<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 Elvitegravir and can you explain it in depth? [/INST] Elvitegravir (EVG) is an integrase inhibitor used to treat HIV infection. It was developed by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008.  The drug gained approval by the U.S. Food and Drug Administration on August 27, 2012 for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild. On September 24, 2014 the FDA approved Elvitegravir as a single pill formulation under the trade name Vitekta. On November 5, 2015 the FDA approved the drug for use in patients affected with HIV-1 as a part of a second fixed dose combination pill known as Genvoya.According to the results of the phase II clinical trial, patients taking once-daily elvitegravir boosted by ritonavir had greater reductions in viral load after 24 weeks compared to individuals randomized to receive a ritonavir-boosted protease inhibitor.

Medical uses
In the United States, elvitegravir can be obtained either as part of the combination pills Stribild or Genvoya, or as the single pill formulation Vitekta.Vitekta is FDA approved to be used for the treatment of HIV-1 infection in adults who have previous treatment experience with antiretroviral therapy. It must be used in combination with a protease inhibitor that is coadministered with ritonavir as well as additional antiretroviral drug(s).

Adverse effects
The most common side effects of taking elvitegravir are diarrhea (in 7% of patients) and nausea (4%). Other side effects that occurred in more than 1% of people are headache, tiredness, rashes, and vomiting.

Interactions and contraindications
Elvitegravir is metabolised via the liver enzyme CYP3A. Substances that induce this enzyme can reduce elvitegravir concentrations in the body, potentially triggering the development of resistant virus strains. Consequently, co-administration of strong CYP3A inducers is contraindicated; examples are rifampicin, the anticonvulsants carbamazepine, phenobarbital and phenytoin, as well as St Johns wort.Glucuronidation of elvitegravir is facilitated by the enzymes UGT1A1 and 3, resulting in increased blood plasma levels when taken together with strong UGT1A inhibitors such as ritonavir and other HIV protease inhibitors. (But ritonavir also increases elvitegravir levels by inhibiting CYP3A.)
Furthermore, elvitegravir is a weak to medium inducer of CYP1A2, CYP2C19, CYP2C9, CYP3A, and a number of UGTs; the clinical relevance of these findings is however unclear.

Pharmacology
Mechanism of action
Elvitegravir inhibits the enzyme integrase of HIV-1, and of HIV-2 to a lesser extent </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 Psyllium and can you explain it in depth? [/INST] Psyllium , or ispaghula , is the common name used for several members of the plant genus Plantago whose seeds are used commercially for the production of mucilage. Psyllium is mainly used as a dietary fiber to relieve symptoms of both constipation and mild diarrhea, and occasionally as a food thickener. Allergy to psyllium is common in workers frequently exposed to the substance.
Use of psyllium in the diet for three weeks or longer often lowers blood cholesterol levels in people with elevated cholesterol, and can lower blood glucose levels in people with type 2 diabetes. Use of psyllium for a month or longer may produce a small reduction in systolic blood pressure.The plants from which the seeds are extracted tolerate dry and cool climates and are mainly cultivated in northern India.

Uses
Dietary supplements containing psyllium are sold mainly to aid weight loss, although there is little scientific evidence for such effects.

Food
Psyllium has been used as a thickener in ice cream and other frozen desserts. A 1.5% weight/volume ratio of psyllium mucilage exhibits binding properties that are superior to a 10% weight/volume ratio of starch mucilage. The viscosity of psyllium mucilage dispersions are relatively unaffected between temperatures of 20 and 50 °C (68 and 122 °F), by pH from 2 to 10, and by salt (sodium chloride) concentrations up to 0.15 M.

Human health
Constipation
Psyllium is mainly used as a viscous, soluble dietary fiber that is not absorbed by the small intestine. The purely mechanical action of psyllium mucilage is to absorb excess water while stimulating normal bowel elimination. Although its main use has been as a laxative, it is more accurately regarded as a dietary fiber and as such can help reduce the symptoms of both constipation and mild diarrhea. The laxative properties of psyllium are attributed to the fiber: it absorbs water and subsequently softens the stool. It increases flatulence (gas) to some degree.

High blood cholesterol
In 1998, the U.S. Food and Drug Administration approved a health claim on food labels for dietary psyllium as a soluble fiber – if consumed regularly – that would reduce the risk of heart disease by lowering blood cholesterol. Clinical research demonstrated that seven grams or more per day of soluble fiber from psyllium seed husk would sufficiently lower total cholesterol and low density lipoprotein cholesterol in people with hypercholesterolemia, two accepted biomarkers for risk of coronary heart disease. The findings were later confirmed in a meta-analysis that incorporated more evidence. To be eligible for the FDA-allowed health claim, one serving of a manufactured food or dietary supplement must contain at least 1.7 g of psyllium as soluble fiber. Whole oats, barley and foods containing beta-glucan soluble fiber were included as eligible sources for the label claim.

Type 2 diabetes
In 2014, the U.S. Food and Drug Administration approved a qualified health claim for psyllium as a possible benefit for people with diabetes, requiring FDA-approved wording on a product label: "Psyllium husk may reduce the risk of type 2 diabetes, although the FDA has concluded that there is very little scientific evidence for this claim." A meta-analysis published after the FDA decision reported that psyllium provided before meals improved fasting blood glucose and glycated hemoglobin, but that the larger effect was seen in people diagnosed with and being treated for type 2 diabetes, and only a modest improvement for people classified as pre-diabetic.

Veterinary medicine
Psyllium fiber dietary supplements are used in veterinary medicine to treat sand impaction in horses to aid in elimination of sand from the horses colon.

Adverse effects
Fiber generally has few side effects.
Psyllium can cause bowel obstructions or bezoars, if taken without adequate amounts of water.
Gas or stomach bloating may also occur.
Choking is a hazard if psyllium is taken without adequate water as it thickens in the throat.

Allergy
Psyllium can cause allergic reactions, including anaphylaxis. Psyllium may act as a potent inhalant allergen capable of eliciting asthma symptoms. Health care professionals at geriatric care hospitals, who are frequently exposed to psyllium in the laxatives administered to patients, are commonly IgE sensitized to psyllium (13.8%), and 8.6% have clinical allergy to psyllium. Pharmaceutical manufacturing employees who have been exposed to psyllium during the processing have developed occupational asthma and IgE sensitization. In order to protect sensitized workers, psyllium has an extremely low occupational exposure limit of 150 ng/m3.

Mechanism of action
The soluble fiber in psyllium is the polysaccharide heteroxylan, a hemicellulose.Psyllium is produced mainly for its mucilage content. The term mucilage describes a group of clear, colorless, gelling agents derived from plants. The mucilage obtained from psyllium comes from the seed coat. Mucilage is obtained by mechanical milling (i.e. grinding) of the outer layer of the seed. Mucilage yield amounts to about 25% (by weight) of the total seed yield. Plantago-seed mucilage is often referred to as husk, or psyllium husk. The milled seed mucilage is a white fibrous material that is hydrophilic, meaning that its molecular structure causes it to attract and bind to water. Upon absorbing water, the clear, colorless, mucilaginous gel that forms increases in volume by tenfold or more.

Cultivation
The genus Plantago contains over 200 species. P. ovata and P. psyllium are produced commercially in several European countries, Russia and surrounding countries, and India. Plantago seed, known commercially as black, French, or Spanish psyllium, is obtained from P. psyllium, also known as P. arenaria. Seed produced from P. ovata is known in trading circles as white or blonde psyllium, Indian plantago, or isabgol. Isabgol is the common name in India for P. ovata. it is known as Aspaghol in Pakistan, coming from the Persian asp and gul, meaning "horse flower", which is descriptive of the shape of the seed. India dominates the world market in the production and export of psyllium.
Plantago ovata is an annual herb that grows to a height of 30–46 cm (12–18 in). Leaves are opposite, linear or linear lanceolate 1 cm × 19 cm (0.39 in × 7.48 in). The root system has a well-developed tap root with few fibrous secondary roots. A large number of flowering shoots arise from the base of the plant. Flowers are numerous, small, and white. Plants flower about 60 days after planting. The seeds are enclosed in capsules that open at maturity.
The fields are generally irrigated prior to seeding to achieve ideal soil moisture, to enhance seed soil contact, and to avoid burying the seed too deeply as a result of later irrigations or rainfall. Maximum germination occurs at a seeding depth of 6 mm (1/4 in). Emerging seedlings are frost sensitive; therefore, planting should be delayed until conditions are expected to remain frost free. Seed is broadcast at 5.5 to 8.25 kg/hectare (5 to 7.5 lb/acre) in India. In Arizonan trials, seeding rates of 22 to 27.5 kg/ha (20 to 25 lb/acre) resulted in stands of 1 plant/25mm (1 inch) in 15 cm (6 inch) rows produced excellent yields. Weed control is normally achieved by one or two hand weedings early in the growing season. Control of weeds by pre-plant irrigation that germinates weed seeds followed by shallow tillage may be effective on fields with minimal weed pressure. Psyllium is a poor competitor with most weed species.
Plantago wilt (Fusarium oxysporum) and downy mildew (Peronospora alta) are the major diseases of Isabgol. White grubs and aphids are the major insect pests.
The flower spikes turn reddish brown at ripening, the lower leaves dry and the upper leaves yellow. The crop is harvested in the morning after the dew is gone to minimize shattering and field losses. In India, mature plants are cut 15 cm above the ground and then bound, left for a few days to dry, thrashed, and winnowed.
Harvested seed must be dried to below 12% moisture to allow for cleaning, milling, and storage. Seed stored for future crops has shown a significant loss in viability after 2 years in storage.

