<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 Methyltestosterone and explain in detail? [/INST] Methyltestosterone, sold under the brand names Android, Metandren, and Testred among others, is an androgen and anabolic steroid (AAS) medication which is used in the treatment of low testosterone levels in men, delayed puberty in boys, at low doses as a component of menopausal hormone therapy for menopausal symptoms like hot flashes, osteoporosis, and low sexual desire in women, and to treat breast cancer in women. It is taken by mouth or held in the cheek or under the tongue.Side effects of methyltestosterone include symptoms of masculinization like acne, increased hair growth, voice changes, and increased sexual desire. It can also cause estrogenic effects like fluid retention, breast tenderness, and breast enlargement in men and liver damage. The drug is a synthetic androgen and anabolic steroid and hence is an agonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has moderate androgenic effects and moderate anabolic effects, which make it useful for producing masculinization.Methyltestosterone was discovered in 1935 and was introduced for medical use in 1936. It was made shortly after the discovery of testosterone and was one of the first synthetic AAS to be developed. In addition to its medical use, methyltestosterone is used to improve physique and performance, although it is not as commonly used as other AAS for such purposes due to its androgenic effects, estrogenic effects, and risk of liver damage. The drug is a controlled substance in many countries and so non-medical use is generally illicit.

Uses
Medical
Methyltestosterone is or has been used in the treatment of delayed puberty, hypogonadism, cryptorchidism, and erectile dysfunction in males, and in low doses to treat menopausal symptoms (specifically for osteoporosis, hot flashes, and to increase libido and energy), postpartum breast pain and engorgement, and breast cancer in women. It is specifically approved in the United States for the treatment of hypogonadism and delayed puberty in males and the treatment of advanced inoperable breast cancer in females. It was also approved in low doses in combination with esterified estrogens for the treatment of moderate to severe vasomotor symptoms associated with menopause in women in the United States, but this formulation was discontinued and hence is no longer used.Methyltestosterone is less effective in inducing masculinization than testosterone, but is useful for maintaining established masculinization in adults.The dosages of methyltestosterone used are 10 to 50 mg/day in men for common medical uses like hypogonadism and delayed puberty as well as physique- and performance-enhancing purposes and 2.5 mg/day in women for menopausal symptoms. Higher dosages of 50 to 200 mg/day have been used to treat women with inoperable breast cancer that has failed to respond to other therapies, although such dosages are associated with severe irreversible virilization.

Non-medical
Methyltestosterone is used for physique- and performance-enhancing purposes by competitive athletes, bodybuilders, and powerlifters, although it is not commonly used relative to other AAS for such purposes.

Available forms
Methyltestosterone is typically used as an oral medication. It is also available under the brand names Metandren and Oreton Methyl for use specifically by buccal or sublingual administration. Methyltestosterone is available in the form of 2, 5, 10, and 25 mg oral tablets. It was also available in combination with estrogens as esterified estrogens/methyltestosterone (0.625 mg/1.25 mg, 1.25 mg/2.5 mg) and conjugated estrogens/methyltestosterone (0.625 mg/5.0 mg, 1.25 mg/10 mg).

Contraindications
Methyltestosterone should be used with caution in women and children, as it can cause irreversible virilization. Due to its estrogenicity, methyltestosterone can also accelerate epiphyseal closure and thereby produce short stature in children and adolescents. It can worsen symptoms in men with benign prostatic hyperplasia. Methyltestosterone should not be used in men with prostate cancer, as androgens can accelerate tumor progression. The drug should be used with caution in patients with pre-existing hepatotoxicity, due to its own potential for hepatotoxicity.

Side effects
Adverse effects of methyltestosterone include androgenic side effects like oily skin, acne, seborrhea, increased facial/body hair growth, scalp hair loss, increased aggressiveness and sex drive, and spontaneous erections, as well as estrogenic side effects like breast tenderness, gynecomastia, fluid retention, and edema. In women, methyltestosterone can cause partially irreversible virilization, for instance voice deepening, hirsutism, clitoromegaly, breast atrophy, and muscle hypertrophy, as well as menstrual disturbances and reversible infertility. In men, the drug may also cause hypogonadism, testicular atrophy, and reversible infertility at sufficiently high dosages.Methyltestosterone can sometimes cause hepatotoxicity, for instance elevated liver enzymes, cholestatic jaundice, peliosis hepatis, hepatomas, and hepatocellular carcinoma, with extended use. It can also have adverse effects on the cardiovascular system. AAS like methyltestosterone stimulate erythropoiesis (red blood cell production) and increase hematocrit levels and at high dosages can cause polycythemia (overproduction of red blood cells), which can greatly increase the risk of thrombic events such as embolism and stroke. With long-term treatment, AAS can increase the risk of benign prostatic hyperplasia and prostate cancer. Violent and even homicidal behavior, hypomania/mania, depression, suicidality, delusions, and psychosis have all been associated with very high dosages of AAS.

Interactions
Aromatase inhibitors can be used to reduce or prevent the estrogenic effects of methyltestosterone and 5α-reductase inhibitors can be used to prevent its potentiation in so-called "androgenic" tissues and thereby improve its ratio of anabolic to androgenic activity and reduce its rate of androgenic side effects. Antiandrogens like bicalutamide and cyproterone acetate can block both the anabolic and androgenic effects of AAS like methyltestosterone.

Pharmacology
Pharmacodynamics
As an AAS, methyltestosterone is an agonist of the androgen receptor (AR), similarly to androgens like testosterone and dihydrotestosterone (DHT). It is a substrate for 5α-reductase like testosterone, and so is potentiated analogously in so-called "androgenic" tissues like the skin, hair follicles, and prostate gland via transformation into the more potent AR agonist mestanolone (17α-methyl-DHT). As such, methyltestosterone has a relatively low ratio of anabolic to androgenic activity, with a similar ratio to that of testosterone (close to 1:1), and this makes it among the most androgenic AAS. Due to efficient aromatization into the potent and metabolism-resistant estrogen methylestradiol (17α-methylestradiol), methyltestosterone has relatively high estrogenicity and hence potential for estrogenic side effects such as gynecomastia and fluid retention. The drug possesses negligible progestogenic activity.Due to its combined disadvantages of a relatively poor ratio of anabolic to androgenic activity, unusually high estrogenicity, and the potential for hepatotoxicity (as with other 17α-alkylated AAS), methyltestosterone has not been used as commonly as many other AAS either in medicine or for physique- or performance-enhancing purposes.

Pharmacokinetics
Absorption
Methyltestosterone has dramatically improved oral bioavailability and metabolic stability relative to testosterone. This difference is due to the C17α methyl group, which results in steric hindrance and prevents metabolism. The oral bioavailability of methyltestosterone is about 70%, and it is well-absorbed from the gastrointestinal tract. Methyltestosterone can also be taken buccally or sublingually. Although effective orally, methyltestosterone is more effective by these non-oral routes, which are said to approximately double its bioavailability and require half the oral dosage.Circulating levels of methyltestosterone with administration of 1.25 to 2.5 mg/day oral methyltestosterone in women are in the range of 20 to 30 ng/dL. For comparison to testosterone, methyltestosterone is at least as potent as an AAS. However, due to the large decrease in sex hormone-binding globulin (SHBG) levels and hence increase in free unbound testosterone caused by methyltestosterone, androgenic effects may be greater than reflected merely by methyltestosterone levels.

Distribution
Methyltestosterone is highly protein-bound, by approximately 98%. The medication has low but significant affinity for human serum sex hormone-binding globulin (SHBG), about 25% of that of testosterone and 5% of that of DHT.

Metabolism
The biological half-life of methyltestosterone is approximately 3 hours (range 2.5–3.5 hours). The duration of action of methyltestosterone is said to be 1 to 3 days, and is described as relatively short among AAS.

Excretion
Methyltestosterone is excreted 90% in the urine as conjugates and other metabolites, and 6% in feces.

Chemistry
Methyltestosterone, also known as 17α-methyltestosterone or as 17α-methylandrost-4-en-17β-ol-3-one, is a synthetic, 17α-alkylated androstane steroid and a derivative of testosterone differing from it only in the presence of a methyl group at the C17α position. Close synthetic relatives of methyltestosterone include metandienone (17α-methyl-δ1-testosterone) and fluoxymesterone (9α-fluoro-11β-hydroxy-17α-methyltestosterone).

Derivatives
Methyltestosterone and ethyltestosterone (17α-ethyltestosterone) are the parent structures of all 17α-alkylated AAS. Major 17α-alkylated AAS include the testosterone derivatives fluoxymesterone, metandienone (methandrostenolone), and methyltestosterone and the DHT derivatives oxandrolone, oxymetholone, and stanozolol.

Synthesis
A chemical synthesis of methyltestosterone from dehydroepiandrosterone (DHEA) with methandriol as an intermediate proceeds as follows:

History
Methyltestosterone was first synthesized in 1935 along with methandriol and mestanolone. It was the second synthetic AAS to be developed, following mesterolone (1α-methyl-DHT) in 1934, and was the first 17α-alkylated AAS to be synthesized. The drug was introduced for medical use in 1936.

