<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 Enalaprilat 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 Rajani 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 Raxibacumab and explain in detail? [/INST] Raxibacumab  is a human monoclonal antibody intended for the prophylaxis and treatment of inhaled anthrax. Its efficacy has been proven in rabbits and monkeys </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 Uridine triacetate 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 Neomycin/polymyxin B/bacitracin and explain in detail? [/INST] Neomycin/polymyxin B/bacitracin, also known as triple antibiotic ointment, is a medication used to reduce the risk of infections following minor skin injuries. It contains three antibiotics: neomycin, polymyxin B, and bacitracin. It is for topical use only and should not be ingested due to risk of kidney damage.Possible side effects include itchiness and skin rash, and in rare cases hearing loss. Use in pregnancy is generally recommended. It is relatively broad spectrum, being effective against both Gram-negative and Gram-positive bacteria.The combination was approved for medical use in the United States in 1971. It is available over the counter in the United States. In 2017, it was the 78th most commonly prescribed medication in the United States, with more than ten million prescriptions. It is sold under the brand name Globe and Neosporin, among others and is available generically at most major pharmaceutical retailers.

Medical uses
Neomycin/polymyxin B/bacitracin ointment is reported to be a safe and effective topical agent for preventing infections in minor skin trauma.It is used for burns, scratches, cuts, and minor skin infections. The ointment is most effective when applied after cleaning the affected area.The use of neomycin/polymyxin B/bacitracin, decreases infection rates in minor-contaminated wounds. However, if the wound is sterile, then there are no benefits compared to petrolatum (placebo).

Side effects
It is for external use only and should not be applied near mucous membranes such as the eyes or mouth. It is not recommended for children under the age of two. Users should immediately seek medical attention if they experience hives, rashes, or itching. Any skin irritations such as pain, burning, or cracked skin that were not present prior to use of ointment must receive immediate care.It has been shown to cause contact dermatitis in some cases.

Antibiotic-resistant bacteria
Concern exists that its use contributes to the emergence of antibiotic-resistant bacteria. In the US, the only large market for the ointment, it may increase antibiotic resistance. For instance, it may increase the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) bacteria, specifically the highly lethal ST8:USA300 strain.

Components
The original ointment contains three different antibiotics: bacitracin, neomycin, and polymyxin B, in a relatively low-molecular-weight base of cocoa butter, cottonseed oil, sodium pyruvate, tocopheryl acetate, and petroleum jelly.The generic name for these products, regardless of the base, is "triple antibiotic ointment".
In China, the product is named "compound polymyxin B ointment" and is manufactured there by Zhejiang Fonow Medicine Co. Ltd. The product was also marketed by the Upjohn Company under the name "Mycitracin", until 1997 when that name was acquired by Johnson & Johnson.Some people have allergic reactions to neomycin, so a "double antibiotic ointment" is sold without it, containing only
bacitracin and polymyxin B: one such example is Polysporin branded product.A "Plus" variant of the ointment exists that adds the analgesic pramoxine, but uses the cheap, simple, long-lasting, but heavier petroleum jelly base, common to many over-the-counter topicals.  The latest version of this analgesic formulation, a high-absorption cream, excludes bacitracin because it is unstable in such a base.

Active ingredients
The three main active ingredients in Neomycin are neomycin sulfate, polymyxin B sulfate, and bacitracin zinc.One of the main components is neomycin sulfate, which is a type of antibiotic discovered in 1949 by microbiologist Selman Waksman at Rutgers University. Neomycin belongs to the aminoglycoside class of antibiotics and fights against Gram positive and gram negative bacteria. The antibiotic is often used to prevent risk of bacterial infections. Aminoglycosides work by binding to bacterial RNA and changing the ability to produce proteins while exerting little to no effect on DNA. Thus, neomycin kills bacteria as a result of irregular protein production in the bacterial cell. When the cell can no longer produce the correct proteins, its membrane becomes damaged. As a result of damaged membrane, the affected bacterial cells die, and the infection is prevented or limited.Like neomycin, polymyxin B is an antibiotic. Polymyxin B forms holes in the bacterial cell wall causing the internal cellular components to leak out, resulting in cell death.
Pramoxine is used to temporarily reduce pain from burns, insect bites, and minor cuts </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 thiosulfate and explain in detail? [/INST] Sodium thiosulfate (sodium thiosulphate) is an inorganic compound with the formula Na2S2O3.xH2O. Typically it is available as the white or colorless pentahydrate, Na2S2O3·5H2O. The solid is an efflorescent (loses water readily) crystalline substance that dissolves well in water.Sodium thiosulfate is used in gold mining, water treatment, analytical chemistry, the development of silver-based photographic film and prints, and medicine.  The medical uses of sodium thiosulfate include treatment of cyanide poisoning and pityriasis. It is on the World Health Organizations List of Essential Medicines.

Uses
Sodium thiosulfate is used predominantly in industry.  For example, it is used to convert dyes to their soluble leuco form.  It is also used to bleach "wool, cotton, silk, ...soaps, glues, clay, sand, bauxite, and... edible oils, edible fats, and gelatin."

Medical uses
Sodium thiosulfate is used in the treatment of cyanide poisoning.  Other uses include topical treatment of ringworm and tinea versicolor, and treating some side effects of hemodialysis and chemotherapy.

Photographic processing
Silver halides, e.g., AgBr, typical components of photographic emulsions, dissolve upon treatment with aqueous thiosulfate.This application as a photographic fixer was discovered by John Herschel.  It is used for both film and photographic paper processing; the sodium thiosulfate is known as a photographic fixer, and is often referred to as hypo, from the original chemical name, hyposulphite of soda. Ammonium thiosulfate is typically preferred to sodium thiosulfate for this application.

Neutralizing chlorinated water
It is used to dechlorinate tap water including lowering chlorine levels for use in aquariums, swimming pools, and spas (e.g., following superchlorination) and within water treatment plants to treat settled backwash water prior to release into rivers.  The reduction reaction is analogous to the iodine reduction reaction.
In pH testing of bleach substances, sodium thiosulfate neutralizes the color-removing effects of bleach and allows one to test the pH of bleach solutions with liquid indicators. The relevant reaction is akin to the iodine reaction: thiosulfate reduces the hypochlorite (active ingredient in bleach) and in so doing becomes oxidized to sulfate. The complete reaction is:

4 NaClO + Na2S2O3 + 2 NaOH → 4 NaCl + 2 Na2SO4 + H2OSimilarly, sodium thiosulfate reacts with bromine, removing the free bromine from solution. Solutions of sodium thiosulfate are commonly used as a precaution in chemistry laboratories when working with bromine and for the safe disposal of bromine, iodine, or other strong oxidizers.

Structure
Two polymorphs are known of the pentahydrate.  The anhydrous salt exists in several polymorphs.  In the solid state, the thiosulfate anion is tetrahedral in shape and is notionally derived by replacing one of the oxygen atoms by a sulfur atom in a sulfate anion.  The S-S distance indicates a single bond, implying that the terminal sulfur holds a significant negative charge and the S-O interactions have more double-bond character.

Production
On an industrial scale, sodium thiosulfate is produced chiefly from liquid waste products of sodium sulfide or sulfur dye manufacture.In the laboratory, this salt can be prepared by heating an aqueous solution of sodium sulfite with sulfur or by boiling aqueous sodium hydroxide and sulfur according to this equation:
6 NaOH + 4 S → 2 Na2S + Na2S2O3 + 3 H2O

Principal reactions
Upon heating to 300 °C, it decomposes to sodium sulfate and sodium polysulfide:

4 Na2S2O3 → 3 Na2SO4 + Na2S5Thiosulfate salts characteristically decompose upon treatment with acids.  Initial protonation occurs at sulfur. When the protonation is conducted in diethyl ether at −78 °C, H2S2O3 (thiosulfuric acid) can be obtained. It is a somewhat strong acid with pKas of 0.6 and 1.7 for the first and second dissociations, respectively.
Under normal conditions, acidification of solutions of this salt excess with even dilute acids results in complete decomposition to sulfur, sulfur dioxide, and water:
Na2S2O3 + 2 HCl → 2 NaCl + 1/8 S8 + SO2 + H2O

Coordination chemistry
Thiosulfate is a potent ligand for soft metal ions </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 Chlortalidone and explain in detail? [/INST] Chlortalidone, also known as chlorthalidone, is a thiazide-like diuretic drug used to treat high blood pressure, swelling including that due to heart failure, liver failure, and nephrotic syndrome, diabetes insipidus, and renal tubular acidosis. Because chlortalidone is reliably effective in most patients with high blood pressure, it is considered a preferred initial treatment. It is also used to prevent calcium-based kidney stones. It is taken by mouth. Effects generally begin within three hours and last for up to three days. Chlortalidone is more effective than hydrochlorothiazide for prevention of heart attack or stroke.Common adverse effects include low blood potassium, low blood sodium, high blood sugar, dizziness, and erectile dysfunction. Other adverse effects may include gout, low blood magnesium, high blood calcium, allergic reactions, and low blood pressure. Some reviews have found chlortalidone and hydrochlorothiazide to have a similar risk of adverse effects, while other reviews have found chlortalidone to have a higher risk. While it may be used in pregnancy it is a less preferred option. How it works is not completely clear but is believed to involve increasing the amount of sodium and water lost by the kidneys.Chlortalidone was patented in 1957 and came into medical use in 1960. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 135th most commonly prescribed medication in the United States, with more than 4 million prescriptions.

