<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 Mirtazapine and can you explain it in depth? [/INST] Mirtazapine, sold under the brand name Remeron amongst others, is an atypical antidepressant, and as such is used primarily to treat depression. Its effects may take up to four weeks, but can also manifest as early as one to two weeks. It is often used in cases of depression complicated by anxiety or insomnia. The effectiveness of Mirtazapine is comparable to other commonly prescribed antidepressants. It is taken by mouth.Common side effects include sleepiness, dizziness, increased appetite and weight gain. Serious side effects may include mania,  low white blood cell count, and increased suicide among children. Withdrawal symptoms may occur with stopping. It is not recommended together with an MAO inhibitor, although evidence supporting the danger of this combination has been refuted. It is unclear if use during pregnancy is safe. How it works is not clear, but it may involve blocking certain adrenergic and serotonin receptors. Chemically, it is a tetracyclic antidepressant (TeCA), and is closely related to mianserin. It also has strong antihistaminergic effects.Mirtazapine came into medical use in the United States in 1996. The patent expired in 2004, and generic versions are available. In 2019, it was the 106th most commonly prescribed medication in the United States, with more than 6 million prescriptions.

Medical uses
Depression
Mirtazapine is primarily used for major depressive disorder and other mood disorders. Onset of action appears faster than some selective serotonin reuptake inhibitors (SSRI) and similar to tricyclic antidepressants.In 2010, NICE recommended generic SSRIs as first line choices, as they are "equally effective as other antidepressants and have a favourable risk–benefit ratio." With respect to mirtazapine, it found: "There is no difference between mirtazapine and other antidepressants on any efficacy measure, although in terms of achieving remission mirtazapine appears to have a statistical though not clinical advantage. In addition, mirtazapine has a statistical advantage over selective serotonin reuptake inhibitors in terms of reducing symptoms of depression, but the difference is not clinically significant. However, there is strong evidence that patients taking mirtazapine are less likely to leave treatment early because of side effects, although this is not the case for patients reporting side effects or leaving treatment early for any reason."A 2011 Cochrane review that compared mirtazapine to other antidepressants found that, while it appears to have a faster onset in people for whom it works (measured at two weeks), its efficacy is about the same as other antidepressants after six weeks use.A 2012 review focused on antidepressants and sleep found that in many people with sleep disorders caused by depression, mirtazapine reduces the time it takes to fall asleep and increases the quality of sleep, but that in some people it can disturb sleep, especially at higher doses, causing restless leg syndrome in 8 to 28% of people and in rare cases causes REM sleep behavior disorder. This seemingly paradoxical dose–response curve of mirtazapine with respect to somnolence is owed to the exceptionally high affinity of the drug for the histamine H1, 5-HT2A, and 5-HT2C receptors; exhibiting near exclusive occupation of these receptors at doses ≤15 mg. However, at higher doses, inverse antagonism and constitutive activation of the  α2A-, α2B-, and α2C-adrenergic receptors begins to offset activity at H1 receptors leading to decreased somnolence and even a subjective sensation of "activation" in treated patients.A 2018 analysis of 21 antidepressants found them to be fairly similar overall. It found tentative evidence for mirtazapine being in the more effective group and middle in tolerability.After one week of usage, mirtazapine was found to have an earlier onset of action compared to SSRIs.

Other
There is also some evidence supporting its use in treating the following conditions, for which it is sometimes prescribed off-label:

Doses of mirtazapine used for sleep range from 7.5 to 45 mg. Doses of 7.5 to 15 mg are recommended as mirtazapine may become more stimulating at higher doses.

Side effects
A 2011 Cochrane review found that, compared with other antidepressants, it is more likely to cause weight gain and sleepiness, but it is less likely to cause tremor than tricyclic antidepressants, and less likely to cause nausea and sexual dysfunction than SSRIs.Very common (≥10% incidence) adverse effects include constipation, dry mouth, sleepiness, increased appetite (17%) and weight gain (>7% increase in <50% of children).Common (1–10% incidence) adverse effects include weakness, confusion, dizziness, fasciculations (muscle twitches), peripheral edema (swelling, usually of the lower limbs), and negative lab results like elevated transaminases, elevated serum triglycerides, and elevated total cholesterol.Mirtazapine is not considered to have a risk of many of the side effects often associated with other antidepressants like the SSRIs, and may actually improve certain ones when taken in conjunction with them. (Those adverse effects include decreased appetite, weight loss, insomnia, nausea and vomiting, diarrhoea, urinary retention, increased body temperature, excessive sweating, pupil dilation and sexual dysfunction.)
In general, some antidepressants, especially selective serotonin reuptake inhibitors (SSRI), can paradoxically exacerbate some peoples depression or anxiety or cause suicidal ideation. Despite its sedating action, mirtazapine is also believed to be capable of this, so in the United States and certain other countries, it carries a black box label warning of these potential effects, especially for people under the age of 25.Mirtazapine may induce arthralgia (non-inflammatory joint pain)A case report published in 2000 noted an instance in which mirtazapine counteracted the action of clonidine, causing a dangerous rise in blood pressure.In a study comparing 32 antidepressants of all pharmacological classes, mirtazapine was one of the antidepressants most likely to cause nightmare disorder, sleepwalking, restless legs syndrome, night terrors and sleep paralysis.Mirtazapine has been associated with an increased risk of death compared to other antidepressants in several studies. However, it is more likely that the residual differences between people prescribed mirtazapine rather than an SSRI account for the difference in risk of mortality.

Withdrawal
Mirtazapine and other antidepressants may cause withdrawal symptoms upon cessation. A gradual and slow reduction in dose is recommended to minimize withdrawal symptoms. Effects of sudden cessation of treatment with mirtazapine may include depression, anxiety, tinnitus, panic attacks, vertigo, restlessness, irritability, decreased appetite, insomnia, diarrhea, nausea, vomiting, flu-like symptoms, allergy-like symptoms such as pruritus, headaches, and sometimes mania or hypomania.

Overdose
Mirtazapine is considered to be relatively safe in the event of an overdose, although it is considered slightly more toxic in overdose than most of the SSRIs (except citalopram). Unlike the tricyclic antidepressants, mirtazapine showed no significant cardiovascular adverse effects at 7 to 22 times the maximum recommended dose. Case reports of overdose with as much as 30 to 50 times the standard dose described the drug as relatively nontoxic, compared to tricyclic antidepressants.Twelve reported fatalities have been attributed to mirtazapine overdose. The fatal toxicity index (deaths per million prescriptions) for mirtazapine is 3.1 (95% CI: 0.1 to 17.2). This is similar to that observed with SSRIs.

Interactions
Concurrent use with inhibitors or inducers of the cytochrome (CYP) P450 isoenzymes CYP1A2, CYP2D6, and/or CYP3A4 can result in altered concentrations of mirtazapine, as these are the main enzymes responsible for its metabolism. As examples, fluoxetine and paroxetine, inhibitors of these enzymes, are known to modestly increase mirtazapine levels, while carbamazepine, an inducer, considerably decreases them. Liver impairment and moderate chronic kidney disease have been reported to decrease the oral clearance of mirtazapine by about 30%; severe kidney disease decreases it by 50%.Mirtazapine in combination with an SSRI, SNRI, or TCA as an augmentation strategy is considered to be relatively safe and is often employed therapeutically, with a combination of venlafaxine and mirtazapine, sometimes referred to as "California rocket fuel". Several case reports document serotonin syndrome induced by the combination of mirtazapine with other agents (olanzapine, quetiapine, tramadol and venlafaxine).
According to information from the manufacturers, mirtazapine should not be started within two weeks of any monoamine oxidase inhibitor (MAOI) usage; likewise, MAOIs should not be administered within two weeks of discontinuing mirtazapine.The addition of mirtazapine to a monoamine oxidase inhibitor (MAOI), while potentially having typical or idiosyncratic (unique to the individual) reactions not herein described, does not appear to cause serotonin syndrome. This is in accordance with the fact that the 5-HT2A receptor is the predominant serotonin receptor thought to be involved in the pathophysiology of serotonin syndrome (with the 5-HT1A receptor seeming to be protective). Mirtazapine is a potent 5-HT2A receptor antagonist, and cyproheptadine, a medication that shares this property, mediates recovery from serotonin syndrome and is an antidote against it.There is a possible interaction that results in a hypertensive crisis when mirtazapine is given to a patient that has already been on steady doses of clonidine.  This involves a subtle consideration, when patients have been on chronic therapy with clonidine and suddenly stop the dosing, a rapid hypertensive rebound sometimes (20%) occurs from increased sympathetic outflow. Clonidines blood pressure lowering effects are due to stimulation of presynaptic α2 autoreceptors in the CNS which suppress sympathetic outflow. Mirtazapine itself blocks these same α2 autoreceptors, so the effect of adding mirtazapine to a patient stabilized on clonidine may precipitate withdrawal symptoms.

Pharmacology
Pharmacodynamics
Mirtazapine is sometimes described as a noradrenergic and specific serotonergic antidepressant (NaSSA), although the actual evidence in support of this label has been regarded as poor. It is a tetracyclic piperazine-azepine.Mirtazapine has antihistamine, α2-blocker, and antiserotonergic activity. It is specifically a potent antagonist or inverse agonist of the α2A-, α2B-, and α2C-adrenergic receptors, the serotonin 5-HT2A, 5-HT2C, and the histamine H1 receptor. Unlike many other antidepressants, it does not inhibit the reuptake of serotonin, norepinephrine, or dopamine, nor does it inhibit monoamine oxidase. Similarly, mirtazapine has weak or no activity as an anticholinergic or blocker of sodium or calcium channels, in contrast to most TCAs. In accordance, it has better tolerability and low toxicity in overdose. As an H1 receptor antagonist, mirtazapine is extremely potent, and is in fact the most potent of all the TCAs and TeCAs. Antagonism of the H1 receptor is by far the strongest activity of mirtazapine, with the drug acting as a selective H1 receptor antagonist at low concentrations.The (S)-(+) enantiomer of mirtazapine is responsible for antagonism of the serotonin 5-HT2A and 5-HT2C receptors, while the (R)-(–) enantiomer is responsible for antagonism of the 5-HT3 receptor. Both enantiomers are involved in antagonism of the H1 and α2-adrenergic receptors, although the (S)-(+) enantiomer is the stronger antihistamine.Although not clinically relevant, mirtazapine has been found to act as a partial agonist of the κ-opioid receptor at high concentrations (EC50 = 7.2 μM).