Society and culture
Generic names
Methyltestosterone is the INN, USAN, USP, BAN, and JAN of the drug and its generic name in English and Japanese, while méthyltestostérone is its DCF and French name and metiltestosterone is its DCIT and Italian name. The generic name of the drug is methyltestosterone in Latin, methyltestosteron in German, and metiltestosterona in Spanish. Methyltestosterone is also known by its former developmental code name NSC-9701.

Brand names
Brand names under which methyltestosterone is or has been marketed for medical use include Afro, Agovirin, Android, Androral, Mesteron, Metandren, Methitest, Methyltestosterone, Methyl Testosterone, Oraviron, Oreton, Oreton Methyl, Testormon, Testovis, Testred, and Virilon, among others.

With an estrogen
Methyltestosterone is available at a low-dose in combination with esterified estrogens for the treatment of menopausal symptoms like hot flashes in women under the brand names Covaryx, Essian, Estratest, Menogen, and Syntest.

Availability
United States
Although it is not commonly used, methyltestosterone is one of the few AAS that remains available for medical use in the United States. The others are testosterone, testosterone cypionate, testosterone enanthate, testosterone undecanoate, oxandrolone, oxymetholone, and fluoxymesterone.

Other countries
Methyltestosterone has also been marketed in many other countries throughout the world.

Legal status
Methyltestosterone, along with other AAS, is a schedule III controlled substance in the United States under the Controlled Substances Act and a schedule IV controlled substance in Canada under the Controlled Drugs and Substances Act.

See also
Esterified estrogens/methyltestosterone
Conjugated estrogens/methyltestosterone

References
Further reading
Phillips EH, Ryan S, Ferrari R, Green C (2003). "Estratest and Estratest HS (esterified estrogens and methyltestosterone) therapy: a summary of safety surveillance data, January 1989 to August 2002". Clin Ther. 25 (12): 3027–43. doi:10.1016/s0149-2918(03)90090-7. PMID 14749144.
Kabat GC, Kamensky V, Heo M, Bea JW, Hou L, Lane DS, Liu S, Qi L, Simon MS, Wactawski-Wende J, Rohan TE (2014). "Combined conjugated esterified estrogen plus methyltestosterone supplementation and risk of breast cancer in postmenopausal women" </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 Potassium chloride (medical use) and explain in detail? [/INST] Potassium chloride, also known as potassium salt, is used as a medication to treat and prevent low blood potassium. Low blood potassium may occur due to vomiting, diarrhea, or certain medications. The concentrated version should be diluted before use. It is given by slow injection into a vein or by mouth.Side effects may include heart problems if given too quickly by injection into a vein. By mouth it can result in abdominal pain, peptic ulcer disease, or gastrointestinal bleeding. Greater care is recommended in those with kidney problems. As long as high blood potassium does not occur, use in pregnancy or breastfeeding is believed to be safe for the baby. Generally, the strength of the formulation for injection into a vein should not be greater than 40 mmol/L (3 mg/L).Potassium chloride came into large scale commercial use as a fertilizer in 1861 and has been used medically since the 1950s. It is on the World Health Organizations List of Essential Medicines </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 Lixisenatide and explain in detail? [/INST] Lixisenatide (trade name Lyxumia in the European Union and Adlyxin in the U.S. and manufactured by Sanofi) is a once-daily injectable GLP-1 receptor agonist for the treatment of type 2 diabetes.

Medical use
Lixisenatide is used as adjunct to diet and exercise to treat type 2 diabetes. In the European Union, its use is limited to complementing insulin therapy. As of 2017 it is unclear if they affect a persons risk of death.It is provided in an autoinjector containing fourteen doses and is injected subcutaneously.Lixisenatide should not be used for people who have problems with stomach emptying. Lixisenatide delays emptying of the stomach, which may change how quickly other drugs that are taken by mouth take effect.

Lixisenatide in neurodegenerative diseases
Results from a research work which was done by McClean PL et al. demonstrated that the GLP-1 receptor agonists liraglutide and lixisenatide which are on the market as treatments for type 2 diabetes show promise as potential drug treatments of Alzheimer disease AD. Lixisenatide was equally effective at a lower dose compared to liraglutide in some of the measured parameters after ten weeks of daily intraperitoneal injections with liraglutide (2.5 or 25 nmol/kg) or lixisenatide (1 or 10 nmol/kg) or saline of APP/PS1 mice at an age when amyloid plaques had already formed. When analyzing synaptic plasticity in the hippocampus, LTP was strongly increased in APP/PS1 mice by either drug, with more effectiveness accomplished with lixisenatide. The reduction of synapse numbers seen in APP/PS1 mice was prevented by the two drugs. The amyloid plaque load and dense-core Congo red positive plaque load in the cortex were reduced by both drugs at all doses. The chronic inflammation response (microglial activation) was also reduced by all treatments
Cai HY et al. demonstrated in a study that lixisenatide could reduce amyloid plaques, neurofibrillary tangles and neuroinflammation in the hippocampi of 12-month-old APP/PS1/tau female mice; activation of PKA-CREB signaling pathway and inhibition of p38-MAPK might be the important mechanisms in the neuroprotective function of lixisenatide. So, lixisenatide might have the potential to be developed as a novel therapy for AD
Liu Wet al found an interesting results when comparing exendin-4 (10 nmol/kg), liraglutide (25 nmol/kg) and lixisenatide (10 nmol/kg), it was found that exendin-4 showed no protective effects at the dose chosen, while both liraglutide and lixisenatide showed effects in preventing the MPTP-induced motor impairment (Rotarod, open-field locomotion, catalepsy test), reduction in tyrosine hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, a reduction of the pro-apoptotic signaling molecule BAX and an increase in the anti-apoptotic signaling molecule B-cell lymphoma-2. The previous results demonstrate that both liraglutide and lixisenatide are superior to exendin-4, and both drugs show promise as a novel treatment of Parkinson disease
Another study done by Kerry Hunter et al. profiled the GLP-1 receptor agonists liraglutide and lixisenatide. The kinetics of crossing the blood brain barrier (BBB), activation of the GLP-1R by measuring cAMP levels, and physiological effects in the brain on neuronal stem cell proliferation and neurogenesis were evaluated. Both drugs were able to cross the BBB. Lixisenatide crossed the BBB at all doses tested (2.5, 25, or 250 nmol/kg ip.) when measured 30 min post-injection and at 2.5-25 nmol/kg ip. 3 h post-injection. Lixisenatide also enhanced neurogenesis in the brain. Liraglutide crossed the BBB at 25 and 250 nmol/kg ip. but no increase was detectable at 2.5 nmol/kg ip. 30 min post-injection, and at 250 nmol/kg ip. at 3 h post-injection. Liraglutide and lixisenatide enhanced cAMP levels in the brain, with lixisenatide being more effective. The previous results suggest that these novel incretin analogues cross the BBB showing physiological activity and neurogenesis in the brain, which makes them good candidates to be used as a treatment of neurodegenerative diseases.

Adverse effects
In about 0.1% of cases people have had anaphylactic reactions to lixisenatide and in about 0.2% of cases the drug has caused pancreatitis.  Use with insulin or sulfonylurea may cause hypoglycemia.  In some cases, people with no kidney disease have had acute kidney injury and in some people with existing kidney disease the condition has gotten worse. Because lixisenatide is a peptide people can and do develop an immune response to it that will eventually make the drug ineffective; people who have developed antibodies to lixisenatide tend to have more inflammation at the injection site.At least 5% of people had nausea, vomiting, diarrhea, headache, or dizziness after taking lixisenatide.

Mechanism of action
Lixisenatide is a member of the class of glucagon-like peptide-1 receptor agonist drugs, each of which activates the GLP-1 receptor. GLP-1 is a hormone that helps pancreatic beta cells to secrete insulin in response to high blood sugar.  Because it works like the normal hormone, insulin is only secreted when blood sugar is high.  Like GLP-1, it also slows gastric emptying.

Chemistry
Lixisenatide is a peptide made of 44 amino acids, with an amide group on its C terminus.has been described as "des-38-proline-exendin-4 (Heloderma suspectum)-(1–39)-peptidylpenta-L-lysyl-L-lysinamide", meaning it is derived from the first 39 amino acids in the sequence of the peptide exendin-4, that was isolated from the Gila monster venom, omitting proline at position 38 and adding six lysine residues. Its complete sequence is:
H–His–Gly–Glu–Gly–Thr–Phe–Thr–Ser–Asp–Leu–Ser–Lys–Gln–Met–Glu–Glu–Glu–Ala–Val–Arg–Leu–Phe–Ile–Glu–Trp–Leu–Lys–Asn–Gly–Gly–Pro–Ser–Ser–Gly–Ala–Pro–Pro–Ser–Lys–Lys–Lys–Lys–Lys–Lys–NH2

History
It was created by Zealand Pharma A/S of Denmark; in 2003 Zealand licensed it to Sanofi which developed the drug.  Lixisenatide was approved by the European Commission on February 1, 2013.  Sanofi submitted an NDA in the US, which was accepted for review by the US FDA in February 2013 but after discussions with the FDA about the cardiovascular safety data included in the package (starting in 2008, the FDA had required stronger CV safety data for new anti-diabetes drugs, following the controversy around the risks of Avandia) Sanofi decided to withdraw the NDA and wait for the results of a Phase III study that was scheduled to be completed in 2015 </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Oxybuprocaine 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 Ibuprofen/paracetamol 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 Teduglutide 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 Thymoglobulin and explain in detail? [/INST] Thymoglobulin (manufactured by Sanofi) is an anti-human thymocyte immunoglobulin preparation made of purified polyclonal antibodies derived from rabbits. While these antibodies have a variety of specificities, their main mechanism of immunosuppression is through depletion of T cells. Thymoglobulin is currently approved for clinical use in Europe and the United States for renal allograft rejection, prevention of graft-vs.-host disease, and conditions involving bone marrow failure, including aplastic anemia and has additional off-label uses.