Medical use
High blood pressure
Chlortalidone is considered a first-line medication for treatment high blood pressure. Some recommend chlortalidone over hydrochlorothiazide. A meta-analysis of randomized controlled trials found that chlortalidone is more effective than hydrochlorothiazide for lowering blood pressure, while the two drugs have similar toxicity.Trials of chlortalidone for high blood pressure found that lower doses of chlortalidone (e.g., 12.5 mg daily in ALLHAT study) had maximal blood pressure lowering effect and that higher doses did not lower it more. Chlortalidone and other thiazide diuretics are effective for lowering high blood pressure in persons with chronic kidney disease, although the risk of adverse effects is higher in these persons.

Left ventricular hypertrophy
Chlortalidone is used to treat left ventricular hypertrophy in the heart; it works chiefly by lowering blood pressure, and thereby reducing systemic vascular resistance. There is evidence that chlortalidone is superior to hydrochlorothiazide for reducing the mass of the left ventricle of the heart in persons with enlargement of the left ventricle of the heart. Chlortalidone is superior to angiotensin converting enzyme Inhibitors or angiotensin II receptor blockers for inducing regression of enlargement of the left ventricle, which is the main pumping chamber of the heart.

Swelling
Chlortalidone reduces edema (swelling) by increasing urinary salt and water excretion, lowering intravascular hydrostatic pressure and thereby lowering transcapillary pressure (see Starling Equation). Edema may be caused by either increased hydrostatic pressure or reduced oncotic pressure in the blood vessels. Edema due to increased hydrostatic pressure may be a result of serious cardiopulmonary disease (which reduces glomerular perfusion in the kidney) or to kidney injury or disease (which may reduce glomerular excretion of salt and water by the kidney) or due to relatively benign conditions such as menstrual-related fluid retention, or as an adverse effect of dihydropyridine calcium channel blockers, which commonly cause swelling of the feet and lower legs. Edema due to decreased oncotic pressure may be a result of leaking of blood proteins through the glomeruli of an injured kidney or a result of diminished synthesis of blood proteins by a damaged liver. Regardless of cause, chlortalidone may reduce the severity of edema by reducing intravascular volume and thereby reducing intravascular hydrostatic pressure.

Bone fracture prevention
Chlortalidone decreases mineral bone loss by promoting calcium retention by the kidney, and by directly stimulating osteoblast differentiation and bone mineral formation. A Cochrane review found tentative evidence that thiazide exposure was associated with a reduced risk of hip fracture. A secondary analysis of data from the ALLHAT study found that chlortalidone reduced risk of hip and pelvis fracture.

Kidney stone prevention
Chlortalidone reduces the amount of calcium excreted in urine, reducing the risk of calcium oxalate kidney stones. In people who have had multiple episodes of calcium oxalate kidney stones, chlortalidone lowers the risk of having another episode of kidney stones. Chlortalidone is more effective than hydrochlorothiazide for lowering urine calcium levels and is therefore probably more effective.

Ménières disease
Chlortalidone reduces the volume and thereby reduces the pressure in the inner ear chambers; elevated endolymph pressure in the inner ear is thought to be the cause of Ménières disease or ’Endolymphatic hydrops.’ Synthesis of evidence from multiple small, low-quality studies indicates that chlortalidone or other thiazide diuretics are effective for Ménières Disease.

Diabetes insipidus
Chlortalidone (or other thiazide medication) is a key component of treatment of nephrogenic diabetes insipidus. Nephrogenic diabetes insipidus occurs when the kidney is unable to produce concentrated urine because it has an inadequate response to vasopressin-dependent removal of free water from the renal tubular filtrate. By blocking sodium ion resorption in the distal convoluted tubule, chlortalidone induces an increase in excretion of sodium ion in urine (natriuresis). Giving chlortalidone while simultaneously restricting dietary sodium intake causes mild hypovolemia (low intravascular volume), which induces isotonic reabsorption of solute from the proximal renal tubule, reducing solute delivery in the renal collecting tubule and renal medullary collecting duct. This reduced delivery of solute to the collecting tubule and medullary collecting duct allows increased water resorption and higher concentration of urine, which leads to reversal of nephrogenic diabetes insipidus by a means that is independent of vasopressin.

Adverse effects
Some reviews have found a similar risk as hydrochlorothiazide, while other reviews found a higher risk of side effects.
Hypokalemia (low blood potassium) occurs occasionally; the risk of hypokalemia is higher in persons who are magnesium deficient
Hypomagnesemia (low blood magnesium) a review of four clinical trials found that low blood magnesium occurred in 20% of persons within a few weeks of beginning treatment with 50 mg of chlortalidone daily. The risk of chlortalidone-associated hypomagnesemia is higher in persons with diabetes mellitus who have low dietary magnesium intake.
Hyponatremia (low blood sodium) occurred in 4.1% of subjects randomized to chlortalidone in the Systolic Hypertension in the Elderly Trial, compared to 1.3% of control subjects. The risk of hyponatremia varies from 5 per 100,000 person-years for those younger than 40 years of age to 730 per 100,000 person-years in those older than 80 years of age. Hyponatremia is more likely in persons with certain genetic variants of the prostaglandin transporter SLCO2A1 associated with elevated urinary PGE2 and inappropriately low plasma ADH levels in the setting of low plasma osmolality. Thiazide-associated hyponatremia is often more severe than loop diuretic-associated hyponatremia because the predominant action of thiazides occurs late in the tubular flow, reducing opportunity to apply additional corrective action further along the tubule.
Hypercalcemia (high blood calcium level) can occur in normal persons exposed to chlortalidone but is more likely to occur when persons with sub-clinical hyperparathyroidism are exposed to chlortalidone.
Hyperuricemia, high levels of uric acid in the blood
Hyperglycemia, high blood sugar is more common in persons who are magnesium deficient
Hyperlipidemia, high cholesterol and triglycerides
Headache
Nausea/vomiting
Photosensitivity increased susceptibility to sunburn of skin with sun exposure
Photoonycholysis detachment of nails from nailbed with sun exposure
Weight gain
Gout; approximately doubles the risk
PancreatitisThe frequency and severity of these adverse effects is much reduced when chlortalidone is used at lower doses (e.g., 12.5 mg per day).

Mechanism of action
Chlortalidone reduces reabsorption of sodium and chloride primarily through inhibition of the Na+/Cl− symporter in the apical membrane of distal convoluted tubule cells in the kidney. Although chlortalidone is often referred to as a "thiazide-like" diuretic, it is unlike thiazide diuretics in that, in addition to its inhibition of the  Na+/Cl− symporter, it also strongly inhibits multiple isoforms of carbonic anhydrase. Some of chlortalidones diuretic effect is also due to this inhibition of carbonic anhydrase in the proximal tubule. Chronic exposure to chlortalidone decreases the glomerular filtration rate. Chlortalidones diuretic effect is diminished in persons with kidney impairment. By increasing the delivery of sodium to the distal renal tubule, chlortalidone indirectly increases potassium excretion via the sodium-potassium exchange mechanism (i.e. apical ROMK/Na channels coupled with basolateral Na+/K ATPases). This can result in a low blood concentration of potassium and chloride as well as a mild metabolic alkalosis; however, the diuretic effect of chlortalidone is not affected by the acid-base balance of the person being treated.
There is uncertainty about the mechanism of the blood pressure-lowering effect that occurs during chronic exposure to chlortalidone. Initially, diuretics lower blood pressure by decreasing cardiac output and reducing plasma and extracellular fluid volume. Eventually, cardiac output returns to normal, and plasma and extracellular fluid volume return to slightly less than normal, but a reduction in peripheral vascular resistance is maintained, thus resulting in an overall lower blood pressure. The reduction in intravascular volume induces an elevation in plasma renin activity and aldosterone secretion, further contributing to the potassium loss associated with thiazide diuretic therapy.

Pharmacokinetics
Chlortalidone is slowly absorbed from the gastrointestinal tract after oral ingestion. It has a long half-life and therefore a prolonged diuretic action, which results in continued diuretic effects despite a skipped dose. This prolonged action of chlortalidone despite missing doses may account for the higher efficacy of chlortalidone compared to the shorter half-life medication, hydrochlorothiazide. Chlortalidone is eliminated from the body mostly by the kidney, as unchanged drug. Thus, in persons with diminished kidney function, the clearance of chlortalidone is reduced and the elimination half-life is increased.As with other thiazide diuretics, chlortalidone crosses the placenta and is excreted in breast milk </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 Efinaconazole 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 Sipuleucel-T and explain in detail? [/INST] Sipuleucel-T, sold under the brand name Provenge, developed by Dendreon Pharmaceuticals, LLC, is a cell-based cancer immunotherapy for prostate cancer (CaP). It is an autologous cellular immunotherapy.

Medical uses
Sipuleucel-T is indicated for the treatment of metastatic, asymptomatic or minimally symptomatic, metastatic castrate-resistant hormone-refractory prostate cancer (HRPC).  Other names for this stage are metastatic castrate-resistant (mCRPC) and androgen independent (AI) or (AIPC). This stage leads to mCRPC with lymph node involvement and distal (distant) tumors; this is the lethal stage of CaP. The prostate cancer staging designation is T4,N1,M1c.

Treatment method
A course of treatment consists of three basic steps:

The patients white blood cells, primarily dendritic cells, a type of antigen-presenting cells (APCs), are extracted in a leukapheresis procedure.
The blood product is sent to a production facility and incubated with a fusion protein (PA2024) consisting of two parts:
The antigen prostatic acid phosphatase (PAP), which is present in 95% of prostate cancer cells and
An immune signaling factor granulocyte-macrophage colony stimulating factor (GM-CSF) that helps the APCs to mature.
The activated blood product (APC8015) is returned from the production facility to the infusion center and reinfused into the patient.Premedication with acetaminophen and antihistamine is recommended to minimize side effects.