α2-Adrenergic receptor
Antagonism of the α2-adrenergic receptors, which function largely as inhibitory autoreceptors and heteroreceptors, enhances adrenergic and serotonergic neurotransmission, notably central 5-HT1A receptor mediated transmission in the dorsal raphe nucleus and hippocampus; hence, mirtazapines classification as a NaSSA. Indirect α1 adrenoceptor-mediated enhancement of serotonin cell firing and direct blockade of inhibitory α2 heteroreceptors located on serotonin terminals are held responsible for the increase in extracellular serotonin. Because of this, mirtazapine has been said to be a functional "indirect agonist" of the 5-HT1A receptor. Increased activation of the central 5-HT1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs.

5-HT2 receptor
Antagonism of the 5-HT2 subfamily of receptors and inverse agonism of the 5-HT2C receptor appears to be in part responsible for mirtazapines efficacy in the treatment of depressive states.
Mirtazapine increases dopamine release in the prefrontal cortex. Accordingly, it was shown that by blocking the α2-adrenergic receptors and 5-HT2C receptors mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats. In addition, mirtazapines antagonism of 5-HT2A receptors has beneficial effects on anxiety, sleep and appetite, as well as sexual function regarding the latter receptor. Mirtazapine has been shown to lower drug seeking behaviour (more specifically to methamphetamine) in various human and animal studies. It is also being investigated in substance abuse disorders to reduce withdrawal effects and improve remission rates.Mirtazapine significantly improves pre-existing symptoms of nausea, vomiting, diarrhea, and irritable bowel syndrome in affected individuals. Mirtazapine may be used as an inexpensive antiemetic alternative to Ondansetron. In conjunction with substance abuse counseling, mirtazapine has been investigated for the purpose of reducing methamphetamine use in dependent individuals with success. In contrast to mirtazapine, the selective serotonin reuptake inhibitors (SSRI), serotonin–norepinephrine reuptake inhibitors (SNRI), Monoamine oxidase inhibitors (MAOI), and some Tricyclic antidepressants (TCA) increase the general activity of the 5-HT2A, 5-HT2C, and 5-HT3 receptors leading to a host of negative changes and side effects, the most prominent of which including anorexia, insomnia, nausea, and diarrhea, among others. Its reduced incidence of sexual dysfunction (such as loss of libido and anorgasmia) could be a product of negligible binding to the serotonin transporter (as is generally the cause of sexual dysfunction with most SSRIs) and antagonism of the 5-HT2A receptors; however, Mirtazapines high affinity towards and inverse agonism of the 5-HT2C receptors may greatly attenuate those pro-sexual factors (as evidenced by the pro-sexual effects of drugs like m-CPP and Lorcaserin which agonize 5-HT2C receptors in a reasonably selective manner). As a result, it is often combined with these drugs to reduce their side-effect profile and to produce a stronger antidepressant effect.Mirtazapine does not have pro-serotonergic activity and thus does not cause serotonin syndrome. This is in accordance with the fact that it is not a serotonin reuptake inhibitor or monoamine oxidase inhibitor (MAOI), nor a serotonin receptor agonist. There are no reports of serotonin syndrome in association with mirtazapine alone, and mirtazapine has not been found to cause serotonin syndrome in overdose. However, there are a handful of case reports of serotonin syndrome occurring with mirtazapine in combination with serotonergic drugs like SSRIs, although such reports are very rare, and do not necessarily implicate mirtazapine as causative.

5-HT3 receptor
It is a potent 5-HT3 blocker. It may relieve chemotherapy-related and advanced cancer-related nausea.

H1 receptor
Mirtazapine is a very strong H1 receptor inverse agonist and, as a result, it can cause powerful sedative and hypnotic effects. A single 15 mg dose of mirtazapine to healthy volunteers has been found to result in over 80% occupancy of the H1 receptor and to induce intense sleepiness. After a short period of chronic treatment, however, the H1 receptor tends to desensitize and the antihistamine effects become more tolerable. Many patients may also dose at night to avoid the effects, and this appears to be an effective strategy for combating them. Blockade of the H1 receptor may improve pre-existing allergies, pruritus, nausea, and insomnia in affected individuals. It may also contribute to weight gain, however. In contrast to the H1 receptor, mirtazapine has only low affinity for the muscarinic acetylcholine receptors, although anticholinergic side effects like dry mouth, constipation, and mydriasis are still sometimes seen in clinical practice.

Pharmacokinetics
The oral bioavailability of mirtazapine is about 50%. It is found mostly bound to plasma proteins, about 85%. It is metabolized primarily in the liver by demethylation and hydroxylation via cytochrome P450 enzymes, CYP1A2, CYP2D6, CYP3A4. One of its major metabolites is desmethylmirtazapine. The overall elimination half-life is 20–40 hours. It is conjugated in the kidney for excretion in the urine, where 75% of the drug is excreted, and about 15% is eliminated in feces.: 430

Chemistry
Mirtazapine is a tetracyclic piperazinoazepine; mianserin was developed by the same team of organic chemists and mirtazapine differs from it via addition of a nitrogen atom in one of the rings.: 429  It is a racemic mixture of enantiomers </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 Talazoparib and can you explain it in depth? [/INST] Talazoparib, sold under the brand name Talzenna, is an orally available poly ADP ribose polymerase (PARP) inhibitor developed by Pfizer for the treatment of advanced breast cancer with germline BRCA mutations. Talazoparib is similar to the first in class PARP inhibitor, olaparib. It was approved in October 2018, in the United States and June 2019, in the European Union for germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer.

Side effects
The most serious side effects in studies were related to the blood forming system and included anaemia (low red blood cell count), neutropenia (low neutrophil blood cell count) and thrombocytopenia (low platelet count). Serious forms of these conditions (grade 3 to 4) occurred in 39%, 21% and 15% of patients, respectively. Other adverse effects such as headache, nausea, hair loss and fatigue were mostly mild.

Interactions
Combination with drugs that inhibit P-glycoprotein or BCRP may increase talazoparib concentrations in the body.

Mechanism of action
Talazoparib acts as an inhibitor of poly ADP ribose polymerase (PARP) which aids in single strand DNA repair. Cells that have BRCA1/2 mutations are susceptible to the cytotoxic effects of PARP inhibitors because of an accumulation of DNA damage. Talazoparib is theorized to have a higher potency than olaparib due to the additional mechanism of action called PARP trapping. PARP trapping is the mechanism of action where the PARP molecule is trapped on the DNA, which interferes with the cells ability to replicate. Talazoparib is found to be ~100 fold more efficient in PARP trapping than olaparib. However, this increased potency may not translate directly to clinical effectiveness as many other factors must be considered.

Commercialization
Talazoparib was originally developed by BioMarin Pharmaceutical Inc </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 Elexacaftor/tezacaftor/ivacaftor and can you explain it in depth? [/INST] Elexacaftor/tezacaftor/ivacaftor, sold under the brand names Trikafta (US) and Kaftrio (EU), is a fixed-dose combination medication used to treat cystic fibrosis. Elexacaftor/tezacaftor/ivacaftor is composed of a combination of ivacaftor, a chloride channel opener, and elexacaftor and tezacaftor, CFTR modulators.It is approved for use in the United States for people aged six years and older who have cystic fibrosis with a F508del mutation or other mutations in the CFTR gene. It is also approved for use in Canada, the European Union and Australia.

Medical uses
The combination is indicated for the treatment of people aged six years and older who have cystic fibrosis with a F508del mutation or other mutations in the CFTR gene.

Side effects
The most common side effects affecting more than 5% of patients are headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, alanine aminotransferase increased, nasal congestion, blood creatine phosphokinase increased, aspartate aminotransferase increased, rhinorrhea, rhinitis, influenza, sinusitis and blood bilirubin increased.

Interactions
Concomitant use with CYP3A inducers is not recommended. Dosage must be adjusted with moderate or strong CYP3A inhibitors.Other drugs with the potential for interaction include: warfarin, digoxin, statins, glyburide, nateglinide, repaglinide.

Pharmacology
Cystic fibrosis and CFTR
Cystic fibrosis is an autosomal recessive genetic disorder of the CFTR protein which reduces chloride and sodium ion transport through the cell membrane, causing thicker than normal mucus secretions. The CFTR protein is found in epithelial cells of the lung, liver, pancreas, digestive tract, and reproductive tracts. CFTR has a role in the production of mucus, sweat, and digestive fluids. The thickened mucus can lead to inflammation, respiratory infections, and clogged ducts.

Mechanism of action
Elexacaftor/tezacaftor/ivacaftor is a tridrug treatment in which the medications work together to increase the transport of chloride and sodium ions, and reducing thick mucus production.

CFTR channel potentiator
Ivacaftor is a selective small-molecule potentiator of the CFTR protein that increases the proteins ability to open chloride channels. Its effectiveness is highly dependent on the amount of CFTR protein at the cell surface and the responsiveness of the mutant CFTR protein. Ivacaftors primary target is to treat class III CFTR gating mutations like G551D as well as other less common mutations. In the crystalline figure, you can see ivacaftor, shown as a gray ball and stick model on the bottom-right, bound to CFTR docked in a cleft formed by transmembrane helices at the protein-lipid interface.

CFTR correctors
Elexacaftor and Tezacaftor act as CFTR correctors to repair F508del processing by binding to the CFTR protein to increase the availability of CFTR protein on the cell surface. They work by modulating the position of the CFTR protein into the right position on the cell surface.The combination of increased CFTR protein in the correct position on the cell surface with ivacaftors potentiation of chloride channel opening results in increased transport of chloride and thinned mucus secretions.

Pharmacokinetics
Elexacaftor/tezacaftor/ivacaftor is primarily metabolized by CYP3A4 /5. This medication should be taken with a high fat meal to improve absorption through the gut. It is excreted as metabolites or unchanged mainly through feces and to a smaller extent urine. The mean effective half-life of elexacaftor, tezacaftor, and ivacaftor is 27.4 hours, 25.1 hours, and 15 hours, respectively.