History of antithymocyte globulin
Antithymocyte globulin (ATG) was originally developed as one of various tested preparations of antilymphocyte globulin (ALG) specifically generated against human lymphocytes within the thymus, or thymocytes. The purpose of this research was largely to produce an effective immunosuppressive agent safe for use in humans. Since the discovery of a link between antilymphocyte serum (ALS) and lymphocyte depletion by Metchnikoff in 1899, various studies have demonstrated the immunosuppressive ability of ALG and ATG. Experiments on ALS that confirmed its efficacy in lymphocyte depletion led to testing of different types of preparations including ALG, which were ALS produced against human lymphocytes, and ATG.A number of studies conducted in the 1960s, including studies by Starzl et al. and Mathe et al., resulted in promising data for the clinical use of ALG for preserving short-term and long-term kidney function in patients immediately after human kidney transplantation. Use of equine ALG was also found to be efficacious in preventing acute graft-vs.-host-disease in patients’ post-allogeneic bone marrow transplantation. Experimentation with ALG and ATG preparations from different sources followed, leading to testing of ATG derived from rabbit serum. Thymoglobulin was the first commercial rabbit-derived ATG to be introduced in Europe and the US in the 1980s. Due to its demonstrated efficacy as an immunosuppressive agent, it remains a commonly used ATG for induction therapy and treatment of other associated conditions, such as graft-vs.-host disease and aplastic anemia.

Mechanism of immunosuppression
As an rATG, thymoglobulin consists of polyclonal antibodies, which, unlike monoclonal antibodies, target a large variety of immune cell surface proteins, including B and T lymphocyte, natural killer cell, and plasma cell surface antigens </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 Palonosetron and explain in detail? [/INST] Palonosetron, sold under the brand name Aloxi, is used for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV). It is a 5-HT3 antagonist.Palonosetron is administered intravenously, or as a single oral capsule. It has a longer duration of action than  other 5-HT3 antagonists. The oral formulation was approved on August 22, 2008, for prevention of acute CINV alone, as a large clinical trial did not show oral administration to be as effective as intravenous use against delayed CINV. It is on the World Health Organizations List of Essential Medicines.The oral combination netupitant/palonosetron is approved for both acute and delayed CINV.

Adverse effects
The most common adverse effects are headache, which occurs in 4–11% of patients, and constipation in up to 6% of patients. In less than 1% of patients, other gastrointestinal disorders occur, as well as sleeplessness, first- and second-degree atrioventricular block, muscle pain and shortness of breath. Palonosetron is similarly well tolerated as other 5-HT3 antagonists, and slightly less than placebo.

Interactions
Palonosetron does not relevantly inhibit or induce cytochrome P450 liver enzymes. There are case reports about serotonin syndrome when the drug is combined with serotonergic substances such as selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), two common types of antidepressants.

Pharmacology
Mechanism of action
Palonosetron is a 5-HT3 antagonist, commonly known as a setron. These drugs act by blocking serotonin from binding to the 5-HT3 receptor.

Pharmacokinetics
Orally taken palonosetron is absorbed well from the gut and has a bioavailability of 97%. Highest blood plasma levels are reached after 5.1±1.7 hours, independently of food intake, and plasma protein binding is 62%. 40% of the substance are eliminated in the unchanged form, and a further 45–50% are metabolized by the liver enzyme CYP2D6 and to a lesser extent by CYP3A4 and CYP1A2 </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 Prothrombin complex concentrate and explain in detail? [/INST] Prothrombin complex concentrate (PCC), also known as factor IX complex, is a medication made up of blood clotting factors II, IX, and X. Some versions also contain factor VII. It is used to treat and prevent bleeding in hemophilia B if pure factor IX is not available. It may also be used for reversal of warfarin therapy. It is given by slow injection into a vein.Common side effects include allergic reactions, headache, vomiting, and sleepiness. Other serious side effects include blood clots which may result in a heart attack, stroke, pulmonary embolism, or deep vein thrombosis. Antibodies may form after long term use such that future doses are less effective.Prothrombin complex concentrate came into medical use in the 1960s. It is on the World Health Organizations List of Essential Medicines. It is made from human plasma. Recombinant factor IX is also available in a stand-alone preparation. In the United States a dose of PCC costs about US$900. A number of different formulations are available globally.

Medical uses
Prothrombin complex concentrate reverses the effects of warfarin and other vitamin K antagonist anti-coagulants and is used in cases of significant bleeding in people with a coagulopathy. It is also used when such a person must undergo an emergency operation. Other uses include a deficiency of one of the included clotting factors, either congenital or due to liver disease, and hemophilia. Several guidelines, including those from the American College of Chest Physicians, recommend prothrombin complex concentrate for warfarin reversal in people with serious bleeding.For rapid anticoagulation reversal for surgery, four-factor prothrombin complex concentrate reduces international normalized ratio (INR) and decreases bleeding during surgery when compared with administration of fresh frozen plasma. No differences in thromboembolic event was found.

Contraindications
The package insert states that prothrombin complex concentrate is contraindicated in patients with disseminated intravascular coagulation, a pathological activation of coagulation, because giving clotting factors would only further fuel this process </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 Sulfasalazine and explain in detail? [/INST] Sulfasalazine (SSZ), sold under the trade name Azulfidine among others, is a medication used to treat rheumatoid arthritis, ulcerative colitis, and Crohns disease. It is considered by some to be a first-line treatment in rheumatoid arthritis. It is taken by mouth.Significant side effects occur in about 25% of people. Commonly these include loss of appetite, nausea, headache, and rash. Severe side effects include bone marrow suppression, liver problems, Stevens–Johnson syndrome, and kidney problems. It should not be used in people allergic to aspirin or sulfonamide. Use during pregnancy appears to be safe for the baby.Sulfasalazine is in the disease-modifying antirheumatic drugs (DMARDs) family of medications. It is unclear exactly how it works. One proposed mechanism is the inhibition of prostaglandins, resulting in local anti-inflammatory effects in the colon. The medication is broken down by intestinal bacteria into sulfapyridine and 5-aminosalicylic acid. That which is absorbed is excreted by the kidneys and in the bile.Sulfasalazine was approved for medical use in the United States in 1950. It is on the World Health Organizations List of Essential Medicines. Sulfasalazine is available as a generic medication.

Medical uses
Sulfasalazine is used in the treatment of inflammatory bowel disease, including ulcerative colitis and Crohns disease. It is also indicated for use in rheumatoid arthritis and used in other types of inflammatory arthritis (e.g. psoriatic arthritis and reactive arthritis).It is usually not given to children under two years of age.

Side effects
Use of sulfasalazine is contraindicated in people with sulfa allergies and in those with urinary tract obstructions, intestinal obstructions, and severe liver or kidney problems.Sulfasalazine metabolizes to sulfapyridine. Serum levels should be monitored every three months, and more frequently at the outset. Serum levels above 50 μg/L are associated with side effects. In rare cases, sulfasalazine can cause severe depression in young males </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 Praziquantel and explain in detail? [/INST] Praziquantel (PZQ), sold under the brandname Biltricide among others, is a medication used to treat a number of types of parasitic worm infections in mammals, birds, amphibians, reptiles, and fish. In humans specifically, it is used to treat schistosomiasis, clonorchiasis, opisthorchiasis, tapeworm infections, cysticercosis, hydatid disease, and other fluke infections. It should not be used for worm infections of the eye. It is taken by mouth.Side effects in humans may include poor coordination, abdominal pain, vomiting, headache, and allergic reactions. While it may be used during pregnancy, it is not recommended for use during breastfeeding. Praziquantel is in the anthelmintic class of medications. It works partly by affecting the function of the worms sucker.Praziquantel was approved for medical use in the United States in 1982. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Praziquantel is used to treat diseases caused by infection with several types of internal/gastrointestinal, and external parasites, including:

Hydatid disease caused by infection of various organs with larval stages of tapeworms of the genus Echinococcus
Cysticercosis caused by infection of the brain and/or muscles with the eggs and larvae of the pork tapeworm Taenia solium (though it has been judged less effective than albendazole in treatment of neurocysticercosis)
In dogs and cats, whose gastrointestinal tracts are infected with the tapeworms Dipylidium caninum or Taenia taeniaeformis, respectively; praziquantel is also often used in fixed combination with pyrantel embonate against the roundworms (ascarids): Toxocara cati and Toxascaris leonina. Praziquantel is also effective against Echinococcus multilocularis.
Schistosomiasis caused by trematodes of the genus Schistosoma: As of 2005, praziquantel is the primary treatment for human schistosomiasis, for which it is usually effective in a single dose.
Clonorchiasis brought on by the Chinese liver fluke Clonorchis sinensis
Paragonimiasis caused by infection with lung flukes, mostly of the species Paragonimus westermani
Fasciolopsiasis caused by intestinal fluke Fasciolopsis buski

Side effects
The majority of side effects develop due to the release of the contents of the parasites as they are killed and the consequent host immune reaction. The heavier the parasite burden, the heavier and more frequent the side effects normally are.