Side effects
Common side effects include: bladder pain; bloating or swelling of the face, arms, hands, lower legs, or feet; bloody or cloudy urine; body aches or pain; chest pain; chills; confusion; cough; diarrhea; difficult, burning, or painful urination; difficulty with breathing; difficulty with speaking up to inability to speak; double vision; sleeplessness; and inability to move the arms, legs, or facial muscles.

Society and culture
Legal status
Sipuleucel-T was approved by the U.S. Food and Drug Administration (FDA) on April 29, 2010, to treat asymptomatic or minimally symptomatic metastatic HRPC.Shortly afterward, sipuleucel-T was added to the compendium of cancer treatments published by the National Comprehensive Cancer Network (NCCN) as a "category 1" (highest recommendation) treatment for HRPC. The NCCN Compendium is used by Medicare and major health care insurance providers to decide whether a treatment should be reimbursed.

Research
Clinical trials
Completed
Sipuleucel-T showed overall survival (OS) benefit to patients in three double-blind randomized phase III clinical trials, D9901, D9902a, and IMPACT.The IMPACT trial served as the basis for FDA licensing. This trial enrolled 512 patients with asymptomatic or minimally symptomatic metastatic HRPC randomized in a 2:1 ratio. The median survival time for sipuleucel-T patients was 25.8 months comparing to 21.7 months for placebo-treated patients, an increase of 4.1 months.  31.7% of treated patients survived for 36 months vs. 23.0% in the control arm.  Overall survival was statistically significant (P=0.032). The longer survival without tumor shrinkage or change in progression is surprising. This may suggest the effect of an unmeasured variable.  The trial was conducted pursuant to a FDA Special Protocol Assessment (SPA), a set of guidelines binding trial investigators to specific agreed-upon parameters with respect to trial design, procedures and endpoints; compliance ensured overall scientific integrity and accelerated FDA approval.The D9901 trial enrolled 127 patients with asymptomatic metastatic HRPC randomized in a 2:1 ratio. The median survival time for patients treated with sipuleucel-T was 25.9 months comparing to 21.4 months for placebo-treated patients. Overall survival was statistically significant (P=0.01).The D9902a trial was designed like the D9901 trial but enrolled 98 patients. The median survival time for patients treated with sipuleucel-T was 19.0 months comparing to 15.3 months for placebo-treated patients, but did not reach statistical significance.

Ongoing
As of August 2014, the PRO Treatment and Early Cancer Treatment (PROTECT) trial, a phase IIIB clinical trial started in 2001, was tracking subjects but no longer enrolling new subjects. Its purpose is to test efficacy for patients whose CaP is still controlled by either suppression of testosterone by hormone treatment or by surgical castration. Such patients have usually failed primary treatment of either surgical removal of the prostate, (EBRT), internal radiation, BNCT or (HIFU) for curative intent. Such failure is called biochemical failure and is defined as a PSA reading of 2.0 ng/mL above nadir (the lowest reading taken post primary treatment).As of August 2014, a clinical trial administering sipuleucel-T in conjunction with ipilimumab (Yervoy) was tracking subjects but no longer enrolling new subjects; the trial evaluates the clinical safety and anti-cancer effects (quantified in PSA, radiographic and T cell response) of the combination therapy in patients with advanced prostate cancer.

References
This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute.

Further reading
Huber ML, Haynes L, Parker C, Iversen P (February 2012). "Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer". Journal of the National Cancer Institute. 104 (4): 273–9. doi:10.1093/jnci/djr514 </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 Tretten and explain in detail? [/INST] Tretten is a village in Øyer Municipality in Innlandet county, Norway. The village is located on the Losna lake, which is part of the Gudbrandsdalslågen river. Tretten is located in the Gudbrandsdal valley, along the Gudbrandsdalslågen river in the southern part of the municipality. It is located along the European route E6 highway, about 25 kilometres (16 mi) north of the town of Lillehammer </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 Efavirenz/lamivudine/tenofovir and explain in detail? [/INST] Efavirenz/lamivudine/tenofovir (EFV/3TC/TDF), sold under the brand name Symfi among others, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It combines efavirenz, lamivudine, and tenofovir disoproxil. As of 2019, it is listed by the World Health Organization as an alternative first line option to dolutegravir/lamivudine/tenofovir. It is taken by mouth.Side effects can include joint pain, sleepiness, headaches, depression, trouble sleeping, and itchiness. Severe side effects may include depression, psychosis, or osteonecrosis. In those with a history of epilepsy, it may increase the frequency of seizures. Greater care should also be taken in those with kidney problems. Its use during pregnancy appears to be unsafe.It is on the World Health Organizations List of Essential Medicines. The combination received tentative approval in the United States in 2014, and was granted approval in February 2018. Its availability and importance is supported by Medecins Sans Frontieres. It is available as a generic medication.

References
External links
"Efavirenz". Drug Information Portal. U.S </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 Flutamide and explain in detail? [/INST] Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growth, and high androgen levels in women. It is taken by mouth, usually three times per day.Side effects in men include breast tenderness and enlargement, feminization, sexual dysfunction, and hot flashes. Conversely, the medication has fewer side effects and is better-tolerated in women with the most common side effect being dry skin. Diarrhea and elevated liver enzymes can occur in both sexes. Rarely, flutamide can cause liver damage, lung disease, sensitivity to light, elevated methemoglobin, elevated sulfhemoglobin, and deficient neutrophils. Numerous cases of liver failure and death have been reported, which has limited the use of flutamide.Flutamide acts as a selective antagonist of the androgen receptor (AR), competing with androgens like testosterone and dihydrotestosterone (DHT) for binding to ARs in tissues like the prostate gland. By doing so, it prevents their effects and stops them from stimulating prostate cancer cells to grow. Flutamide is a prodrug to a more active form. Flutamide and its active form stay in the body for a relatively short time, which makes it necessary to take flutamide multiple times per day.
Flutamide was first described in 1967 and was first introduced for medical use in 1983. It became available in the United States in 1989. The medication has largely been replaced by newer and improved NSAAs, namely bicalutamide and enzalutamide, due to their better efficacy, tolerability, safety, and dosing frequency (once per day), and is now relatively little-used. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Prostate cancer
GnRH is released by the hypothalamus in a pulsatile fashion; this causes the anterior pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates the testes to produce testosterone, which is metabolized to DHT by the enzyme 5α-reductase.DHT, and to a significantly smaller extent, testosterone, stimulate prostate cancer cells to grow. Therefore, blocking these androgens can provide powerful treatment for prostate cancer, especially metastatic disease. Normally administered are GnRH analogues, such as leuprorelin or cetrorelix. Although GnRH agonists stimulate the same receptors that GnRH does, since they are present continuously and not in a pulsatile manner, they serve to inhibit the pituitary gland and therefore block the whole chain. However, they initially cause a surge in activity; this is not solely a theoretical risk but may cause the cancer to flare. Flutamide was initially used at the beginning of GnRH agonist therapy to block this surge, and it and other NSAAs continue in this use. In contrast to GnRH agonists, GnRH antagonists dont cause an initial androgen surge, and are gradually replacing GnRH agonists in clinical use.There have been studies to investigate the benefit of adding an antiandrogen to surgical orchiectomy or its continued use with a GnRH analogue (combined androgen blockade (CAB)). Adding antiandrogens to orchiectomy showed no benefit, while a small benefit was shown with adding antiandrogens to GnRH analogues.Unfortunately, therapies which lower testosterone levels, such as orchiectomy or GnRH analogue administration, also have significant side effects. Compared to these therapies, treatment with antiandrogens exhibits "fewer hot flashes, less of an effect on libido, less muscle wasting, fewer personality changes, and less bone loss." However, antiandrogen therapy alone is less effective than surgery. Nevertheless, given the advanced age of many with prostate cancer, as well as other features, many men may choose antiandrogen therapy alone for a better quality of life.Flutamide has been found to be similarly effective in the treatment of prostate cancer to bicalutamide, although indications of inferior efficacy, including greater compensatory increases in testosterone levels and greater reductions in PSA levels with bicalutamide, were observed. The medication, at a dosage of 750 mg/day (250 mg three times daily), has also been found to be equivalent in effectiveness to 250 mg/day oral cyproterone acetate as a monotherapy in the treatment of prostate cancer in a large-scale clinical trial of 310 patients, though its side effect and toxicity profiles (including gynecomastia, diarrhea, nausea, loss of appetite, and liver disturbances) were regarded as considerably worse than those of cyproterone acetate.A dosage of 750 mg/day flutamide (250 mg/three times a day) is roughly equivalent in terms of effectiveness to 50 mg/day bicalutamide when used as the antiandrogen component in combined androgen blockade in the treatment of advanced prostate cancer.Flutamide has been used to prevent the effects of the testosterone flare at the start of GnRH agonist therapy in men with prostate cancer.The combination of flutamide with an estrogen such as ethinylestradiol sulfonate has been used as a form of combined androgen blockade and as an alternative to the combination of flutamide with surgical or medical castration.

Skin and hair conditions
Flutamide has been researched and used extensively in the treatment of androgen-dependent skin and hair conditions in women including acne, seborrhea, hirsutism, and scalp hair loss, as well as in hyperandrogenism (e.g., in polycystic ovary syndrome or congenital adrenal hyperplasia), and is effective in improving the symptoms of these conditions. The dosages used are lower than those used in the treatment of prostate cancer. Although flutamide continues to be used for these indications, its use in recent years has been limited due to the risk of potentially fatal hepatotoxicity, and it is no longer recommended as a first- or second-line therapy. The related NSAA bicalutamide has also been found to be effective in the treatment of hirsutism in women and appears to have comparable effectiveness to that of flutamide, but has a far lower and only small risk of hepatotoxicity in comparison.Aside from its risk of liver toxicity and besides other nonsteroidal antiandrogens, it has been said that flutamide is likely the best typically used antiandrogen medication for the treatment of androgen-dependent symptoms in women. This is related to its high effectiveness and minimal side effects.