Commercial history
Metamucil
Introduced in 1934 by G. D. Searle & Company, Metamucil was acquired by Procter & Gamble in 1985 </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 Chlorpropamide and can you explain it in depth? [/INST] Chlorpropamide is a drug in the sulfonylurea class used to treat diabetes mellitus type 2. It is a long-acting first-generation sulfonylurea.

Mechanism of action
Like other sulfonylureas, chlorpropamide acts to increase the secretion of insulin, so it is only effective in patients who have some pancreatic beta cell function. It can cause relatively long episodes of hypoglycemia; this is one reason why shorter-acting sulfonylureas such as gliclazide or tolbutamide are used instead. The risk of hypoglycemia makes this drug a poor choice for the elderly and patients with mild to moderate hepatic and renal impairment. Chlorpropamide is also used in partial central diabetes insipidus.

Pharmacokinetics
Maximal plasma concentrations are reached 3 to 5 hours after quick and nearly complete (>90%) resorption from the gut. Plasma half life is 36 hours; the drug is effective for about 24 hours, longer than other sulfonylureas. A stable plasma level is only reached after three days of continuous application. 90% of the drug are bound to plasma proteins; at least two albumin binding sites exist. More than 99% of chlorpropamide are excreted unchanged via the kidneys </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 Megestrol acetate and can you explain it in depth? [/INST] Megestrol acetate (MGA), sold under the brand name Megace among others, is a progestin medication which is used mainly as an appetite stimulant to treat wasting syndromes such as cachexia. It is also used to treat breast cancer and endometrial cancer, and has been used in birth control. MGA is generally formulated alone, although it has been combined with estrogens in birth control formulations. It is usually taken by mouth.Side effects of MGA include increased appetite, weight gain, vaginal bleeding, nausea, edema, low sex hormone levels, sexual dysfunction, osteoporosis, cardiovascular complications, glucocorticoid effects, and others. MGA is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has weak partial androgenic activity, weak glucocorticoid activity, and no other important hormonal activity. Due to its progestogenic activity, MGA has antigonadotropic effects. The mechanism of action of the appetite stimulant effects of MGA is unknown.MGA was discovered in 1959 and was introduced for medical use, specifically in birth control pills, in 1963. It may be considered a "first-generation" progestin. The medication was withdrawn in some countries in 1970 due to concerns about mammary toxicity observed in dogs, but this turned out not to apply to humans. MGA was approved for the treatment of endometrial cancer in 1971 and wasting syndromes in 1993. It is marketed widely throughout the world. It is available as a generic medication.In Bangladesh and India, megestrol is marketed under the trade name Megestol by Ziska Pharmaceuticals, Mezest by Beacon Pharmaceuticals, and under the trade name Varigestrol by Laboratorio Varifarma, Argentina.

Medical uses
MGA is used mainly as an appetite stimulant to promote weight gain in a variety of situations. When given at very high dosages, it can substantially increase appetite in most individuals, even those with advanced cancer, and is often used to boost appetite and induce weight gain in patients with cancer or HIV/AIDS-associated cachexia. In addition to its effects on appetite, MGA appears to have antiemetic effects. MGA is also used as an antineoplastic agent in the treatment of breast cancer and endometrial cancer. It is significantly inferior to aromatase inhibitors in both clinical effectiveness and tolerability as a second-line therapy for breast cancer after tamoxifen failure. MGA was formerly used in combined oral contraceptives in combination with ethinylestradiol or mestranol, and has been used in a combined injectable contraceptive in combination with estradiol as well.Although it has not been approved for these uses, MGA has been studied and/or used off-label for a variety of indications including menopausal hormone therapy and the treatment of hot flashes, gynecological/menstrual disorders, endometriosis, endometrial hyperplasia, ovarian cancer, prostate cancer, benign prostatic hyperplasia, male breast cancer, and precocious puberty. MGA can also be used to treat pattern hair loss in men, but its side effects generally make it unacceptable for this purpose.Appetite stimulation is achieved with MGA with oral dosages of 400 to 800 mg/day. The optimal dosage with maximum effect for appetite stimulation has been determined to be 800 mg/day. The recommended oral dosage of MGA for breast cancer is 40 mg four times per day (160 mg/day total), while the medication is used at an oral dosage of 40 to 320 mg/day in divided doses for endometrial cancer. It has been used at far lower dosages (e.g., 1–5 mg/day oral, 25 mg/month i.m.) in combination with an estrogen for contraceptive purposes.

Available forms
MGA is available as 5 mg, 20 mg, and 40 mg oral tablets and in oral suspensions of 40 mg/mL, 125 mg/mL, 625 mg/5 mL, and 820 mg/20 mL. It was used at doses of 1 mg, 2 mg, 4 mg, and 5 mg in combined oral contraceptives. MGA is formulated at a dose of 25 mg in combination with a dose of 3.75 mg estradiol in a microcrystalline aqueous suspension for use as a once-monthly combined injectable contraceptive in women.

Contraindications
Contraindications of MGA include hypersensitivity to MGA or any component of its formulation, known or suspected pregnancy, and breastfeeding. MGA is a teratogen in animals and may have the potential to cause fetal harm, such as decreased fetal weight and feminization of male fetuses.

Side effects
The most common side effect of MGA is weight gain, with an incidence of 15 to 70% at the high dosages used to treat breast cancer. Other side effects include vaginal bleeding (7–8%), nausea (7%), and edema (5%), as well as others such as dizziness and shortness of breath. MGA can cause hypogonadism and associated symptoms like diminished secondary sexual characteristics, sexual dysfunction, osteoporosis, and reversible infertility in men and premenopausal women. Combining MGA with an androgen/anabolic steroid like oxandrolone, nandrolone decanoate, or testosterone in men can alleviate MGA-associated symptoms of hypoandrogenism as well as further increase appetite and weight gain. Less common but more serious side effects of MGA include cardiovascular/thromboembolic complications such as thrombophlebitis. It may also cause glucocorticoid side effects such as Cushing syndrome-like symptoms, steroid diabetes, and adrenal insufficiency at high dosages. Case reports of deep vein thrombosis, pulmonary embolism, jaundice, intrahepatic cholestasis, and meningiomas in association with high-dosage MGA have been published. In older patients who take MGA, one in 23 will have an adverse event leading to death.

Overdose
MGA has been studied at very high dosages of as much as 1,600 mg/day with no serious adverse effects observed. No clear increase in rate or severity of side effects have been observed up to 1,600 mg/day MGA except for weight gain, mild increases in blood pressure, and some fluid retention. In post-marketing experience, limited reports of overdose have been received. Signs and symptoms described in these reports have included diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain. There is no specific antidote for overdose of MGA. Treatment should be supportive and based on symptoms. MGA has not been assessed for dialyzability. However, due to its low solubility, it is thought that dialysis would not be useful for treating MGA overdose.

Interactions
Interactions of MGA include significantly decreased exposure to indinavir, which may necessitate an increased dosage of the medication. When MGA is co-administered with zidovudine and rifabutin, there is no significant change in exposure to these medications and no dosage adjustment is necessary.

Pharmacology
Pharmacodynamics
MGA has progestogenic activity, antigonadotropic effects, weak partial androgenic activity, and weak glucocorticoid activity.

Progestogenic activity
MGA is a progestogen, or an agonist of the progesterone receptor (PR). It has about 65% of the affinity of promegestone and 130% of the affinity of progesterone for the PR. Like other progestogens, MGA has functional antiestrogenic effects in certain tissues such as the endometrium and has antigonadotropic effects. The total endometrial transformation dose of MGA is 50 mg per cycle.

Antigonadotropic and anticorticotropic effects
MGA has antigonadotropic effects in humans at sufficient doses, capable of profoundly suppressing circulating androgen and estrogen concentrations. The antigonadotropic effects of MGA are the result of activation of the PR, which suppresses the secretion of the gonadotropins—peptide hormones responsible for signaling the body to produce not only progesterone but also the androgens and the estrogens—from the pituitary gland as a form of negative feedback inhibition, and hence downregulates the hypothalamic–pituitary–gonadal axis (HPG axis), resulting in decreased levels of the sex hormones and interference with fertility. As such, MGA has functional antiandrogenic and antiestrogenic effects as well as contraceptive effects via its antigonadotropic effects.The precise ovulation-inhibiting dosage of MGA is unknown. However, doses of 1 to 5 mg MGA were previously used in combined birth control pills in combination with the estrogen ethinylestradiol or mestranol. MGA is an effective contraceptive by itself at dosages of 0.35 to 0.5 mg/day, but is not effective at a dosage of 0.25 mg/day. MGA alone does not inhibit ovulation at a dosage of 0.5 mg/day, nor does it fully inhibit ovulation at a dosage of 0.7 mg/day or even at a dosage of 5 mg/day. The combination of 2 to 5 mg/day MGA and 100 μg/day mestranol has been found to consistently inhibit ovulation, whereas either medication alone did not completely inhibit ovulation in all women.Suppression of testosterone levels by MGA is responsible for its effectiveness in the treatment of conditions like prostate cancer and benign prostatic hyperplasia. In one study, 120 to 160 mg/day MGA suppressed testosterone levels in men by 72%. However, a recovery or "escape" of testosterone levels, gradually returning to near-normal values, has been observed in most men after 2 to 6 months of MGA therapy, and this has limited the usefulness of the medication. The combination of a lower dosage of MGA (40–80 mg/day) and a low oral dosage of an estrogen such as estradiol (0.5–1.5 mg/day), diethylstilbestrol (0.1–0.2 mg/day) or ethinylestradiol (50 µg/day) is able to suppress testosterone levels into the castrate range in men, maintain this suppression long-term, and achieve equivalent effectiveness to high-dosage estrogen monotherapy in the treatment of prostate cancer with comparatively greatly reduced toxicity and side effects. In spite of these results, however, this combination has been very rarely used to treat prostate cancer in the United States.The antigonadotropic as well as anticorticotropic effects of MGA may be involved in its effectiveness in the treatment of postmenopausal breast cancer via substantially decreasing gonadal and adrenal production of sex steroids and by extension circulating levels of estrogens, by about 80%.

