<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 Oxcarbazepine and can you explain it in depth? [/INST] Oxcarbazepine, sold under the brand name Trileptal among others, is a medication used to treat epilepsy. For epilepsy it is used for both focal seizures and generalized seizures. It has been used both alone and as add-on therapy in people with bipolar disorder who have had no success with other treatments. It is taken by mouth.Common side effects include nausea, vomiting, dizziness, drowsiness, double vision and trouble with walking. Serious side effects may include anaphylaxis, liver problems, pancreatitis, suicide ideation, and an abnormal heart beat. While use during pregnancy may harm the baby, use may be less risky than having a seizure. Use is not recommended during breastfeeding. In those with an allergy to carbamazepine there is a 25% risk of problems with oxcarbazepine. How it works is not entirely clear.Oxcarbazepine was patented in 1969 and came into medical use in 1990. It is available as a generic medication. In 2019, it was the 162nd most commonly prescribed medication in the United States, with more than 3 million prescriptions.

Medical uses
Oxcarbazepine is an anticonvulsant used to reduce the occurrence of epileptic episodes, and is not intended to cure epilepsy. Oxcarbazepine is used alone or in combination with other medications for the treatment of focal (partial) seizures in adults. In pediatric populations, it can be used by itself for the treatment of partial seizures for children 4 years and older, or in combination with other medications for children 2 years and older.  There is some evidence to support its effectiveness in reducing seizure frequency when used as an add-on therapy for drug-resistant focal epilepsy but there are concerns over tolerability.

Pregnancy
There is limited data analyzing the impact of oxcarbazepine on a human fetus. Animal studies have shown increased fetal abnormalities in pregnant rats and rabbits exposed to oxcarbazepine during pregnancy. In addition, oxcarbazepine is structurally similar to carbamazepine, which is considered to be teratogenic in humans (pregnancy category D). Oxcarbazepine should only be used during pregnancy if the benefits justify the risks.Pregnant women on oxcarbazepine should be closely monitored, as plasma levels of the active metabolite licarbazepine have been shown to potentially decrease during pregnancy.

Breastfeeding
Oxcarbazepine and its metabolite licarbazepine are both present in human breast milk and thus, some of the active drug can be transferred to a nursing infant. When considering whether to continue this medication in nursing mothers, the impact of the drugs side effect profile on the infant, should be weighed against its anti-epileptic benefit for the mother.

Side effects
Side effects are dose-dependent. The most common include dizziness, blurred or double vision, nystagmus, ataxia, fatigue, headaches, nausea, vomiting, sleepiness, difficulty in concentration and mental sluggishness.Other rare side effects of oxcarbazepine include severe low blood sodium (hyponatremia), anaphylaxis / angioedema, hypersensitivity (especially if experienced with carbamazepine), toxic epidermal necrolysis, Stevens–Johnson syndrome, and thoughts of suicide.Measurement of serum sodium levels should be considered in maintenance treatment or if symptoms of hyponatremia develop. Low blood sodium is seen in 20-30% of people taking oxcarbazepine and 8-12% of those experience severe hyponatremia. Some side effects, such as headaches, are more pronounced shortly after a dose is taken and tend to fade with time (60 to 90 minutes). Other side effects include stomach pain, tremor, rash, diarrhea, constipation, decreased appetite and dry mouth. Photosensitivity is a potential side-effect and people could experience severe sunburns as a result of sun exposure.Oxcarbazepine may lead to hypothyroxinemia. The well-known reduction in free and total thyroxine concentration may be due to both peripheral and central mechanisms.

Interactions
Oxcarbazepine, licarbazepine and many other common drugs influence each other through interaction with the Cytochrome P450 family of enzymes. This leads to a cluster of dozens of common drugs interacting with one another to varying degrees, some of which are especially noteworthy:
Oxcarbazepine and licarbazepine are potent inhibitors of CYP2C19 and thus have the potential to increase plasma concentration of drugs, which are metabolized through this pathway. Other antiepileptics, which are CYP2C19 substrates and thus may be metabolised at a reduced rate when combined with oxcarbazepine include diazepam, hexobarbital, mephenytoin, methylphenobarbital, nordazepam, phenobarbital, phenytoin, primidone. However, many classes of drugs are ligands to CYP2C19.
In addition, oxcarbazepine and licarbazepine are CYP3A4 and CYP3A5 inducers and thus have the potential to decrease the plasma concentration of CYP3A4 and CYP3A5 substrates. Drugs which are CYP3A4 or CYP3A5 substrates and therefore may have reduced efficacy include calcium channel antagonists against high blood pressure and oral contraceptives. However, whether the extent of CYP3A4/5 induction at therapeutic doses reaches clinical significance is unclear.
Furthermore, for example phenytoin and phenobarbital are known to reduce plasma levels of licarbazepine through induction of Cytochrome P450 enzymes.

