological disorder myasthenia gravis are the subject of "black box" warnings in the United States. The most severe form of tendonopathy associated with fluoroquinolone administration is tendon rupture, which in the great majority of cases involves the Achilles tendon. Younger people typically experience good recovery, but permanent disability is possible, and is more likely in older patients.  The overall frequency of fluoroquinolone-associated Achilles tendon rupture in patients treated with ciprofloxacin or levofloxacin has been estimated at 17 per 100,000 treatments. Risk is substantially elevated in the elderly and in those with recent exposure to topical or systemic corticosteroid therapy. Simultaneous use of corticosteroids is present in almost one-third of quinolone-associated tendon rupture. Tendon damage may manifest during and up to a year after fluoroquinolone therapy has been completed.Fluoroquinolones prolong the QT interval by blocking voltage-gated potassium channels. Prolongation of the QT interval can lead to torsades de pointes, a life-threatening arrhythmia, but in practice, this appears relatively uncommon in part because the most widely prescribed fluoroquinolones (ciprofloxacin and levofloxacin) only minimally prolong the QT interval.Clostridium difficile-associated diarrhea may occur in connection with the use of any antibacterial drug, especially those with a broad spectrum of activity such as clindamycin, cephalosporins, and fluoroquinolones. Fluoroquinoline treatment is associated with risk similar to or less than that associated with broad spectrum cephalosporins. Fluoroquinoline administration may be associated with the acquisition and outgrowth of a particularly virulent Clostridium strain.The U.S. prescribing information contains a warning regarding uncommon cases of peripheral neuropathy, which can be permanent. Other nervous system effects include insomnia, restlessness, and rarely, seizure, convulsions, and psychosis Other rare and serious adverse events have been observed with varying degrees of evidence for causation.Events that may occur in acute overdose are rare, and include kidney failure and seizure. Susceptible groups of patients, such as children and the elderly, are at greater risk of adverse reactions during therapeutic use.Ofloxacin, like some other fluoroquinolones, may inhibit drug-metabolizing enzymes, and thereby increase blood levels of other drugs such as cyclosporine, theophylline, and warfarin, among others. These increased blood levels may result in a greater risk of side effects.
Careful monitoring of serum glucose is advised when ofloxacin or other fluorquinolones are used by people who are taking sulfonylurea antidiabetes drugs.
The concomitant administration of a nonsteroidal anti-inflammatory drug with a quinolone, including ofloxacin, may increase the risk of central nervous system stimulation and convulsive seizures.
The fluoroquinolones have been shown to increase the anticoagulant effect of acenocoumarol, anisindione, and dicumarol. Additionally, the risk of cardiotoxicity and arrhythmias is increased when co-administered with drugs such as dihydroquinidine barbiturate, quinidine, and quinidine barbiturate.Current or past treatment with oral corticosteroids is associated with an increased risk of Achilles tendon rupture, especially in elderly patients who are also taking the fluoroquinolones.

Contraindications
As noted above, under licensed use, ofloxacin is now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance. Caution should be used in people with liver disease. The excretion of ofloxacin may be reduced in patients with severe liver function disorders (e.g., cirrhosis with or without ascites). Ofloxacin is also considered to be contraindicated within the pediatric population, pregnancy, nursing mothers, patients with psychiatric illnesses and in patients with epilepsy or other seizure disorders.