Acne and seborrhea
Flutamide has been found to be effective in the treatment of acne and seborrhea in women in a number of studies. In a long-term study of 230 women with acne, 211 of whom also had seborrhea, very-low-dose flutamide alone or in combination with an oral contraceptive caused a marked decrease in acne and seborrhea after 6 months of treatment, with maximal effect by 1 year of treatment and benefits maintained in the years thereafter. In the study, 97% of the women reported satisfaction with the control of their acne with flutamide. In another study, flutamide decreased acne and seborrhea scores by 80% in only 3 months. In contrast, spironolactone decreased symptoms by only 40% in the same time period, suggesting superior effectiveness for flutamide for these indications. Flutamide has, in general, been found to reduce symptoms of acne by as much as 90% even at low doses, with several studies showing complete acne clearance.

Excessive hair growth
Flutamide has been found to be effective in the treatment of hirsutism (excessive body/facial hair growth) in numerous studies. It possesses moderate effectiveness for this indication, and the overall quality of the evidence is considered to be moderate. The medication shows equivalent or superior effectiveness to other antiandrogens including spironolactone, cyproterone acetate, and finasteride in the treatment of hirsutism, although its relatively high risk of hepatotoxicity makes it unfavorable compared to these other options. It has been used to treat hirsutism at dosages ranging from 62.5 mg/day to 750 mg/day. A study found that multiple dosages of flutamide significantly reduced hirsutism in women with polycystic ovary syndrome and that there were no significant differences in the effectiveness for dosages of 125 mg/day, 250 mg/day, and 375 mg/day. In addition, a study found that combination of 125 mg/day flutamide with finasteride was no more effective than 125 mg/day flutamide alone in the treatment of hirsutism. These findings support the use of flutamide at lower doses for hirsutism without loss of effectiveness, which may help to lower the risk of hepatotoxicity. However, the risk has been found to remain even at very low doses.

Scalp hair loss
Flutamide has been found to be effective in the treatment of female pattern hair loss in a number of studies. In one study of 101 pre- and postmenopausal women, flutamide alone or in combination with an oral contraceptive produced a marked decrease in hair loss scores after 1 year of treatment, with maximum effect after 2 years of treatment and benefits maintained for another 2 years. In a small study of flutamide with an oral contraceptive, the medication caused an increase in cosmetically acceptance hair density in 6 of 7 women with diffuse scalp hair loss. In a comparative study, flutamide significantly improved scalp hair growth (21% reduction in Ludwig scores) in hyperandrogenic women after 1 year of treatment, whereas cyproterone acetate and finasteride were ineffective.

Transgender hormone therapy
Flutamide has been used as a component of feminizing hormone therapy for transgender women. At least two centers have been reported to use flutamide as an antiandrogen in transgender women. However, the use of flutamide for such purposes, as well as in biological women with androgen-dependent dermatological conditions, is discouraged due to reports of hepatotoxicity in men with prostate cancer at comparable doses.

Other uses
Flutamide has been used in case reports to decrease the frequency of spontaneous orgasms, for instance in men with post-orgasmic illness syndrome.

Available forms
Flutamide is available in the form of 125 mg oral capsules and 250 mg oral tablets.

Side effects
The side effects of flutamide are sex-dependent. In men, a variety of side effects related to androgen deprivation may occur, the most common being gynecomastia and breast tenderness. Others include hot flashes, decreased muscle mass, decreased bone mass and an associated increased risk of fractures, depression, and sexual dysfunction including reduced libido and erectile dysfunction. In women, flutamide is, generally, relatively well tolerated, and does not interfere with ovulation. The only common side effect of flutamide in women is dry skin (75%), which can be attributed to a reduction of androgen-mediated sebum production. General side effects that may occur in either sex include dizziness, lack of appetite, gastrointestinal side effects such as nausea, vomiting, and diarrhea, a greenish-bluish discoloration of the urine, and hepatic changes. Because flutamide is a pure antiandrogen, unlike steroidal antiandrogens like cyproterone acetate and megestrol acetate (which additionally possess progestogenic activity), it does not appear to have a risk of cardiovascular side effects (e.g., thromboembolism) or fluid retention.

Gynecomastia
Flutamide, as a monotherapy, causes gynecomastia in 30 to 79% of men, and also produces breast tenderness. However, more than 90% of cases of gynecomastia with NSAAs including flutamide are mild to moderate. Tamoxifen, a selective estrogen receptor modulator (SERM) with predominantly antiestrogenic actions, can counteract flutamide-induced gynecomastia and breast pain in men.

Diarrhea
Diarrhea is more common and sometimes more severe with flutamide than with other NSAAs. In a comparative trial of combined androgen blockade for prostate cancer, the rate of diarrhea was 26% for flutamide and 12% for bicalutamide. Moreover, 6% of flutamide-treated patients discontinued the medication due to diarrhea, whereas only 0.5% of bicalutamide-treated patients did so. In the case of antiandrogen monotherapy for prostate cancer, the rates of diarrhea are 5 to 20% for flutamide, 2 to 5% for bicalutamide, and 2 to 4% for nilutamide. In contrast to diarrhea, the rates of nausea and vomiting are similar among the three medications.

Rare reactions
Liver toxicity
Although rare, flutamide has been associated with severe hepatotoxicity and death. By 1996, 46 cases of severe cholestatic hepatitis had been reported, with 20 fatalities. There have been continued case reports since, including liver transplants and death. A 2021 review of the literature found 15 cases of serious hepatotoxicity in women treated with flutamide, including 7 liver transplantations and 2 deaths.Based on the number of prescriptions written and the number of cases reported in the MedWatch database, the rate of serious hepatotoxicity associated with flutamide treatment was estimated in 1996 as approximately 0.03% (3 per 10,000). However, other research has suggested that the true incidence of significant hepatotoxicity with flutamide may be much greater, as high as 0.18 to 10%. Flutamide is also associated with liver enzyme elevations in up to 42 to 62% of patients, although marked elevations in liver enzymes (above 5 times upper normal limit) occur only in 3 to 5%. The risk of hepatotoxicity with flutamide is much higher than with nilutamide or bicalutamide. Lower doses of the medication appear to have a possibly reduced but still significant risk. Liver function should be monitored regularly with liver function tests during flutamide treatment. In addition, due to the high risk of serious hepatotoxicity, flutamide should not be used in the absence of a serious indication.The mechanism of action of flutamide-induced hepatotoxicity is thought to be due to mitochondrial toxicity. Specifically, flutamide and particularly its major metabolite hydroxyflutamide inhibit enzymes in the mitochondrial electron transport chain in hepatocytes, including respiratory complexes I (NADH ubiquinone oxidoreductase), II (succinate dehydrogenase), and V (ATP synthase), and thereby reduce cellular respiration via ATP depletion and hence decrease cell survival. Inhibition of taurocholate (a bile acid) efflux has also been implicated in flutamide-induced hepatotoxicity. In contrast to flutamide and hydroxyflutamide, which severely compromise hepatocyte cellular respiration in vitro, bicalutamide does not significantly do so at the same concentrations and is regarded as non-mitotoxic. It is thought that the nitroaromatic group of flutamide and hydroxyflutamide enhance their mitochondrial toxicity; bicalutamide, in contrast, possesses a cyano group in place of the nitro moiety, greatly reducing the potential for such toxicity.The hepatotoxicity of flutamide appears to depend on hydrolysis of flutamide catalyzed by an arylacetamide deacetalyse enzyme. This is analogous to the hepatotoxicity that occurs with the withdrawn paracetamol (acetominophen)-related medication phenacetin. In accordance, the combination of paracetamol (acetaminophen) and flutamide appears to result in additive to synergistic hepatotoxicity, indicating a potential drug interaction.

Others
Flutamide has also been associated with interstitial pneumonitis (which can progress to pulmonary fibrosis). The incidence of interstitial pneumonitis with flutamide was found to be 0.04% (4 per 10,000) in a large clinical cohort of 41,700 prostate cancer patients. A variety of case reports have associated flutamide with photosensitivity. Flutamide has been associated with several case reports of methemoglobinemia. Bicalutamide does not appear to share this risk with flutamide. Flutamide has also been associated with reports of sulfhemoglobinemia and neutropenia.

Birth defects
Out of the available endocrine-disrupting compounds looked at, flutamide has a notable effect on anogenital distance in rats.)