Pharmacology
Oxcarbazepine is a prodrug, which is largely metabolized to its pharmacologically active 10-monohydroxy derivative licarbazepine (sometimes abbreviated MHD). Oxcarbazepine and MHD exert their action by blocking voltage-sensitive sodium channels, thus leading to the stabilization of hyper-excited neural membranes, suppression of repetitive neuronal firing and diminishment propagation of synaptic impulses. Furthermore, anticonvulsant effects of these compounds could be attributed to enhanced potassium conductance and modulation of high-voltage activated calcium channels.

Pharmacokinetics
Oxcarbazepine has high bioavailability upon oral administration. In a study in humans, only 2% of oxcarbazepine remained unchanged, 70% were reduced to licarbazepine; the rest were minor metabolites. The half-life of oxcarbazepine is considered to be about 2 hours, whereas licarbazepine has a half-life of nine hours. Through its chemical difference to carbamazepine metabolic epoxidation is avoided, reducing hepatic risks. Licarbazepine is metabolised by conjugation with Glucuronic acid. Approximately 4% are oxidised to the inactive 10,11-dihydroxy derivative. Elimination is almost completely renal, with faeces accounting to less than 4%. 80% of the excreted substances are to be attributed to licarbazepine or its glucuronides.

Pharmacodynamics
Both oxcarbazepine and licarbazepine were found to show anticonvulsant properties in seizure models done on animals. These compounds had protective functions whenever tonic extension seizures were induced electrically, but such protection was less apparent whenever seizures were induced chemically. There was no observable tolerance during a four weeks course of treatment with daily administration of oxcarbazepine or licarbazepine in electroshock test on mice and rats. Most of the antiepileptic activity can be attributed to licarbazepine. Aside from its reduction in side effects, it is presumed to have the same main mechanism as carbamazepine, sodium channel inhibition, and is generally used to treat the same conditions.

Pharmacogenetics
The human leukocyte antigen (HLA) allele B*1502 has been associated with an increased incidence of Stevens–Johnson syndrome and toxic epidermal necrolysis in people treated with carbamazepine, and thus those treated with oxcarbazepine might have similar risks. People of Asian descent are more likely to carry this genetic variant, especially some Malaysian populations, Koreans (2%), Han Chinese (2–12%), Indians (6%), Thai (8%), and Philippines (15%) </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 Dostarlimab and can you explain it in depth? [/INST] Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody used as a medication for the treatment of endometrial cancer. Dostarlimab is a programmed death receptor-1 (PD-1)–blocking monoclonal antibody.The most common side effects reported in the US include fatigue/asthenia, nausea, diarrhea, anemia, and constipation. Additional side effects reported in the European Union include vomiting, joint pain, itching, rash, fever, and hypothyroidism (low levels of thyroid hormones).Dostarlimab was approved for the treatment of endometrial cancer in both the United States and the European Union in April 2021.Based on the GARNET trial, Dostarlimab (Jemperli) gained accelerated approval from the Food and Drug Administration (FDA) in April 2022. Jemperlis mechanism of action allows it to act directly on cancerous cells. Follow-up appointments accompanying long-term treatments or long-term post-operative therapies are not necessary with dostarlimab.

Medical uses
In the United States, dostarlimab is indicated for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen. Platinum-based agents such as cisplatin, carboplatin and oxaliplatin are mainstays of treatment when it comes to cancer chemotherapy treatment. It is also indicated for the treatment of solid tumors.In the European Union, dostarlimab is indicated as monotherapy for the treatment of adults with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI H) recurrent or advanced endometrial cancer (EC) that has progressed on or following prior treatment with a platinum-containing regimen.In August 2021, the US Food and Drug Administration (FDA) granted accelerated approval to dostarlimab for adults with mismatch repair deficient (dMMR) recurrent or advanced solid tumors, as determined by an FDA-approved test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.