Pregnancy
Ofloxacin has not been shown to have any teratogenic effects at oral doses as high as 810 mg/kg/day (11 times the recommended maximum human dose based on mg/m2 or 50 times based on mg/kg) and 160 mg/kg/day (four times the recommended maximum human dose based on mg/m2 or 10 times based on mg/kg) when administered to pregnant rats and rabbits, respectively. Additional studies in rats with oral doses up to 360 mg/kg/day (five times the recommended maximum human dose based on mg/m2 or 23 times based on mg/kg) demonstrated no adverse effect on late fetal development, labor, delivery, lactation, neonatal viability, or growth of the newborn. Doses equivalent to 50 and 10 times the recommended maximum human dose of ofloxacin (based on mg/kg) were fetotoxic (i.e., decreased fetal body weight and increased fetal mortality) in rats and rabbits, respectively. Minor skeletal variations were reported in rats receiving doses of 810 mg/kg/day, which is more than 10 times higher than the recommended maximum human dose based on mg/m2.There are, however, no adequate and well-controlled studies in pregnant women. Ofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Children
Oral and intravenous ofloxacin are not licensed for use in children, except as noted above, due to the risk of musculoskeletal injury. In one study, 1534 juvenile patients (age 6 months to 16 years) treated with levofloxacin as part of three efficacy trials were followed up to assess all musculoskeletal events occurring up to 12 months after treatment. At 12 months follow-up, the cumulative incidence of musculoskeletal adverse events was 3.4%, compared to 1.8% among 893 patients treated with other antibiotics.  In the levafloxacin-treated group, about two-thirds of these musculoskeletal adverse events occurred in the first 60 days, 86% were mild, 17% were moderate, and all resolved without long-term sequelae.
In a study comparing the safety and efficacy of levofloxacin to that of azithromycin or ceftriaxone in 712 children with community-acquired pneumonia, adverse events were experienced by 6% of those treated with levofloxacin and 4% of those treated with comparator antibiotics. Most of these adverse events were thought to be unrelated or doubtfully related to the levofloxacin. Two deaths were observed in the levofloxacin group, neither of which was thought to be treatment-related. Spontaneous reports to the FDA Adverse Effects Reporting System at the time of the 20 September 2011 FDA Pediatric Drugs Advisory Committee include musculoskeletal events (39, including five cases of tendon rupture) and central nervous system events (19, including five cases of seizures) as the most common spontaneous reports between April 2005 and March 2008. An estimated 130,000 pediatric prescriptions for levofloxacin were filled on behalf of 112,000 pediatric patients during that period.

Overdose
Limited information is available on overdose with ofloxacin. Advice for the management of an acute overdose of ofloxacin is emptying of the stomach, along with close observation, and making sure that the patient is appropriately hydrated. Hemodialysis or peritoneal dialysis is of only limited effectiveness. Overdose may result in central nervous system toxicity, cardiovascular toxicity, tendon/articular toxicity, and hepatic toxicity as well as kidney failure and seizure. Both seizures and severe psychiatric reactions have, however, been reported to occur at therapeutic dosage.

Pharmacokinetics
The bioavailability of ofloxacin in the tablet form is roughly 98% following oral administration, reaching maximum serum concentrations within one to two hours. Between 65% and 80% of an administered oral dose of ofloxacin is excreted unchanged via the kidneys within 48 hours of dosing. Therefore, elimination is mainly by renal excretion. However, 4-8% of an ofloxacin dose is excreted in the feces. This would indicate a small degree of biliary excretion, as well. Plasma elimination half-life is around 4 to 5 hours in patients and 6.4 to 7.4 hours in elderly patients.Ofloxacin is a racemic mixture, which consists of 50% levofloxacin (the biologically active component) and 50% of its “mirror image” or enantiomer dextrofloxacin."After multiple-dose administration of 200 mg and 300 mg doses, peak serum levels of 2.2  and 3.6 μg/ml, respectively, are predicted at steady-state. In vitro, approximately 32% of the drug in plasma is protein bound. Floxin is widely distributed to body tissues. Ofloxacin has been detected in blister fluid, cervix, lung tissue, ovary, prostatic fluid, prostatic tissue, skin, and sputum. Pyridobenzoxazine ring appears to decrease the extent of parent compound metabolism. Less than 5% is eliminated by the kidneys as desmethyl or N-oxide metabolites; 4% to 8% by feces."A number of the endogenous compounds have been reported to be affected by ofloxacin as inhibitors, alteraters, and depletors. See the latest package insert for ofloxacin for additional details.

Mode of action
Ofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting two bacterial type II topoisomerases, DNA gyrase and topoisomerase IV. Topoisomerase IV is an enzyme necessary to separate (mostly in prokaryotes, in bacteria in particular) replicated DNA, thereby inhibiting bacterial cell division.