Central nervous system (CNS): Frequently occurring side effects are dizziness, headache, and malaise. Drowsiness, somnolence, fatigue, and vertigo have also been seen. Almost all patients with cerebral cysticercosis experience CNS side effects related to the cell-death of the parasites (headache, worsening of pre-existing neurological problems, seizures, arachnoiditis, and meningism). These side effects may be life-threatening and can be reduced by coadministration of corticosteroids. All patients with cerebral cysticercosis are strongly recommended to be  hospitalized during treatment.
Gastrointestinal tract: About 90% of all patients have abdominal pain or cramps with or without nausea and vomiting. Diarrhea may develop and may be severe with colic. Sweating, fever, and sometimes bloody stools may occur together with diarrhea.
Liver: Asymptomatic and transient increases of liver enzymes (AST and ALT) are noted frequently (up to 27%). No case of symptomatic liver damage has been seen so far.
Sensitivity reactions: Urticaria, rash, pruritus and eosinophilia in white blood cell counts
Other locations/body as a whole: Lower back pain, myalgia, arthralgia, fever, sweating, various cardiac arrhythmias, and hypotension

Pregnancy
The WHO states praziquantel is safe during pregnancy. Animal studies have failed to reveal evidence of fetal harm. Praziquantel is effective in reducing schistosomiasis during pregnancy. Another trial found that treatment with praziquantel did not increase the rates of low birthweight, fetal death, or congenital anomalies.

Drug interactions
The antibiotic rifampicin decreases plasma concentrations of praziquantel.Carbamazepine and phenytoin are reported to reduce the bioavailability of praziquantel. Chloroquine also reduces its bioavailability.The drug cimetidine heightens praziquantel bioavailability.

Mechanism of action
The drugs mode of action is not exactly known at present, but experimental evidence indicates praziquantel increases the permeability of the membranes of schistosome cells towards calcium ions. The drug thereby induces contraction of the parasites muscle, resulting in paralysis in the contracted state. The dying parasites are dislodged from their site of action in the host organism and may enter systemic circulation or may be destroyed by host immune reaction (phagocytosis). Additional mechanisms including focal disintegrations and disturbances of oviposition (laying of eggs) are seen in other types of sensitive parasites.
Another hypothesis regarding the mechanism of action is that it interferes with adenosine uptake in worms. This effect may have therapeutical relevance given that the schistosome, as the Taenia and the Echinococcus (other praziquantel-sensitive parasites), is unable to synthesize purines, such as adenosine, de novo.
Bayers Animal Health Division website states, "Praziquantel is active against cestodes (tapeworms). Praziquantel is absorbed, metabolized in the liver, and excreted in the bile. Upon entering the digestive tract from the bile, cestocidal activity is exhibited. Following exposure to praziquantel, the tapeworm loses its ability to resist digestion by the mammalian host. Because of this, whole tapeworms, including the scolices (plural of "scolex"), are very rarely passed after administration of praziquantel. In many instances, only disintegrated and partially digested pieces of tapeworms will be seen in the stool. The majority of tapeworms are digested and are not found in the feces."Praziquantel is administered as a racemate, but only the (R)-enantiomer is biologically active; the enantiomers may be separated using a resolution of an amine obtained from praziquantel.

Pharmacokinetics
Praziquantel is well absorbed (about 80%) from the gastrointestinal tract. However, due to extensive first-pass metabolism, only a relatively small amount enters systemic circulation. Praziquantel has a serum half-life of 0.8 to 1.5 hours in adults with normal renal and liver function. Metabolites have a half-life of 4 to 5 hours. In patients with significantly impaired liver function (Child-Pugh score B and C), the serum half-life is increased to 3 to 8 hours. Praziquantel and its metabolites are mainly excreted renally; within 24 h after a single oral dose, 70 to 80% is found in urine, but less than 0.1% as the unchanged drug. Praziquantel is metabolized through the cytochrome P450 pathway via CYP3A4.  Agents that induce or inhibit CYP3A4 such as phenytoin, rifampin, and azole antifungals will affect the metabolism of praziquantel.
Praziquantel has a particularly dramatic effect on patients with schistosomiasis. Studies of those treated have shown that within six months of receiving a dose of praziquantel, up to 90% of the damage done to internal organs due to schistosomiasis infection can be reversed.

History
Praziquantel was developed in the laboratories for parasitological research of Bayer AG and Merck KGaA in Germany (Elberfeld and Darmstadt) in the mid-1970s.

Society and culture
Brand names
Biltricide (Bayer) Tablets (for human use)
Cesol (Merck) Tablets
Cestoved (Vedco) both tablets and injectable for veterinary use
Cysticide (Merck) Tablets
Distocide (Shin Poong Pharm </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 Oxandrolone and explain in detail? [/INST] Oxandrolone, sold under the brand names Oxandrin and Anavar, among others, is an androgen and anabolic steroid (AAS) medication which is used to help promote weight gain in various situations, to help offset protein catabolism caused by long-term corticosteroid therapy, to support recovery from severe burns, to treat bone pain associated with osteoporosis, to aid in the development of girls with Turner syndrome, and for other indications. It is taken by mouth.Side effects of oxandrolone include symptoms of masculinization such as acne, increased hair growth, voice changes, and increased sexual desire. The drug is a synthetic androgen and anabolic steroid, hence is an agonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone. It has strong anabolic effects and weak androgenic effects, which give it a mild side effect profile and make it especially suitable for use in women.Oxandrolone was first described in 1962 and was introduced for medical use in 1964. It is used mostly in the United States. In addition to its medical use, oxandrolone is used to improve physique and performance. The drug is a controlled substance in many countries, so nonmedical use is generally illicit.

Medical uses
Oxandrolone has been researched and prescribed as a treatment for a wide variety of conditions. It is FDA-approved for treating bone pain associated with osteoporosis, aiding weight gain following surgery or physical trauma, during chronic infection, or in the context of unexplained weight loss, and counteracting the catabolic effect of long-term corticosteroid therapy.As of 2016, it is often prescribed off-label to quicken recovery from severe burns, aid the development of girls with Turner syndrome, and counteract HIV/AIDS-induced wasting. Oxandrolone improves both short-term and long-term outcomes in people recovering from severe burns and is well-established as a safe treatment for this indication. It is also used in the treatment of idiopathic short stature, anemia, hereditary angioedema, alcoholic hepatitis, and hypogonadism.Medical research has established the effectiveness of oxandrolone in aiding the development of girls with Turner syndrome. Although oxandrolone has long been used to accelerate growth in children with idiopathic short stature, it is unlikely to increase adult height, and in some cases may even decrease it. Oxandrolone has, therefore, largely been replaced by growth hormone for this use. Children with idiopathic short stature or Turner syndrome are given doses of oxandrolone far smaller than those given to people with burns  to minimize the likelihood of virilization and premature maturation.

Non-medical uses
Many bodybuilders and athletes use oxandrolone illicitly for its muscle-building effects. It is much more anabolic than androgenic, so women and those seeking less intense steroid regimens use it particularly often. Many also value oxandrolones low hepatotoxicity relative to most other orally active AASs.

Contraindications
Like other AASs, oxandrolone may worsen hypercalcemia by increasing osteolytic bone resorption. When taken by pregnant women, oxandrolone may have unintended effects such as masculinization on the fetus.

Side effects
Women who are administered oxandrolone may experience virilization, irreversible development of masculine features such as voice deepening, hirsutism, menstruation abnormalities, male-pattern hair loss, and clitoral enlargement. Oxandrolone may disrupt growth in children, reducing their adult height. Because of these side effects, doses given to women and children are minimized and people are usually monitored for virilization and growth abnormalities. Like other androgens, oxandrolone can cause or worsen acne and priapism (unwanted or prolonged erections). Oxandrolone can also reduce males fertility, another side effect common among androgens. In an attempt to compensate for the exogenous increase in androgens, the body may reduce testosterone production via testicular atrophy and inhibition of gonadotropic activity.Unlike some AASs, oxandrolone does not generally cause gynecomastia because it is not aromatized into estrogenic metabolites. However, although no reports of gynecomastia were made in spite of widespread use, oxandrolone was reported in a publication in 1991 to have been associated with 33 cases of gynecomastia in adolescent boys treated with it for short stature. The gynecomastia developed during oxandrolone therapy in 19 of the boys and after the therapy was completed in 14 of the boys, and 10 of the boys had transient gynecomastia, while 23 had persistent gynecomastia that necessitated mastectomy. Though transient gynecomastia is a natural and common occurrence in pubertal boys, the gynecomastia associated with oxandrolone was of a late/delayed onset and was persistent in a high percentage of the cases. As such, the researchers stated, "although oxandrolone cannot be implicated as stimulatory [in] gynecomastia", a possible relationship should be considered in clinicians using oxandrolone in adolescents for growth stimulation.Uniquely among 17α-alkylated AASs, oxandrolone shows little to no hepatotoxicity, even at high doses. No cases of severe hepatotoxicity have been singularly attributed to oxandrolone. However, elevated liver enzymes have been observed in some people, particularly with high doses and/or prolonged treatment, although they return to normal ranges following discontinuation.