Androgenic and antiandrogenic activity
MGA is a weak partial agonist of the androgen receptor (AR). It has been reported to bind to this receptor with 5% of the affinity of the anabolic steroid metribolone. Despite its weak intrinsic activity at the AR, at clinical doses in humans, MGA appears to behave, for all intents and purposes, purely as an antiandrogen. This is based on the fact that no virilizing side effects have been observed with the use of MGA in patients of either sex at dosages up to as high as 1,600 mg per day, the highest that has been assessed. Furthermore, MGA produces detectable androgenic effects in animals only at a dose that is the equivalent of approximately 200 times that typically used for the treatment of prostate cancer in men. However, the medication does have moderate androgenic effects on serum lipids in humans, causing a significant reduction of HDL and LDL cholesterol levels and no change in triglyceride levels at a dosage of only 5 mg/day. Conversely, MGA does not decrease SHBG levels. The weak but significant androgenic activity of MGA may serve to limit its clinical effectiveness in the treatment of prostate cancer.

Glucocorticoid activity
MGA is an agonist of the glucocorticoid receptor (GR), the biological target of glucocorticoids like cortisol. It has been found to possess 30% of the affinity of the corticosteroid dexamethasone for this receptor. MGA shows the lowest ratio of PR affinity to GR affinity of a broad selection of marketed progestins, suggesting that it may have among the highest relative glucocorticoid effect of the progestins used in medicine. MGA produces observable glucocorticoid effects, with one study finding that, in the dose range tested, it possessed about 50% of the eosinopenic and hyperglycemic activity (markers of glucocorticoid activity) of an equal amount of medroxyprogesterone acetate and about 25% that of hydrocortisone. Accordingly, manifestations of its glucocorticoid activity, including symptoms of Cushings syndrome, steroid diabetes, and adrenal insufficiency, have been reported with the use of MGA in the literature, albeit sporadically.

Appetite stimulation
MGA is frequently used as an appetite stimulant to promote weight gain. The direct mechanism of appetite enhancement is unclear, but it is known that MGA induces a variety of downstream changes to cause the effect, including stimulation of the release of neuropeptide Y in the hypothalamus, neurosteroid-like modulation of calcium channels in the ventromedial hypothalamus, and inhibition of the secretion of proinflammatory cytokines including interleukin 1α, interleukin 1β, interleukin 6, and tumor necrosis factor α, all of which have been implicated in facilitation of appetite. Increased levels of insulin-like growth factor 1 (IGF-1) may also be involved, specifically in its anabolic effects. Studies of MGA in elderly patients who experience weight loss are limited and of poor quality with most showing minimal or no weight gain, with no nutritional or clinically significant beneficial outcomes observed. In patients who take MGA, one in 12 will have an increase in weight.

Miscellaneous
Unlike the case of the AR, MGA has no significant affinity for the ER. As such, it does not possess the capacity to directly activate the ER. Furthermore, unlike antiandrogens such as spironolactone and bicalutamide but similarly to cyproterone acetate, there is relatively little risk of indirectly mediated estrogenic side effects (e.g., gynecomastia) with MGA. This is because MGA strongly suppresses both androgen and estrogen levels at the same time. Similarly to the case of the ER, MGA has negligible affinity for the mineralocorticoid receptor (MR), and hence does not possess mineralocorticoid or antimineralocorticoid activity.MGA has been found to dose-dependently increase total and free IGF-1 levels up to a dosage of 120 mg/day. Total IGF-1 levels were described as "profoundly" increased, gradually increasing, significantly by 3 days of treatment, up to a maximum of 2.66-fold by 5 to 6 months of treatment. Free (readily dissociable) concentrations of IGF-1 were increased to a smaller extent, by 1.23–2.15-fold, and were described as increasing "moderately". It was suggested that the increase in IGF-1 levels with high-dosage MGA therapy may explain the anabolic effects of MGA in patients with cachexia.

Pharmacokinetics
The oral bioavailability of MGA is approximately 100%. After a single low oral dose of 4 mg MGA, peak serum concentrations of MGA were about 7 ng/dL (18 nmol/L) and occurred after 3 hours. Following a single high oral dose of 160 mg micronized MGA in men, peak circulating levels of MGA were 125 ng/mL (325 nmol/L) and occurred after 6.3 hours. This study found that micronized MGA at this dose showed considerably improved absorption relative to its conventional tablet form. In terms of plasma protein binding, MGA is bound mostly to albumin (82.4%) and is not bound to sex hormone-binding globulin or to corticosteroid-binding globulin. MGA metabolized in the liver mainly by hydroxylation of the C21, C2α, and C6 positions, as well as by reduction and conjugation. Its elimination half-life is 34 hours on average, with a range of 13 to 105 hours. MGA is excreted 57 to 78% in urine and 8 to 30% in feces.At high doses, MGA appears to have far greater bioavailability and potency than medroxyprogesterone acetate, regardless of whether the route of administration of the latter is oral or parenteral. Following oral administration of 80 to 160 mg MGA or 500 to 1,000 mg medroxyprogesterone acetate, circulating levels of MGA were 2- to 10-fold higher than those of medroxyprogesterone acetate. Similar findings have been found for oral MGA relative to medroxyprogesterone acetate administered via intramuscular injection. MGA also reaches steady-state levels more quickly than medroxyprogesterone acetate. The improved potency of MGA compared to medroxyprogesterone acetate may be due to increased resistance to metabolism of MGA afforded by its C6(7) double bond (medroxyprogesterone acetate being identical to MGA in structure except lacking this feature).The pharmacokinetics of MGA have been reviewed.

Chemistry
MGA, also known as 17α-acetoxy-6-dehydro-6-methylprogesterone or as 17α-acetoxy-6-methylpregna-4,6-diene-3,20-dione, is a synthetic pregnane steroid and a derivative of progesterone. It is specifically a derivative of 17α-hydroxyprogesterone with a methyl group at the C6 position, a double bond between the C6 and C7 positions, and an acetate ester at the C17α position. MGA is the C17α acetate ester of megestrol, which, in contrast to MGA, was never marketed. Analogues of MGA include other 17α-hydroxyprogesterone derivatives such as acetomepregenol, anagestone acetate, chlormadinone acetate, cyproterone acetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, and nomegestrol acetate. MGA differs from medroxyprogesterone acetate only by its C6(7) double bond. Close analogues of MGA that were never marketed include cymegesolate (megestrol acetate 3β-cypionate) and megestrol caproate.

Synthesis
Chemical syntheses of MGA have been published.