History
A phase III trial showed people treated with elexacaftor/tezacaftor/ivacaftor improved in FEV1 at four weeks with sustained improvement at 24 weeks. Rate of pulmonary exacerbation was 63% lower and sweat chloride concentration was 41.8 mmol/L lower. Its effectiveness is dependent on the type of CF mutations the patient has.

Society and culture
Legal status
United States
The combination was approved for use in the United States in 2019 for people twelve years and older with cystic fibrosis who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent 90% of the cystic fibrosis population. In December 2020, after an additional clinical trial was completed, and FDA approval was expanded for 177 other cystic fibrosis mutations. FDA approval for children aged 6–11 was added in January 2021, after a third clinical trial was completed.The U.S. Food and Drug Administration (FDA) granted the application priority review, in addition to fast track, breakthrough therapy, and orphan drug designations. The drugs manufacturer Vertex Pharmaceuticals will receive a rare pediatric disease priority review voucher for having developed this therapy.

Australia
In March 2021, health regulators in Australia approved trikafta for patients aged 12 years and older with at least one copy of the F508del mutation. At the end of April 2022, it was placed on PBS, thus reducing the cost from tens of thousands of dollars a month, to tens of dollars a month.

Canada
In June 2020, Health Canada approved Trikafta for patients ages 12 and up. In September 2021, the provinces Alberta and Saskatchewan announced they will join Ontario in funding the medication </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 Desiccated thyroid extract and can you explain it in depth? [/INST] Desiccated thyroid, also known as thyroid extract, is thyroid gland that has been dried and powdered for medical use. It is used to treat hypothyroidism. It is less preferred than levothyroxine. It is taken by mouth. Maximal effects may take up to 3 weeks to occur.Side effects may occur from excessive doses. This may include weight loss, fever, headache, anxiety, trouble sleeping, arrythmias, and heart failure. Other side effects may include allergic reactions. Use in pregnancy and breastfeeding is generally safe. Regular blood tests are recommended to verify the appropriateness of the dose. They contain a mixture of thyroxine (T4) and triiodothyronine (T3).Desiccated thyroid has been used since the late 1800s. It is usually made from pigs, sheep, or cows. It is available as a generic medication. In 2017, it was the 130th most commonly prescribed medication in the United States, with more than five million prescriptions. Usage has decreased since the 1960s.

Medical uses
The American Association of Clinical Endocrinologists and the Royal College of Physicians recommend against the use of thyroid extract for the treatment of hypothyroidism. Concerns include the potential for adverse effects from superphysiological levels of T3 and the absence of long-term safety data from randomized clinical trials. They recommend levothyroxine as the preferred treatment. Some practitioners refuse to use desiccated thyroid.About 65 mg of thyroid extract is equivalent to 100 μg of levothyroxine.Arguments against desiccated thyroid include:

Desiccated thyroid preparations have a greater variability from batch to batch than synthetic ones.
Desiccated thyroid has roughly a 4:1 ratio of thyroxine (T4) to triiodothyronine (T3).  In humans, the ratio is 11:1.
A combination of various ratios of T4 and T3 might not provide benefits over T4 alone. Some controlled trials have shown inconsistent benefits of various ratios of T4 and T3.
The use of desiccated thyroid is usually accompanied with the practice of dosing according to symptoms instead of dosing to achieve "ideal" lab results (e.g. serum levels of TSH).  While there is debate as to what the ideal serum levels are, dosing according to symptoms often results in higher dosages.  Most endocrinologists are opposed to these higher dosages as there may be risks of hyperthyroidism and osteoporosis.
The preference for "natural" treatment seems to stem from philosophical belief as opposed to science.Arguments for desiccated thyroid include:

Desiccated thyroid contains all the natural thyroid hormones produced exclusively by the thyroid gland, including calcitonin which plays a crucial but still quite unclear role in promoting and sustaining bone density, however it is already used in therapy for osteoporosis when other treatments fail.
Desiccated thyroid therapy can be combined with synthetic thyroxine (T4) to balance out the T4/T3 correctly.

Chemistry
Desiccated thyroid has been described in the United States Pharmacopoeia for a century as the cleaned, dried, and powdered thyroid gland previously deprived of connective tissue and fat... obtained from domesticated animals that are used for food by man (USP XVI). In the last few decades, pork alone is the usual source. Before modern assays, the potency was specified only by iodine content ("not less than 0.17% and not more than 0.23%"), rather than hormonal content or activity.

History
The earliest oral treatment for hypothyroidism consisted of thyroid extract. George Redmayne Murray of the United Kingdom first described treatment of myxedema with thyroid extract in 1891, and published a description of long-term successful treatment (28 years) of a patient with myxedema (severe hypothyroidism) in 1920 His treatment was quickly adopted in North America and Europe. The first recorded American use dates to 1891 by a woman who was still taking it 52 years later at 84 years of age Desiccated thyroid extract is prepared from pig thyroid glands. The glands are dried (desiccated), ground to powder, combined with binder chemicals, and pressed into pills. This was a new use for parts that were previously unwanted slaughterhouse offal, and Armour and Company, the dominant American meatpacker in the 20th century, supplied the best-known brand of thyroid extract.Replacement by thyroid extract in hypothyroidism was one of the most effective treatments of any disease available to physicians before the middle of the 20th century, and in severe cases afforded dramatic relief of the myriad symptoms. The decision to treat was usually based on the presence of signs and symptoms of hypothyroidism because there were no accurate, readily available laboratory tests of thyroid function. Many less severe cases of hypothyroidism went untreated. Dosage was regulated by improvement of symptoms.
Desiccated Thyroid became a commercial treatment option in 1934 with Westhroid,. In the early 1960s, desiccated thyroid hormones (thyroid extract) began to be replaced by  levothyroxine (synthetic T4), or by combinations of T4 and T3. Replacement occurred faster in the United Kingdom than in North America, but by the 1980s more patients were being prescribed synthetic T4 (levothyroxine) or synthetic T4/T3 combinations than desiccated thyroid extract.Several reasons have been identified as to why prescriptions changed from desiccated thyroid treatment.

Although thyroid extract was useful and usually effective, some patients continued to complain of fatigue, weight gain, or other symptoms. Dosing until the 1960s was often a matter of prolonged adjustment trials.
It was known that not all of the iodine content of thyroid extract was in the form of effective T4 and T3 and that actual content of available preparations varied more than the permitted 15%. It was hoped that better dosing precision with levothyroxine (synthetic) alone would increase the proportion of patients effectively treated. In 1980, a widely publicized investigation published in JAMA revealed continued large ranges of hormone content and potency in all of the available thyroid extracts on the American market.
By the 1960s, it was known that thyroxine was the essential hormone produced by the thyroid gland, and that most T3 was manufactured in other parts of the body by deiodination of thyroxine </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 Norepinephrine (medication) and can you explain it in depth? [/INST] Norepinephrine, also known as noradrenaline, is a medication used to treat people with very low blood pressure. It is the typical medication used in sepsis if low blood pressure does not improve following intravenous fluids. It is the same molecule as the hormone and neurotransmitter norepinephrine. It is given by slow injection into a vein.Common side effects include headache, slow heart rate, and anxiety. Other side effects include an irregular heartbeat. If it leaks out of the vein at the site it is being given, norepinephrine can result in limb ischemia. If leakage occurs the use of phentolamine in the area affected may improve outcomes. Norepinephrine works by binding and activating alpha adrenergic receptors.Norepinephrine was discovered in 1946 and was approved for medical use in the United States in 1950. It is available as a generic medication.

Medical uses
Norepinephrine is used mainly as a sympathomimetic drug to treat people in vasodilatory shock states such as septic shock and neurogenic shock, while showing fewer adverse side-effects compared to dopamine treatment.

Mechanism of action
It stimulates α1 and α2 adrenergic receptors to cause blood vessel contraction, thus increases peripheral vascular resistance and resulted in increased blood pressure </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 Prasterone and can you explain it in depth? [/INST] Prasterone, also known as dehydroepiandrosterone (DHEA) and sold under the brand names Intrarosa, Diandrone, and Gynodian Depot among others, is a medication as well as over-the-counter dietary supplement which is used to correct DHEA deficiency due to adrenal insufficiency or old age, as a component of menopausal hormone therapy, to treat painful sexual intercourse due to vaginal atrophy, and to prepare the cervix for childbirth, among other uses. It is taken by mouth, by application to the skin, in through the vagina, or by injection into muscle.Side effects of prasterone in women include symptoms of masculinization like oily skin, acne, increased hair growth, voice changes, and increased sexual desire, headaches, insomnia, and others. The compound is a naturally occurring prohormone of androgens and estrogens and hence is an agonist of the androgen and estrogen receptors, the respective biological targets of androgens like testosterone and estrogens like estradiol. Prasterone also has a variety of activities of its own, including neurosteroid and other activities.DHEA, the active ingredient of prasterone, was discovered in 1934. An association between DHEA levels and aging was first reported in 1965. The compound started being used as a medication in the late 1970s and as a supplement in the early 1980s. The marketing of prasterone over-the-counter as a supplement is allowed in the United States but is banned in many other countries.

Medical uses
Deficiency
DHEA and DHEA sulfate (DHEA-S) are produced by the adrenal glands. In people with adrenal insufficiency such as in Addisons disease, there may be deficiency of DHEA and DHEA-S. In addition, levels of these steroids decrease throughout life and are 70 to 80% lower in the elderly relative to levels in young adults. Prasterone can be used to increase DHEA and DHEA-S levels in adrenal insufficiency and older age. Although there is deficiency of these steroids in such individuals, clinical benefits of supplementation, if any, are uncertain, and there is insufficient evidence at present to support the use of prasterone for such purposes.

Menopause
Prasterone is sometimes used as an androgen in menopausal hormone therapy. In addition to prasterone itself, a long-lasting ester prodrug of prasterone, prasterone enanthate, is used in combination with estradiol valerate for the treatment of menopausal symptoms under the brand name Gynodian Depot.

Vaginal atrophy
Prasterone, under the brand name Intrarosa, is approved in the United States in a vaginal insert formulation for the treatment of atrophic vaginitis. The mechanism of action of prasterone for this indication is unknown, though it may involve local metabolism of prasterone into androgens and estrogens.

Sexual desire
Prasterone has been used orally at a dosage of 10 mg/day to increase sexual desire in women.