Interactions
Oxandrolone greatly increases warfarins blood-thinning effect, sometimes dangerously so. In April 2004, Savient Pharmaceuticals published a safety alert through the FDA warning healthcare professionals of this. Oxandrolone can also inhibit the metabolism of oral hypoglycemic agents. It may worsen edema when taken alongside corticosteroids or adrenocorticotropic hormone.

Pharmacology
Pharmacodynamics
Like other AASs, oxandrolone is an agonist of the androgen receptor, similar to androgens such as testosterone and DHT. The relative binding affinity of oxandrolone for the androgen receptor is about 0.8% of that of metribolone. Activation of the androgen receptor stimulates protein synthesis, which increases muscle growth, lean body mass, and bone mineral density.Compared to testosterone and many other AASs, oxandrolone is less androgenic relative to its strength as an anabolic. Oxandrolone has about 322 to 633% of the anabolic potency and 24% of the androgenic potency of methyltestosterone. Similarly, oxandrolone has as much as 6 times the anabolic potency of testosterone and has significantly reduced androgenic potency in comparison. The reduced ratio of anabolic to androgenic activity of oxandrolone often motivates its medical use in children and women because less androgenic effect implies less risk of virilization. The bodybuilding community also considers this fact when choosing between AASs.As oxandrolone is already 5α-reduced, it is not a substrate for 5α-reductase, hence is not potentiated in androgenic tissues such as the skin, hair follicles, and prostate gland. This is involved in its reduced ratio of anabolic to androgenic activity. Due to the substitution of one of the carbon atoms with an oxygen atom at the C2 position in the A ring, oxandrolone is resistant to inactivation by 3α-hydroxysteroid dehydrogenase in skeletal muscle. This is in contrast to DHT, and is thought to underlie the preserved anabolic potency with oxandrolone. Because it is 5α-reduced, oxandrolone is not a substrate for aromatase, hence cannot be aromatized into metabolites with estrogenic activity. Oxandrolone similarly possesses no progestogenic activity.Oxandrolone is, uniquely, far less hepatotoxic than other 17α-alkylated AASs, which may be due to differences in metabolism.

Pharmacokinetics
The oral bioavailability of oxandrolone is 97%. Its plasma protein binding is 94 to 97%. The drug is metabolized primarily by the kidneys and to a lesser extent by the liver. Oxandrolone is the only AAS that is not primarily or extensively metabolized by the liver, and this is thought to be related to its diminished hepatotoxicity relative to other AASs. Its elimination half-life is reported as 9.4 to 10.4 hours, but is extended to 13.3 hours in the elderly. About 28% of an oral dose of oxandrolone is eliminated unchanged in the urine and 3% is excreted in the feces.

Chemistry
Oxandrolone is a synthetic androstane steroid and a 17α-alkylated derivative of DHT. It is also known as 2-oxa-17α-methyl-5α-dihydrotestosterone (2-oxa-17α-methyl-DHT) or as 2-oxa-17α-methyl-5α-androstan-17β-ol-3-one, and is DHT with a methyl group at the C17α position and the C2 carbon replaced with an oxygen atom. Closely related AASs include the marketed AAS mestanolone (17α-methyl-DHT), oxymetholone (2-hydroxymethylene-17α-methyl-DHT), and stanozolol (a 2,3-pyrazole A ring-fused derivative of 17α-methyl-DHT) and the never-marketed/designer AAS desoxymethyltestosterone (3-deketo-17α-methyl-δ2-DHT), methasterone (2α,17α-dimethyl-DHT), methyl-1-testosterone (17α-methyl-δ1-DHT), and methylstenbolone (2,17α-dimethyl-δ1-DHT).

History
Oxandrolone was first made by Raphael Pappo and Christopher J. Jung while at Searle Laboratories (now part of Pfizer). The researchers first described the drug in 1962. They were immediately interested in oxandrolones very weak androgenic effects relative to its anabolic effects. It was introduced as a pharmaceutical drug in the United States in 1964.The drug was prescribed to promote muscle regrowth in disorders which cause involuntary weight loss, and is used as part of treatment for HIV/AIDS. It had also been shown to be partially successful in treating cases of osteoporosis. However, in part due to bad publicity from its illicit use by bodybuilders, production of Anavar was discontinued by Searle Laboratories in 1989. It was picked up by Bio-Technology General Corporation, which changed its name to Savient Pharmaceuticals, which following successful clinical trials in 1995, released it under the brand name Oxandrin. BTG subsequently won approvals for orphan drug status by the Food and Drug Administration for treating alcoholic hepatitis, Turner syndrome, and HIV-induced weight loss. It is also indicated as an offset to protein catabolism caused by long-term administration of corticosteroids.

Society and culture
Generic names
Oxandrolone is the generic name of the drug and its INN, USAN, USP, BAN, DCF, DCIT, and JAN, while ossandrolone is or was formerly the DCIT.

Brand names
The original brand name of oxandrolone was Anavar, which was marketed in the United States and the Netherlands. This product was eventually discontinued and replaced in the United States with a new product named Oxandrin, which is the sole remaining brand name for oxandrolone in the United States </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Oxycodone/aspirin and explain in detail? [/INST] Oxycodone/aspirin (trade name Percodan) is a combination drug marketed by Endo Pharmaceuticals. It is a tablet containing a mixture of 325 mg  (5 grains) of aspirin and 4.8355 mg of oxycodone HCl (equivalent to 4.3346 mg of oxycodone as the free base); it is an opioid/non-opioid combination used to treat moderate to moderately severe pain. The safety of the combination during pregnancy has not been established, although aspirin is generally contraindicated during pregnancy, and the drug has been placed in pregnancy category D. Inactive ingredients include D&C Yellow 10, FD&C Yellow 6, microcrystalline cellulose, and corn starch </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 Cholic acid and explain in detail? [/INST] Cholic acid, also known as 3α,7α,12α-trihydroxy-5β-cholan-24-oic acid is a primary bile acid that is insoluble in water (soluble in alcohol and acetic acid),  it is a white crystalline substance.  Salts of cholic acid are called cholates </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 Brimonidine and explain in detail? [/INST] Brimonidine is a medication used to treat open-angle glaucoma, ocular hypertension, and rosacea. In rosacea it improves the redness. It is used as eye drops or applied to the skin.Common side effects when used in the eyes include itchiness, redness, and a dry mouth. Common side effects when used on the skin include redness, burning, and headaches. More significant side effects may include allergic reactions and low blood pressure. Use in pregnancy appears to be safe. When applied to the eye it works by decreasing the amount of aqueous humor made while increasing the amount that drains from the eye. When applied to the skin it works by causing blood vessels to contract.Brimonidine was patented in 1972 and came into medical use in 1996. It is available as a generic medication. In 2019, it was the 217th most commonly prescribed medication in the United States, with more than 2 million prescriptions.

Medical uses
Brimonidine is indicated for the lowering of intraocular pressure in patients with open-angle glaucoma or ocular hypertension. It is also the active ingredient of brimonidine/timolol along with timolol maleate.
A 2017 Cochrane review found insufficient evidence to determine if brimonidine slows optic nerve damage.In 2013, the FDA approved topical application of brimonidine 0.33% gel for persistent facial redness of rosacea.

Mechanism of action
Brimonidine is an α2 adrenergic agonist.α2 agonists, through the activation of a G protein-coupled receptor, inhibit the activity of adenylate cyclase. This reduces cAMP and hence aqueous humour production by the ciliary body.
Peripheral α2 agonist activity results in vasoconstriction of blood vessels (as opposed to central α2 agonist activity that decreases sympathetic tone, as can be seen by the medication clonidine). This vasoconstriction may explain the acute reduction in aqueous humor flow. The increased uveoscleral outflow from prolonged use may be explained by increased prostaglandin release due to α adrenergic stimulation. This may lead to relaxed ciliary muscle and increased uveoscleral outflow.

Society and culture
Names
It is sold under the brand names Alphagan, Alphagan-P, Mirvaso, Lumify, Brymont, and others.

Over the counter
In July 2018, Bausch and Lomb began to market over the counter (OTC) eye drops, using brimonidines tartrate formulation in a concentration of 0.025%, as an ophthalmic vasoconstrictor under the brand name Lumify. Intended to relieve redness in the sclerae of the eyes for periods of up to eight hours at a time through its vasoconstrictive effects, Lumify was marketed as an alternative to Visine, the brand of tetrahydrozoline hydrochloride solution most commonly used for that purpose.