History
MGA was synthesized at Syntex in 1959. It was derived from medroxyprogesterone acetate, which had been synthesized at Syntex in 1957. MGA was the third synthetic derivative of progesterone to be developed for use as a medication, following hydroxyprogesterone caproate in 1954 and medroxyprogesterone acetate in 1957. The medication was introduced for medical use in combination with ethinylestradiol (EE) as an oral contraceptive in 1963 by British Drug Houses in the United Kingdom under the brand name Volidan (4 mg MGA and 50 μg EE tablets), and this was followed by Serial 28 (1 mg MGA and 100 μg EE tablets) and Volidan 21 (4 mg MGA and 50 μg EE tablets) in 1964 and Nuvacon (2 mg MGA and 100 μg EE tablets) in 1967, all by British Drug Houses also in the United Kingdom. It was also marketed under the brand name Delpregnin (5 mg MGA and 100 μg mestranol tablets) by 1965, among others. MGA-containing birth control pills were withdrawn after reports in the early 1970s of a high incidence of venous thromboembolism with the preparations.In the early 1970s, MGA was found to be associated with mammary tumors in beagle dogs, and along with several other progestogens, was withdrawn as an oral contraceptive from several markets including the United Kingdom, Canada, and Germany. It was also under investigation for use as a contraceptive in the United States, but development was discontinued in 1972 following the mammary toxicity findings in dogs, and MGA was never marketed as an oral contraceptive in the United States. Subsequent research, such as monkey studies, revealed that there is no similar risk in humans. Following its withdrawal from the market, MGA was eventually reintroduced for the treatment of hormone-sensitive cancers. In addition, MGA was marketed for veterinary use in dogs in 1969 in the United Kingdom and in 1974 in the United States.Progesterone was first found to be effective in the treatment of endometrial hyperplasia in 1951, and progestins were first found to be effective in the treatment of endometrial cancer in 1959. MGA was reported to be effective in the treatment of endometrial hyperplasia in the mid-1960s. It first started to be studied as a treatment for endometrial cancer in 1967, with findings published in 1973. MGA was reportedly introduced for the treatment of endometrial cancer in the United States in 1971. Progesterone was studied in the treatment of breast cancer in 1951 and 1952, but with relatively modest results. MGA was first studied in the treatment of breast cancer in 1967, and was one of the first progestins to be evaluated for the treatment of this disease. A second study was conducted in 1974. A "breakthrough" and surge of interest in progestins for breast cancer occurred in 1978 when a study using a massive dosage of medroxyprogesterone acetate to treat breast cancer was published. A third study of MGA for breast cancer was published in 1980, and this was followed by additional studies in the 1980s and beyond. MGA was approved for the treatment of breast cancer in the United States by at least 1983.Progestogens, including progesterone and ethisterone, were studied in the treatment prostate cancer in 1949. MGA was first studied in the treatment of prostate cancer in 1970. Additional studies were conducted in 1975 and 1978, followed by others thereafter. However, results of MGA therapy for prostate cancer have been "disappointing", and the medication has not been approved for the treatment of prostate cancer in the United States or elsewhere.Clinical studies of very high dosages of MGA for breast cancer conducted in the 1980s observed markedly increased appetite and weight gain in treated patients despite them having advanced cancer. This led to potential interest in MGA as an appetite stimulant, and in 1986, a paper was published proposing the study and potential use of MGA in cachexia. MGA was subsequently studied for this indication and, following completion of phase III clinical trials, was approved as an oral suspension for the treatment of anorexia–cachexia syndrome due to cancer and other chronic conditions such as HIV/AIDS in the United States in 1993. Thereafter, the branded product, Megace ES, has been heavily promoted by its maker, Par Pharmaceutical, for treatment of unintentional weight loss in elderly patients, especially those living in long-term care facilities. In March 2013, Par settled a $45 million federal and multi-state criminal and civil lawsuit in which the company was accused of promoting the branded version of MGA, over the generic version, for use in treating non-AIDS-related geriatric wasting </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 Hydrocodone and can you explain it in depth? [/INST] Hydrocodone (dihydrocodeinone) is an opioid used to treat pain and as a cough suppressant. It is taken by mouth. Typically it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone for pain severe enough to require an opioid and in combination with homatropine methylbromide to relieve cough. It is also available by itself in a long-acting form under the brand name Zohydro ER, among others, to treat severe pain of a prolonged duration. Hydrocodone is a controlled drug, in the United States a Schedule II Controlled Substance.
Common side effects include dizziness, sleepiness, nausea, and constipation. Serious side effects may include low blood pressure, seizures, QT prolongation, respiratory depression, and serotonin syndrome. Rapidly decreasing the dose may result in opioid withdrawal. Use during pregnancy or breastfeeding is generally not recommended. Hydrocodone is believed to work by activating opioid receptors, mainly in the brain and spinal cord. Hydrocodone 10 mg is equivalent to about 10 mg of morphine by mouth.Hydrocodone was patented in 1923, while the long-acting formulation was approved for medical use in the United States in 2013.  It is most commonly prescribed in the United States, which consumed 99% of the worldwide supply as of 2010. In 2017, it was the 118th most commonly prescribed medication in the United States, with more than six million prescriptions. Hydrocodone is a semisynthetic opioid, converted from codeine or less often from thebaine. Production using genetically engineered yeasts have been developed but are not used commercially.

Medical uses
Hydrocodone is used to treat moderate to severe pain. In liquid formulations, it is used to treat cough. In one study comparing the potency of hydrocodone to that of oxycodone, it was found that it took 50% more hydrocodone to achieve the same degree of miosis (pupillary contraction). The investigators interpreted this to mean that oxycodone is about 50% more potent than hydrocodone.
However, in a study of emergency department patients with fractures, it was found that an equal amount of either drug provided about the same degree of pain relief, indicating that there is little practical difference between them when used for that purpose. Some references state that the analgesic action of hydrocodone begins in 20–30 minutes and lasts about 4–8 hours. The manufacturers information says onset of action is about 10–30 minutes and duration is about 4–6 hours. Recommended dosing interval is 4–6 hours.

Available forms
Hydrocodone is available in a variety of formulations for oral administration:
The original oral form of hydrocodone alone, Dicodid, as immediate-release 5- and 10-mg tablets is available for prescription in Continental Europe per national drug control and prescription laws and Title 76 of the Schengen Treaty, but dihydrocodeine has been more widely used for the same indications since the beginning in the early 1920s, with hydrocodone being regulated the same way as morphine in the German Betäubungsmittelgesetz, the similarly named law in Switzerland and the Austrian Suchtmittelgesetz, whereas dihydrocodeine is regulated like codeine. For a number of decades, the liquid hydrocodone products available have been cough medicines.
Hydrocodone plus homatropine (Hycodan) in the form of small tablets for coughing and especially neuropathic moderate pain (the homatropine, an anticholinergic, is useful in both of those cases and is a deterrent to intentional overdose) was more widely used than Dicodid and was labelled as a cough medicine in the United States whilst Vicodin and similar drugs were the choices for analgesia.
Extended-release hydrocodone in a time-release syrup also containing chlorphenamine/chlorpheniramine is a cough medicine called Tussionex in North America. In Europe, similar time-release syrups containing codeine (numerous), dihydrocodeine (Paracodin Retard Hustensaft), nicocodeine (Tusscodin), thebacon, acetyldihydrocodeine, dionine, and nicodicodeine are used instead.
Immediate-release hydrocodone with paracetamol (acetaminophen) (Vicodin, Lortab, Lorcet, Maxidone, Norco, Zydone)
Immediate-release hydrocodone with ibuprofen (Vicoprofen, Ibudone, Reprexain)
Immediate-release hydrocodone with aspirin (Alor 5/500, Azdone, Damason-P, Lortab ASA, Panasal 5/500)
Controlled-release hydrocodone (Hysingla ER by Purdue Pharma, Zohydro ER)Hydrocodone is not available in parenteral or any other non-oral forms.

Side effects
Common side effects of hydrocodone are nausea, vomiting, constipation, drowsiness, dizziness, lightheadedness, anxiety, abnormally happy or sad mood, dry throat, difficulty urinating, rash, itching, and contraction of the pupils. Serious side effects include slowed or irregular breathing and chest tightness.Several cases of progressive bilateral hearing loss unresponsive to steroid therapy have been described as an infrequent adverse reaction to hydrocodone/paracetamol misuse. This adverse effect has been considered by some to be due to the ototoxicity of hydrocodone. Other researchers have suggested that paracetamol is the primary agent responsible for the ototoxicity.Hydrocodone is in U.S. Food and Drug Administration (FDA) pregnancy category C. No adequate and well-controlled studies in humans have been conducted. A newborn of a mother taking opioid medications regularly prior to the birth will be physically dependent. The baby may also exhibit respiratory depression if the opioid dose was high. An epidemiological study indicated that opioid treatment during early pregnancy results in increased risk of various birth defects.Symptoms of hydrocodone overdose include narrowed or widened pupils; slow, shallow, or stopped breathing; slowed or stopped heartbeat; cold, clammy, or blue skin; excessive sleepiness; loss of consciousness; seizures; or death.Hydrocodone can be habit forming, causing physical and psychological dependence. Its abuse liability is similar to morphine and less than oxycodone.

Interactions
Patients consuming alcohol, other opioids, anticholinergic antihistamines, anti-psychotics, anti-anxiety agents, or other central nervous system (CNS) depressants together with hydrocodone may exhibit an additive CNS depression. Hydrocodone may interact with serotonergic medications.

Pharmacology
Pharmacodynamics
Hydrocodone is a highly selective full agonist of the μ-opioid receptor (MOR). This is the main biological target of the endogenous opioid neuropeptide β-endorphin. Hydrocodone has low affinity for the δ-opioid receptor (DOR) and the κ-opioid receptor (KOR), where it is an agonist similarly.Studies have shown hydrocodone is stronger than codeine but only one-tenth as potent as morphine at binding to receptors and reported to be only 59% as potent as morphine in analgesic properties. However, in tests conducted on rhesus monkeys, the analgesic potency of hydrocodone was actually higher than morphine. Oral hydrocodone has a mean equivalent daily dosage (MEDD) factor of 0.4, meaning that 1 mg of hydrocodone is equivalent to 0.4 mg of intravenous morphine. However, because of morphines low oral bioavailability, there is a 1:1 correspondence between orally administered morphine and orally administered hydrocodone.

Pharmacokinetics
Absorption
Hydrocodone is only pharmaceutically available as an oral medication. It is well-absorbed, but the oral bioavailability of hydrocodone is only approximately 25%. The onset of action of hydrocodone via this route is 10 to 20 minutes, with a peak effect (Tmax) occurring at 30 to 60 minutes, and it has a duration of 4 to 8 hours.

Distribution
The volume of distribution of hydrocodone is 3.3 to 4.7 L/kg. The plasma protein binding of hydrocodone is 20 to 50%.