Childbirth
As the sodium salt of prasterone sulfate (brand names Astenile, Mylis, Teloin), an ester prodrug of prasterone, prasterone is used in Japan as an injection for the treatment of insufficient cervical ripening and cervical dilation during childbirth.

Available forms
Prasterone was previously marketed as a pharmaceutical medication under the brand name Diandrone in the form of a 10 mg oral tablet in the United Kingdom.

Side effects
Prasterone is produced naturally in the human body, but the long-term effects of its use are largely unknown. In the short term, several studies have noted few adverse effects. In a study by Chang et al., prasterone was administered at a dose of 200 mg/day for 24 weeks with slight androgenic effects noted. Another study utilized a dose up to 400 mg/day for 8 weeks with few adverse events reported. A longer-term study followed patients dosed with 50 mg of prasterone for 12 months with the number and severity of side effects reported to be small. Another study delivered a dose of 50 mg of prasterone for 10 months with no serious adverse events reported.As a hormone precursor, there have been reports of side effects possibly caused by the hormone metabolites of prasterone.It is not known whether prasterone is safe for long-term use. Some researchers believe prasterone supplements might actually raise the risk of breast cancer, prostate cancer, heart disease, diabetes, and stroke. Prasterone may stimulate tumor growth in types of cancer that are sensitive to hormones, such as some types of breast, uterine, and prostate cancer. Prasterone may increase prostate swelling in men with benign prostatic hyperplasia (BPH), an enlarged prostate gland.Prasterone is a steroid hormone. High doses may cause aggressiveness, irritability, trouble sleeping, and the growth of body or facial hair on women. It also may stop menstruation and lower the levels of HDL cholesterol, which could raise the risk of heart disease. Other reported side effects include acne, heart rhythm problems, liver problems, hair loss (from the scalp), and oily skin. It may also alter the bodys regulation of blood sugar.Prasterone may promote tamoxifen resistance in breast cancer. It may also increase the risk of uterine and prostate cancers due to metabolism into estrogens and androgens, respectively. Patients on hormone replacement therapy may have more estrogen-related side effects when taking prasterone. This supplement may also interfere with other medicines, and potential interactions between it and drugs and herbs are possible.Prasterone is possibly unsafe for individuals experiencing pregnancy, breastfeeding, hormone sensitive conditions, liver problems, diabetes, depression or mood disorders, polycystic ovarian syndrome (PCOS), or cholesterol problems.Prasterone has been reported to possess few or no side effects even at very high dosages (e.g., 50 times the recommended over-the-counter supplement dosage). However, it may cause masculinization and other androgenic side effects in women and gynecomastia and other estrogenic side effects in men.

Pharmacokinetics
Oral uptake of prasterone is excellent. Its volume of distribution is 17.0-38.5L (whereas it is 8.5-9.3L for its active metabolite DHEA-S). Prasterone (DHEA) has a biological half-life of 15-38 min (whereas it is 7-22h for DHEA-S). 51-73% of DHEA-S and its metabolites are excreted via the renal route.

Prasterone is metabolized into androgens and estrogens in the body, including androstenedione, testosterone, estrone, estradiol, and estriol. The transformation of prasterone into androgens and estrogens is tissue-specific, for instance occurring in the liver, fat, vagina, prostate gland, skin, and hair follicles (as well as other tissues).

Metabolism
Prasterone is also reversibly transformed into its active metabolite prasterone sulfate (DHEA-S) by steroid sulfotransferase (specifically SULT1E1 and SULT2A1), which in turn can be converted back into prasterone by steroid sulfatase. Interconversion takes place in both adrenal and peripheral tissues.It is transformed into androstenedione by 3β-hydroxysteroid dehydrogenase (3β-HSD), and into androstenediol by 17β-hydroxysteroid dehydrogenase (17β-HSD). Then, androstenedione and androstenediol can be converted into testosterone by 17β-HSD and 3β-HSD, respectively. Subsequently, testosterone can be metabolized into dihydrotestosterone by 5α-reductase.In addition, androstenedione and testosterone can be converted into estrone and estradiol by aromatase, respectively.

Dose-response of hormone levels
At a high dosage of 1,600 mg/day orally for 4 weeks, treatment of postmenopausal women with prasterone has been found to increase serum levels of DHEA by 15-fold, testosterone by 9-fold, DHEA-S, androstenedione, and DHT all by 20-fold, and estrone and estradiol both by 2-fold.Although prasterone can reliably increase testosterone levels in women, this isnt similarly the case in men. A high dosage of 1,600 mg/day prasterone in men for 4 weeks was found to increase DHEA and androstenedione levels but did not significantly affect testosterone levels.

Dosing
In clinical studies of prasterone supplementation, dosages have ranged from 20 to 1,600 mg per day.In people with adrenal insufficiency, oral dosages of 20 to 50 mg/day prasterone have been found to restore DHEA and DHEA-S levels to physiological levels seen in young healthy adults. Conversely, oral dosages of 100 to 200 mg/day prasterone have been found to result in supraphysiological levels of DHEA and DHEA-S.Micronization of prasterone has been found to significantly increase levels of DHEA-S achieved with oral administration, but to produce no significant change in levels of DHEA or testosterone levels achieved.

Chemistry
Prasterone, also known as androst-5-en-3β-ol-17-one, is a naturally occurring androstane steroid and a 17-ketosteroid. It is closely related structurally to androstenediol (androst-5-ene-3β,17β-diol), androstenedione (androst-4-ene-3,17-dione), and testosterone (androst-4-en-17β-ol-3-one). Prasterone is the δ5 (5(6)-dehydrogenated) analogue of epiandrosterone (5α-androstan-3β-ol-17-one), and is also known as 5-dehydroepiandrosterone (5-DHEA) or δ5-epiandrosterone. A positional isomer of prasterone which may have similar biological activity is 4-dehydroepiandrosterone (4-DHEA).

Derivatives
Prasterone is used medically as the C3β esters prasterone enanthate and prasterone sulfate. The C19 demethyl analogue of prasterone is 19-nordehydroepiandrosterone (19-nor-DHEA), which is a prohormone of nandrolone (19-nortestosterone). The 5α-reduced and δ1 (1(2)-dehydrogenated) analogue of prasterone is 1-dehydroepiandrosterone (1-DHEA or 1-androsterone), which is a prohormone of 1-testosterone (δ1-DHT or dihydroboldenone). Fluasterone (3β-dehydroxy-16α-fluoro-DHEA) is a derivative of prasterone with minimal or no hormonal activity but other biological activities preserved.

History
DHEA was discovered, via isolation from male urine, by Adolf Butenandt and Hans Dannenbaum in 1934, and the compound was isolated from human blood plasma by Migeon and Plager in 1954. DHEA sulfate, the 3β-sulfate ester of DHEA, was isolated from urine in 1944, and was found by Baulieu to be the most abundant steroid hormone in human plasma in 1954. From its discovery in 1934 until 1959, DHEA was referred to by a number of different names in the literature, including dehydroandrosterone, transdehydroandrosterone, dehydroisoandrosterone, and androstenolone. The name dehydroepiandrosterone, also known as DHEA, was first proposed by Fieser in 1949, and subsequently became the most commonly used name of the hormone. For decades after its discovery, DHEA was considered to be an inactive compound that served mainly as an intermediate in the production of androgens and estrogens from cholesterol. In 1965, an association between DHEA sulfate levels and aging was reported by De Nee and Vermeulen. Following this, DHEA became of interest to the scientific community, and numerous studies assessing the relationship between DHEA and DHEA sulfate levels and aging were conducted.Prasterone, the proposed INN and recommended INN of DHEA and the term used when referring to the compound as a medication, were published in 1970 and 1978, respectively. The combination of 4 mg estradiol valerate and 200 mg prasterone enanthate in an oil solution was introduced for use in menopausal hormone therapy by intramuscular injection under the brand name Gynodian Depot in Europe by 1978. In the early 1980s, prasterone became available and was widely sold over-the-counter as a non-prescription supplement in the United States, primarily as a weight loss aid. It was described as a "miracle drug", with supposed anti-aging, anti-obesity, and anti-cancer benefits. This continued until 1985, when the marketing of prasterone was banned by the Food and Drug Administration (FDA) due to a lack of evidence for health benefits and due to the long-term safety and risks of the compound being unknown at the time. Subsequently, prasterone once again became available over-the-counter as a dietary supplement in the United States following the passage of the Dietary Supplement Health and Education Act of 1994. Conversely, it has remained banned as a supplement in Canada, the United Kingdom, Australia, and New Zealand.In 2001, Genelabs submitted a New Drug Application of prasterone for the treatment of systemic lupus erythematosus (SLE) to the FDA. It had the tentative brand names Anastar, Aslera, and Prestara. However, this application was not approved, and while development of prasterone for SLE in both the United States and Europe continued until up to 2010, the medication was ultimately never approved for the treatment of this condition. In 2016, the FDA approved prasterone in an intravaginal gel formulation for the treatment of painful sexual intercourse due to vulvovaginal atrophy in the United States under the brand name Intrarosa. This was the first prasterone-containing medication to be approved by the FDA in this country.

Society and culture
Generic names
Prasterone is the generic name of DHEA in English and Italian and its International Nonproprietary Name, United States Adopted Name and Italian Common Name, while its generic name is prasteronum in Latin, prastérone in French and its French popular name, and prasteron in German.

Marketing
In the United States, prasterone or prasterone sulfate have been advertised, under the names DHEA and DHEA-S, with claims that they may be beneficial for a wide variety of ailments. Prasterone and prasterone sulfate are readily available in the United States, where they are sold as over-the-counter dietary supplements.In 1996, reporter Harry Wessel of the Orlando (Florida) Sentinel wrote about DHEA that "Thousands of people have gotten caught up in the hoopla and are buying the stuff in health food stores, pharmacies and mail-order catalogs" but that "such enthusiasm is viewed as premature by many in the medical field." He noted that "National publications such as  Time, Newsweek and USA Today have run articles recently about the hormone, while several major publishers have come out with books touting it." His column was widely syndicated and reprinted in other U.S. newspapers.
The product was being "widely marketed to and used by bodybuilders," Dr. Paul Donahue wrote in 2012 for King Features syndicate.

Regulation
By country
Australia
In Australia, a prescription is required to buy prasterone, where it is also comparatively expensive compared to off-the-shelf purchases in US supplement shops. Australian customs classify prasterone as an "anabolic steroid[s] or precursor[s]" and, as such, it is only possible to carry prasterone into the country through customs if one possesses an import permit which may be obtained if one has a valid prescription for the hormone.