Pharmacology
Pharmacodynamics
Antiandrogenic activity
Flutamide acts as a selective, competitive, silent antagonist of the androgen receptor (AR). Its active form, hydroxyflutamide, has between 10- to 25-fold higher affinity for the AR than does flutamide, and hence is a much more potent AR antagonist in comparison. However, at high concentrations, unlike flutamide, hydroxyflutamide is able to weakly activate the AR. Flutamide has far lower affinity for the AR than do steroidal antiandrogens like spironolactone and cyproterone acetate, and it is a relatively weak antiandrogen in terms of potency by weight, but the large dosages at which flutamide is used appear to compensate for this. In accordance with its selectivity for the AR, flutamide does not interact with the progesterone, estrogen, glucocorticoid, or mineralocorticoid receptor, and possesses no intrinsic progestogenic, estrogenic, glucocorticoid, or antigonadotropic activity. However, it can have some indirect estrogenic effects via increased levels of estradiol secondary to AR blockade, and this involved in the gynecomastia it can produce. Because flutamide does not have any estrogenic, progestogenic, or antigonadotropic activity, the medication does not cause menstrual irregularities in women. This is in contrast to steroidal antiandrogens like spironolactone and cyproterone acetate. Similarly to nilutamide, bicalutamide, and enzalutamide, flutamide crosses the blood–brain barrier and exerts central antiandrogen actions.Flutamide has been found to be equal to slightly more potent than cyproterone acetate and substantially more potent than spironolactone as an antiandrogen in bioassays. This is in spite of the fact that hydroxyflutamide has on the order of 10-fold lower affinity for the AR relative to cyproterone acetate. Hydroxyflutamide shows about 2- to 4-fold lower affinity for the rat and human AR than does bicalutamide. In addition, whereas bicalutamide has an elimination half-life of around 6 days, hydroxyflutamide has an elimination half-life of only 8 to 10 hours, a roughly 17-fold difference. In accordance, at dosages of 50 mg/day bicalutamide and 750 mg/day flutamide (a 15-fold difference), circulating levels of flutamide at steady-state have been found to be approximately 7.5-fold lower than those of bicalutamide. Moreover, whereas flutamide at this dosage has been found to produce a 75% reduction in prostate-specific antigen levels in men with prostate cancer, a fall of 90% has been demonstrated with this dosage of bicalutamide. In accordance, 50 mg/day bicalutamide has been found to possess equivalent or superior effectiveness to 750 mg/day flutamide in a large clinical trial for prostate cancer. Also, bicalutamide has been shown to be 5-fold more potent than flutamide in rats and 50-fold more potent than flutamide in dogs. Taken together, flutamide appears to be a considerably less potent and efficacious antiandrogen than is bicalutamide.Dose-ranging studies of flutamide in men with benign prostatic hyperplasia and prostate cancer alone and in combination with a GnRH agonist have been performed.Flutamide increases testosterone levels by 5- to 10-fold in gonadally intact male rats.

CYP17A1 inhibition
Flutamide and hydroxyflutamide have been found in vitro to inhibit CYP17A1 (17α-hydroxylase/17,20-lyase), an enzyme which is required for the biosynthesis of androgens. In accordance, flutamide has been found to slightly but significantly lower androgen levels in GnRH analogue-treated male prostate cancer patients and women with polycystic ovary syndrome. In a directly comparative study of flutamide monotherapy (375 mg once daily) versus bicalutamide monotherapy (80 mg once daily) in Japanese men with prostate cancer, after 24 weeks of treatment flutamide decreased dehydroepiandrosterone (DHEA) levels by about 44% while bicalutamide increased them by about 4%. As such, flutamide is a weak inhibitor of androgen biosynthesis. However, the clinical significance of this action may be limited when flutamide is given without a GnRH analogue to non-castrated men, as the medication markedly elevates testosterone levels into the high normal male range via prevention of AR activation-mediated negative feedback on the hypothalamic–pituitary–gonadal axis in this context.

Other activities
Flutamide has been identified as an agonist of the aryl hydrocarbon receptor. This may be involved in the hepatotoxicity of flutamide.

Pharmacokinetics
The absorption of flutamide is complete upon oral ingestion. Food has no effect on the bioavailability of flutamide. Steady-state levels of hydroxyflutamide, the active form of flutamide, are achieved after 2 to 4 days administration. Levels of hydroxyflutamide are approximately 50-fold higher than those of flutamide at steady-state.The plasma protein binding of flutamide and hydroxyflutamide are high; 94 to 96% and 92 to 94%, respectively. Flutamide and its metabolite hydroxyflutamide are known to be transported by the multidrug resistance-associated protein 1 (MRP1; ABCC1).Flutamide is metabolized by CYP1A2 (via α-hydroxylation) in the liver during first-pass metabolism to its main metabolite hydroxyflutamide (which accounts for 23% of an oral dose of flutamide one hour post-ingestion), and to at least five other, minor metabolites. Flutamide has at least 10 inactive metabolites total, including 4-nitro-3-fluoro-methylaniline.Flutamide is excreted in various forms in the urine, the primary form being 2-amino-5-nitro-4-(trifluoromethyl)phenol.Flutamide and hydroxyflutamide have elimination half-lives of 4.7 hours and 6 hours in adults, respectively. However, the half-life of hydroxyflutamide is extended to 8 hours after a single dose and to 9.6 hours at steady state) in elderly individuals. The elimination half-lives of flutamide and hydroxyflutamide are regarded as too short to allow for once-daily dosing, and for this reason, flutamide is instead administered three times daily at 8-hour intervals. In contrast, the newer NSAAs nilutamide, bicalutamide, and enzalutamide all have much longer half-lives, and this allows for once-daily administration in their cases.

Chemistry
Unlike the hormones with which it competes, flutamide is not a steroid; rather, it is a substituted anilide. Hence, it is described as nonsteroidal in order to distinguish it from older steroidal antiandrogens such as cyproterone acetate and megestrol acetate.

Synthesis
History
Flutamide was first synthesized in 1967 by Neri and colleagues at Schering Plough Corporation. It was originally synthesized as a bacteriostatic agent, but was subsequently, and serendipitously found to possess antiandrogen activity. The code name of flutamide during development was SCH-13521. Clinical research of the medication began in 1971, and it was first marketed in 1983, specifically in Chile under the brand name Drogenil and in West Germany under the brand name Flugerel. Flutamide was not introduced in the United States until 1989; it was specifically approved by the U.S. Food and Drug Administration for the treatment of metastatic prostate cancer in combination with a gonadotropin-releasing hormone (GnRH) analogue. The medication was first studied for the treatment of hirsutism in women in 1989. It was the first "pure antiandrogen" to be studied in the treatment of hirsutism. Flutamide was the first NSAA to be introduced, and was followed by nilutamide in 1989 and then bicalutamide in 1995.

Society and culture
Generic names
Flutamide is the generic name of the drug and its INN, USAN, BAN, DCF, and JAN. Its names in Latin, German, and Spanish are flutamidum, flutamid, and flutamida, respectively. The medication has also been referred to by the name niftolide.

Brand names
Brand names of flutamide include or have included Cebatrol, Cytomid, Drogenil, Etaconil, Eulexin, Flucinom, Flumid, Flutacan, Flutamid, Flutamida, Flutamin, Flutan, Flutaplex, Flutasin, Fugerel, Profamid, and Sebatrol, among others.

Availability
Flutamide is marketed widely throughout the world, including in the United States, Canada, Europe, Australia, New Zealand, South Africa, Central and South America, East and Southeast Asia, India, and the Middle East.

Research
Prostate cancer
The combination of an estrogen and flutamide as a form of combined androgen blockade for the treatment of prostate cancer has been researched.

Enlarged prostate
Flutamide has been studied in the treatment of benign prostatic hyperplasia (BPH; enlarged prostate) in men in several clinical studies. It has been found to reduce prostate volume by about 25%, which is comparable to the reduction achieved with the 5α-reductase inhibitor finasteride. Unfortunately, it has been associated with side effects in these studies including gynecomastia and breast tenderness (in about 50% of patients), gastrointestinal disturbances such as nausea, diarrhea, and flatulence, and hepatotoxicity, although sexual function including libido and erectile potency were maintained.

Breast cancer
Flutamide was studied for the treatment of advanced breast cancer in two phase II clinical trials but was found to be ineffective. Out of a total of 47 patients, only three short-term responses occurred. However, the patients in the studies were selected irrespective of AR, ER, PR, or HER2 status, which were all unknown.

Psychiatric disorders
Flutamide has been studied in the treatment of bulimia nervosa in women.Flutamide was found to be effective in the treatment of obsessive–compulsive disorder (OCD) in men with comorbid Tourettes syndrome in one small randomized controlled trial. Conversely, it was ineffective in patients with OCD in another study. More research is necessary to determine whether flutamide is effective in the treatment of OCD.

References
Further reading
Sogani PC, Whitmore WF (1988). "Flutamide and other antiandrogens in the treatment of advanced prostatic carcinoma". Cancer Treat. Res. Cancer Treatment and Research. 39: 131–45. doi:10.1007/978-1-4613-1731-9_9. ISBN 978-1-4612-8974-6. PMID 2908604.
Brogden RN, Clissold SP (1989). "Flutamide. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in advanced prostatic cancer". Drugs. 38 (2): 185–203. doi:10.2165/00003495-198938020-00003. PMID 2670515.
Neri R (1989). "Pharmacology and pharmacokinetics of flutamide". Urology. 34 (4 Suppl): 19–21, discussion 46–56. doi:10.1016/0090-4295(89)90230-6. PMID 2477934.
Newling DW (1989). "The use of flutamide as monotherapy in the treatment of advanced prostate cancer". Prog. Clin. Biol. Res. 303: 117–21. PMID 2674980.
Labrie F, Dupont A, Cusan L, Manhès G, Bergeron N, Lacourcière Y, Pineault S, Bélanger A, Monfette G, Emond J (1989). "Combination therapy with castration and flutamide: todays treatment of choice for prostate cancer". J. Steroid Biochem. 33 (4B): 817–21. doi:10.1016/0022-4731(89)90499-8. PMID 2689788.
Goldspiel BR, Kohler DR (1990). "Flutamide: an antiandrogen for advanced prostate cancer". DICP. 24 (6): 616–23. doi:10.1177/106002809002400612. PMID 2193461. S2CID 26125621.
Brogden RN, Chrisp P (1991). "Flutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in advanced prostatic cancer". Drugs Aging. 1 (2): 104–15. doi:10.2165/00002512-199101020-00003. PMID 1794008.
Labrie F (1993). "Mechanism of action and pure antiandrogenic properties of flutamide". Cancer. 72 (12 Suppl): 3816–27. doi:10.1002/1097-0142(19931215)72:12+<3816::aid-cncr2820721711>3.0.co;2-3. PMID 8252497. S2CID 2195250.
Iversen P, Melezinek I, Schmidt A (2001). "Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function". BJU Int. 87 (1): 47–56. doi:10.1046/j.1464-410x.2001.00988.x. PMID 11121992. S2CID 28215804.
Ibáñez L, de Zegher F (2006). "Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women". Hum. Reprod. Update. 12 (3): 243–52. doi:10.1093/humupd/dmi054 </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 Cefotaxime and explain in detail? [/INST] Cefotaxime is an antibiotic used to treat a number of bacterial infections in human, other animals and plant tissue culture. Specifically in human it is used to treat joint infections, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, sepsis, gonorrhea, and cellulitis. It is given either by injection into a vein or muscle.Common side effects include nausea, allergic reactions, and inflammation at the site of injection. Another side effect may include Clostridium difficile diarrhea. It is not recommended in people who have had previous anaphylaxis to a penicillin. It is relatively safe for use during pregnancy and breastfeeding. It is in the third-generation cephalosporin family of medications and works by interfering with the bacterias cell wall.Cefotaxime was discovered in 1976, and came into commercial use in 1980. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication.