Metabolism
In the liver, hydrocodone is transformed into several metabolites, including norhydrocodone, hydromorphone, 6α-hydrocodol (dihydrocodeine), and 6β-hydrocodol. 6α- and 6β-hydromorphol are also formed, and the metabolites of hydrocodone are conjugated (via glucuronidation). Hydrocodone has a terminal half-life that averages 3.8 hours (range 3.3–4.4 hours). The hepatic cytochrome P450 enzyme CYP2D6 converts hydrocodone into hydromorphone, a more potent opioid (5-fold higher binding affinity to the MOR). However, extensive and poor cytochrome 450 CYP2D6 metabolizers had similar physiological and subjective responses to hydrocodone, and CYP2D6 inhibitor quinidine did not change the responses of extensive metabolizers, suggesting that inhibition of CYP2D6 metabolism of hydrocodone has no practical importance. Ultra-rapid CYP2D6 metabolizers (1–2% of the population) may have an increased response to hydrocodone; however, hydrocodone metabolism in this population has not been studied.Norhydrocodone, the major metabolite of hydrocodone, is predominantly formed by CYP3A4-catalyzed oxidation. In contrast to hydromorphone, it is described as inactive. However, norhydrocodone is actually a MOR agonist with similar potency to hydrocodone, but has been found to produce only minimal analgesia when administered peripherally to animals (likely due to poor blood–brain barrier and thus central nervous system penetration). Inhibition of CYP3A4 in a child who was, in addition, a poor CYP2D6 metabolizer, resulted in a fatal overdose of hydrocodone. Approximately 40% of hydrocodone metabolism is attributed to non-cytochrome P450-catalyzed reactions.

Elimination
Hydrocodone is excreted in urine, mainly in the form of conjugates.

Chemistry
Detection in body fluids
Hydrocodone concentrations are measured in blood, plasma, and urine to seek evidence of misuse, to confirm diagnoses of poisoning, and to assist in investigations into deaths. Many commercial opiate screening tests react indiscriminately with hydrocodone, other opiates, and their metabolites, but chromatographic techniques can easily distinguish hydrocodone uniquely. Blood and plasma hydrocodone concentrations typically fall into the 5–30 µg/L range among people taking the drug therapeutically, 100–200 µg/L among recreational users, and 100–1,600 µg/L in cases of acute, fatal overdosage. Co-administration of the drug with food or alcohol can very significantly increase the resulting plasma hydrocodone concentrations that are subsequently achieved.

Synthesis
Hydrocodone is most commonly synthesized from Thebaine, a constituent of opium latex from the dried poppy plant. Once Thebaine is obtained, the reaction undergoes hydrogenation using a palladium catalyst.

Structure
There are three important structures in hydrocodone: the amine group, which binds to the tertiary nitrogen binding site in the central nervous systems opioid receptor, the hydroxy group that binds to the anionic binding side, and the phenyl group which binds to the phenolic binding site. This triggers a G protein activation and subsequent release of dopamine.

History
Hydrocodone was first synthesized in Germany in 1920 by Carl Mannich and Helene Löwenheim. It was approved by the Food and Drug Administration on 23 March 1943 for sale in the United States and approved by Health Canada for sale in Canada under the brand name Hycodan.Hydrocodone was first marketed by Knoll as Dicodid, starting in February 1924 in Germany. This name is analogous to other products the company introduced or otherwise marketed: Dilaudid (hydromorphone, 1926), Dinarkon (oxycodone, 1917), Dihydrin (dihydrocodeine, 1911), and Dimorphan (dihydromorphine). Paramorfan is the trade name of dihydromorphine from another manufacturer, as is Paracodin, for dihydrocodeine.The name Dicodid was registered in the United States and appears without a monograph as late as 1978 in the Physicians Desk Reference; Dicodid may have been marketed to one extent or another in North America in the 1920s and early 1930s. The drug was pure hydrocodone in small 5 and 10 mg tablets, physically similar to the Dilaudid tablets. It is no longer manufactured by Knoll in Germany, nor is a generic available. Hydrocodone was never as common in Europe as it is in North America—dihydrocodeine is used for its spectrum of indications. Germany was the number two consumer of hydrocodone until the manufacture of the drug was discontinued there </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 Remimazolam and can you explain it in depth? [/INST] Remimazolam, sold under the brand name Byfavo, is a medication for the induction and maintenance of procedural sedation in adults for invasive diagnostic or surgical procedures lasting 30 minutes or less. is a benzodiazepine drug, developed by PAION AG in collaboration with several regional licensees as an alternative to the short-acting imidazobenzodiazepine midazolam, for use in the induction of anesthesia and conscious sedation for minor invasive procedures. Remimazolam was found to have both a more rapid onset and a shorter duration than midazolam, and human clinical trials showed a faster recovery time and predictable, consistent pharmacokinetics, suggesting some advantages over existing drugs for these applications.The most common side effects for procedural sedation include low blood pressure, high blood pressure, diastolic hypertension, systolic hypertension, low blood oxygen level, and diastolic hypotension.Remimazolam was approved for medical use in the United States in July 2020, and in the European Union in March 2021.

Medical uses
Remimazolam is indicated for the induction and maintenance of procedural sedation in adults lasting 30 minutes or less.

History
Remimazolam was approved for medical use in the United States in July 2020.The U.S. Food and Drug Administration (FDA) approved remimazolam based on evidence from three clinical trials (Trial 1/NCT02290873, Trial 2/NCT02296892 and Trial 3/NCT02532647) in adults undergoing short procedures </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 Cambia 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 Sitagliptin/simvastatin and can you explain it in depth? [/INST] Sitagliptin/simvastatin, sold under the brand name Juvisync, is a fixed-dose combination anti-diabetic medication used to treat type 2 diabetes and hypercholesterolemia. It contains sitagliptin and simvastatin. Sitagliptin is a dipeptidyl peptidase-4 inhibitor  and simvastatin is an HMG-CoA reductase inhibitor.  These two disorders commonly occur in people at the same time, and have been typically treated with administration of these medications separately. The combination was approved in 2011, and sold under the brand name Juvisync by Merck. Juvisync was later removed from the market in 2013, due to business reasons.

History
In 1991, Merck & Cos simvastatin was approved as an HMG-COA inhibitor to lower the levels of LDL cholesterol. In 2006, Merck & Cos sitagliptin was approved by the FDA for treatment of diabetes mellitus type 2.

Regulation
Juvisync was the first product to combine a cholesterol lowering drug with a type 2 diabetes drug in the same tablet.

Nonclinical toxicology
Sitagliptin: Using male and female rats, a two-year carcinogenicity study was carried out with doses of 50, 150, and 500 mg/kg/day. The 500 mg/kg dose has exposure limits of 60 times what would be seen in the highest dose in humans. At this dose, liver adenoma/carcinoma was seen </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 Plasminogen (medication) and can you explain it in depth? [/INST] Plasminogen, sold under the brand name Ryplazim, is a biologic medication for the treatment of hypoplasminogenemia (plasminogen deficiency type 1). It is purified from human plasma and is administered intravenously.The most common side effects include abdominal pain, bloating, nausea, bleeding, limb pain, fatigue, constipation, dry mouth, headache, dizziness, joint pain, and back pain.Individuals with hypoplasminogenemia lack a protein called plasminogen, which is responsible for the ability of the body to break down fibrin clots </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 Butorphanol and can you explain it in depth? [/INST] Butorphanol is a morphinan-type synthetic agonist–antagonist opioid analgesic developed by Bristol-Myers. Butorphanol is most closely structurally related to levorphanol. Butorphanol is available as the tartrate salt in injectable, tablet, and intranasal spray formulations. The tablet form is only used in dogs, cats and horses due to low bioavailability in humans.
It was patented in 1971 and approved for medical use in 1979.

Medical uses
The most common indication for butorphanol is management of migraine using the intranasal spray formulation. It may also be used parenterally for management of moderate-to-severe pain, as a supplement for balanced general anesthesia, and management of pain during labor.  Butorphanol is also quite effective at reducing post-operative shivering (owing to its Kappa agonist activity). Butorphanol is more effective in reducing pain in women than in men.

Pharmacology
Butorphanol exhibits partial agonist and antagonist activity at the μ-opioid receptor, as well as partial agonist activity at the κ-opioid receptor (Ki = 2.5 nM; EC50 = 57 nM; Emax = 57%). Stimulation of these receptors on central nervous system neurons causes an intracellular inhibition of adenylate cyclase, closing of influx membrane calcium channels, and opening of membrane potassium channels. This leads to hyperpolarization of the cell membrane potential and suppression of action potential transmission of ascending pain pathways.
Because of its κ-agonist activity, at analgesic doses butorphanol increases pulmonary arterial pressure and cardiac work. Additionally, κ-agonism can cause dysphoria at therapeutic or supertherapeutic doses; this gives butorphanol a lower potential for abuse than other opioid drugs.

Side effects
As with other opioid analgesics, central nervous system effects (such as sedation, confusion, and dizziness) are considerations with butorphanol. Nausea and vomiting are common. Less common are the gastrointestinal effects of other opioids (mostly constipation).  Another side effect experienced by people taking the medication is increased perspiration.

Name
Within the INN, USAN, BAN, and AAN naming systems this drug is known as butorphanol, while within JAN it is named torbugesic. As the tartrate salt, butorphanol is known as butorphanol tartrate (USAN, BAN).Its tradename Stadol was recently discontinued by the manufacturer. It is now only available in its generic formulations manufactured by Apotex, Mylan, Novex and Ben Venue Laboratories.

Availability
Butorphanol is available in the U.S. as a generic drug; it is available in various nations under one of any number of trade names, including Moradol and Beforal (Brand name Stadol no longer available in the US); veterinary trade names include Butorphic, Dolorex, Morphasol, Torbugesic, and Torbutrol.