Canada
In Canada, prasterone is a Controlled Drug listed under Section 23 of Schedule IV of the Controlled Drugs and Substances Act and as such is available by prescription only.

United Kingdom
Prasterone is listed as an anabolic steroid and is thus a class C controlled drug.

United States
Prasterone is legal to sell in the United States as a dietary supplement. It is currently grandfathered in as an "Old Dietary Ingredient" being on sale prior to 1994. Prasterone is specifically exempted from the Anabolic Steroid Control Act of 1990 and 2004.

Sports and athletics
Prasterone is banned from use in athletic competition.
 It is a prohibited substance under the World Anti-Doping Code of the World Anti-Doping Agency, which manages drug testing for Olympics and other sports.

Yulia Efimova, who holds the world record pace for both the 50-meter and 200-meter breaststroke, and won the bronze medal in the 200-meter breaststroke in the 2012 London Olympic Games, tested positive for prasterone in an out-of-competition doping test.
Rashard Lewis, then with the Orlando Magic, tested positive for prasterone and was suspended 10 games before the start of the 2009–10 season.
In 2016 MMA fighter Fabio Maldonado revealed he was taking prasterone during his time with the UFC.
In January 2011, NBA player O. J. Mayo was given a 10-game suspension after testing positive for prasterone. Mayo termed his use of prasterone as "an honest mistake," saying the prasterone was in an over-the-counter supplement and that he was unaware the supplement was banned by the NBA. Mayo was the seventh player to test positive for performance-enhancing drugs since the league began testing in 1999.
Olympic 400-meter champion Lashawn Merritt tested positive for prasterone in 2010 and was banned from the sport for 21 months.
Tennis player Venus Williams had permission from the International Tennis Federation to use DHEA along with hydrocortisone as a treatment for "adrenal insufficiency," but it was revoked in 2016 by the World Anti-Doping Agency, which believed DHEA use would enhance Williams athletic performance.

Research
Anabolic uses
A meta-analysis of intervention studies shows that prasterone supplementation in elderly men can induce a small but significant positive effect on body composition that is strictly dependent on prasterone conversion into its bioactive metabolites such as androgens or estrogens. Evidence is inconclusive in regards to the effect of prasterone on strength in the elderly. In middle-aged men, no significant effect of prasterone supplementation on lean body mass, strength, or testosterone levels was found in a randomized placebo-controlled trial.

Cancer
There is no evidence prasterone is of benefit in treating or preventing cancer.

Cardiovascular disease
A review in 2003 found the then-extant evidence sufficient to suggest that low serum levels of DHEA-S may be associated with coronary heart disease in men, but insufficient to determine whether prasterone supplementation would have any cardiovascular benefit.Prasterone may enhance G6PD mRNA expression, confounding its inhibitory effects.

Lupus
There is some evidence of short-term benefit in those with systemic lupus erythematosus but little evidence of long-term benefit or safety. Prasterone was under development for the treatment of systemic lupus erythematosus in the United States and Europe in the 1990s and 2000s and reached phase III clinical trials and preregistration for this indication, respectively, but ultimately development was not continued past 2010.

Memory
Prasterone supplementation has not been found to be useful for memory function in normal middle aged or older adults. It has been studied as a treatment for Alzheimers disease, but there is no evidence that it is effective or ineffective. More research is needed to determine its benefits.

Mood
A few small, short term clinical studies have found that prasterone improves mood but its long-term efficacy and safety, and how it compares to antidepressants, was unknown as of 2015.

References
Further reading
Keppel Hesselink JM (December 1997). "[Prasterone (dihydroepiandrosterone): a modern source of eternal youth?]". Ned Tijdschr Geneeskd (in Dutch). 141 (51): 2484–7. PMID 9555138.
Zelissen PM, Thijssen JH (October 2001). "[Role of prasterone (dehydroepiandrosterone) in substitution therapy for adrenocortical insufficiency]". Ned Tijdschr Geneeskd (in Dutch). 145 (42): 2018–22. PMID 11695098.
Pope, JE; Cupp, MJ; Tracy, TS (2003). Dehydroepiandrosterone (DHEA) (Prasterone). Dietary Supplements. Totowa, NJ: Humana Press. pp. 123–147. doi:10.1007/978-1-59259-303-3_8 (inactive 31 July 2022). ISBN 9781592593033.{{cite book}}:  CS1 maint: DOI inactive as of July 2022 (link)
Kocis P (November 2006). "Prasterone". Am J Health Syst Pharm. 63 (22): 2201–10. doi:10.2146/ajhp060100. PMID 17090740.
Mendivil Dacal JM, Borges VM (April 2009). "[Dehydroepiandrosterone (DHEA), review of its efficiency in the managing of the libido decrease and other symptoms of aging]". Actas Urol Esp (in Spanish). 33 (4): 390–401. doi:10.4321/s0210-48062009000400009. PMID 19579890.
Alkatib AA, Cosma M, Elamin MB, Erickson D, Swiglo BA, Erwin PJ, Montori VM (October 2009). "A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency". J. Clin. Endocrinol. Metab. 94 (10): 3676–81. doi:10.1210/jc.2009-0672. PMID 19773400.
Panjari M, Davis SR (June 2010). "DHEA for postmenopausal women: a review of the evidence". Maturitas. 66 (2): 172–9. doi:10.1016/j.maturitas.2009.12.017. PMID 20089375.
Oberbeck R, Kobbe P (2010). "Dehydroepiandrosterone (DHEA): a steroid with multiple effects. Is there any possible option in the treatment of critical illness?". Curr. Med. Chem. 17 (11): 1039–47. doi:10.2174/092986710790820570. PMID 20156161.
Prati A, Santagni S, Rattighieri E, Campedelli A, Ricchieri F, Chierchia E, Despini G, Genazzani AR, Genazzani AD (June 2014). "[The putative role and use of DHEA and its association with the hormone replacement therapy]". Minerva Ginecol (in Italian). 66 (3): 313–24. PMID 24971788.
Genazzani AR, Pluchino N (August 2010). "DHEA therapy in postmenopausal women: the need to move forward beyond the lack of evidence". Climacteric. 13 (4): 314–6. doi:10.3109/13697137.2010.492496. PMID 20540592. S2CID 5578070.
Luci M, Valenti G, Maggio M (September 2010). "[Dehydroepiandrosterone [DHEA(S)]: anabolic hormone?]". Recenti Prog Med (in Italian). 101 (9): 333–44. hdl:11381/2436727. PMID 21268370.
Gleicher N, Barad DH (May 2011). "Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR)". Reprod. Biol. Endocrinol. 9: 67. doi:10.1186/1477-7827-9-67. PMC 3112409. PMID 21586137.
Davis SR, Panjari M, Stanczyk FZ (June 2011). "Clinical review: DHEA replacement for postmenopausal women". J. Clin. Endocrinol. Metab. 96 (6): 1642–53. doi:10.1210/jc.2010-2888. PMID 21411558.
Panjari M, Davis SR (September 2011). "Vaginal DHEA to treat menopause related atrophy: a review of the evidence". Maturitas. 70 (1): 22–5. doi:10.1016/j.maturitas.2011.06.005. PMID 21733647.
Traish AM, Kang HP, Saad F, Guay AT (November 2011). "Dehydroepiandrosterone (DHEA)--a precursor steroid or an active hormone in human physiology". J Sex Med. 8 (11): 2960–82, quiz 2983. doi:10.1111/j.1743-6109.2011.02523.x. PMID 22032408.
Savineau JP, Marthan R, Dumas de la Roque E (March 2013). "Role of DHEA in cardiovascular diseases". Biochem. Pharmacol. 85 (6): 718–26. doi:10.1016/j.bcp.2012.12.004. PMID 23270992.
Labrie F, Labrie C (April 2013). "DHEA and intracrinology at menopause, a positive choice for evolution of the human species". Climacteric. 16 (2): 205–13. doi:10.3109/13697137.2012.733983. PMID 23126249. S2CID 6546179.
Rutkowski K, Sowa P, Rutkowska-Talipska J, Kuryliszyn-Moskal A, Rutkowski R (July 2014). "Dehydroepiandrosterone (DHEA): hypes and hopes". Drugs. 74 (11): 1195–207. doi:10.1007/s40265-014-0259-8. PMID 25022952. S2CID 26554413.
Peixoto C, Devicari Cheda JN, Nardi AE, Veras AB, Cardoso A (2014). "The effects of dehydroepiandrosterone (DHEA) in the treatment of depression and depressive symptoms in other psychiatric and medical illnesses: a systematic review". Curr Drug Targets. 15 (9): 901–14. doi:10.2174/1389450115666140717111116. PMID 25039497.
Elraiyah T, Sonbol MB, Wang Z, Khairalseed T, Asi N, Undavalli C, Nabhan M, Altayar O, Prokop L, Montori VM, Murad MH (October 2014). "Clinical review: The benefits and harms of systemic dehydroepiandrosterone (DHEA) in postmenopausal women with normal adrenal function: a systematic review and meta-analysis". J. Clin. Endocrinol. Metab. 99 (10): 3536–42. doi:10.1210/jc.2014-2261. PMC 5393492. PMID 25279571.
Maggio M, De Vita F, Fisichella A, Colizzi E, Provenzano S, Lauretani F, Luci M, Ceresini G, DallAglio E, Caffarra P, Valenti G, Ceda GP (January 2015). "DHEA and cognitive function in the elderly". J. Steroid Biochem. Mol. Biol. 145: 281–92. doi:10.1016/j.jsbmb.2014.03.014. PMID 24794824. S2CID 33768697.
Pluchino N, Drakopoulos P, Bianchi-Demicheli F, Wenger JM, Petignat P, Genazzani AR (January 2015). "Neurobiology of DHEA and effects on sexuality, mood and cognition". J. Steroid Biochem. Mol. Biol. 145: 273–80. doi:10.1016/j.jsbmb.2014.04.012. PMID 24892797. S2CID 12382989.
Warner M, Gustafsson JA (January 2015). "DHEA - a precursor of ERβ ligands". J. Steroid Biochem. Mol. Biol. 145: 245–7. doi:10.1016/j.jsbmb.2014.08.003. PMID 25125389. S2CID 26043868.
Lang K, Burger-Stritt S, Hahner S (January 2015). "Is DHEA replacement beneficial in chronic adrenal failure?". Best Pract. Res. Clin. Endocrinol. Metab. 29 (1): 25–32. doi:10.1016/j.beem.2014.09.007. PMID 25617170.
Vuksan-Ćusa B, Šagud M, Radoš I (March 2016). "The role of dehydroepiandrosterone (DHEA) in schizophrenia". Psychiatr Danub. 28 (1): 30–3. PMID 26938818.
Prough RA, Clark BJ, Klinge CM (April 2016). "Novel mechanisms for DHEA action". J. Mol. Endocrinol. 56 (3): R139–55. doi:10.1530/JME-16-0013. PMID 26908835.
Qin JC, Fan L, Qin AP (May 2016). "The effect of dehydroepiandrosterone (DHEA) supplementation on women with diminished ovarian reserve (DOR) in IVF cycle: Evidence from a meta-analysis". J Gynecol Obstet Biol Reprod (Paris). 46: 1–7. doi:10.1016/j.jgyn.2016.01.002. PMID 27212610.
Ohnaka K (July 2016). "[Dehydroepiandrosterone (DHEA) and bone metabolism]". Clin Calcium (in Japanese). 26 (7): 987–93. PMID 27346309.
Handelsman DJ, Matsumoto AM, Gerrard DF (January 2017). "Doping Status of DHEA Treatment for Female Athletes with Adrenal Insufficiency". Clin J Sport Med. 27 (1): 78–85. doi:10.1097/JSM.0000000000000300. PMID 26844622. S2CID 24168278.
Qin JC, Fan L, Qin AP (January 2017). "The effect of dehydroepiandrosterone (DHEA) supplementation on women with diminished ovarian reserve (DOR) in IVF cycle: Evidence from a meta-analysis". J Gynecol Obstet Hum Reprod. 46 (1): 1–7. doi:10.1016/j.jgyn.2016.01.002. PMID 28403950.
Labrie F, Martel C, Bélanger A, Pelletier G (April 2017). "Androgens in women are essentially made from DHEA in each peripheral tissue according to intracrinology". J. Steroid Biochem. Mol. Biol. 168: 9–18. doi:10.1016/j.jsbmb.2016.12.007. PMID 28153489. S2CID 2620899.
Triantafyllidou O, Sigalos G, Vlahos N (June 2017). "Dehydroepiandrosterone (DHEA) supplementation and IVF outcome in poor responders". Hum Fertil (Camb). 20 (2): 80–87. doi:10.1080/14647273.2016.1262065. PMID 27927044. S2CID 3425127.
Archer DF, Labrie F, Montesino M, Martel C (November 2017). "Comparison of intravaginal 6.5mg (0.50%) prasterone, 0.3mg conjugated estrogens and 10μg estradiol on symptoms of vulvovaginal atrophy". J </s>