History
Ofloxacin is a second-generation fluoroquinolone, being a broader-spectrum analog of norfloxacin, and was synthesized and developed by scientists at Daiichi Seiyaku.It was first approved for marketing in Japan in 1985, for oral administration, and Daiichi marketed it there under the brand name Tarvid.  Daiichi, working with Johnson & Johnson, obtained FDA approval in December 1990, under the brand name Floxin, labelled for use in adults with lower respiratory tract infections, skin and skin structure infections, urinary tract infections, prostatitis, and sexually transmitted diseases.   By 1991, it was also marketed as Tarvid by Hoechst in the UK, Germany, Belgium, and Portugal; as Oflocet in France, Portugal, Tunisia, and several African countries by Roussel-Uclaf, as Oflocin by Glaxo in Italy, and as Flobacin by Sigma-Tau in Italy.The market for ofloxacin was seen as difficult from its launch; it was approved as a "1C" drug, a new molecular entity with little or no therapeutic gain over existing therapies, and ciprofloxacin, which had a broader spectrum, was already on the market.By 1992, an intravenous solution was approved for marketing,In 1997, an indication for pelvic inflammatory disease was approved by the U.S. Food and Drug Administration (FDA) for the oral formulation, and in the same year, a solution for ear infections was approved under the brand Daiichi and J&J also cannibalized its own market by introducing levofloxacin, the levo-enantiomer of ofloxacin, in 1996; Johnson and Johnsons annual sales of Floxin in 2003 was about $30 million, whereas their combined sales of Levaquin/Floxin exceeded $1.15 billion in the same year. Johnson & Johnson withdrew the marketing application in 2009.

Society and culture
Available forms
Ofloxacin for systemic use is available as a tablet (multiple strengths), an oral suspension, and an injectable solution (multiple strengths). It is also used as eye drops and ear drops and is available in combination with ornidazole.

Dosage
Ofloxacin should be administered as described within the Dosage Guidelines table found within the most recent package insert. The status of the patients renal function and hepatic function must also be taken into consideration to avoid an accumulation that may lead to a fatal drug overdose. Ofloxacin is eliminated primarily by renal excretion. However, the drug is also metabolized and partially cleared through the liver </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Sodium hyaluronate and explain in detail? [/INST] Sodium hyaluronate is the sodium salt of hyaluronic acid, a glycosaminoglycan found in various connective tissue of humans.

Chemistry
Sodium hyaluronate is the sodium salt of hyaluronic acid. It is a glycosaminoglycan and long-chain polymer of disaccharide units of Na-glucuronate-N-acetylglucosamine. It can bind to specific receptors for which it has a high affinity.
The polyanionic form, commonly referred to as hyaluronan, is a visco-elastic polymer found in the aqueous and vitreous humour of the eye and in the fluid of articulating joints.

Natural occurrence
Sodium hyaluronate, as hyaluronic acid, is distributed widely in the extracellular matrix of mammalian connective, epithelial, and neural tissues, as well as the corneal endothelium.

Mechanism of action
Sodium hyaluronate functions as a tissue lubricant and is thought to play an important role in modulating the interactions between adjacent tissues. It forms a viscoelastic solution in water. Mechanical protection for tissues (iris, retina) and cell layers (corneal, endothelium, and epithelium) are provided by the high viscosity of the solution. Elasticity of the solution assists in absorbing mechanical stress and providing a protective buffer for tissues. In facilitating wound healing, it is thought that it acts as a protective transport vehicle, taking peptide growth factors and other structural proteins to a site of action. It is then enzymatically degraded and active proteins are released to promote tissue repair.

Pharmacokinetics
Sodium hyaluronate is cleared within hours of injection but appears to have residual effects on contacted cells. In the eye it is eliminated via the canal of Schlemm.

Adverse effects
Adverse effects are relatively rare when used to treat the joints.When used in ophthalmological procedures, sodium hyaluronate may cause postoperative inflammation, corneal edema or decompensation, and short-term increases in intraocular pressure.