Legality
Butorphanol is listed under the Single Convention on Narcotic Drugs 1961 and in the United States is a Schedule IV Narcotic controlled substance with a DEA ACSCN of 9720; being in Schedule IV it is not subject to annual aggregate manufacturing quotas </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 Desloratadine/pseudoephedrine 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 Digoxin immune fab and can you explain it in depth? [/INST] Digoxin immune fab or digoxin-specific antibody is an antidote for overdose of digoxin. It is made from immunoglobulin fragments from sheep that have already been immunized with a digoxin derivative, digoxindicarboxymethoxylamine (DDMA). Its brand names include Digibind (GlaxoSmithKline) and DigiFab (BTG plc).

Medical uses
It is used for digoxin toxicity. Digoxin toxicity can emerge during long-term therapy as well as after an overdose. It can occur even when the serum digoxin concentration is within the therapeutic range when one of the following is present:
Hemodynamically unstable arrhythmia
End organ damage
digoxin level > 4 ng/ml if chronic ingestion
digoxin level > 10 ng/ml if acute ingestion
potassium > 5 mEq/L and symptomaticSide effects of digoxin immune fab may occur:

hives
difficult breathing
swelling of the lips, tongue, face, or throat
itching
skin redness
wheezing
cough
lightheadedness

Contraindications
Avoid use in hypokalemia as this drug, while reversing the effects of digitalis, will further reduce serum potassium levels and could precipitate dangerous and even fatal cardiac arrhythmias.
The patient must be closely monitored for anaphylactic shock, and anyone allergic to sheep protein, papain, bromelain, or papaya extracts (papain is used to cleave the antibody into Fab and Fc fragments) should not use ovine digoxin immune fab. Because it is relatively new, no drug interaction studies have been performed yet.

Pharmacology
It works by binding to the digoxin, rendering it unable to bind to its action sites on target cells. The complexes accumulate in the blood and are expelled by the kidney.

Regulatory information and clinical studies
Case series have reported benefits from anti‐digoxin Fab, but data regarding the response in acute or chronic poisoning are conflicting. Recent observational data support an effect in acute poisoning, but efficacy in chronic poisoning be minimally effective in alleviating cardiac toxicities in chronic digoxin poisoning.
Data also support outcomes of acute digoxin poisoning without use of anti‐digoxin Fab. A case series of 147 patients showed that not all cases of acute digoxin overdose require anti‐digoxin Fab, nor should anti‐digoxin Fab dose be calculated based on ingested dose. In contrast, a higher mortality (7.6%) was noted in a case series of acute and chronic digoxin and digitoxin poisoning despite Fab being used first line. Further, a retrospective case‐controlled study of chronic digoxin poisoning did not observe a beneficial effect of anti‐digoxin Fab on mortality.
An RCT (n = 66) in yellow oleander poisoning showed an early improvement in cardiac rhythm and hyperkalaemia from anti‐digoxin Fab, prompting early termination of the trial. It was not powered to detect a change in mortality and no deaths were noted.
As with all foreign proteins, anaphylaxis, serum sickness or febrile reactions are a source of concern, especially with repeated administration. These reactions appear uncommon for example, in a study of 717 adults where only six patients (0.8%) exhibited any evidence of allergic response.
Nevertheless, theoretically, patients previously dependent upon the inotropic effects of digoxin could develop heart failure and hypokalaemia could result within 1–5 hours, owing to intracellular shifts of potassium, as the effects of digoxin are reversed. Patients who require redigitalization must wait for the complexes to be eliminated from the body by the kidneys, this taking 2–3 days with normal renal function. Unfortunately, fab fragments interfere with both fluorescence excitation transfer immunoassays and radioimmunoassays for digoxin. This means that serum drug levels cannot be monitored until the drug-antibody complexes are cleared from the circulation.

Intellectual property
DigiFab is used as an antidote to treat a life-threatening overdose of digoxin or digitoxin. DigiFab is manufactured and distributed by BTG international Inc. under U.S. License No. 186. DigiFab is a sterile, lyophilized preparation of digoxin-immune ovine Fab (monovalent) immunoglobulin fragments. It is prepared by isolating the immunoglobulin fraction of the ovine serum, digesting it with papain and isolating the digoxin-specific Fab fragments by affinity chromatography </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 Zinc sulfate and can you explain it in depth? [/INST] Zinc sulfate is an inorganic compound. It is used as a dietary supplement to treat zinc deficiency and to prevent the condition in those at high risk. Side effects of excess supplementation may include abdominal pain, vomiting, headache, and tiredness.The most common form includes water of crystallization as the heptahydrate, with the formula ZnSO4·7H2O. It was historically known as "white vitriol". Zinc sulfate and its hydrates are colourless solids.

Uses
Medicine
In medicine it is used together with oral rehydration therapy (ORT) and an astringent.

Manufacturing
The hydrates, especially the heptahydrate, are the primary forms used commercially.  The main application is as a coagulant in the production of rayon.  It is also a precursor to the pigment lithopone.
It is also used as an electrolyte for zinc electroplating, as a mordant in dyeing, and as a preservative for skins and leather.

Other
Zinc sulfate is used to supply zinc in animal feeds, fertilizers, toothpaste, and agricultural sprays.  Zinc sulfate, like many zinc compounds, can be used to control moss growth on roofs.Zinc sulfate can be used to supplement zinc in the brewing process. Zinc is a necessary nutrient for optimal yeast health and performance, although it is not a necessary supplement for low-gravity beers, as the grains commonly used in brewing already provide adequate zinc. It is a more common practice when pushing yeast to their limit by increasing alcohol content beyond their comfort zone </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 Pegvaliase 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 Tramadol and can you explain it in depth? [/INST] Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It is available in combination with paracetamol (acetaminophen).
As is typical of opioids, common side effects include constipation, itchiness, and nausea. Serious side effects may include hallucinations, seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction. A change in dosage may be recommended in those with kidney or liver problems. It is not recommended in those who are at risk of suicide or in those who are pregnant. While not recommended in women who are breastfeeding, those who take a single dose should not generally stop breastfeeding. Tramadol is converted in the liver to O-desmethyltramadol (desmetramadol), an opioid with a stronger affinity to the μ-opioid receptor. Tramadol is also a serotonin–norepinephrine reuptake inhibitor (SNRI).Tramadol was patented in 1963 and launched under the name "Tramal" in 1977 by the West German pharmaceutical company Grünenthal GmbH. In the mid-1990s, it was approved in the United Kingdom and the United States. It is available as a generic medication and marketed under many brand names worldwide. In 2020, it was the 35th most commonly prescribed medication in the United States, with more than 17 million prescriptions.

Medical uses
Tramadol (a schedule IV drug in the US) is used primarily to treat mild to severe pain, both acute and chronic. There is moderate evidence for use as a second-line treatment for fibromyalgia but it is not FDA approved for this use; however, its use is approved for treatment of fibromyalgia as a secondary painkiller by the NHS.Its analgesic effects take about one hour to come into effect and 2 to 4 h to peak after oral administration with an immediate-release formulation. On a dose-by-dose basis, tramadol has about one-tenth the potency of morphine (thus 100 mg is commensurate with 10 mg morphine but may vary) and is practically equally potent when compared with pethidine and codeine. For pain moderate in severity, its effectiveness is equivalent to that of codeine at low doses, and hydrocodone at very high doses; for severe pain it is less effective than morphine.These painkilling effects last about 6 h. The potency of analgesia varies considerably as it depends on an individuals genetics. People with specific variants of CYP2D6 enzymes may not produce adequate amounts of the active metabolite (desmetramadol) for effective pain control.Sleep medicine physicians sometimes prescribe tramadol (or other opiate medications) for refractory restless legs syndrome (RLS); that is, RLS that does not respond adequately to treatment with first-line medications such as dopamine agonists (like pramipexole) or alpha-2-delta (α2δ) ligands (gabapentinoids), often due to augmentation.

Contraindications
Tramadol may not provide adequate pain control for individuals with certain genetic variants of CYP2D6 enzymes as they metabolize tramadol to the inactive molecule. These genetic polymorphisms are not currently routinely tested for in clinical practice.

Pregnancy and lactation
Tramadols use in pregnancy is generally avoided, as it may cause some reversible withdrawal effects in the newborn. A small prospective study in France found, while an increased risk of miscarriages existed, no major malformations were reported in the newborn. Its use during lactation is also generally advised against, but a small trial found that infants breastfed by mothers taking tramadol were exposed to about 2.88% of the dose the mothers were taking. No evidence of this dose harming the newborn was seen.

Labor and delivery
Its use as an analgesic during labor is not advised due to its long onset of action (1 hour). The ratio of the mean concentration of the drug in the fetus compared to that of the mother when it is given intramuscularly for labor pains has been estimated to be 1:94.

Children
Its use in children is generally advised against, although it may be done under the supervision of a specialist. On 21 September 2015, the FDA started investigating the safety of tramadol in use in persons under the age of 17. The investigation was initiated because some of these people have experienced slowed or difficult breathing. The FDA lists age under 12 years old as a contraindication.

Elderly
The risk of opioid-related adverse effects such as respiratory depression, falls, cognitive impairment and sedation is increased. Tramadol may interact with other medications and increase the risk for adverse events.

Liver and kidney failure
The drug should be used with caution in those with liver or kidney failure, due to metabolism in the liver (to the active molecule desmetramadol) and elimination by the kidneys.