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<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 Fulvestrant and can you explain it in depth? [/INST] Fulvestrant, sold under the brand name Faslodex among others, is a medication used to treat hormone receptor (HR)-positive metastatic breast cancer in postmenopausal women with disease progression as well as HR-positive, HER2-negative advanced breast cancer in combination with palbociclib in women with disease progression after endocrine therapy. It is given by injection into a muscle.Fulvestrant is a selective estrogen receptor degrader (SERD) and was first-in-class to be approved. It works by binding to the estrogen receptor and destabilizing it, causing the cells normal protein degradation processes to destroy it.Fulvestrant was approved for medical use in the United States in 2002.

Medical uses
Breast cancer
Fulvestrant is used for the treatment of hormone receptor positive metastatic breast cancer or locally advanced unresectable disease in postmenopausal women; it is given by injection. A 2017 Cochrane review found it is as safe and effective as first line or second line endocrine therapy.It is also used to treat ER-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib in women with disease progression after first-line endocrine therapy.Due to the medications having a chemical structure similar to that of estrogen, it can interact with immunoassays for blood estradiol concentrations and show falsely elevated results. This can improperly lead to discontinuing the treatment.

Early puberty
Fulvestrant has been used in the treatment of peripheral precocious puberty in girls with McCune–Albright syndrome.

Available forms
Fulvestrant is provided in a castor oil solution also containing alcohol, benzyl alcohol, and benzyl benzoate. It is supplied at a concentration of 250 mg/5 mL.

Contraindications
Fulvestrant should not be used in women with kidney failure or who are pregnant.

Side effects
Very common (occurring in more than 10% of people) adverse effects include nausea, injection site reactions, weakness, and elevated transaminases. Common (between 1% and 10%) adverse effects include urinary tract infections, hypersensitivity reactions, loss of appetite, headache, blood clots in veins, hot flushes, vomiting, diarrhea, elevated bilirubin, rashes, and back pain. In a large clinical trial, the incidence of venous thromboembolism (VTE) with fulvestrant was 0.9%.

Pharmacology
Pharmacodynamics
Fulvestrant is an antiestrogen which acts as an antagonist of the estrogen receptor (ER) and additionally as a selective estrogen receptor degrader (SERD). It works by binding to the estrogen receptor and making it more hydrophobic, which makes the receptor unstable and misfold, which in turn leads normal processes inside the cell to degrade it.In addition to its antiestrogenic activity, fulvestrant is an agonist of the G protein-coupled estrogen receptor (GPER), albeit with relatively low affinity (10–100 nM, relative to 3–6 nM for estradiol).

Pharmacokinetics
Fulvestrant after an intramuscular injection is slowly absorbed and maximal levels (Cmax) are reached after 5 days on average with a range of 2 to 19 days. The elimination half-life of fulvestrant with intramuscular injection is 40 to 50 days. This is 40 times longer than the half-life of fulvestrant by intravenous injection, indicating that its long half-life with intramuscular injection is due to slow absorption from the injection site. Levels of fulvestrant with 500 mg/month by intramuscular injection (and a single additional 500 mg loading dose on day 15 of therapy) in postmenopausal women with advanced breast cancer were 25.1 ng/mL (25,100 pg/mL) at peak and 28.0 ng/mL (28,000 pg/mL) at trough with a single dose and 28.0 ng/mL (28,000 pg/mL) at peak and 12.2 ng/mL (12,200 pg/mL) at trough after multiple doses at steady state.Fulvestrant does not cross the blood–brain barrier in animals and may not in humans as well. Accordingly, no effects of fulvestrant on brain function have been observed in preclinical or clinical research. Fulvestrant is highly (99%) bound to plasma proteins. It is bound to very low density lipoprotein, low density lipoprotein, and high density lipoprotein, but not to sex hormone-binding globulin.Fulvestrant appears to be metabolized along similar pathways as endogenous steroids; CYP3A4 may be involved, but non-cytochrome P450 routes appear to be more important. It does not inhibit any cytochrome P450 enzymes. Elimination is almost all via feces.Fulvestrant can form colloidal aggregates at certain concentration ranges and this can limit its activity as well as produce bell-shaped concentration–response curves.

Chemistry
Fulvestrant, also known as 7α-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estradiol, is a synthetic estrane steroid and a derivative of estradiol. An alkyl-sulfinyl moiety was added to the endogenous estrogen receptor ligand.It was discovered through rational drug design, but was selected for further development via phenotypic screening.

History
Fulvestrant was the first selective estrogen receptor degrader to be approved. It was approved in the United States in 2002 and in Europe in 2004.

Society and culture
NICE evaluation
The U.K. National Institute for Health and Clinical Excellence (NICE) said in 2011 that it found no evidence Faslodex was significantly better than existing treatments, so its widespread use would not be a good use of resources for the countrys National Health Service. The first months treatment of Faslodex, which starts with a loading dose, costs £1,044.82 ($1,666), and subsequent treatments cost £522.41 a month </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 Ciltacabtagene autoleucel 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 Eflornithine and can you explain it in depth? [/INST] Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis (sleeping sickness) and excessive hair growth on the face in women. Specifically it is used for the 2nd stage of sleeping sickness caused by T. b. gambiense and may be used with nifurtimox. It is used by injection or applied to the skin.Common side effects when applied as a cream include rash, redness, and burning. Side effects of the injectable form include bone marrow suppression, vomiting, and seizures. It is unclear if it is safe to use during pregnancy or breastfeeding. It is recommended typically for children over the age of 12.Eflornithine was developed in the 1970s and came into medical use in 1990. It is on the World Health Organizations List of Essential Medicines. In the United States the injectable form can be obtained from the Centers for Disease Control and Prevention. In regions of the world where the disease is common eflornithine is provided for free by the World Health Organization.

Medical uses
Sleeping sickness
Sleeping sickness, or trypanosomiasis, is treated with pentamidine or suramin (depending on subspecies of parasite) delivered by intramuscular injection in the first phase of the disease, and with melarsoprol and eflornithine intravenous injection in the second phase of the disease. Efornithine is commonly given in combination with nifurtimox, which reduces the treatment time to 7 days of eflornithine infusions plus 10 days of oral nifurtimox tablets.Eflornithine is also effective in combination with other drugs, such as melarsoprol and nifurtimox. A study in 2005 compared the safety of eflornithine alone to melarsoprol and found eflornithine to be more effective and safe in treating second-stage sleeping sickness Trypanosoma brucei gambiense. Eflornithine is not effective in the treatment of Trypanosoma brucei rhodesiense due to the parasites low sensitivity to the drug. Instead, melarsoprol is used to treat Trypanosoma brucei rhodesiense. Another randomized control trial in Uganda compared the efficacy of various combinations of these drugs and found that the nifurtimox-eflornithine combination was the most promising first-line theory regimen.A randomized control trial was conducted in Congo, Côte dIvoire, the Democratic Republic of the Congo, and Uganda to determine if a 7-day intravenous regimen was as efficient as the standard 14-day regimen for new and relapsing cases. The results showed that the shortened regimen was efficacious in relapse cases, but was inferior to the standard regimen for new cases of the disease.Nifurtimox-eflornithine combination treatment (NECT) is an effective regimen for the treatment of second stage gambiense African trypanosomiasis.