Medical uses
It is a broad-spectrum antibiotic with activity against numerous gram-positive and gram-negative bacteria.
Given its broad spectrum of activity, cefotaxime is used for a variety of infections, including:

Lower respiratory tract infections – e.g. pneumonia (most commonly caused by S. pneumoniae)
Genitourinary system infections – urinary tract infections (e.g. E. coli, S. epidermidis, P. mirabilis) and cervical/urethral gonorrhea
Gynecologic infections – e.g. pelvic inflammatory disease, endometritis, and pelvic cellulitis
Sepsis – secondary to Streptococcus spp., S. aureus, E. coli, and Klebsiella spp.
Intra-abdominal infections – e.g. peritonitis
Bone and joint infections – S. aureus, Streptococcus spp.
CNS infections – e.g. meningitis/ventriculitis secondary to N. meningitidis, H. influenzae, S. pneumoniaeAlthough cefotaxime has demonstrated efficacy in these infections, it is not necessarily considered to be the first-line agent.  In meningitis, cefotaxime crosses the blood–brain barrier better than cefuroxime.

Spectrum of activity
As a β-lactam antibiotic in the third-generation class of cephalosporins, cefotaxime is active against numerous Gram-positive and Gram-negative bacteria, including several with resistance to classic β-lactams such as penicillin.  These bacteria often manifest as infections of the lower respiratory tract, skin, central nervous system, bone, and intra-abdominal cavity.  While regional susceptibilities must always be considered, cefotaxime typically is effective against these organisms (in addition to many others):
Staphylococcus aureus (not including MRSA) and S. epidermidis
Streptococcus pneumoniae and S. pyogenes
Escherichia coli
Haemophilus influenzae
Neisseria gonorrhoeae and N. meningitidis
Klebsiella spp.
Burkholderia cepacia
Proteus mirabilis and P. vulgaris
Enterobacter spp.
Bacteroides spp.
Fusobacterium spp.Notable organisms against which cefotaxime is not active include Pseudomonas and Enterococcus. As listed, it has modest activity against the anaerobic Bacteroides fragilis.
The following represents MIC susceptibility data for a few medically significant microorganisms:

H. influenzae: ≤0.007 – 0.5 µg/mL
S. aureus: 0.781 – 172 µg/mL
S. pneumoniae: ≤0.007 – 8 µg/mLHistorically, cefotaxime has been considered to be comparable to ceftriaxone (another third-generation cephalosporin) in safety and efficacy for the treatment of bacterial meningitis, lower respiratory tract infections, skin and soft tissue infections, genitourinary tract infections, and bloodstream infections, as well as prophylaxis for abdominal surgery. The majority of these infections are caused by organisms traditionally sensitive to both cephalosporins. However, ceftriaxone has the advantage of once-daily dosing, whereas the shorter half-life of cefotaxime necessitates two or three daily doses for efficacy.  Changing patterns in microbial resistance suggest cefotaxime may be suffering greater resistance than ceftriaxone, whereas the two were previously considered comparable.  Considering regional microbial sensitivities is also important when choosing any antimicrobial agent for the treatment of infection.

Adverse reactions
Cefotaxime is contraindicated in patients with a known hypersensitivity to cefotaxime or other cephalosporins.  Caution should be used and risks weighed against potential benefits in patients with an allergy to penicillin, due to cross-reactivity between the classes.
The most common adverse reactions experienced are:

Pain and inflammation at the site of injection/infusion (4.3%)
Rash, pruritus, or fever (2.4%)
Colitis, diarrhea, nausea, vomiting (1.4%)

Mechanism of action
Cefotaxime is a β-lactam antibiotic (which refers to the structural components of the drug molecule itself).  As a class, β-lactams inhibit bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs). This inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) in the absence of cell wall assembly.  Due to the mechanism of their attack on bacterial cell wall synthesis, β-lactams are considered to be bactericidal.Unlike β-lactams such as penicillin and amoxicillin, which are highly susceptible to degradation by β-lactamase enzymes (produced, for example, nearly universally by S </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 Salbutamol and explain in detail? [/INST] Salbutamol, also known as albuterol and sold under the brand name Ventolin among others, is a medication that opens up the medium and large airways in the lungs. It is a short-acting β2 adrenergic receptor agonist which works by causing relaxation of airway smooth muscle. It is used to treat asthma, including asthma attacks, exercise-induced bronchoconstriction, and chronic obstructive pulmonary disease (COPD). It may also be used to treat high blood potassium levels. Salbutamol is usually used with an inhaler or nebulizer, but it is also available in a pill, liquid, and intravenous solution. Onset of action of the inhaled version is typically within 15 minutes and lasts for two to six hours.Common side effects include shakiness, headache, fast heart rate, dizziness, and feeling anxious. Serious side effects may include worsening bronchospasm, irregular heartbeat, and low blood potassium levels. It can be used during pregnancy and breastfeeding, but safety is not entirely clear.Salbutamol was patented in 1966 in Britain and became commercially available in the UK in 1969. It was approved for medical use in the United States in 1982. It is on the World Health Organizations List of Essential Medicines. Salbutamol is available as a generic medication. In 2020, it was the seventh most commonly prescribed medication in the United States, with more than 61 million prescriptions.

Medical uses
Salbutamol is typically used to treat bronchospasm (due to any cause—allergic asthma or exercise-induced), as well as chronic obstructive pulmonary disease. It is also one of the most common medicines used in rescue inhalers (short-term bronchodilators to alleviate asthma attacks).As a β2 agonist, salbutamol also has use in obstetrics. Intravenous salbutamol can be used as a tocolytic to relax the uterine smooth muscle to delay premature labor. While preferred over agents such as atosiban and ritodrine, its role has largely been replaced by the calcium channel blocker nifedipine, which is more effective and better tolerated.Salbutamol has been used to treat acute hyperkalemia, as it stimulates potassium flow into cells, thus lowering the potassium in the blood.

Adverse effects
The most common side effects are fine tremor, anxiety, headache, muscle cramps, dry mouth, and palpitation. Other symptoms may include tachycardia, arrhythmia, flushing of the skin, myocardial ischemia (rare), and disturbances of sleep and behaviour. Rarely occurring, but of importance, are allergic reactions of paradoxical bronchospasms, urticaria (hives), angioedema, hypotension, and collapse. High doses or prolonged use may cause hypokalemia, which is of concern especially in patients with kidney failure and those on certain diuretics and xanthine derivatives.Salbutamol metered dose inhalers have been described as the “single biggest source of carbon emissions from NHS medicines prescribing” due to the propellants used in the inhalers. Dry powder inhalers are recommended as a low-carbon alternative.

Pharmacology
The tertiary butyl group in salbutamol makes it more selective for β2 receptors, which are the predominant receptors on the bronchial smooth muscles. Activation of these receptors causes adenylyl cyclase to convert ATP to cAMP, beginning the signalling cascade that ends with the inhibition of myosin phosphorylation and lowering the intracellular concentration of calcium ions (myosin phosphorylation and calcium ions are necessary for muscle contractions). The increase in cAMP also inhibits inflammatory cells in the airway, such as basophils, eosinophils, and most especially mast cells, from releasing inflammatory mediators and cytokines. Salbutamol and other β2 receptor agonists also increase the conductance of channels sensitive to calcium and potassium ions, leading to hyperpolarization and relaxation of bronchial smooth muscles.Salbutamol is either filtered out by the kidneys directly or is first metabolized into the 4′-O-sulfate, which is excreted in the urine.

Chemistry
Salbutamol is sold as a racemic mixture. The (R)-(−)-enantiomer (CIP nomenclature) is shown in the image at right (top), and is responsible for the pharmacologic activity; the (S)-(+)-enantiomer (bottom) blocks metabolic pathways associated with elimination of itself and of the pharmacologically active enantiomer (R). The slower metabolism of the (S)-(+)-enantiomer also causes it to accumulate in the lungs, which can cause airway hyperreactivity and inflammation. Potential formulation of the R form as an enantiopure drug is complicated by the fact that the stereochemistry is not stable, but rather the compound undergoes racemization within a few days to weeks, depending on pH.