Side effects
The most common adverse effects of tramadol include nausea, dizziness, dry mouth, indigestion, abdominal pain, vertigo, vomiting, constipation, drowsiness, and headache. Other side effects may result from interactions with other medications. Tramadol has the same dose-dependent adverse effects as morphine including respiratory depression.

Dependence and withdrawal
Long-term use of high doses of tramadol causes physical dependence and withdrawal syndrome. These include both symptoms typical of opioid withdrawal and those associated with serotonin–norepinephrine reuptake inhibitor (SNRI) withdrawal; symptoms include numbness, tingling, paresthesia, and tinnitus.  Psychiatric symptoms may include hallucinations, paranoia, extreme anxiety, panic attacks, and confusion. In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary. Tramadol withdrawal typically lasts longer than that of other opioids. Seven days or more of acute withdrawal symptoms can occur as opposed to typically 3 or 4 days for other codeine analogues.

Overdose
Recognised risk factors for tramadol overdose include respiratory depression, addiction, and seizures. Naloxone only partially reverses the toxic effects of tramadol overdose and may increase the risk of seizures.Deaths with tramadol overdose have been reported and are increasing in frequency in Northern Ireland; the majority of these overdoses involve other drugs including alcohol. There were 254 tramadol-related deaths in England and Wales in 2013, and 379 in Florida in 2011. In 2011, 21,649 emergency room visits in the United States were related to tramadol.

Interactions
Tramadol can interact with other medications with similar mechanisms of action.
Tramadol acts as a serotonin-norephinephrine reuptake inhibitor and thus can interact with other serotonergic medications (selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, triptans, cough and cold medications containing dextromethorphan, herbal products containing St. John’s wort, and medications that inhibit the metabolism of serotonin, such as monoamine oxidase inhibitors) and, in combination, may lead to serotonin syndrome. It may also make some  serotonergic antagonist anti-emetic medications (ondansetron) less effective.Tramadol also acts as an opioid agonist and thus can increase the risk for side effects when used with other opioid analgesics (such as morphine, pethidine, tapentadol, oxycodone, and fentanyl).Tramadol is metabolized by CYP2D6 enzymes which contribute to the metabolism of approximately 25% of all medications. Any medications with the ability to inhibit or induce these enzymes may interact with tramadol.Tramadol increases the risk for seizures by lowering the seizure threshold. Using other medications that lower seizure threshold (such as antipsychotic medications or amphetamines), further increases this risk.

Pharmacology
Mechanism of action
Tramadol induces analgesic effects through a variety of different targets on the noradrenergic system, serotoninergic system and opioid receptors system. Tramadol exists as a racemic mixture, the positive enantiomer inhibits serotonin reuptake while the negative enantiomer inhibits noradrenaline re-uptake, by binding to and blocking the transporters. Tramadol has also been shown to act as a serotonin releasing agent. Both enantiomers of tramadol are agonists of the μ-opioid receptor and its M1 metabolite, O-desmetramadol, is also a μ-opioid receptor agonist but is 6 times more potent than tramadol itself. All these effects work synergistically to induce analgesia.

Tramadol has been found to possess these actions:
Agonist of the μ-opioid receptor (MOR) and to a far lesser extent of the δ-opioid receptor (DOR) and κ-opioid receptor (KOR)
Serotonin reuptake inhibitor (SRI) and norepinephrine reuptake inhibitor; hence, an SNRI
Serotonin 5-HT2C receptor antagonist
M1 and M3 muscarinic acetylcholine receptor antagonist
α7 nicotinic acetylcholine receptor antagonist
NMDA receptor antagonist (very weak)
TRPA1 inhibitorTramadol acts on the opioid receptors through its major active metabolite desmetramadol, which has as much as 700-fold higher affinity for the MOR relative to tramadol. Moreover, tramadol itself has been found to possess no efficacy in activating the MOR in functional activity assays, whereas desmetramadol activates the receptor with high intrinsic activity (Emax equal to that of morphine). As such, desmetramadol is exclusively responsible for the opioid effects of tramadol. Both tramadol and desmetramadol have pronounced selectivity for the MOR over the DOR and KOR in terms of binding affinity.Tramadol is well-established as an SRI. In addition, a few studies have found that it also acts as a serotonin releasing agent (1–10 μM), similar in effect to fenfluramine. The serotonin releasing effects of tramadol could be blocked by sufficiently high concentrations of the serotonin reuptake inhibitor 6-nitroquipazine, which is in accordance with other serotonin releasing agents such as fenfluramine and MDMA. However, two more recent studies failed to find a releasing effect of tramadol at respective concentrations up to 10 and 30 μM. In addition to serotonergic activity, tramadol is also a norepinephrine reuptake inhibitor. It is not a norepinephrine releasing agent. Tramadol does not inhibit the reuptake or induce the release of dopamine.A positron emission tomography imaging study found that single oral 50-mg and 100-mg doses of tramadol to human volunteers resulted in 34.7% and 50.2% respective mean occupation of the serotonin transporter (SERT) in the thalamus. The estimated median effective dose (ED50) for SERT occupancy hence was 98.1 mg, which was associated with a plasma tramadol level of about 330 ng/ml (1,300 nM). The estimated maximum daily dosage of tramadol of 400 mg (100 mg q.i.d.) would result in as much as 78.7% occupancy of the SERT (in association with a plasma concentration of 1,220 ng/ml or 4,632 nM). This is close to that of SSRIs, which occupy the SERT by 80% or more.Peak plasma concentrations during treatment with clinical dosages of tramadol have generally been found to be in the range of 70 to 592 ng/ml (266–2,250 nM) for tramadol and 55 to 143 ng/ml (221–573 nM) for desmetramadol. The highest levels of tramadol were observed with the maximum oral daily dosage of 400 mg per day divided into one 100-mg dose every 6 hours (i.e., four 100-mg doses evenly spaced out per day). Some accumulation of tramadol occurs with chronic administration; peak plasma levels with the maximum oral daily dosage (100 mg q.i.d.) are about 16% higher and the area-under-the-curve levels 36% higher than following a single oral 100-mg dose. Positron emission tomography imaging studies have reportedly found that tramadol levels are at least four-fold higher in the brain than in plasma. Conversely, brain levels of desmetramadol "only slowly approach those in plasma". The plasma protein binding of tramadol is only 4 to 20%; hence, almost all tramadol in circulation is free, thus bioactive.

Correspondence to effects
Co-administration of quinidine, a potent CYP2D6 enzyme inhibitor, with tramadol, a combination which results in markedly reduced levels of desmetramadol, was found not to significantly affect the analgesic effects of tramadol in human volunteers. However, other studies have found that the analgesic effects of tramadol are significantly decreased or even absent in CYP2D6 poor metabolizers. The analgesic effects of tramadol are only partially reversed by naloxone in human volunteers, hence indicating that its opioid action is unlikely the sole factor; tramadols analgesic effects are also partially reversed by α2-adrenergic receptor antagonists such as yohimbine, the 5-HT3 receptor antagonist ondansetron, and the 5-HT7 receptor antagonists SB-269970 and SB-258719. Pharmacologically, tramadol is similar to tapentadol and methadone in that it not only binds to the MOR, but also inhibits the reuptake of serotonin and norepinephrine due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.Tramadol has inhibitory actions on the 5-HT2C receptor. Antagonism of 5-HT2C could be partially responsible for tramadols reducing effect on depressive and obsessive–compulsive symptoms in patients with pain and co-morbid neurological illnesses. 5-HT2C blockade may also account for its lowering of the seizure threshold, as 5-HT2C knockout mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to tramadols putative inhibition of GABAA receptors at high doses (significant inhibition at 100 μM). In addition, desmetramadol is a high-affinity ligand of the DOR, and activation of this receptor could be involved in tramadols ability to provoke seizures in some individuals, as DOR agonists are well known for inducing seizures.Nausea and vomiting caused by tramadol are thought to be due to activation of the 5-HT3 receptor via increased serotonin levels. In accordance, the 5-HT3 receptor antagonist ondansetron can be used to treat tramadol-associated nausea and vomiting. Tramadol and desmetramadol themselves do not bind to the 5-HT3 receptor.

Pharmacokinetics
Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2B6, CYP2D6, and CYP3A4, being O- and N-demethylated to five different metabolites. Of these, desmetramadol (O-desmethyltramadol) is the most significant, since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of 9 hours, compared with 6 hours for tramadol itself. As with codeine, in the 6% of the population who have reduced CYP2D6 activity (hence reducing metabolism), a reduced analgesic effect is seen. Those with decreased CYP2D6 activity require a dose increase of 30% to achieve the same degree of pain relief as those with a normal level of CYP2D6 activity.Phase II hepatic metabolism renders the metabolites water-soluble, which are excreted by the kidneys. Thus, reduced doses may be used in renal and hepatic impairment.Its volume of distribution is around 306 L after oral administration and 203 L after parenteral administration.

Chemistry
Tramadol is marketed as a racemic mixture of both R- and S-stereoisomers, because the two isomers complement each others analgesic activities.  The (+)-isomer is predominantly active as an opiate with a higher affinity for the µ-opiate receptor (20 times higher affinity than the (-)-isomer).