Trypanosome resistance
After its introduction to the market in the 1980s, eflornithine has replaced melarsoprol as the first line medication against Human African trypanosomiasis (HAT) due to its reduced toxicity to the host. Trypanosoma brucei resistant to eflornithine was reported as early as the mid-1980s.The gene TbAAT6, conserved in the genome of Trypanosomes, is believed to be responsible for the transmembrane transporter that brings eflornithine into the cell. The loss of this gene due to specific mutations causes resistance to eflornithine in several trypanosomes. If eflornithine is prescribed to a patient with Human African trypanosomiasis caused by a trypanosome that contains a mutated or ineffective TbAAT6 gene, then the medication will be ineffective against the disease. Resistance to eflornithine has increased the use of melarsoprol despite its toxicity, which has been linked to the deaths of 5% of recipient HAT patients.

Excess facial hair in women
The topical cream is indicated for treatment of facial hirsutism in women. It is the only topical prescription treatment that slows the growth of facial hair. It is applied in a thin layer twice daily, a minimum of eight hours between applications. In clinical studies with Vaniqa, 81% percent of women showed clinical improvement after twelve months of treatment. Positive results were seen after eight weeks. However, discontinuation of the cream caused regrowth of hair back to baseline levels within 8 weeks.Vaniqa treatment significantly reduces the psychological burden of facial hirsutism.

Chemo preventative therapy
It has been noted that ornithine decarboxylase (ODC) exhibits high activity in tumor cells, promoting cell growth and division, while absence of ODC activity leads to depletion of putrescine, causing impairment of RNA and DNA synthesis. Typically, drugs that inhibit cell growth are considered candidates for cancer therapy, so eflornithine was naturally believed to have potential utility as an anti-cancer agent. By inhibiting ODC, eflornithine inhibits cell growth and division of both cancerous and noncancerous cells.
However, several clinical trials demonstrated minor results. It was found that inhibition of ODC by eflornithine does not kill proliferating cells, making eflornithine ineffective as a chemotherapeutic agent. The inhibition of the formation of polyamines by ODC activity can be ameliorated by dietary and bacterial means because high concentrations are found in cheese, red meat, and some intestinal bacteria, providing reserves if ODC is inhibited. Although the role of polyamines in carcinogenesis is still unclear, polyamine synthesis has been supported to be more of a causative agent rather than an associative effect in cancer.Other studies have suggested that eflornithine can still aid in some chemoprevention by lowering polyamine levels in colorectal mucosa, with additional strong preclinical evidence available for application of eflornithine in colorectal and skin carcinogenesis. This has made eflornithine a supported chemopreventive therapy specifically for colon cancer in combination with other medications. Several additional studies have found that eflornithine in combination with other compounds decreases the carcinogen concentrations of ethylnitrosourea, dimethylhydrazine, azoxymethane, methylnitrosourea, and hydroxybutylnitrosamine in the brain, spinal cord, intestine, mammary gland, and urinary bladder.

Contraindications
Topical
Topical use is contraindicated in people hypersensitive to eflornithine or to any of the excipients.Throughout clinical trials, data from a limited number of exposed pregnancies indicate that there is no clinical evidence that treatment with Vaniqa adversely affects pregnant women or fetuses.

By mouth
When taken by mouth the risk-benefit should be assessed in people with impaired renal function or pre-existing hematologic abnormalities, as well as those with eighth-cranial-nerve impairment.
Adequate and well-controlled studies with eflornithine have not been performed regarding pregnancy in humans. Eflornithine should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus. However, since African trypanosomiasis has a high mortality rate if left untreated, treatment with eflornithine may justify any potential risk to the fetus.

Side effects
Eflornithine is not genotoxic; no tumour-inducing effects have been observed in carcinogenicity studies, including one photocarcinogenicity study. No teratogenic effects have been detected.

Topical
The topical form of elflornithine is sold under the brand name Vaniqa. The most frequently reported side effect is acne (7–14%). Other side effects commonly (> 1%) reported are skin problems, such as skin reactions from in-growing hair, hair loss, burning, stinging or tingling sensations, dry skin, itching, redness or rash.

Intravenous
The intravenous dosage form of eflornithine is sold under the brand name Ornidyl. Most side effects related to systemic use through injection are transient and reversible by discontinuing the drug or decreasing the dose. Hematologic abnormalities occur frequently, ranging from 10 to 55%. These abnormalities are dose-related and are usually reversible. Thrombocytopenia is thought to be due to a production defect rather than to peripheral destruction. Seizures were seen in approximately 8% of patients, but may be related to the disease state rather than the drug. Reversible hearing loss has occurred in 30–70% of patients receiving long-term therapy (more than 4–8 weeks of therapy or a total dose of >300 grams); high-frequency hearing is lost first, followed by middle- and low-frequency hearing. Because treatment for African trypanosomiasis is short-term, patients are unlikely to experience hearing loss.

Interactions
Topical
No interaction studies with the topical form have been performed.

Mechanism of action
Description
Eflornithine is a "suicide inhibitor," irreversibly binding to ornithine decarboxylase (ODC) and preventing the natural substrate ornithine from accessing the active site (Figure 1). Within the active site of ODC, eflornithine undergoes decarboxylation with the aid of cofactor pyridoxal 5-phosphate (PLP). Because of its additional difluoromethyl group in comparison to ornithine, eflornithine is able to bind to a neighboring Cys-360 residue, permanently remaining fixated within the active site.During the reaction, eflornithines decarboxylation mechanism is analogous to that of ornithine in the active site, where transamination occurs with PLP followed by decarboxylation. During the event of decarboxylation, the fluoride atoms attached to the additional methyl group pull the resulting negative charge from the release of carbon dioxide, causing a fluoride ion to be released. In the natural substrate of ODC, the ring of PLP accepts the electrons that result from the release of CO2.
The remaining fluoride atom that resides attached to the additional methyl group creates an electrophilic carbon that is attacked by the nearby thiol group of Cys-360, allowing eflornithine to remain permanently attached to the enzyme following the release of the second fluoride atom and transimination.

Evidence
The reaction mechanism of Trypanosoma bruceis ODC with ornithine was characterized by UV-VIS spectroscopy in order to identify unique intermediates that occurred during the reaction. The specific method of multiwavelength stopped-flow spectroscopy utilized monochromatic light and fluorescence to identify five specific intermediates due to changes in absorbance measurements. The steady-state turnover number, kcat, of ODC was calculated to be 0.5 s−1 at 4 °C. From this characterization, the rate-limiting step was determined to be the release of the product putrescine from ODCs reaction with ornithine.
In studying the hypothetical reaction mechanism for eflornithine, information collected from radioactive peptide and eflornithine mapping, high pressure liquid chromatography, and gas phase peptide sequencing suggested that Lys-69 and Cys-360 are covalently bound to eflornithine in T. brucei ODCs active site. Utilizing fast-atom bombardment mass spectrometry (FAB-MS), the structural conformation of eflornithine following its interaction with ODC was determined to be (S)-((2-(1-pyrroline-methyl) cysteine, a cyclic imine adduct. Presence of this particular product was supported by the possibility to further reduce the end product to (S)-((2-pyrrole) methyl) cysteine in the presence of NaBH4 and oxidize the end product to (S)-((2-pyrrolidine) methyl) cysteine (Figure 2).

Active site
Eflornithines suicide inhibition of ODC physically blocks the natural substrate ornithine from accessing the active site of the enzyme (Figure 3). There are two distinct active sites formed by the homodimerization of ornithine decarboxylase. The size of the opening to the active site is approximately 13.6 Å. When these openings to the active site are blocked, there are no other ways through which ornithine can enter the active site. During the intermediate stage of eflornithine with PLP, its position near Cys-360 allows an interaction to occur. As the phosphate of PLP is stabilized by Arg 277 and a Gly-rich loop (235-237), the difluoromethyl group of eflornithine is able to interact and remain fixated to both Cys-360 and PLP prior to transimination.
As shown in the figure, the pyrroline ring interferes with ornithines entry (Figure 4). Eflornithine will remain permanently bound in this position to Cys-360. As ODC has two active sites, two eflornithine molecules are required to completely inhibit ODC from ornithine decarboxylation.

History
Eflornithine was initially developed for cancer treatment at Merrell Dow Research Institute in the late 1970s, but was found to be ineffective in treating malignancies. However, it was discovered to be highly effective in reducing hair growth, as well as in the treatment of  African trypanosomiasis (sleeping sickness), especially the West African form (Trypanosoma brucei gambiense).

Hirsutism
In the 1980s, Gillette was awarded a patent for the discovery that topical application of eflornithine HCl cream inhibits hair growth. In the 1990s, Gillette conducted dose-ranging studies with eflornithine in hirsute women that demonstrated that the drug slows the rate of facial hair growth. Gillette then filed a patent for the formulation of eflornithine cream. In July 2000, the U.S. Food and Drug Administration (FDA) granted a New Drug Application for Vaniqa. The following year, the European Commission issued its Marketing Authorisation.

Sleeping sickness treatment
The drug was registered for the treatment of gambiense sleeping sickness on November 28, 1990. However, in 1995 Aventis (now Sanofi-Aventis) stopped producing the drug, whose main market was African countries, because it did not make a profit.In 2001, Aventis and the WHO formed a five-year partnership, during which more than 320,000 vials of pentamidine, over 420,000 vials of melarsoprol, and over 200,000 bottles of eflornithine were produced by Aventis, to be given to the WHO and distributed by the association Médecins sans Frontières (also known as Doctors Without Borders) in countries where sleeping sickness is endemic.
According to Médecins sans Frontières, this only happened after "years of international pressure," and coinciding with the period when media attention was generated because of the launch of another eflornithine-based product (Vaniqa, for the prevention of facial-hair in women), while its life-saving formulation (for sleeping sickness) was not being produced.
From 2001 (when production was restarted) through 2006, 14 million diagnoses were made. This greatly contributed to stemming the spread of sleeping sickness, and to saving nearly 110,000 lives.

Society and culture
Available forms
Vaniqa is a cream, which is white to off-white in colour. It is supplied in tubes of 30 g and 60 g in Europe. Vaniqa contains 15% w/w eflornithine hydrochloride monohydrate, corresponding to 11.5% w/w anhydrous eflornithine (EU), respectively 13.9% w/w anhydrous eflornithine hydrochloride (U.S.), in a cream for topical administration.
Ornidyl, intended for injection, was supplied in the strength of 200 mg eflornithine hydrochloride per ml.