Medical uses
Intra-articular injection
It is used to treat knee pain in patients with osteoarthritis who have not received relief from other treatments. It is injected into the joint capsule, to act as both a shock absorber and a lubricant for the joint.
Thus sodium hyaluronate is used as a viscosupplement, administered through a series of injections into the knee, increasing the viscosity of the synovial fluid, which helps lubricate, cushion and reduce pain in the joint. It is generally used as a last resort before surgery and provides symptomatic relief, by recovering the viscoelasticity of the articular fluid, and by stimulating new production from synovial fluid. Use of sodium hyaluronate may reduce the need for joint replacement.  Injections appear to increase in effectiveness over the course of four weeks, reaching a peak at eight weeks and retaining some effectiveness at six months, with greater benefit for osteoarthritis than oral analgesics.  It may also be effective when used with the ankle joint.

Intraocular viscoelastic injection
It is used as an aid in  ophthalmic surgery acting as aqueous and vitreous humor, e.g. in cataract extraction (intra- and extracapsular), intraocular lens implantation, corneal transplant, glaucoma filtration, and retina attachment surgery and in the treatment of dry eyes. In surgical procedures in the anterior segment of eyeball, instillation of sodium hyaluronate its viscoelasticity enables maintenance of a deep chamber during surgical manipulation since the solution does not flow out of the open anterior chamber, allowing for efficient manipulation with less trauma to the corneal endothelium and other surrounding tissues. Its viscoelasticity also helps to push back the vitreous face and prevent formation of a postoperative flat chamber. In posterior segment surgery, sodium hyaluronate serves as a surgical aid to gently separate, maneuver, and hold tissues. It creates a clear field of vision, facilitating intra-operative and post-operative inspection of the retina and photocoagulation.

Skin injections in plastic surgery
Sodium hyaluronate is injected to reduce wrinkles on the face </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Carglumic acid and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Leuprorelin and explain in detail? [/INST] Leuprorelin, also known as leuprolide, is a manufactured version of a hormone used to treat prostate cancer, breast cancer, endometriosis, uterine fibroids, and early puberty, to perform chemical castration of violent sex offenders, or as part of transgender hormone therapy. It is given by injection into a muscle or under the skin.Leuprorelin is in the gonadotropin-releasing hormone (GnRH) analogue family of medications. It works by decreasing gonadotropin and therefore decreasing testosterone and estradiol. Common side effects include hot flashes, unstable mood, trouble sleeping, headaches, and pain at the site of injection. Other side effects may include high blood sugar, allergic reactions, and problems with the pituitary gland. Use during pregnancy may harm the baby.Leuprorelin was patented in 1973 and approved for medical use in the United States in 1985. It is on the World Health Organizations List of Essential Medicines. It is sold under the brand name Lupron among others.

Medical use
Leuprorelin may be used in the treatment of hormone-responsive cancers such as prostate cancer and breast cancer. It may also be used for estrogen-dependent conditions such as endometriosis or uterine fibroids.
It may be used for precocious puberty in both males and females, and to prevent premature ovulation in cycles of controlled ovarian stimulation for in vitro fertilization (IVF). This use is controversial since the Lupron label advises against using the drug when one is considering pregnancy, due to a risk of birth defects.It may be used to reduce the risk of premature ovarian failure in women receiving cyclophosphamide for chemotherapy.Along with triptorelin and goserelin, it has been used to delay puberty in transgender youth until they are old enough to begin hormone replacement therapy. Researchers have recommended puberty blockers after age 12, when the person has developed to Tanner stages 2–3, and then cross-sex hormones treatment at age 16. This use of the drug is off-label, however, not having been approved by the Food and Drug Administration and without data on long-term effects of this use.They are also sometimes used as alternatives to antiandrogens like spironolactone and cyproterone acetate for suppressing testosterone production in transgender women. It also is used for suppressing estrogen production in transgender men.It is considered a possible treatment for paraphilias. Leuprorelin has been tested as a treatment for reducing sexual urges in pedophiles and other cases of paraphilia.