History
Salbutamol was discovered in 1966, by a team led by David Jack at the Allen and Hanburys laboratory (a subsidiary of Glaxo) in Ware, Hertfordshire, England, and was launched as Ventolin in 1969.The 1972 Munich Olympics were the first Olympics where anti-doping measures were deployed, and at that time β2 agonists were considered to be stimulants with high risk of abuse for doping. Inhaled salbutamol was banned from those games, but by 1986 was permitted (although oral β2 agonists were not). After a steep rise in the number of athletes taking β2 agonists for asthma in the 1990s, Olympic athletes were required to provide proof that they had asthma in order to be allowed to use inhaled β2 agonists.In February 2020, the U.S. Food and Drug Administration (FDA) approved the first generic of an albuterol sulfate inhalation aerosol for the treatment or prevention of bronchospasm in people four years of age and older with reversible obstructive airway disease and the prevention of exercise-induced bronchospasm in people four years of age and older. The FDA granted approval of the generic albuterol sulfate inhalation aerosol to Perrigo Pharmaceutical.In April 2020, the FDA approved the first generic of Proventil HFA (albuterol sulfate) metered dose inhaler, 90 μg per inhalation, for the treatment or prevention of bronchospasm in patients four years of age and older who have reversible obstructive airway disease, as well as the prevention of exercise-induced bronchospasm in this age group </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 Nasal spray and explain in detail? [/INST] Nasal sprays are used to deliver medications locally in the nasal cavities or systemically. They are used locally for conditions such as nasal congestion and allergic rhinitis. In some situations, the nasal delivery route is preferred for systemic therapy because it provides an agreeable alternative to injection or pills. Substances can be assimilated extremely quickly and directly through the nose. Many pharmaceutical drugs exist as nasal sprays for systemic administration (e.g. sedative-analgesics, treatments for migraine, osteoporosis and nausea). Other applications include hormone replacement therapy, treatment of Alzheimers disease and Parkinsons disease. Nasal sprays are seen as a more efficient way of transporting drugs with potential use in crossing the blood–brain barrier.

Antihistamines
Antihistamines work by competing for receptor sites to block the function of histamine, thereby reducing the inflammatory effect. Antihistamine nasal sprays include:

Azelastine hydrochloride
Levocabastine hydrochloride
Olopatadine hydrochloride

Corticosteroids
Corticosteroid nasal sprays can be used to relieve the symptoms of sinusitis, hay fever, allergic rhinitis and non-allergic (perennial) rhinitis. They can reduce inflammation and histamine production in the nasal passages, and have been shown to relieve nasal congestion, runny nose, itchy nose and sneezing. Side effects may include headaches, nausea and nose bleeds. Corticosteroid nasal sprays include:

Beclomethasone dipropionate
Budesonide
Ciclesonide
Flunisolide
Fluticasone furoate
Fluticasone propionate
Mometasone
Triamcinolone acetonide

Saline
Saline sprays are typically non medicated. A mist of saline solution containing sodium chloride is delivered to help moisturize dry or irritated nostrils. This is a form of nasal irrigation. They can also relieve nasal congestion and remove airborne irritants such as pollen and dust thereby providing sinus allergy relief.
Three types of nasal sprays preparations of sodium chloride are available including hypertonic (3% sodium chloride or sea water), isotonic (0.9% sodium chloride) and hypotonic (0.65% sodium chloride). Isotonic solutions have the same salt concentration as the human body, whereas hypertonic solutions have a higher salt content and hypotonic solutions have a lower salt content </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 Cariprazine and explain in detail? [/INST] Cariprazine, sold under the brand names Vraylar and Reagila among others, is an  on oral atypical antipsychotic originated by Gedeon Richter, which is used in the treatment of schizophrenia, bipolar mania, and bipolar depression. It acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and  5-HT2A receptors, with high selectivity for the D3 receptor. Positive Phase III study results were published for schizophrenia and mania in early 2012, and for bipolar disorder I depression from a Phase II trial in 2015.Cariprazine was approved for medical use in the United States in September 2015.

Medical uses
Cariprazine is used to treat schizophrenia and manic, depressive, or mixed episodes associated with bipolar I disorder. In the United States it is approved for schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and treatment of depressive episodes associated with bipolar I disorder (bipolar depression).Cariprazine consistently improved depressive symptoms across a spectrum of patients with bipolar I depression. In Australia, UK and Europe it is currently approved only for schizophrenia.

Side effects
Side effects may first appear on the first day after starting cariprazine. The most prevalent side effects for cariprazine include akathisia, and insomnia. Cariprazine does not appear to impact prolactin levels, and unlike many other antipsychotics, does not increase the QT interval on the electrocardiogram (ECG). In short term clinical trials extrapyramidal effects, sedation, akathisia, nausea, dizziness, vomiting, anxiety, and constipation were observed. One review characterized the frequency of these events as "not greatly different from that seen in patient treated with placebo" but a second called the incidence of movement-related disorders "rather high".Regarding side effects, the label of cariprazine states, "The possibility of lenticular changes or cataracts cannot be excluded at this time."Because cariprazine and its active metabolites have long half-lives, many healthcare professionals monitor for adverse effects up to several weeks after starting cariprazine. A longer monitoring period is also indicated for dosage changes, whether they represent an increase or a decrease, because elimination may take several weeks

Pharmacology
Pharmacodynamics
Unlike many antipsychotics that are D2 and 5-HT2A receptor antagonists, cariprazine is a D2 and D3 partial agonist It also has a higher affinity for D3 receptors. The D2 and D3 receptors are important targets for the treatment of schizophrenia, because the overstimulation of dopamine receptors has been implicated as a possible cause of schizophrenia. Cariprazine acts to inhibit overstimulated dopamine receptors (acting as an antagonist) and stimulate the same receptors when the endogenous dopamine levels are low. Cariprazines high selectivity towards D3 receptors could prove to reduce side effects associated with the other antipsychotic drugs, because D3 receptors are mainly located in the ventral striatum and would not incur the same motor side effects (extrapyramidal symptoms) as drugs that act on dorsal striatum dopamine receptors. Cariprazine also acts on 5-HT1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (seen in monkey and rat brain studies). In the same studies, cariprazine has been noted to produce pro-cognitive effects, the mechanisms of which are currently under investigation. An example of pro-cognitive effects occurred in pre-clinical trials with rats: rats with cariprazine performed better in a scopolamine-induced learning impairment paradigm in a water labyrinth test. This may be due to the selective antagonist nature of D3 receptors, though further studies need to be conducted. This result could be very useful for schizophrenia, as one of the symptoms includes cognitive deficits.
Cariprazine has partial agonist as well as antagonist properties depending on the endogenous dopamine levels. When endogenous dopamine levels are high (as is hypothesized in schizophrenic patients), cariprazine acts as an antagonist by blocking dopamine receptors. When endogenous dopamine levels are low, cariprazine acts more as an agonist, increasing dopamine receptor activity. In monkey studies, the administration of increasing doses of cariprazine resulted in a dose-dependent and saturable reduction of specific binding. At the highest dose (300 μg/kg), the D2/D3 receptors were 94% occupied, while at the lowest dose (1 μg/kg), receptors were 5% occupied </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 Hydroxycarbamide and explain in detail? [/INST] Hydroxycarbamide, also known as hydroxyurea, is a medication used in sickle-cell disease, essential thrombocythemia, chronic myelogenous leukemia and cervical cancer. In sickle-cell disease it increases fetal hemoglobin and decreases the number of attacks. It is taken by mouth.Common side effects include bone marrow suppression, fevers, loss of appetite, psychiatric problems, shortness of breath, and headaches. There is also concern that it increases the risk of later cancers. Use during pregnancy is typically harmful to the baby. Hydroxycarbamide is in the antineoplastic family of medications. It is believed to work by blocking the making of DNA.Hydroxycarbamide was approved for medical use in the United States in 1967. It is on the World Health Organizations List of Essential Medicines. Hydroxycarbamide is available as a generic medication.

Medical uses
Hydroxycarbamide is used for the following indications:

Myeloproliferative disease (primarily essential thrombocythemia and polycythemia vera). It has been found to be superior to anagrelide for the control of ET.
Sickle-cell disease (increases production of fetal hemoglobin that then interferes with the hemoglobin polymerisation as well as by reducing white blood cells that contribute to the general inflammatory state in sickle cell patients.)
Second line treatment for psoriasis (slows down the rapid division of skin cells)
Systemic mastocytosis
Chronic myelogenous leukemia (largely replaced by imatinib, but still in use for its cost-effectiveness)

Side effects
Reported side effects are: neurological reactions (e.g., headache, dizziness, drowsiness, disorientation, hallucinations, and convulsions), nausea, vomiting, diarrhea, constipation, mucositis, anorexia, stomatitis, bone marrow toxicity (dose-limiting toxicity; may take 7–21 days to recover after the drug has been discontinued), megaloblastic anemia, thrombocytopenia, bleeding, hemorrhage, gastrointestinal ulceration and perforation, immunosuppression, leukopenia, alopecia (hair loss), skin rashes (e.g., maculopapular rash), erythema, pruritus, vesication or irritation of the skin and mucous membranes, pulmonary edema, abnormal liver enzymes, creatinine and blood urea nitrogen.Due to its negative effect on the bone marrow, regular monitoring of the full blood count is vital, as well as early response to possible infections. In addition, renal function, uric acid and electrolytes, as well as liver enzymes, are commonly checked. Moreover, because of this, its use in people with leukopenia, thrombocytopenia or severe anemia is contraindicated.Hydroxycarbamide has been used primarily for the treatment of myeloproliferative diseases, which has an inherent risk of transforming to acute myeloid leukemia. There has been a longstanding concern that hydroxycarbamide itself carries a leukemia risk, but large studies have shown that the risk is either absent or very small. Nevertheless, it has been a barrier for its wider use in patients with sickle-cell disease.