References
Further reading
Oh DJ, Chen JL, Vajaranant TS, Dikopf MS (January 2019). "Brimonidine tartrate for the treatment of glaucoma". Expert Opin Pharmacother </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Obeticholic acid and explain in detail? [/INST] Obeticholic acid (OCA), sold under the brand name Ocaliva, is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid.  It is used as a medication used to treat primary biliary cholangitis. Intercept Pharmaceuticals Inc. hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma.

Invention and development
The natural bile acid chenodeoxycholic acid was identified in 1999 as the most active physiological ligand for the farnesoid X receptor (FXR), which is involved in many physiological and pathological processes.  A series of alkylated bile acid analogues were designed, studied and patented by Roberto Pellicciari and colleagues at the University of Perugia, with 6α-ethyl-chenodeoxycholic acid emerging as the most highly potent FXR agonist.  FXR-dependent processes in liver and intestine were proposed as therapeutic targets in human diseases.  Obeticholic acid is the first FXR agonist to be used in human drug studies.

Clinical studies
Obeticholic acid is undergoing development in phase II and III studies for specific liver and gastrointestinal conditions. The U.S. Food and Drug Administration (FDA) approved obeticholic acid on May 27, 2016, for the treatment of primary biliary cholangitis. It was approved as an orphan drug based on its reduction in the level of the biomarker alkaline phosphatase as a surrogate endpoint for clinical benefit. It is indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA. Additional studies are being required to prove its clinical benefit.

Primary biliary cholangitis
Primary biliary cholangitis (PBC), also known as primary biliary cirrhosis, is an auto-immune, inflammatory liver disease which produces bile duct injury, fibrosis, cholestasis and eventual cirrhosis. It is much more common in women than men and can cause jaundice, itching (pruritus) and fatigue. Ursodeoxycholic acid therapy is beneficial, but the disease often progresses and may require liver transplantation. Animal studies suggested that treatment with FXR agonists should be beneficial in cholestatic diseases such as PBC. OCA at doses between 10 mg and 50 mg was shown to provide significant biochemical benefit, but pruritus was more frequent with higher doses.  The results of a randomized, double-blind phase III study of OCA, 5 mg or 10 mg, compared to placebo (POISE) were presented in April 2014, and showed that the drug met the trials primary endpoint of a significant reduction in serum alkaline phosphatase, a biomarker predictive of disease progression, liver transplantation or death.

Nonalcoholic steatohepatitis (NASH)
Non-alcoholic steatohepatitis is a common cause of abnormal liver function with histological features of fatty liver,  inflammation and fibrosis. It may progress to cirrhosis and is becoming an increasing indication for liver transplantation. It is increasing in prevalence. OCA is proposed to treat NASH. A phase II trial published in 2013, showed that administration of OCA at 25 mg or 50 mg daily for six weeks reduced markers of liver inflammation and fibrosis and increased insulin sensitivity.The Farnesoid X Receptor Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis Treatment (FLINT) trial, sponsored by NIDDK, was halted early in January 2014, after about half of the 283 subjects had completed the study, when a planned interim analysis showed that a) the primary endpoint had been met and b) lipid abnormalities were detected and arose safety concerns. Treatment with OCA (25 mg/day for 72 weeks) resulted in a highly statistically significant improvement in the primary histological endpoint, defined as a decrease in the NAFLD Activity Score of at least two points, with no worsening of fibrosis </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 Estramustine phosphate and explain in detail? [/INST] Estramustine phosphate (EMP), also known as estradiol normustine phosphate and sold under the brand names Emcyt and Estracyt, is a dual estrogen and chemotherapy medication which is used in the treatment of prostate cancer in men. It is taken multiple times a day by mouth or by injection into a vein.Side effects of EMP include nausea, vomiting, gynecomastia, feminization, demasculinization, sexual dysfunction, blood clots, and cardiovascular complications. EMP is a dual cytostatic and hence chemotherapeutic agent and a hormonal anticancer agent of the estrogen type. It is a prodrug of estramustine and estromustine in terms of its cytostatic effects and a prodrug of estradiol in relation to its estrogenic effects. EMP has strong estrogenic effects at typical clinical dosages, and consequently has marked antigonadotropic and functional antiandrogenic effects.EMP was introduced for medical use in the early 1970s. It is available in the United States, Canada, the United Kingdom, other European countries, and elsewhere in the world.

Medical uses
EMP is indicated, in the United States, for the palliative treatment of metastatic and/or progressive prostate cancer, whereas in the United Kingdom it is indicated for the treatment of unresponsive or relapsing prostate cancer. The medication is usually reserved for use in hormone-refractory cases of prostate cancer, although it has been used as a first-line monotherapy as well. Response rates with EMP in prostate cancer are said to be equivalent to conventional high-dose estrogen therapy.Due to its relatively severe side effects and toxicity, EMP has rarely been used in the treatment of prostate cancer. This is especially true in Western countries today. As a result, and also due to the scarce side effects of gonadotropin-releasing hormone modulators (GnRH modulators) like leuprorelin, EMP was almost abandoned. However, encouraging clinical research findings resulted in renewed interest of EMP for the treatment of prostate cancer.EMP has been used at doses of 140 to 1,400 mg/day orally in the treatment of prostate cancer. However, oral EMP is most commonly used at a dose of 560 to 640 mg/day (280–320 mg twice daily). The recommended dosage of oral EMP in the Food and Drug Administration (FDA) label for Emcyt is 14 mg per kg of body weight (i.e., one 140 mg oral capsule for each 10 kg or 22 lbs of body weight) given in 3 or 4 divided doses per day. The label states that most patients in studies of oral EMP in the United States have received 10 to 16 mg per kg per day. This would be about 900 to 1,440 mg/day for a 90-kg or 200-lb man. Lower doses of oral EMP, such as 280 mg/day, have been found to have comparable effectiveness as higher doses but with improved tolerability and reduced toxicity. Doses of 140 mg/day have been described as a very low dosage. EMP has been used at doses of 240 to 450 mg/day intravenously.EMP and other estrogens such as polyestradiol phosphate and ethinylestradiol are far less costly than newer therapies such as GnRH modulators, abiraterone acetate, and enzalutamide. In addition, estrogens may offer significant benefits over other means of androgen deprivation therapy, for instance in terms of bone loss and fractures, hot flashes, cognition, and metabolic status.EMP has been used to prevent the testosterone flare at the start of GnRH agonist therapy in men with prostate cancer.

Available forms
EMP is or has been available in the form of both capsules (140 mg, 280 mg) for oral administration and aqueous solutions (300 mg) for intravenous injection.

Contraindications
EMP is contraindicated when used in children, patients hypersensitive to estrogens or nitrogen mustards, those with peptic ulcer (an ulcer in the digestive tract), those with severely compromised liver function, those with weak heart muscle (also known as myocardial insufficiency) and those with thromboembolic disorders or complications related to fluid retention.

Side effects
The side effects of EMP overall have been described as relatively severe. The most common side effects of EMP have been reported to be gastrointestinal side effects like nausea, vomiting, and diarrhea, with nausea and vomiting occurring in 40% of men. They are usually mild or moderate in severity, and the nausea and vomiting can be managed with prophylactic antiemetic medications. Nonetheless, severe cases of gastrointestinal side effects with EMP may require dose reduction or discontinuation of therapy. Although nausea and vomiting have been reported to be the most common side effects of EMP, gynecomastia (male breast development) has been found to occur in as many as 83% of men treated with EMP, and the incidence of erectile dysfunction is possibly similar to or slightly less than the risk of gynecomastia. As a rule, feminization, a gynoid fat distribution, demasculinization, and impotence are said to occur in virtually or nearly 100% of men treated with high-dose estrogen therapy. Decreased sexual activity has also been reported in men treated with EMP. These side effects are due to high estrogen levels and low testosterone levels. Prophylactic irradiation of the breasts can be used to decrease the incidence and severity of gynecomastia with estrogens.Severe adverse effects of EMP are thromboembolic and cardiovascular complications including pulmonary embolism, deep vein thrombosis, stroke, thrombophlebitis, coronary artery disease (ischemic heart disease; e.g., myocardial infarction), thrombophlebitis, and congestive heart failure with fluid retention. EMP produces cardiovascular toxicity similarly to diethylstilbestrol, but to a lesser extent in comparison at low doses (e.g., 280 mg/day oral EMP vs. 1 mg/day oral diethylstilbestrol). The prostate cancer disease state also increases the risk of thromboembolism, and combination with docetaxel may exacerbate the risk of thromboembolism as well. Meta-analyses of clinical trials have found that the overall risk of thromboembolism with EMP is 4 to 7%, relative to 0.4% for chemotherapy regimens without EMP. Thromboembolism is the major toxicity-related cause of discontinuation of EMP. Anticoagulant therapy with medications such as aspirin, warfarin, unfractionated and low-molecular-weight heparin, and vitamin K antagonists can be useful for decreasing the risk of thromboembolism with EMP and other estrogens like diethylstilbestrol and ethinylestradiol.Adverse liver function tests are commonly seen with EMP, but severe liver dysfunction is rare with the medication. Central nervous system side effects are rarely seen with EMP, although enlarged ventricles and neuronal pigmentation have been reported in monkeys treated with very high doses of EMP (20–140 mg/kg/day) for 3 to 6 months. EMP does not appear to have cytostatic effects in normal brain tissue. In women treated with EMP in clinical studies, a few instances of minor gynecological hemorrhages have been observed. EMP is described as relatively well tolerated among cytostatic antineoplastic and nitrogen-mustard agents, rarely or not at all being associated with significant hematologic toxicity such as myelosuppression (bone marrow suppression), gastrointestinal toxicity, or other more marked toxicity associated with such agents. In contrast to most other cytostatic agents, which often cause myelosuppression, leukopenia (decreased white blood cell count), and neutropenia (decreased neutrophil count), EMP actually produces leukocytosis (increased white blood cell count) as a side effect.In a small low-dose study using 280 mg/day oral EMP for 150 days, tolerability was significantly improved, with gastrointestinal irritation occurring in only 15% of men, and there was no incidence of severe cardiovascular toxicity or deep vein thrombosis. In addition, no other side effects besides slight transient elevated liver enzymes were observed. These findings suggest that lower doses of oral EMP may be a safer option than higher doses for the treatment of prostate cancer. However, a subsequent 2004 meta-analysis of 23 studies of thromboembolic events with EMP found substantial incidence of thromboembolic events regardless of dosage and no association of EMP dose with risk of these complications.