Side effects
Common side effects of leuprorelin injection include redness/burning/stinging/pain/bruising at the injection site, hot flashes (flushing), increased sweating, night sweats, tiredness, headache, upset stomach, nausea, diarrhea, impotence, testicular shrinkage, constipation, stomach pain, breast swelling or tenderness, acne, joint/muscle aches or pain, trouble sleeping (insomnia), reduced sexual interest, vaginal discomfort/dryness/itching/discharge, vaginal bleeding, swelling of the ankles/feet, increased urination at night, dizziness, breakthrough bleeding in a female child during the first two months of leuprorelin treatment, weakness, chills, clammy skin, skin redness, itching, or scaling, testicle pain, impotence, depression, or memory problems. The rates of gynecomastia with leuprorelin have been found to range from 3 to 16%.

Pharmacology
Mechanism of action
Leuprorelin is a gonadotropin-releasing hormone (GnRH) analogue acting as an agonist at pituitary GnRH receptors. Agonism of GnRH receptors initially results in the stimulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion by the anterior pituitary ultimately leading to increased serum estradiol and testosterone levels via the normal physiology of the hypothalamic–pituitary–gonadal axis (HPG axis); however, because propagation of the HPG axis is incumbent upon pulsatile hypothalamic GnRH secretion, pituitary GnRH receptors become desensitised after several weeks of continuous leuprorelin therapy. This protracted downregulation of GnRH receptor activity is the targeted objective of leuprorelin therapy and ultimately results in decreased LH and FSH secretion, leading to hypogonadism and thus a dramatic reduction in estradiol and testosterone levels regardless of sex.In the treatment of prostate cancer, the initial increase in testosterone levels associated with the initiation of leuprorelin therapy is counterproductive to treatment goals. This effect is avoided with concurrent utilisation of 5α-reductase inhibitors, such as finasteride, or flutamide which function to block the downstream effects of testosterone.

Available forms
Leuprorelin is available in the following forms, among others:
Short-acting daily intramuscular injection (Lupron)
Long-acting depot intramuscular injection (Lupron Depot)
Long-acting depot subcutaneous injection (Eligard)
Long-acting subcutaneous injection (Fensolvi)
Long-acting subcutaneous implant (Viadur)
Long-acting leuprolide mesylate (Camcevi) for the treatment of advanced prostate cancer.
Leuprolide acetate and norethindrone acetate combination pack (Lupaneta Pack)

Chemistry
The peptide sequence is Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt (Pyr = L-pyroglutamyl).

History
Leuprorelin was discovered and first patented in 1973 and was introduced for medical use in 1985. It was initially marketed only for daily injection, but a depot injection formulation was introduced in 1989.

Approvals
Lupron injection was approved by the FDA for treatment of advanced prostate cancer on April 9, 1985.
Lupron depot for monthly intramuscular injection was approved by the FDA for palliative treatment of advanced prostate cancer on January 26, 1989.
Viadur was approved by the FDA for palliative treatment of advanced prostate cancer on March 6, 2000.
Eligard was approved by the FDA for palliative treatment of advanced prostate cancer on January 24, 2002.
Fensolvi was approved by the FDA for children with central precocious puberty on May 4, 2020.

Society and culture
Legal status
On 24 March 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Camcevi, intended for the treatment of the cancer of the prostate in adult men when the cancer is "hormone-dependent", which means that it responds to treatments that reduce the levels of the hormone testosterone. The applicant for this medicinal product is Accord Healthcare S.L.U.

Names
Leuprorelin is the generic name of the drug and its INN and BAN, while leuprorelin acetate is its BANM and JAN, leuprolide acetate is its USAN and USP, leuprorelina is its DCIT, and leuproréline is its DCF. It is also known by its developmental code names A-43818, Abbott-43818, DC-2-269, and TAP-144.Leuprorelin is marketed by Bayer AG under the brand name Viadur, by Tolmar under the brand names Eligard and Fensolvi, and by TAP Pharmaceuticals (1985–2008), by Varian Darou Pajooh under the brand name Leupromer and Abbott Laboratories (2008–present) under the brand name Lupron.