Market
Vaniqa, granted marketing approval by the US FDA, as well as by the European Commission among others, is currently the only topical prescription treatment that slows the growth of facial hair. Besides being a non-mechanical and non-cosmetic treatment, it is the only non-hormonal and non-systemic prescription option available for women with facial hirsutism. Vaniqa is marketed by Almirall in Europe, SkinMedica in the US, Triton in Canada, Medison in Israel, and Menarini in Australia.Ornidyl, the injectable form of eflornithine hydrochloride, is licensed by Sanofi-Aventis, but is currently discontinued in the US.

In other animals
Eflornithine is effective in mice </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 Bromocriptine and can you explain it in depth? [/INST] Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinsons disease, hyperprolactinaemia, neuroleptic malignant syndrome, and, as an adjunct, type 2 diabetes.
It was patented in 1968 and approved for medical use in 1975.

Medical uses
Bromocriptine is used to treat acromegaly and conditions associated with hyperprolactinemia like amenorrhea, infertility, hypogonadism, and prolactin-secreting adenomas. It is also used to prevent ovarian hyperstimulation syndrome and to treat Parkinsons disease.Since the late 1980s it has been used, off-label, to reduce the symptoms of cocaine withdrawal but the evidence for this use is poor.A quick-release formulation of bromocriptine, Cycloset, is also used to treat type 2 diabetes. When administered within 2 hours of awakening, it increases hypothalamic dopamine level and as a result decreases hepatic glucose production. It therefore acts as an adjunct to diet and exercise to improve glycemic control.

Side effects
Most frequent side effects are nausea, orthostatic hypotension, headaches, and vomiting through stimulation of the brainstem vomiting centre </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 Mitomycins and can you explain it in depth? [/INST] The mitomycins are a family of aziridine-containing natural products isolated from Streptomyces caespitosus or Streptomyces lavendulae. They include mitomycin A, mitomycin B, and mitomycin C. When the name mitomycin occurs alone, it usually refers to mitomycin C, its international nonproprietary name. Mitomycin C is used as a medicine for treating various disorders associated with the growth and spread of cells.

Biosynthesis
In general, the biosynthesis of all mitomycins proceeds via combination of 3-amino-5-hydroxybenzoic acid (AHBA), D-glucosamine, and carbamoyl phosphate, to form the mitosane core, followed by specific tailoring steps </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 Insulin lispro and can you explain it in depth? [/INST] Insulin lispro, sold under the brand name Humalog among others, is a modified type of medical insulin used to treat type 1 and type 2 diabetes. Typically it is taken around the time of eating. It is used by injection under the skin or within an insulin pump. Onset of effects typically occurs within 30 minutes and lasts about 5 hours. Often a longer-acting insulin like insulin NPH is also needed.Common side effects include low blood sugar. Other serious side effects may include low blood potassium. Use in pregnancy and breastfeeding is generally safe. It works the same as human insulin by increasing the amount of glucose that tissues take in and decreasing the amount of glucose made by the liver.Insulin lispro was first approved for use in the United States in 1996. It is a manufactured form of human insulin where an amino acid has been switched. In 2019, it was the 65th most commonly prescribed medication in the United States, with more than 11 million prescriptions.

Medical uses
Insulin lispro is used to treat people with type 1 diabetes or type 2 diabetes. People doing well on regular insulin should not generally be changed to insulin lispro.

Side effects
Common side effects include skin irritation at the site of injection, hypoglycemia, hypokalemia, and lipodystrophy </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 Methocarbamol and can you explain it in depth? [/INST] Methocarbamol, sold under the brand name Robaxin among others, is a medication used for short-term musculoskeletal pain. It may be used together with rest, physical therapy, and pain medication. It is less preferred in low back pain. It has limited use for rheumatoid arthritis and cerebral palsy. Effects generally begin within half an hour. It is taken by mouth or injection into a vein.Common side effect include headaches, sleepiness, and dizziness. Serious side effects may include anaphylaxis, liver problems, confusion, and seizures. Use is not recommended in pregnancy and breastfeeding. Because of risk of injury, skeletal muscle relaxants should generally be avoided in geriatric patients. Methocarbamol is a centrally acting muscle relaxant. How it works is unclear, but it does not appear to affect muscles directly.Methocarbamol was approved for medical use in the United States in 1957. It is available as a generic medication. It is relatively inexpensive as of 2016. In 2019, it was the 136th most commonly prescribed medication in the United States, with more than 4 million prescriptions.

Medical use
Methocarbamol is a muscle relaxant used to treat acute, painful musculoskeletal spasms in a variety of musculoskeletal conditions. However, there is limited and inconsistent published research on the medications efficacy and safety in treating musculoskeletal conditions, primarily neck and back pain.Methocarbamol injection may have a beneficial effect in the control of the neuromuscular spasms of tetanus. It does not, however, replace the current treatment regimen.It is not useful in chronic neurological disorders, such as cerebral palsy or other dyskinesias.Currently, there is some suggestion that muscle relaxants may improve the symptoms of rheumatoid arthritis; however, there is insufficient data to prove its effectiveness as well as answer concerns regarding optimal dosing, choice of muscle relaxant, adverse effects, and functional status.

Comparison to similar agents
The clinical effectiveness of methocarbamol compared to other muscle relaxants is not well-known. One trial of methocarbamol versus cyclobenzaprine, a well-studied muscle relaxant, in those with localized muscle spasm found there was no significant differences in their effects on improved muscle spasm, limitation of motion, or limitation of daily activities.

Contraindications
There are few contraindications to methocarbamol. They include:

Hypersensitivity to methocarbamol or to any of the injection components.
For the injectable form, suspected kidney failure or renal pathology, due to large content of polyethylene glycol 300 that can increase pre-existing acidosis and urea retention.

Side effects
Methocarbamol is a centrally acting skeletal muscle relaxant that has significant adverse effects, especially on the central nervous system.Potential side effects of methocarbamol include:

Most commonly drowsiness, blurred vision, headache, nausea, and skin rash.
Possible clumsiness (ataxia), upset stomach, flushing, mood changes, trouble urinating, itchiness, and fever.
Both tachycardia (fast heart rate) and bradycardia (slow heart rate) have been reported.
Hypersensitivity reactions and anaphylatic reactions are also reported.
May cause respiratory depression when combined with benzodiazepines, barbiturates, codeine, or other muscle relaxants.
May cause urine to turn black, blue or green.While the product label states that methocarbamol can cause jaundice, there is minimal evidence to suggest that methocarbamol causes liver damage. During clinical trials of methocarbamol, there were no laboratory measurements of liver damage indicators, such as serum aminotransferase (AST/ALT) levels, to confirm hepatotoxicity. Although unlikely, it is impossible to rule out that methocarbamol may cause mild liver injury with use.

Elderly
Skeletal muscle relaxants are associated with an increased risk of injury among older adults. Methocarbamol appeared to be less sedating than other muscle relaxants, most notably cyclobenzaprine, but had similar increased risk of injury. Methocarbamol is cited along with "most muscle relaxants" in the 2012 Beers Criteria as being "poorly tolerated by older adults, because of anticholinergic adverse effects, sedation, increased risk of fractures," noting that "effectiveness dosages tolerated by older adults is questionable."

Pregnancy
Methocarbamol is labeled by the FDA as a pregnancy category C medication. The teratogenic effects of the medication are not known and should be given to pregnant women only when clearly indicated.

Overdose
There is limited information available on the acute toxicity of methocarbamol. Overdose is used frequently in conjunction with CNS depressants such as alcohol or benzodiazepines and will have symptoms of nausea, drowsiness, blurred vision, hypotension, seizures, and coma. There are reported deaths with an overdose of methocarbamol alone or in the presence of other CNS depressants.

Abuse
Unlike other carbamates such as meprobamate and its prodrug carisoprodol, methocarbamol has greatly reduced abuse potential.  Studies comparing it to the benzodiazepine lorazepam and the antihistamine diphenhydramine, along with placebo, find that methocarbamol produces increased "liking" responses and some sedative-like effects; however, at higher doses dysphoria is reported.  It is considered to have an abuse profile similar to, but weaker than, lorazepam.

Interactions
Methocarbamol may inhibit the effects of pyridostigmine bromide. Therefore, methocarbamol should be used with caution in those with myasthenia gravis taking anticholinesterase medications.Methocarbamol may disrupt certain screening tests as it can cause color interference in laboratory tests for 5-hydroxy-indoleacetic acid (5-HIAA) and in urinary testing for vanillylmandelic acid (VMA) using the Gitlow method.

Pharmacology
Mechanism of action
The mechanism of action of methocarbamol has not currently been established. Its effect is thought to be localized to the central nervous system rather than a direct effect on skeletal muscles. It has no effect on the motor end plate or the peripheral nerve fiber. The efficacy of the medication is likely related to its sedative effect. Alternatively, methocarbamol may act via inhibition of acetylcholinesterase, similarly to carbamate.

Pharmacokinetics
In healthy individuals, the plasma clearance of methocarbamol ranges between 0.20 and 0.80 L/h/kg. The mean plasma elimination half-life ranges between 1 and 2 hours, and the plasma protein binding ranges between 46% and 50%. The elimination half-life was longer in the elderly, those with kidney problems, and those with liver problems.

Metabolism
Methocarbamol is the carbamate derivative of guaifenesin, but does not produce guaifenesin as a metabolite, because the carbamate bond is not hydrolyzed metabolically; its metabolism is by Phase I ring hydroxylation and O-demethylation, followed by Phase II conjugation. All the major metabolites are unhydrolyzed carbamates. Small amounts of unchanged methocarbamol are also excreted in the urine.

Society and culture
Methocarbamol was approved as a muscle relaxant for acute, painful musculoskeletal conditions in the United States in 1957. Muscle relaxants are widely used to treat low back pain, one of the most frequent health problems in industrialized countries. Currently, there are more than 3 million prescriptions filled yearly. Methocarbamol and orphenadrine are each used in more than 250,000 U.S. emergency department visits for lower back pain each year. In the United States, low back pain is the fifth most common reason for all physician visits and the second most common symptomatic reason. In 80% of primary care visits for low back pain, at least one medication was prescribed at the initial office visit and more than one third were prescribed two or more medications. The most commonly prescribed drugs for low back pain included skeletal muscle relaxants. Cyclobenzaprine and methocarbamol are on the U.S </s>