Mechanism of action
Hydroxycarbamide decreases the production of deoxyribonucleotides via inhibition of the enzyme ribonucleotide reductase by scavenging tyrosyl free radicals as they are involved in the reduction of nucleoside diphosphates (NDPs).In the treatment of sickle-cell disease, hydroxycarbamide increases the concentration of fetal hemoglobin. The precise mechanism of action is not yet clear, but it appears that hydroxycarbamide increases nitric oxide levels, causing soluble guanylyl cyclase activation with a resultant rise in cyclic GMP, and the activation of gamma globin gene expression and subsequent gamma chain synthesis necessary for fetal hemoglobin (HbF) production (which does not polymerize and deform red blood cells like the mutated HbS, responsible for sickle cell disease). Adult red cells containing more than 1% HbF are termed F cells. These cells are progeny of a small pool of immature committed erythroid precursors (BFU-e) that retain the ability to produce HbF. Hydroxyurea also suppresses the production of granulocytes in the bone marrow which has a mild immunosuppressive effect particularly at vascular sites where sickle cells have occluded blood flow.

Natural occurrence
Hydroxyurea has been reported as endogenous in human blood plasma at concentrations of approximately 30 to 200 ng/ml.

Chemistry
Hydroxyurea has been prepared in many different ways since its initial synthesis in 1869. Medical chemists, Dresler and Stein created Hydroxyurea from hydroxylamine, hydrochloric acid and potassium cyanide as a technical exercise in organic chemistry, as part of a series of experiments generating derivatives of urea. Hydroxyurea lay dormant for more than fifty years until it was studied as part of an investigation into the toxicity of protein metabolites. Due to its chemical properties hydroxyurea was explored as an antisickling agent in the treatment of hematological conditions.
One common mechanism for synthesizing hydroxyurea is by the reaction of calcium cyanate with hydroxylamine nitrate in absolute ethanol and by the reaction of salt (i.e. sodium or potassium) cyanates and hydroxylamine hydrochloride in aqueous solution </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 Rifamycin and explain in detail? [/INST] The rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium Amycolatopsis rifamycinica or artificially. They are a subclass of the larger family of ansamycins.  Rifamycins are particularly effective against mycobacteria, and are therefore used to treat tuberculosis, leprosy, and mycobacterium avium complex (MAC) infections.
The rifamycin group includes the "classic" rifamycin drugs as well as the rifamycin derivatives rifampicin (or rifampin), rifabutin, rifapentine, rifalazil and rifaximin. Rifamycin, sold under the trade name Aemcolo, is approved in the United States for treatment of travelers diarrhea in some circumstances.

Bacterium
Streptomyces mediterranei was first isolated in 1957 from a soil sample collected near the beach-side town of St Raphael in southern France. The name was originally given by two microbiologists working with the Italian drug company Group Lepetit SpA in Milan, the Italian Grazia Beretta, and Pinhas Margalith of Israel.In 1969, the bacterium was renamed Nocardia mediterranei when another scientist named Thiemann found that it has a cell wall typical of the Nocardia species. Then, in 1986, the bacterium was renamed again Amycolatopsis mediterranei, as the first species of a new genus, because a scientist named Lechevalier discovered that the cell wall lacks mycolic acid and is not able to be infected by the Nocardia and Rhodococcus phages.
Based on 16S ribosomal RNA sequences, Bala et al. renamed the species in 2004 Amycolatopsis rifamycinica.

First drugs
Rifamycins were first isolated in 1957 from a fermentation culture of Streptomyces mediterranei at the laboratory of Gruppo Lepetit SpA in Milan by two scientist named Piero Sensi and Maria Teresa Timbal, working with the Israeli scientist Pinhas Margalith. Initially, a family  of closely related antibiotics was discovered referred to as  Rifamycin A, B, C, D, E. The only component of this mixture sufficiently stable to isolate in a pure form was Rifamycin B, which unfortunately was poorly active. However, further studies showed that while Rifamycin B was essentially inactive, it was spontaneously oxidized and hydrolyzed in aqueous solutions to yield the highly active Rifamycin S. Simple reduction of Rifamycin S yielded the hydroquinone form called Rifamycin SV, which became the first member of this class to enter clinical use as an intravenous antibiotic. Further chemical modification of Rifamycin SV yielded an improved analog Rifamide, which was also introduced into clinical practice, but was similarly limited to intravenous use. After an extensive modification program, Rifampin was eventually produced, which is orally available and has become a mainstay of Tuberculosis therapy

Lepetit filed for patent protection of Rifamycin B in the UK in August 1958, and in the US in March 1959. The British patent GB921045 was granted in March 1963, and U.S. Patent 3,150,046 was granted in September 1964. The drug is widely regarded as having helped conquer the issue of drug-resistant tuberculosis in the 1960s.

Clinical trials
Rifamycins have been used for the treatment of many diseases, the most important one being HIV-related tuberculosis. A systematic review of clinical trials on alternative regimens for prevention of active tuberculosis in HIV-negative individuals with latent TB found that a weekly, directly observed regimen of rifapentine with isoniazid for three months was as effective as a daily, self-administered regimen of isoniazid for nine months. But the rifapentine-isoniazid regimen had higher rates of treatment completion and lower rates of hepatotoxicity. However, the rate of treatment-limiting adverse events was higher in the rifapentine-isoniazid regimen.The rifamycins have  a unique mechanism of action, selectively inhibiting bacterial DNA-dependent RNA polymerase, and show no cross-resistance with other antibiotics in clinical use. However, despite their activity against bacteria resistant to other antibiotics, the rifamycins themselves suffer from a rather high frequency of resistance. Because of this, Rifampin  and other rifamycins are typically  used in  combination with other antibacterial drugs. This is routinely practiced in TB therapy and serves to prevent the formation of mutants that are resistant to any of the drugs in the combination. Rifampin rapidly kills fast-dividing bacilli strains as well as "persisters" cells, which remain biologically inactive for long periods of time that allow them to evade antibiotic activity.  In addition, rifabutin and rifapentine have both been used against tuberculosis acquired in HIV-positive patients. Although Tuberculosis therapy remains the most important use of Rifampin, an increasing  problem with serious Multiple Drug Resistant bacterial infections has led to some  use of antibiotic combinations containing Rifampin to treat them.

Mechanism of action
The antibacterial activity of rifamycins relies on the inhibition of bacterial DNA-dependent RNA synthesis.  This is due to the high affinity of rifamycins for the  prokaryotic RNA polymerase. The selectivity of the rifamycins depends on the fact that they have a very poor affinity for  the analogous mammalian enzyme.  Crystal structure data of the antibiotic bound to RNA polymerase indicates that rifamycin blocks synthesis by causing strong steric clashes with the growing oligonucleotide ("steric-occlusion" mechanism).  If rifamycin binds the polymerase after the chain extension process has started, no inhibition is observed on the biosynthesis, consistent with a steric-occlusion mechanism. Single step high level resistance to the rifamycins occurs as the result of a single amino acid change in the bacterial DNA dependent RNA polymerase.

Biosynthesis
The first information on the biosynthesis of the rifamycins came from studies using the stable isotope Carbon-13 and NMR spectroscopy to establish the origin of the carbon skeleton. These studies showed that the ansa chain was derived from acetate and propionate, in common with other polyketide antibiotics. The naphthalenic chromophore was shown to derive from a propionate unit coupled with a seven carbon amino moiety of unknown origin. The general scheme of biosynthesis starts with the uncommon starting unit, 3-amino-5-hydroxybenzoic acid (AHBA), via type I polyketide pathway (PKS I) in which chain extension is performed using 2 acetate and 8 propionate units.  AHBA is believed to have originated from the Shikimate pathway, however this was not incorporated into the biosynthetic mechanism.  This is due to the observation that 3 amino-acid analogues converted into AHBA in cell-free extracts of  A. mediterranei.

The rif cluster is responsible for the biosynthesis of rifamycins.  It contains genes rifG through rifN, which were shown to biosynthesize AHBA.[10]  RifK, rifL, rifM, and rifN are believed to act as transaminases in order to form the AHBA precursor kanosamine.  "RifH" encodes aminoDAHP synthase that catalyzes the condensation between 1-deoxy-1-imino-d-erythrose 4-phosphate and phosphoenolpyruvate.  RifA through rifE encode a type I polyketide synthase module, with the loading module being a non-ribosomal peptide synthetase.  In all, rifA-E assemble a linear undecaketide and are followed by rifF, which encodes an amide synthase and causes the undecaketide to release and form a macrolactam structure.  Moreover, the rif cluster contains various regulatory proteins and glycosylating genes that appear to be silent.  Other types of genes seem to perform post-synthase modifications of the original polyketide.

Derivatives
Lepetit introduced Rifampicin, an orally active rifamycin, around 1966. Rifabutin, a derivative of rifamycin S, was invented around 1975 and came onto the US market in 1993. Hoechst Marion Roussel (now part of Aventis) introduced rifapentine in 1999.
Rifaximin is an oral rifamycin marketed in the US by Salix Pharmaceuticals that is poorly absorbed from the intestine.  It has been used to treat hepatic encephalopathy and travelers diarrhea.

Currently available rifamycins
Rifampicin or Rifampin
Rifabutin
Rifapentine
Rifaximin
Aemcolo

References
Bibliography
Sensi. et al., Farmaco Ed. Sci. (1959) 14, 146-147 - the paper announcing the discovery of the rifamycins.
Thieman et al. Arch. Microbiol. (1969), 67 147-151 - the paper which renamed Streptomyces mediterranei as Nocardia mediterranei.
Lechevalier et al., Int. J. Syst. Bacteriol. (1986), 36, 29) - the paper which renamed Nocardia mediterranei as Amycolatopsis mediterranei.
Bala S (2004) </s>