Endometrial cancer
Endometrial cancer (EC) is a disease where cancerous cells reside in the lining of the uterus (endometrium). There are four stages in EC, ranging from staying settled in the endometrium to the cancer spreading to other organs in the body. This disease can be treated if discovered at the beginning of development. In those with chemoresistant MSI-high tumors, studies conducted on dostarlimab and pembrolizumab display promising results of the tumors reacting well to the therapies.

Solid tumors
Solid tumors are tumors that do not contain any liquid or cysts, which can occur in many places including bones, muscles and organs. The most common types of solid tumors are sarcomas and carcinomas. Dostarlimab can used to treat recurrent or advance tumors for patients who have tried alternative treatment options.

Side effects
Serious adverse reactions in >2% of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and fever (pyrexia).Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrine disease (endocrinopathies), and nephritis.The most common side effects reported while taking this medication during a trial were dyspnea, asthenia, fatigue, and nausea.Symptoms of overdose are similar to the side effect profile of the medication, so it could involve significant immune-mediated reactions.

Immune-mediated adverse reactions
Dostarlimab is a monoclonal antibody that binds to PD-1 to block it from binding PD-1 ligands to remove inhibition of immune response. With this, it causes risk for immune-mediated adverse reactions. These reactions can be severe or fatal and occur in any part of the body: organs or tissues.Examples of immune-mediated adverse reactions include immune-mediated pneumonitis, colitis, hepatitis, adrenal insufficiency, hypophysitis, thyroid disorders, nephritis with renal dysfunction, and dermatologic reactions.

Pregnancy and lactation
Dostarlimab can cause harm to a fetus. The death of the fetus can occur from the immune systems reaction to the fetus through the examination of its mechanism in animal studies. Dostarlimab is a human immunoglobulin G (IgG4), which could permeate through the placental barrier. This may risk harm to the developing fetus as the drug may be passed on from the mother.Data is not available regarding the presence of dostarlimab in breastmilk.

Hepatotoxicity
Dostarlimab causes mild to moderate elevations to serum aminotransferase and alkaline phosphatase in 15-25% of recipients. Serum ALT elevation above five times the normal range occurs in 2-3% of recipients. Some people treated with dostarlimab can develop immune related liver injury.Some symptoms of liver injury or acute liver failure can include jaundice, pain in the upper right abdomen, ascites, nausea/vomiting, and disorientation or confusion.

Pharmacology
Dostarlimab is a humanized IgG4 monoclonal antibody that was derived from a mouse antibody which was humanized via Complementarity Determining Region (CDR) grafting. Its serum half-life is 25.4 days.Other PD-1 antibodies included nivolumab (Opdivo) and pembrolizumab (Keytruda), both of which have uses in many different types of cancers which include classical Hodgkin lymphoma, renal cell carcinoma, and breast cancer. Another PD-1 antibody is cemiplimab (Libtayo) which was approved for treatment of squamous cell carcinoma, basal cell carcinoma and non-small cell lung cancer.

Mechanism of action
Dostarlimab binds to the PD-1 receptor, with high affinity, to block its activity with PD-1 ligands (PD-L1) and PD-L2). PD-1 is a co-inhibitory receptor that is an important checkpoint protein for regulating T-cell tolerance. When PD-1 is constantly stimulated by PD-1 ligands, which are highly expressed in cancer cells, it allows cancer cells to dodge T-cell mediated immune responses. Therefore, blocking the binding of PD-1 to these ligands can allow T-cells to function normally and prevent tumor cells from bypassing immune surveillance. In mouse tumor models, it was shown that inhibiting PD-1 activity decreased tumor growth.

Efficacy
In the GARNET Trial, dostarlimab achieved favorable results in decreasing the size of the tumor in those with endometrial cancer. The study observed people with endometrial cancer from seven different countries and the size of the tumor was reduced in 42% of the population studied.Dostarlimab exhibits better efficacy than other PD-1 inhibitors, such as avelumab and durvalumab, in dMMR advanced endometrial cancers. Efficacy of the drug is measured by the response rate, which is 47% for dostarlimab.