Overdose
There has been no clinical experience with overdose of EMP. Overdose of EMP may result in pronounced manifestations of the known adverse effects of the medication. There is no specific antidote for overdose of EMP. In the event of overdose, gastric lavage should be used to evacuate gastric contents as necessary and treatment should be symptom-based and supportive. In the case of dangerously low counts of red blood cells, white blood cells, or platelets, whole blood may be given as needed. Liver function should be monitored with EMP overdose. After an overdose of EMP, hematological and hepatic parameters should continue to be monitored for at least 6 weeks.EMP has been used at high doses of as much as 1,260 mg/day by the oral route and 240 to 450 mg/day by intravenous injection.

Interactions
EMP has been reported to increase the efficacy and toxicity of tricyclic antidepressants like amitriptyline and imipramine. When products containing calcium, aluminium, and/or magnesium, such as dairy products like milk, various foods dietary supplements, and antacids, are consumed concomitantly with EMP, an insoluble chelate complex/phosphate salt between EMP and these metals can be formed, and this can markedly impair the absorption and hence oral bioavailability of EMP. There may be an increased risk of angioedema in those concurrently taking ACE inhibitors.

Pharmacology
Pharmacodynamics
EMP, also known as estradiol normustine phosphate, is a combined estrogen ester and nitrogen mustard ester. It consists of estradiol, an estrogen, linked with a phosphate ester as well as an ester of normustine, a nitrogen mustard. In terms of its pharmacodynamic effects, EMP is a prodrug of estramustine, estromustine, and estradiol. As a prodrug of estradiol, EMP is an estrogen and hence an agonist of the estrogen receptors. EMP itself has only very weak affinity for the estrogen receptors. The medication is of about 91% higher molecular weight than estradiol due to the presence of its C3 normustine and C17β phosphate esters. Because EMP is a prodrug of estradiol, it may be considered to be a natural and bioidentical form of estrogen, although it does have additional cytostatic activity via estramustine and estromustine.EMP acts by a dual mechanism of action: 1) direct cytostatic activity via a number of actions; and 2) as a form of high-dose estrogen therapy via estrogen receptor-mediated antigonadotropic and functional antiandrogenic effects. The antigonadotropic and functional antiandrogenic effects of EMP consist of strong suppression of gonadal androgen production and hence circulating levels of androgens such as testosterone; greatly increased levels of sex hormone-binding globulin and hence a decreased fraction of free androgens in the circulation; and direct antiandrogenic actions in prostate cells. The free androgen index with oral EMP has been found to be on average 4.6-fold lower than with orchiectomy. As such, EMP therapy results in considerably stronger androgen deprivation than orchiectomy. Metabolites of EMP, including estramustine, estromustine, estradiol, and estrone, have been found to act as weak antagonists of the androgen receptor (EC50 = 0.5–3.1 μM), although the clinical significance of this is unknown.Extremely high levels of estradiol and estrone occur during EMP therapy.  The estrogenic metabolites of EMP are responsible for its most common adverse effects and its cardiovascular toxicity. EMP has been described as having relatively weak estrogenic effects in some publications. However, it has shown essentially the same rates and degrees of estrogenic effects, such as breast tenderness, gynecomastia, cardiovascular toxicity, changes in liver protein synthesis, and testosterone suppression, as high-dose diethylstilbestrol and ethinylestradiol in clinical studies. The notion that EMP has relatively weak estrogen activity may have been based on animal research, which found that EMP had 100-fold lower uterotrophic effects than estradiol in rats, and may also not have taken into account the very high doses of EMP used clinically in humans.The mechanism of action of the cytostatic effects of EMP is complex and only partially understood. EMP is considered to mainly be a mitotic inhibitor, inhibiting mechanisms involved in the mitosis phase of the cell cycle. Specifically, it binds to microtubule-associated proteins and/or to tubulin and produces depolymerization of microtubules (Kd = 10–20 μM for estramustine), resulting in the arrest of cell division in the G2/M phase (specifically metaphase). EMP was originally thought to mediate its cytostatic effects as a prodrug of normustine, a nitrogen mustard, and hence was thought to be an alkylating antineoplastic agent. However, subsequent research has found that EMP is devoid of alkylating actions, and that the influence of EMP on microtubules is mediated by intact estramustine and estromustine, with normustine or estradiol alone having only minor or negligible effects. As such, the unique properties of the estramustine and estromustine structures, containing a carbamate-ester bond, appear to be responsible for the cytostatic effects of EMP. In addition to its antimitotic actions, EMP has also been found to produce other cytostatic effects, including induction of apoptosis, interference with DNA synthesis, nuclear matrix interaction, cell membrane alterations, induction of reactive oxygen species (free oxygen radicals), and possibly additional mechanisms. EMP has been found to have a radiosensitizing effect in prostate cancer and glioma cells, improving sensitivity to radiation therapy as well.The cytostatic metabolites of EMP are accumulated in tissues in a selective manner, for instance in prostate cancer cells. This may be due to the presence of a specific estramustine-binding protein (EMBP) (Kd = 10–35 nM for estramustine), also known as prostatin or prostatic secretion protein (PSP), which has been detected in prostate cancer, glioma, melanoma, and breast cancer cells. Because of its tissue selectivity, EMP is said to produce minimal cytostatic effects in healthy tissues, and its tissue selectivity may be responsible for its therapeutic cytostatic efficacy against prostate cancer cells.EMP was originally developed as a dual ester prodrug of an estrogen and normustine as a nitrogen mustard alkylating antineoplastic agent which, due to the affinity of the estrogen moiety for estrogen receptors, would be selectively accumulated in estrogen target tissues and hence estrogen receptor-positive tumor cells. Consequentially, it was thought that EMP would preferentially deliver the alkylating normustine moiety to these tissues, allowing for reduced cytostatic effects in healthy tissues and hence improved efficacy and tolerability. However, subsequent research found that there is very limited and slow cleavage of the normustine ester and that EMP is devoid of alkylating activity. In addition, it appears that estramustine and estromustine may be preferentially accumulated in estrogen target tissues not due to affinity for the estrogen receptors, but instead due to affinity for the distinct EMBP.Extremely high, pregnancy-like levels of estradiol may be responsible for the leukocytosis (increased white blood cell count) that is observed in individuals treated with EMP. This side effect is in contrast to most other cytotoxic agents, which instead cause myelosuppression (bone marrow suppression), leukopenia (decreased white blood cell count), and neutropenia (decreased neutrophil count).

Antigonadotropic effects
EMP at a dosage 280 mg/day has been found to suppress testosterone levels in men into the castrate range (to 30 ng/dL) within 20 days and to the low castrate range (to 10 ng/dL) within 30 days. Similarly, a dosage of 70 mg/day EMP suppressed testosterone levels into the castrate range within 4 weeks.