Synthesis and stereoisomerism
The chemical synthesis of tramadol is described in the literature. Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the cyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in four different configurational forms:

(1R,2R)-isomer
(1S,2S)-isomer
(1R,2S)-isomer
(1S,2R)-isomerThe synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides.
The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(−)-enantiomers.
The resolution of the racemate [(1R,2R)-(+)-isomer / (1S,2S)-(−)-isomer] was described employing (R)-(−)- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals and in humans.

Detection in biological fluids
Tramadol and desmetramadol may be quantified in blood, plasma, serum, or saliva to monitor for abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a sudden death. Most commercial opiate immunoassay screening tests do not cross-react significantly with tramadol or its major metabolites, so chromatographic techniques must be used to detect and quantitate these substances. The concentration of desmetramadol in the blood or plasma of a person who has taken tramadol is generally 10–20% those of the parent drug.

Society and culture
Formulations
Available dosage forms include liquids, syrups, drops, elixirs, effervescent tablets and powders for mixing with water, capsules, tablets including extended-release formulations, suppositories, compounding powder, and injections.

Patent history
The U.S. Food and Drug Administration (FDA) approved tramadol in March 1995, and an extended-release (ER) formulation in September 2005. ER Tramadol was protected by US patents nos. 6,254,887 and 7,074,430. The FDA listed the patents expiration as 10 May 2014. However, in August 2009, US District Court for the District of Delaware ruled the patents invalid, a decision upheld the following year by the Court of Appeals for the Federal Circuit. Manufacture and distribution of generic equivalents of Ultram ER in the United States was therefore permitted prior to the expiration of the patents.

Legal status
Effective 18 August 2014, tramadol has been placed into Schedule IV of the federal Controlled Substances Act in the United States. Before that, some US states had already classified tramadol as a Schedule IV controlled substance under their respective state laws.Tramadol is classified in Schedule 4 (prescription only) in Australia, rather than as a Schedule 8 Controlled Drug (Possession without authority illegal) like most other opioids.Effective May 2008, Sweden classified tramadol as a controlled substance in the same category as codeine and dextropropoxyphene, but allows a normal prescription to be used.The UK classified tramadol as a Class C, Schedule 3 controlled drug on 10 June 2014, but exempted it from the safe custody requirement.

Misuse
Illicit use of the drug is thought to be a major factor in the success of the Boko Haram terrorist organization. When used at higher doses, the drug "can produce similar effects to heroin." Said one former member, "whenever we took tramadol, nothing mattered to us anymore except what we were sent to do because it made us very high and very bold, it was impossible to go on a mission without taking it." Tramadol is also used as a coping mechanism in the Gaza Strip. It is also abused in the United Kingdom, inspiring the title of the TV show Frankie Boyles Tramadol Nights (2010).From March 2019, the Union Cycliste Internationale (UCI) banned the drug, after riders were using the painkiller to improve their performance.

Research
Investigational uses
Diabetic neuropathy
Antidepressant
Postherpetic neuralgia
Premature ejaculation
Adjunct to local anaesthesia

False findings about sources in nature
In 2013, researchers reported that tramadol was found in relatively high concentrations (1%+) in the roots of the African pin cushion tree (Nauclea latifolia). In 2014, however, it was reported that the presence of tramadol in the tree roots was the result of tramadol having been administered to cattle by farmers in the region: tramadol and its metabolites were present in the animals excreta, which contaminated the soil around the trees. Therefore, tramadol and its mammalian metabolites were found in tree roots in the far north of Cameroon, but not in the south where it is not administered to farm animals.A 2014 editorial in Lab Times online contested the notion that tramadol in tree roots was the result of anthropogenic contamination, stating that samples were taken from trees that grew in national parks, where livestock were forbidden; it also quoted researcher Michel de Waard, who stated that "thousands and thousands of tramadol-treated cattle sitting around a single tree and urinating there" would be required to produce the concentrations discovered.In 2015, radiocarbon analysis confirmed that the tramadol found in N.latifolia roots could not be plant-derived and was of synthetic origin.

Veterinary medicine
Tramadol may be used to treat post-operative, injury-related, and chronic (e.g., cancer-related) pain in dogs and cats as well as rabbits, coatis, many small mammals including rats and flying squirrels, guinea pigs, ferrets, and raccoons.

See also
Tramadol/paracetamol

References
Further reading
Dean L (2015). "Tramadol Therapy and CYP2D6 Genotype".  In Pratt VM, McLeod HL, Rubinstein WS,  et al. (eds.) </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 Lidocaine/prilocaine and can you explain it in depth? [/INST] Lidocaine/prilocaine is a eutectic mixture of equal quantities (by weight) of lidocaine and prilocaine. A 5% emulsion preparation, containing 2.5% each of lidocaine/prilocaine, is marketed by APP Pharmaceuticals under the trade name EMLA (an abbreviation for Eutectic Mixture of Local Anesthetics). As a spray, it is marketed under the name Tempe (topical eutectic-like mixture for premature ejaculation) (PSD502) that can be used by men to help with premature ejaculation. The spray is manufactured by Plethora Solutions and branded as Fortacin in the UK and Recordati in the EU.

Eutectic mixture
Separately, lidocaine and prilocaine are solid bases. When mixed in equal quantities by weight, however, they form a eutectic mixture – that is the melting point of the mixture is lower than the melting points of the individual components. The lidocaine/prilocaine eutectic mixture is an oil with a melting point of 18 °C, and can be formulated into preparations without the use of a non-aqueous solvent. This allows higher concentrations of anaesthetic to be formulated into the preparation and maintained during application.

Clinical use
Indications
The lidocaine/prilocaine combination is indicated for dermal anaesthesia. Specifically it is applied to prevent pain associated with intravenous catheter insertion, blood sampling, superficial surgical procedures, and topical anaesthesia of leg ulcers for cleansing or debridement. Also, it can be used to numb the skin before tattooing as well as electrolysis and laser hair removal. It is also sometimes used in advance of injected local anaesthetics for minor surgery and biopsies.
A topical spray consisting of an aerosol formulation of lidocaine and prilocaine was evaluated under the name PSD502 for use in treating premature ejaculation. The spray is applied on the penile skin prior to intercourse. While this formulation was not approved by the FDA, a similar product, Promescent, is available over-the-counter in the U.S.

Dosage forms
Lidocaine/prilocaine eutectic mixture is marketed as a 5% oil-in-water emulsion incorporated in a cream base (EMLA cream) or  a cellulose disk (EMLA patch). The cream is applied under an occlusive dressing, while the patch incorporates an occlusive dressing to facilitate absorption of lidocaine and prilocaine into the area where anaesthesia is required. Local dermal anaesthesia is achieved after approximately 60 minutes, whereupon the occlusive dressing (or patch) is removed. The duration of anaesthesia is approximately two hours following removal of the occlusive dressing.
E. Fougera & Co., makers of the generic cream widely used in the United States as Lidocaine and Prilocaine Cream, 2.5%/2.5%, recommends different timing for application of the cream as well as length of anesthesia </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 Ebanga 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 Dimenhydrinate and can you explain it in depth? [/INST] Dimenhydrinate, sold under the brand name Dramamine, among others, is an over-the-counter drug used to treat motion sickness and nausea. Dimenhydrinate is a theoclate salt composed of diphenhydramine, an ethanolamine derivative, and 8-chlorotheophylline, a chlorinated theophylline derivative, in a 1∶1 ratio.

Medical uses
Nausea
Dimenhydrinate is an over-the-counter (OTC) antihistamine indicated for the prevention and relief of nausea and vomiting from a number of causes. It is an H1 receptor antagonist that demonstrates anticholinergic activity.

Medicinal chemistry
Diphenhydramine is the primary constituent of dimenhydrinate and dictates the primary effect. The main difference relative to pure diphenhydramine is a lower potency due to being combined with 8-chlorotheophylline. By weight, dimenhydrinate is between 53% to 55.5% diphenhydramine.

Side effects
Common side effects may include:
Drowsiness
Dry mouth, nose, or throat
Constipation
Blurred vision
Feeling restless or excited (especially in children)

Recreational use
Dimenhydrinate is recreationally used as a deliriant. Slang terms for Dramamine used this way include "drama", "dime", "dime tabs", "D-Q", "substance D", "d-house", and "drams". Abusing Dramamine is sometimes referred to as Dramatizing or "going a dime a dozen", a reference to the amount of Dramamine tablets generally necessary for a trip.Many users report a side-effect profile consistent with tropane alkaloid (e.g. atropine) poisoning as both show antagonism of muscarinic acetylcholine receptors in both the central and autonomic nervous system, which inhibits various signal transduction pathways.Other CNS effects occur within the limbic system and hippocampus, causing confusion and temporary amnesia due to decreased acetylcholine signaling. Toxicology also manifests in the autonomic nervous system, primarily at the neuromuscular junction, resulting in ataxia and extrapyramidal side effects and the feeling of heaviness in the legs, and at sympathetic post-ganglionic junctions, causing urinary retention, pupil dilation, tachycardia, irregular urination, and dry red skin caused by decreased exocrine gland secretions, and mucous membranes </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 Cenegermin and can you explain it in depth? [/INST] Cenegermin, sold under the brand name Oxervate, also known as recombinant human nerve growth factor (rhNGF), is a recombinant form of human nerve growth factor (NGF). In July 2017, it was approved in the European Union as an eye drop formulation for the treatment of moderate or severe neurotrophic keratitis in adults.As a recombinant form of NGF, cenegermin is a peripherally selective agonist of the TrkA and LNGFR (p75NTR) which must be administered parenterally.The U.S </s>