History
In 2020, dostarlimab, a PD-1inhibitor, was undergoing phase I/II and phase III clinical trials.In 2020, the manufacturer, Tesaro, announced preliminary successful results from the phase I/II GARNET study.In 2020, the GARNET study announced that dostarlimab had promising potential to treat a specific subset of individuals with recurrent or advanced endometrial cancer.In April 2021, dostarlimab was approved for the treatment of recurrent or advanced endometrial cancer with mismatch repair deficient (dMMR), which are genetic abnormalities that disrupt DNA repair, in individuals who had previously been treated with platinum-containing regimens.In April 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GSK) </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 Bethanechol 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 DTaP-IPV vaccine 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 Fluoxymesterone and can you explain it in depth? [/INST] Fluoxymesterone, sold under the brand names Halotestin and Ultandren among others, is an androgen and anabolic steroid (AAS) medication which is used in the treatment of low testosterone levels in men, delayed puberty in boys, breast cancer in women, and anemia. It is taken by mouth.Side effects of fluoxymesterone include symptoms of masculinization like acne, increased hair growth, voice changes, and increased sexual desire. It can also cause liver damage and cardiovascular side effects like high blood pressure. The drug is a synthetic androgen and anabolic steroid and hence is an agonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has strong androgenic effects and moderate anabolic effects, which make it useful for producing masculinization.Fluoxymesterone was first described in 1956 and was introduced for medical use in 1957. In addition to its medical use, fluoxymesterone is used to improve physique and performance. The drug is a controlled substance in many countries and so non-medical use is generally illicit.

Medical uses
Fluoxymesterone is or has been used in the treatment of hypogonadism, delayed puberty, and anemia in males and the treatment of breast cancer in women. It is specifically approved in one or more countries for the treatment of hypogonadism in men, delayed puberty in boys, and breast cancer in women. Current prescribing guidelines in the United States list only the treatment of androgen deficiency in males and breast cancer in females as indications.Fluoxymesterone is less effective in inducing masculinization than testosterone, but is useful for maintaining established masculinization in adults.

Available forms
Fluoxymesterone is available in the form of 2, 5, and 10 mg oral tablets.

Non-medical uses
Fluoxymesterone is used for physique- and performance-enhancing purposes by competitive athletes, bodybuilders, and powerlifters.

Side effects
Side effects that have been associated with fluoxymesterone include acne, edema, seborrhea/seborrheic dermatitis, alopecia, hirsutism, voice deepening, virilization in general, flushing, gynecomastia, breast pain, menstrual disturbances, hypogonadism, testicular atrophy, clitoral enlargement, penile enlargement, priapism, increased aggressiveness, prostate enlargement, cardiovascular toxicity, and hepatotoxicity, among others.

Pharmacology
Pharmacodynamics
As an AAS, fluoxymesterone is an agonist of the androgen receptor (AR), similarly to androgens like testosterone and DHT. It is a substrate for 5α-reductase like testosterone, and so is potentiated in so-called "androgenic" tissues like the skin, hair follicles, and prostate gland via transformation into 5α-dihydrofluoxymesterone. As such, fluoxymesterone has a relatively poor ratio of anabolic to androgenic activity similarly to testosterone and methyltestosterone. However, fluoxymesterone is nonetheless proportionally less androgenic and more anabolic than methyltestosterone and testosterone.Fluoxymesterone has been reported to be non-aromatizable due to steric hindrance by its C11β hydroxyl group, and hence is not considered to have a propensity for producing estrogenic effects such as gynecomastia or fluid retention. However, paradoxically, a case report of severe fluoxymesterone-induced gynecomastia exists, and gynecomastia associated with fluoxymesterone has also been reported in other publications, although this may not be due to estrogenic activity. Fluoxymesterone is thought to possess little or no progestogenic activity.Because of the presence of its 17α-methyl group, the metabolism of fluoxymesterone is impeded, resulting in it being orally active, although also hepatotoxic.

11β-HSD inhibition
Fluoxymesterone has been found to act as a potent inhibitor of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) (IC50 = 60–630 nM), with a potency comparable to that of the 11β-HSD2 inhibitor glycyrrhetinic acid. This action of fluoxymesterone is unique among AAS and is likely related to its 11β-hydroxyl group. 11β-HSD2 is responsible for the inactivation of the glucocorticoids cortisol and corticosterone (into cortisone and 11-dehydrocorticosterone, respectively). Inhibition of 11β-HSD2 by fluoxymesterone may result in mineralocorticoid receptor overactivation and associated side effects such as hypertension and fluid retention, and has been hypothesized to be involved in the cardiovascular and other adverse effects of fluoxymesterone.

Glucocorticoid activity
Unlike other AAS, fluoxymesterone has structural features in common with corticosteroids, including its C9α fluoro and C11β hydroxyl groups. In relation to this, it has weak (micromolar) but potentially clinically significant affinity for the glucocorticoid receptor.