Controversy
In October 2001, the US Department of Justice, states attorneys general, and TAP Pharmaceutical Products, a subsidiary of Abbott Laboratories, settled criminal and civil charges against TAP related to federal and state medicare fraud and illegal marketing of the drug leuprorelin. TAP paid a total of $875 million, which was a record high at the time. The $875 million settlement broke down to $290 million for violating the Prescription Drug Marketing Act, $559.5 million to settle federal fraud charges for overcharging Medicare, and $25.5 million reimbursement to 50 states and Washington, D.C., for filing false claims with the states Medicaid programs. The case arose under the False Claims Act with claims filed by Douglas Durand, a former TAP vice president of sales, and Joseph Gerstein, a doctor at Tufts Universitys HMO practice. Durand, Gerstein, and Tufts shared $95 million of the settlement.There have since been various suits concerning leuprorelin use, none successful. They either concern the oversubscription of the drug or undue warning about the side effects. Between 2010 and 2013, the FDA updated the Lupron drug label to include new safety information on the risk of thromboembolism, loss of bone density and convulsions. The FDA then asserted that the benefits of leuprorelin outweigh its risks when used according to its approved labeling. Since 2017, the FDA has been evaluating leuprorelins connection to pain and discomfort in musculoskeletal and connective tissue.

"Lupron protocol"
A 2005 paper in the controversial and non-peer reviewed journal Medical Hypotheses suggested leuprorelin as a possible treatment for autism, the hypothetical method of action being the now defunct hypothesis that autism is caused by mercury, with the additional unfounded assumption that mercury binds irreversibly to testosterone and therefore leuprorelin can help cure autism by lowering the testosterone levels and thereby mercury levels. However, there is no scientifically valid or reliable research to show its effectiveness in treating autism. This use has been termed the "Lupron protocol" and Mark Geier, the proponent of the hypothesis, has frequently been barred from testifying in vaccine-autism related cases on the grounds of not being sufficiently expert in that particular issue and has had his medical license revoked. Medical experts have referred to Geiers claims as "junk science".

Research
As of 2006, leuprorelin was under investigation for possible use in the treatment of mild to moderate Alzheimers disease.A by mouth formulation of leuprorelin is under development for the treatment of endometriosis. It was also under development for the treatment of precocious puberty, prostate cancer, and uterine fibroids, but development for these uses was discontinued. The formulation has the tentative brand name Ovarest. As of July 2018, it is in phase II clinical trials for endometriosis.

Veterinary use
Leuprorelin is frequently used in ferrets for the treatment of adrenal disease.  Its use has been reported in a ferret with concurrent primary hyperaldosteronism, and one with concurrent diabetes mellitus. It is also used to treat pet parrots with  chronic egg laying behavior.

References
Further reading
Shajnfeld A, Krueger RB (July 2006). "Reforming (Purportedly) Non-Punitive Responses to Sexual Offending". Developments in Mental Health Law. 25: 81 </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Muromonab-CD3 and explain in detail? [/INST] Muromonab-CD3 (trade name Orthoclone OKT3, marketed by Janssen-Cilag) is an immunosuppressant drug given to reduce acute rejection in patients with organ transplants. It is a monoclonal antibody targeted at the CD3 receptor, a membrane protein on the surface of T cells. It was the first monoclonal antibody to be approved for clinical use in humans.

History
Muromonab-CD3 was approved by the U.S. Food and Drug Administration (FDA) in 1986, making it the first monoclonal antibody to be approved anywhere as a drug for humans. In the European Communities, it was the first drug to be approved under the directive 87/22/EWG, a precursor of the European Medicines Agency (EMEA) centralised approval system in the European Union. This process included an assessment by the Committee for Proprietary Medicinal Products (CPMP, now CHMP), and a subsequent approval by the national health agencies; in Germany, for example, in 1988 by the Paul Ehrlich Institute in Frankfurt. However, the manufacturer of muromonab-CD3 has voluntarily withdrawn it from the United States market in 2010 due to numerous side-effects, better-tolerated alternatives and declining usage.

Indications
Muromonab-CD3 is approved for the therapy of acute, glucocorticoid-resistant rejection of allogeneic renal, heart and liver transplants. Unlike the monoclonal antibodies basiliximab and daclizumab, it is not approved for prophylaxis of transplant rejection, although a 1996 review has found it to be safe for that purpose.It has also been investigated for use in treating T-cell acute lymphoblastic leukemia.