Pharmacokinetics
Upon oral ingestion, EMP is rapidly and completely dephosphorylated by phosphatases into estramustine during the first pass in the gastrointestinal tract. Estramustine is also partially but considerably oxidized into estromustine by 17β-hydroxysteroid dehydrogenases during the first pass. As such, EMP reaches the circulation as estramustine and estromustine, and the major metabolite of EMP is estromustine. A limited quantity of approximately 10 to 15% of estramustine and estromustine is further slowly metabolized via hydrolysis of the normustine ester into estradiol and estrone, respectively. This reaction is believed to be catalyzed by carbamidases, although the genes encoding the responsible enzymes have not been characterized. The circulating levels of normustine formed from EMP are insignificant. Release of nitrogen mustard gas from normustine via cleavage of the carboxylic acid group has not been demonstrated and does not seem to occur.The oral bioavailability of EMP is low, which is due to profound first-pass metabolism; specifically, dephosphorylation of EMP. The oral bioavailability of EMP specifically as estramustine and estromustine is 44 to 75%, suggesting that absorption may be incomplete. In any case, there is a linear relationship between the oral dose of EMP and circulating levels of estramustine and estromustine. Consumption of calcium, aluminium, or magnesium with oral EMP can markedly impair its bioavailability due to diminished absorption from the intestines, and this may interfere with its therapeutic effectiveness at low doses.Following a single oral dose of 420 mg EMP in men with prostate cancer, maximal levels of estromustine were 310 to 475 ng/mL (475,000 pg/mL) and occurred after 2 to 3 hours. Estradiol levels with 280 mg/day oral EMP have been found to increase to very high concentrations within one week of therapy. In one study, levels of estradiol were over 20,000 pg/mL after 10 days, were about 30,000 pg/mL after 30 days, and peaked at about 40,000 pg/mL at 50 days. Another study found lower estradiol levels of 4,900 to 9,000 pg/mL during chronic therapy with 560 mg/day oral EMP. An additional study found estradiol levels of about 17,000 pg/mL with 140 mg/day oral EMP and 38,000 pg/mL with 280 mg/day oral EMP.  The circulating levels of estradiol and estrone during EMP therapy have been reported to exceed normal levels in men by more than 100- and 1,000-fold, respectively. Levels of estramustine and estradiol in the circulation are markedly lower than those of estromustine and estrone, respectively, with a ratio of about 1:10 in both cases. Nonetheless, estradiol levels during EMP therapy appear to be similar to those that occur in mid-to-late pregnancy, which range from 5,000 to 40,000 pg/mL. No unchanged EMP is seen in the circulation with oral administration.The pharmacokinetics of EMP are different with intravenous injection. Following a single intravenous injection of 300 mg EMP, levels of EMP were higher than those of its metabolites for the first 8 hours. This is likely due to the bypassing of first-pass metabolism. However, by 24 hours after the dose, unchanged EMP could no longer be detected in the circulation. The clearance of EMP from blood plasma is 4.85 ± 0.684 L/h. The volumes of distribution of EMP with intravenous injection were small; under a two-compartment model, the volume of distribution for the central compartment was 0.043 L/kg and for the peripheral compartment was 0.11 L/kg. The plasma protein binding of EMP is high. Estramustine is accumulated in tumor tissue, for instance prostate cancer and glioma tissue, with estramustine levels much higher in these tissues than in plasma (e.g., 6.3- and 15.9-fold, respectively). Conversely, levels of estromustine in tumor versus plasma are similar (1.0- and 0.5-fold, respectively). Estramustine and estromustine appear to accumulate in adipose tissue.The elimination half-life of estromustine with oral EMP was 13.6 hours on average, with a range of 8.8 to 22.7 hours. Conversely, the elimination half-life of estromustine with intravenous injection was 10.3 hours, with a range of 7.36 to 12.3 hours. For comparison, the corresponding elimination half-lives of estrone were 16.5 and 14.7 hours for oral and intravenous administration, respectively. Estramustine and estromustine are mainly excreted in bile and hence in feces. They are not believed to be excreted in urine.

Chemistry
EMP, also known as estradiol 3-normustine 17β-phosphate or as estradiol 3-(bis(2-chloroethyl)carbamate) 17β-(dihydrogen phosphate), is a synthetic estrane steroid and a derivative of estradiol. It is an estrogen ester; specifically, EMP is a diester of estradiol with a C3 normustine (nitrogen mustard–carbamate moiety) ester and a C17β phosphate ester. EMP is provided as the sodium or meglumine salt. EMP is similar as a compound to other estradiol esters such as estradiol sulfate and estradiol valerate, but differs in the presence of its nitrogen mustard ester moiety. Antineoplastic agents related to EMP, although none of them were marketed, include alestramustine, atrimustine, cytestrol acetate, estradiol mustard, ICI-85966, and phenestrol.Due to its hydrophilic phosphate ester moiety, EMP is a readily water-soluble compound. This is in contrast to most other estradiol esters, which are fatty acid esters and lipophilic compounds that are not particularly soluble in water. Unlike EMP, estramustine is highly lipophilic, practically insoluble in water, and non-ionizable. The phosphate ester of EMP was incorporated into the molecule in order to increase its water solubility and allow for intravenous administration.The molecular weight of EMP sodium is 564.3 g/mol, of EMP meglumine is 715.6 g/mol, of EMP is 520.4 g/mol, of estramustine is 440.4 g/mol, and of estradiol is 272.4 g/mol. As a result of these differences in molecular weights, EMP contains about 52%, EMP sodium about 48%, and EMP meglumine about 38% of the amount of estradiol within their structures as does an equal-mass quantity of estradiol.

History
EMP was first synthesized in the mid-1960s and was patented in 1967. It was initially developed for the treatment of breast cancer. The idea for EMP was inspired by the uptake and accumulation of radiolabeled estrogens into breast cancer tissue </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 Trimethoprim and explain in detail? [/INST] Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers diarrhea. With sulfamethoxazole or dapsone it may be used for Pneumocystis pneumonia in people with HIV/AIDS. It is taken by mouth.Common side effects include nausea, changes in taste, and rash. Rarely it may result in blood problems such as not enough platelets or white blood cells. Trimethoprim may cause sun sensitivity. There is evidence of potential harm during pregnancy in some animals but not humans. It works by blocking folate metabolism via dihydrofolate reductase in some bacteria which results in their death.Trimethoprim was first used in 1962. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication.

Medical uses
It is primarily used in the treatment of urinary tract infections, although it may be used against any susceptible aerobic bacterial species. It may also be used to treat and prevent Pneumocystis jirovecii pneumonia. It is generally not recommended for the treatment of anaerobic infections such as Clostridium difficile colitis (the leading cause of antibiotic-induced diarrhea). Trimethoprim has been used in trials to treat retinitis.Resistance to trimethoprim is increasing, but it is still a first line antibiotic in many countries.

Spectrum of susceptibility
Cultures and susceptibility tests should be done to make sure bacteria are treated by trimethoprim.
Escherichia coli
Proteus mirabilis
Klebsiella pneumoniae
Enterobacter species
Coagulase-negative Staphylococcus species, including S. saprophyticus
Streptococcus pneumoniae
Haemophilus influenzae

Side effects
Common
Nauseas
Change in taste
Vomiting
Diarrhea
Rashes
Sun sensitivity
Itchiness

Rare
Can cause thrombocytopenia (low levels of platelets) by lowering folic acid levels; this may also cause megaloblastic anemia.
Trimethoprim antagonizes the epithelial sodium channel  in the distal tubule, thus acting like amiloride.  This can cause increased potassium levels in the body (hyperkalemia).
Can compete with creatinine for secretion into the renal tubule.  This can cause an artificial rise in the serum creatinine.
Use in EHEC infections may lead to an increase in expression of Shiga toxin.

Contraindications
Known hypersensitivity to trimethoprim
History of megaloblastic anemia due to folate deficiency

Pregnancy
Based on the studies that show that trimethoprim crosses the placenta and can affect folate metabolism, there has been growing evidence of the risk of structural birth defects associated with trimethoprim, especially during the first trimester of pregnancy. It may be involved in a reaction similar to disulfiram when alcohol is consumed after it is used, in particular when used in combination with sulfamethoxazole.
The trophoblasts in the early fetus are sensitive to changes in the folate cycle </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 Pretomanid and explain in detail? [/INST] Pretomanid is an antibiotic medication used for the treatment of multi-drug-resistant tuberculosis affecting the lungs. It is generally used together with bedaquiline and linezolid. It is taken by mouth.The most common side effects include nerve damage, acne, vomiting, headache, low blood sugar, diarrhea, and liver inflammation. It is in the nitroimidazole class of medications.Pretomanid was approved for medical use in the United States in August 2019, and in the European Union in July 2020. Pretomanid was developed by TB Alliance. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.

Medical uses
Pretomanid is indicated in combination with bedaquiline and linezolid, in adults, for the treatment of pulmonary extensively drug resistant (XDR), or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB).

History
Pretomanid is the generic, nonproprietary name for the novel anti-bacterial drug compound formerly called PA-824.  Pretomanid is referred to as "Pa" in regimen abbreviations, such as BPaL. The "preto" part of the compounds name honors Pretoria, South Africa, the home of a TB Alliance clinical development office where much of the drugs development took place, while the "-manid" stem designates compounds with similar chemical structures.  This class of drug is variously referred to as nitroimidazoles or nitroimidazooxazines.  Development of this compound was initiated because of the urgent need for new antibacterial drugs effective against resistant strains of tuberculosis. Also, current anti-TB drugs are mainly effective against replicating and metabolically active bacteria, creating a need for drugs effective against persisting or latent bacterial infections as often occur in patients with tuberculosis.

Discovery and pre-clinical development
Pretomanid was first identified in 2000, in a series of 100 nitroimidazopyran derivatives synthesized and tested for antitubercular activity, by PathoGenesis (now a subsidiary of Novartis). Importantly, pretomanid has activity against static M. tuberculosis isolates that survive under anaerobic conditions, with bactericidal activity comparable to that of the existing drug metronidazole.  Pretomanid requires metabolic activation by Mycobacterium for antibacterial activity.  Pretomanid was not the most potent compound in the series against cultures of M </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 Ethinylestradiol/desogestrel and explain in detail? [/INST]  </s>