Pharmacokinetics
Fluoxymesterone has approximately 80% oral bioavailability, unlike testosterone, as the C17α methyl group of fluoxymesterone inhibits first-pass metabolism. It has very low affinity for human serum sex hormone-binding globulin (SHBG), less than 5% of that of testosterone and less than 1% of that of DHT. The drug is metabolized in the liver, mainly by 6β-hydroxylation, 5α- and 5β-reduction, 3α- and 3β-keto-oxidation, and 11β-hydroxy-oxidation. Its known active metabolites include 5α-dihydrofluoxymesterone and 11-oxofluoxymesterone. Fluoxymesterone has an elimination half-life of approximately 9.2 hours, which is long relative to that of testosterone. It is eliminated in the urine, with less than 5% excreted unchanged.

Chemistry
Fluoxymesterone, also known as 9α-fluoro-11β-hydroxy-17α-methyltestosterone or as 9α-fluoro-17α-methylandrost-4-en-11β,17β-diol-3-one, is a synthetic androstane steroid and a 17α-alkylated derivative of testosterone (androst-4-en-17β-ol-3-one). It is specifically the derivative of testosterone with a fluorine atom at the C9α position, a hydroxyl group at the C11β position, and a methyl group at the C17α position.

Synthesis
Step one: The first step in the synthesis of fluoxymesterone is the microbiological oxidation of commercially available androstenedione (1.11) by Actinomyces; this introduces a hydroxyl group to the 11α-position (1.12), which is then oxidised to a ketone using Jones reagent, yielding the 3,11,17-triketone, adrenosterone (1.13). Pyrrolidine then reacts to form an enamine (1.14) by reaction with the 3α-keto group, protecting it from alkylation in a subsequent step. The regioselectivity of pyrrolidine for reaction at the 3α-position occurs inherently in the structure of adrenosterone, due to the position of the sterically bulky methyl groups. In subsequent steps, alkylation of the 17-keto group (1.14) using Grignard reagent, addition of hydride at the 11-position (1.15) and regeneration of the protected 3-keto group yields the starting material (1.16) for the final steps of the fluoxymesterone synthesis. This involves more standard synthetic transformations.

Step two: The 11α-hydroxyl of the starting material (1.16) is sulfonylated by p-toluenesulfonyl chloride; addition of trimethylamine (base) deprotonates the 11α-carbon, yielding an (E2) elimination of tosylate (pka - 5) to give olefin (1.17). Stereospecificity of reaction between olefin and hypobromous acid (HOBr) in base, N-bromosuccinimide (NBS), is determined by the formation of a bromonium intermediate; the electrophilic bromonium cation approaches the rings less sterically hindered α-face and is attacked by the π-electron density of the alkene </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 Demeclocycline and can you explain it in depth? [/INST] Demeclocycline (INN, BAN, USAN, brand name Declomycin) is a tetracycline antibiotic which was derived from a mutant strain of Streptomyces aureofaciens.

Uses
Demeclocycline is officially indicated for the treatment of various types of bacterial infections. It is used as an antibiotic in the treatment of Lyme disease, acne, and bronchitis. Resistance, though, is gradually becoming more common, and demeclocycline is now rarely used for treatment of infections.It is widely used (though off-label in many countries including the United States) in the treatment of hyponatremia (low blood sodium concentration) due to the syndrome of inappropriate antidiuretic hormone (SIADH) when fluid restriction alone has been ineffective </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 Fluphenazine and can you explain it in depth? [/INST] Fluphenazine, sold under the brand name Prolixin among others, is a high-potency typical antipsychotic medication. It is used in the treatment of chronic psychoses such as schizophrenia, and appears to be about equal in effectiveness to low-potency antipsychotics like chlorpromazine. It is given by mouth, injection into a muscle, or just under the skin. There is also a long acting injectable version that may last for up to four weeks. Fluphenazine decanoate, the depot injection form of fluphenazine, should not be used by people with severe depression.Common side effects include movement problems, sleepiness, depression and increased weight. Serious side effects may include neuroleptic malignant syndrome, low white blood cell levels, and the potentially permanent movement disorder tardive dyskinesia. In older people with psychosis as a result of dementia it may increase the risk of dying. It may also increase prolactin levels which may result in milk production, enlarged breasts in males, impotence, and the absence of menstrual periods. It is unclear if it is safe for use in pregnancy.Fluphenazine is a typical antipsychotic of the phenothiazine class. Its mechanism of action is not entirely clear but believed to be related to its ability to block dopamine receptors. In up to 40% of those on long term phenothiazines, liver function tests become mildly abnormal.Fluphenazine came into use in 1959. The injectable form is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. It was discontinued in Australia in 2017.