Pharmacodynamics and chemistry
T cells recognise antigens primarily via the T cell receptor (TCR).: 160  CD3 is one of the proteins that make up the TCR complex.: 166  The TCR transduces the signal for the T cell to proliferate and attack the antigen.: 160 Muromonab-CD3 is a murine (mouse) monoclonal IgG2a antibody which was created using hybridoma technology. It binds to the T cell receptor-CD3-complex (specifically the CD3 epsilon chain) on the surface of circulating T cells, initially leading to an activation, but subsequently inducing the clearance of TCR complex from cell surface and apoptosis of the T cells. This protects the transplant against the T cells </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Felbamate and explain in detail? [/INST] Felbamate (marketed under the brand name Felbatol by MedPointe) is an anticonvulsant used in the treatment of epilepsy. It is used to treat partial seizures (with and without generalization) in adults and partial and generalized seizures associated with Lennox–Gastaut syndrome in children. However, an increased risk of potentially fatal aplastic anemia and/or liver failure limit the drugs usage to severe refractory epilepsy.

Mechanism of action
Felbamate has been proposed to have a unique dual mechanism of action as a positive modulator of GABAA receptors and as a blocker of NMDA receptors, particularly isoforms containing the NR2B subunit. Although it is clear that felbamate does cause pharmacological inhibition of NMDA receptors, the relevance of NMDA receptor blockade as a strategy for the treatment of human epilepsy has been questioned. Therefore, the importance of the effects of felbamate on NMDA receptors to its therapeutic action in epilepsy is uncertain.

Approval history
United States
August 1993. Felbamate was approved for partial seizures with and without secondary generalization in adults and for Lennox–Gastaut Syndrome, a serious form of childhood epilepsy. Over the following year 150,000 people were started on felbamate therapy and a third of these became established.
August 1, 1994. It was urgently withdrawn after 10 cases of aplastic anemia </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Metolazone and explain in detail? [/INST] Metolazone is a thiazide-like diuretic marketed under the brand names Zytanix, Metoz, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure and high blood pressure. Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the kidney, so that blood volume decreases and urine volume increases. This lowers blood pressure and prevents excess fluid accumulation in heart failure. Metolazone is sometimes used together with loop diuretics such as furosemide or bumetanide, but these highly effective combinations can lead to dehydration and electrolyte abnormalities.
It was patented in 1966 and approved for medical use in 1974.

Medical uses
One of the primary uses of metolazone is for treating edema (fluid retention) associated with congestive heart failure (CHF). In mild heart failure, metolazone or another diuretic may be used alone, or combined with other diuretics for moderate or severe heart failure. In addition to preventing fluid buildup, the use of metolazone may allow the patient to relax the amount of sodium restriction that is required. Although most thiazide diuretics lose their effectiveness in kidney failure, metolazone remains active even when the glomerular filtration rate (GFR) is below 30–40 mL/min (moderate chronic kidney disease). This gives it a considerable advantage over other thiazide diuretics, since renal and heart failure often coexist and contribute to fluid retention.Metolazone may also be used in kidney disease, such as chronic kidney disease or the nephrotic syndrome. Chronic kidney disease causes excess fluid retention that is often treated with diet adjustments and diuretics. Metolazone may be combined with other diuretics (typically loop diuretics) to treat diuretic resistance in congestive heart failure, chronic kidney disease, and nephrotic syndrome. Metolazone and a loop diuretic will synergistically enhance diuresis over the use of either agent alone. Using this combination, diuretic effects will occur at two different segments of the nephron; namely, the loop diuretic will act at the loop of Henle, and metolazone will act at the distal convoluted tubule. Metolazone is frequently prescribed in addition to the loop diuretic. Metolazone may be used for edema caused by liver cirrhosis as well.
The other major use of metolazone is in treating hypertension (high blood pressure). Thiazide diuretics, though usually not metolazone, are very often used alone as first-line treatment for mild hypertension. They are also used in combination with other drugs for difficult-to-treat or more severe hypertension. "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" (JNC 7) recommends thiazide diuretics as the initial medication for treatment of hypertension. Hydrochlorothiazide is by far the most commonly used, as it is both better-studied and cheaper (about four times) than metolazone, although as mentioned above metolazone is used in patients with moderate chronic kidney disease.

