<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Oxandrolone and can you explain it in depth? [/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 responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Oxycodone/aspirin and can you explain it in depth? [/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 responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Cholic acid and can you explain it in depth? [/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 responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Brimonidine and can you explain it in depth? [/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 responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Obeticholic acid and can you explain it in depth? [/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 responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Estramustine phosphate and can you explain it in depth? [/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 responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Trimethoprim and can you explain it in depth? [/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 responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Pretomanid and can you explain it in depth? [/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 responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ethinylestradiol/desogestrel and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ofloxacin and can you explain it in depth? [/INST] Ofloxacin is a quinolone antibiotic useful for the treatment of a number of bacterial infections. When taken by mouth or injection into a vein, these include pneumonia, cellulitis, urinary tract infections,
prostatitis, plague, and certain types of infectious diarrhea. Other uses, along with other medications, include treating multidrug resistant tuberculosis. An eye drop may be used for a superficial bacterial infection of the eye and an ear drop may be used for otitis media when a hole in the ear drum is present.When taken by mouth, common side effects include vomiting, diarrhea, headache, and rash. Other serious side effect include tendon rupture, numbness due to nerve damage, seizures, and psychosis. Use in pregnancy is typically not recommended. Ofloxacin is in the fluoroquinolone family of medications. It works by interfering with the bacteriums DNA.Ofloxacin was patented in 1980 and approved for medical use in 1985. It is on the World Health Organizations List of Essential Medicines. Ofloxacin is available as a generic medication. In 2017, it was the 278th most commonly prescribed medication in the United States, with more than one million prescriptions.

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

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

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

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

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

Chlamydia trachomatis

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

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

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

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

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

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

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

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

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

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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Sodium hyaluronate and can you explain it in depth? [/INST] Sodium hyaluronate is the sodium salt of hyaluronic acid, a glycosaminoglycan found in various connective tissue of humans.

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

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

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

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

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

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

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

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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Carglumic acid and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Leuprorelin and can you explain it in depth? [/INST] Leuprorelin, also known as leuprolide, is a manufactured version of a hormone used to treat prostate cancer, breast cancer, endometriosis, uterine fibroids, and early puberty, to perform chemical castration of violent sex offenders, or as part of transgender hormone therapy. It is given by injection into a muscle or under the skin.Leuprorelin is in the gonadotropin-releasing hormone (GnRH) analogue family of medications. It works by decreasing gonadotropin and therefore decreasing testosterone and estradiol. Common side effects include hot flashes, unstable mood, trouble sleeping, headaches, and pain at the site of injection. Other side effects may include high blood sugar, allergic reactions, and problems with the pituitary gland. Use during pregnancy may harm the baby.Leuprorelin was patented in 1973 and approved for medical use in the United States in 1985. It is on the World Health Organizations List of Essential Medicines. It is sold under the brand name Lupron among others.

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

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

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

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

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

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

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

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

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

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

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

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

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

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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Muromonab-CD3 and can you explain it in depth? [/INST] Muromonab-CD3 (trade name Orthoclone OKT3, marketed by Janssen-Cilag) is an immunosuppressant drug given to reduce acute rejection in patients with organ transplants. It is a monoclonal antibody targeted at the CD3 receptor, a membrane protein on the surface of T cells. It was the first monoclonal antibody to be approved for clinical use in humans.

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

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

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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Felbamate and can you explain it in depth? [/INST] Felbamate (marketed under the brand name Felbatol by MedPointe) is an anticonvulsant used in the treatment of epilepsy. It is used to treat partial seizures (with and without generalization) in adults and partial and generalized seizures associated with Lennox–Gastaut syndrome in children. However, an increased risk of potentially fatal aplastic anemia and/or liver failure limit the drugs usage to severe refractory epilepsy.

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

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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Metolazone and can you explain it in depth? [/INST] Metolazone is a thiazide-like diuretic marketed under the brand names Zytanix, Metoz, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure and high blood pressure. Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the kidney, so that blood volume decreases and urine volume increases. This lowers blood pressure and prevents excess fluid accumulation in heart failure. Metolazone is sometimes used together with loop diuretics such as furosemide or bumetanide, but these highly effective combinations can lead to dehydration and electrolyte abnormalities.
It was patented in 1966 and approved for medical use in 1974.

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

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

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

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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Taliglucerase alfa and can you explain it in depth? [/INST] Taliglucerase alfa, sold under the brand name Elelyso among others, is a biopharmaceutical medication developed by Protalix and Pfizer. The drug, a recombinant glucocerebrosidase used to treat Gauchers disease, is the first plant-made pharmaceutical to win approval by the U.S. Food and Drug Administration (FDA) </s>