Medical use
A 2018 Cochrane review found that fluphenazine was an imperfect treatment and other inexpensive drugs less associated with side effects may be an equally effective choice for people with schizophrenia.

Side effects
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Sodium phosphates and can you explain it in depth? [/INST] Sodium phosphate is a generic term for a variety of salts of sodium (Na+) and phosphate (PO43−). Phosphate also forms families or condensed anions including di-, tri-, tetra-, and polyphosphates. Most of these salts are known in both anhydrous (water-free) and hydrated forms. The hydrates are more common than the anhydrous forms.

Uses
Sodium phosphates have many applications in food and for water treatment. For example, sodium phosphates are often used as emulsifiers (as in processed cheese), thickening agents, and leavening agents for baked goods. They are also used to control pH of processed foods. They are also used in medicine for constipation and to prepare the bowel for medical procedures. Moreover, they are used in detergents for softening water, and as an efficient anti rust solution.

Adverse effects
Sodium phosphates are popular in commerce in part because they are inexpensive and because they are nontoxic at normal levels of consumption.  However, oral sodium phosphates when taken at high doses for bowel preparation for colonoscopy may in some individuals carry a risk of kidney injury under the form of phosphate nephropathy. There are several oral phosphate formulations which are prepared extemporaneously. Oral phosphate prep drugs have been withdrawn in the United States, although evidence of causality is equivocal. Since safe and effective replacements for phosphate purgatives are available, several medical authorities have recommended general disuse of oral phosphates.

Monophosphates
Three families of sodium monophosphates are common, those derived from orthophosphate (PO43−), hydrogen phosphate (HPO42−), and dihydrogenphosphate (H2PO4−) </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 Avapritinib and can you explain it in depth? [/INST] Avapritinib, sold under the brand name Ayvakit among others, is a medication used for the treatment of advanced systemic mastocytosis and for the treatment of tumors due to one specific rare mutation: it is specifically intended for adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) that harbor a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation.Common side effects include edema (swelling), nausea, fatigue/asthenia (abnormal physical weakness or lack of energy), cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation (secretion of tears), abdominal pain, constipation, rash and dizziness.Avapritinib is a kinase inhibitor.

Medical uses
Avapritinib is indicated for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring the platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.Avapritinib is also indicated for the treatment of adults with advanced systemic mastocytosis, aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, and mast cell leukemia (MCL).

History
The U.S. Food and Drug Administration (FDA) approved avapritinib in January 2020. The application for avapritinib was granted fast track designation, breakthrough therapy designation, and orphan drug designation. The FDA granted approval of Ayvakit to Blueprint Medicines Corporation.Avapritinib was approved based on the results from the Phase I NAVIGATOR clinical trial involving 43 subjects with GIST harboring a PDGFRA exon 18 mutation, including 38 subjects with PDGFRA D842V mutation. Subjects received avapritinib 300 mg or 400 mg orally once daily until disease progression or they experienced unacceptable toxicity. The recommended dose was determined to be 300 mg once daily. The trial measured how many subjects experienced complete or partial shrinkage (by a certain amount) of their tumors during treatment (overall response rate). For subjects harboring a PDGFRA exon 18 mutation, the overall response rate was 84%, with 7% having a complete response and 77% having a partial response. For the subgroup of subjects with PDGFRA D842V mutations, the overall response rate was 89%, with 8% having a complete response and 82% having a partial response. While the median duration of response was not reached, 61% of the responding subjects with exon 18 mutations had a response lasting six months or longer (31% of subjects with an ongoing response were followed for less than six months).The FDA approved avapritinib based on evidence from one clinical trial (NCT02508532) of 204 subjects with GIST. The trial was conducted at 17 sites in the United States, Europe and Asia.Avapritinib showed a median PFS of 4.2 months compared to 5.6 months for regorafenib. The difference in median PFS between the avapritinib and regorafenib groups was not statistically significant. The overall response rate was 17 percent for the avapritinib group and 7 percent for the regorafenib group. The VOYAGER trial evaluated the efficacy and safety of avapritinib (N=240) versus regorafenib (N=236) in patients with third- or fourth-line GIST.Avapritinib was approved for medical use in the European Union in September 2020.Ayvakit was granted approval for advanced systemic mastocytosis by the FDA on June 16th 2021.