Toxicity
Since thiazide diuretics affect the transport of electrolytes and water in the kidney, they can be responsible for abnormalities of water balance and electrolyte levels. Removal of too much fluid can cause volume depletion and hypotension. Various electrolyte abnormalities may result, including hyponatremia (low sodium), hypokalemia (low potassium), hypochloremia (low chloride), hypomagnesemia (low magnesium), hypercalcemia (high calcium), and hyperuricemia (high uric acid). These may result in dizziness, headache, or heart arrhythmias (palpitations). Serious, though rare, side effects include aplastic anemia, pancreatitis, agranulocytosis, and angioedema. Metolazone, like other thiazide diuretics, may unmask latent diabetes mellitus or exacerbate gout, especially by interacting with medicines used to treat gout. In addition, thiazide diuretics, including metolazone, are sulfonamides; those with hypersensitivity to sulfonamides ("sulfa allergy") may also be allergic to metolazone.

Mechanism of action
The primary target of all thiazide diuretics, including metolazone, is the distal convoluted tubule, part of the nephron in the kidney, where they inhibit the sodium-chloride symporter.
In the kidney, blood is filtered into the lumen, or open space, of the nephron tubule. Whatever remains in the tubule will travel to the bladder as urine and eventually be excreted. The cells lining the tubule modify the fluid inside, absorbing some material and excreting others. One side of the cell (the apical side) faces the lumen; the opposite side (the basolateral side) faces the interstitial space near blood vessels. The other sides are tightly joined to neighboring cells.
As with other regions, tubule cells in the distal convoluted tubule possess the ATP-powered sodium-potassium antiporter (Na+/K+-ATPase), which uses energy from ATP to transfer three sodium ions out from the basolateral surface (toward blood vessels) while simultaneously transferring two potassium ions in. The distal convoluted tubule cells also possess a sodium-chloride symporter on the apical side, which passively allows one sodium ion and one chloride ion to diffuse together in from the lumen (where urine is forming) into the cell interior. As sodium is pumped out of the cell by the ATPase, its intracellular concentration falls, and additional sodium begins to diffuse in from the tubule lumen as replacement. The symporter requires chloride to be transported in as well. Water passively follows to maintain isotonicity; excess chloride and potassium passively diffuse out the cell through basolateral channels into the interstitial space, and water accompanies them. The water and chloride, as well as the sodium pumped out by the ATPase, will be absorbed into the bloodstream.
Metolazone and the other thiazide diuretics inhibit the function of the sodium-chloride symporter, preventing sodium and chloride, and therefore water too, from leaving the lumen to enter the tubule cell. As a result, water remains in the lumen and is excreted as urine, instead of being reabsorbed into the bloodstream. Since most of the sodium in the lumen has already been reabsorbed by the time the filtrate reaches the distal convoluted tubule, thiazide diuretics have limited effects on water balance and on electrolyte levels. Nevertheless, they can be associated with low sodium levels, volume depletion, and low blood pressure, among other adverse effects.

Pharmacokinetics
Metolazone is only available in oral preparations. Approximately 65% of the amount ingested becomes available in the bloodstream. Its half-life is approximately fourteen hours, similar to indapamide but considerably longer than hydrochlorothiazide. Metolazone is around ten times as potent as hydrochlorothiazide </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Taliglucerase alfa and explain in detail? [/INST] Taliglucerase alfa, sold under the brand name Elelyso among others, is a biopharmaceutical medication developed by Protalix and Pfizer. The drug, a recombinant glucocerebrosidase used to treat Gauchers disease, is the first plant-made pharmaceutical to win approval by the U.S. Food and Drug Administration (FDA) </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Colistin and explain in detail? [/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 helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Oxycodone/ibuprofen and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Onasemnogene abeparvovec and explain in detail? [/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 helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Acebutolol and explain in detail? [/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 helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Sodium nitrite and explain in detail? [/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 helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Nilutamide and explain in detail? [/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 helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Lodine and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Ganirelix and explain in detail? [/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>