References
Further reading
Wu CP, Lusvarghi S, Wang JC,  et al. (July 2019). "Avapritinib: A Selective Inhibitor of KIT and PDGFRα that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines". Mol. Pharm. 16 (7): 3040–3052. doi:10.1021/acs.molpharmaceut.9b00274. PMC 6620786. PMID 31117741.
Gebreyohannes YK, Wozniak A, Zhai ME,  et al. (January 2019). "Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors". Clin. Cancer Res </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 Sonidegib 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 Avacopan and can you explain it in depth? [/INST] Avacopan, sold under the brand name Tavneos, is a medication used to treat anti-neutrophil cytoplasmic autoantibody-associated vasculitis.The most common side effects include nausea (feeling sick), headache, decrease in white blood cell count, upper respiratory tract (nose and throat) infection, diarrhea, vomiting, and nasopharyngitis (inflammation of the nose and throat).Avacopan was approved for medical use in Japan in September 2021, and in the United States in October 2021. It is the first orally-administered inhibitor of the complement C5a receptor approved by the U.S. Food and Drug Administration (FDA). Avacopan is a complement 5a receptor antagonist and a cytochrome P450 3A4 (CYP3A4) inhibitor.

Medical uses
In the United States, avacopan is indicated as an adjunctive treatment of adults with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis) in combination with standard therapy including glucocorticoids.In the European Union, avacopan, in combination with a rituximab or cyclophosphamide regimen, is indicated for the treatment of adults with severe, active granulomatosis with polyangiitis or microscopic polyangiitis (MPA).

Society and culture
Legal status
In November 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Tavneos, intended, in combination with a rituximab or cyclophosphamide regimen, for the treatment of adults with severe, active granulomatosis with polyangiitis or microscopic polyangiitis. The applicant for this medicinal product is Vifor Fresenius Medical Care Renal Pharma France. The EMA considers avacopan to be a first-in-class medicine. Avacopan was approved for medical use in the European Union in January 2022.

Names
Avacopan is the international nonproprietary name (INN).

References
Further reading
Jayne DR, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P,  et al. (September 2017). "Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis". J Am Soc Nephrol. 28 (9): 2756–2767. doi:10.1681/ASN.2016111179. PMC 5576933. PMID 28400446.
Jayne DR, Merkel PA, Schall TJ, Bekker P (February 2021). "Avacopan for the Treatment of ANCA-Associated Vasculitis". N Engl J Med. 384 (7): 599–609. doi:10.1056/NEJMoa2023386. PMID 33596356.
Merkel PA, Jayne DR, Wang C, Hillson J, Bekker P (April 2020). "Evaluation of the Safety and Efficacy of Avacopan, a C5a Receptor Inhibitor, in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Treated Concomitantly With Rituximab or Cyclophosphamide/Azathioprine: Protocol for a Randomized, Double-Blind, Active-Controlled, Phase 3 Trial". JMIR Res Protoc. 9 (4): e16664. doi:10.2196/16664. PMC 7175182. PMID 32088663.
Merkel PA, Niles J, Jimenez R, Spiera RF, Rovin BH, Bomback A,  et al </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 Tranylcypromine and can you explain it in depth? [/INST] Tranylcypromine, sold under the brand name Parnate among others, is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.
Tranylcypromine is a propylamine formed from the cyclization of amphetamines side chain; therefore, it is classified as a substituted amphetamine.

Medical uses
Tranylcypromine is used to treat major depressive disorder, including atypical depression, especially when there is an anxiety component, typically as a second-line treatment. It is also used in depression that is not responsive to reuptake inhibitor antidepressants, such as the SSRIs, TCAs, or bupropion.Systematic reviews and meta-analyses have reported that tranylcypromine is significantly more effective in the treatment of depression than placebo and has efficacy over placebo similar to that of other antidepressants such as tricyclic antidepressants.

Contraindications
Contraindications include:
Porphyria
Cardiovascular or cerebrovascular disease
Pheochromocytoma
Tyramine, found in several foods, is metabolized by MAO. Ingestion and absorption of tyramine causes extensive release of norepinephrine, which can rapidly increase blood pressure to the point of causing hypertensive crisis.
Concomitant use of serotonin-enhancing drugs, including SSRIs, serotonergic TCAs, dextromethorphan, and meperidine may cause serotonin syndrome.
Concomitant use of MRAs, including fenfluramine, amphetamine, and pseudoephedrine may cause toxicity via serotonin syndrome or hypertensive crisis.
L-DOPA given without carbidopa may cause hypertensive crisis.

Dietary restrictions
Tyramine is a common component in many foods, and is normally rapidly metabolized by MAO-A. Individuals not taking MAOIs may consume at least 2 grams of tyramine in a meal and not experience an increase in blood pressure, whereas those taking MAOIs such as tranylcypromine may experience a sharp increase in blood pressure following consumption of as little as 10 mg of tyramine, which can lead to hypertensive crisis.Foods containing tyramine include aged cheeses, cured meats, tofu and certain red wines. Some, such as yeast extracts, contain enough tyramine to be potentially fatal in a single serving. Spoiled food is also likely to contain dangerous levels of tyramine.

Adverse effects
Incidence of adverse effectsVery common (>10% incidence) adverse effects include:

Dizziness secondary to orthostatic hypotension (17%)Common (1-10% incidence) adverse effects include:

Tachycardia (5–10%)
Hypomania (7%)
Paresthesia (5%)
Weight loss (2%)
Confusion (2%)
Dry mouth (2%)
Sexual function disorders (2%)
Hypertension (1–2 hours after ingestion) (2%)
Rash (2%)
Urinary retention (2%)Other (unknown incidence) adverse effects include:

Increased/decreased appetite
Blood dyscrasias
Chest pain
Diarrhea
Edema
Hallucinations
Hyperreflexia
Insomnia
Jaundice
Leg cramps
Myalgia
Palpitations
Sensation of cold
Suicidal ideation
TremorOf note, there has not been found to be a correlation between sex and age below 65 regarding incidence of adverse effects.Tranylcypromine is not associated with weight gain and has a low risk for hepatotoxicity compared to the hydrazine MAOIs.It is generally recommended that MAOIs be discontinued prior to anesthesia; however, this creates a risk of recurrent depression. In a retrospective observational cohort study, patients on tranylcypromine undergoing general anesthesia had a lower incidence of intraoperative hypotension, while there was no difference between patients not taking an MAOI regarding intraoperative incidence of bradycardia, tachycardia, or hypertension. The use of indirect sympathomimetic drugs or drugs affecting serotonin reuptake, such as meperidine or dextromethorphan poses a risk for hypertension and serotonin syndrome respectively; alternative agents are recommended. Other studies have come to similar conclusions. Pharmacokinetic interactions with anesthetics are unlikely, given that tranylcypromine is a high-affinity substrate for CYP2A6 and does not inhibit CYP enzymes at therapeutic concentrations.Tranylcypromine abuse has been reported at doses ranging from 120 to 600 mg per day. It is thought that higher doses have more amphetamine-like effects and abuse is promoted by the fast onset and short half-life of tranylcypromine.Cases of suicidal ideation and suicidal behaviours have been reported during tranylcypromine therapy or early after treatment discontinuation.Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects.

Interactions
In addition to contraindicated concomitant medications, tranylcypromine inhibits CYP2A6, which may reduce the metabolism and increase the toxicity of substrates of this enzyme, such as:
Dexmedetomidine
nicotine
TSNAs (found in cured tobacco products, including cigarettes)
ValproateNorepinephrine reuptake inhibitors prevent neuronal uptake of tyramine and may reduce its pressor effects.

Pharmacology
Pharmacodynamics
Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase. Regarding the isoforms of monoamine oxidase, it shows slight preference for the MAOB isoenzyme over MAOA. This leads to an increase in the availability of monoamines, such as serotonin, norepinephrine, and dopamine, epinephrine  as well as a marked increase in the availability of trace amines, such as tryptamine, octopamine, and phenethylamine. The clinical relevance of increased trace amine availability is unclear.
It may also act as a norepinephrine reuptake inhibitor at higher therapeutic doses. Compared to amphetamine, tranylcypromine shows low potency as a dopamine releasing agent, with even weaker potency for norepinephrine and serotonin release.Tranylcypromine has also been shown to inhibit the histone demethylase, BHC110/LSD1. Tranylcypromine inhibits this enzyme with an IC50 < 2 μM, thus acting as a small molecule inhibitor of histone demethylation with an effect to derepress the transcriptional activity of BHC110/LSD1 target genes. The clinical relevance of this effect is unknown.
Tranylcypromine has been found to inhibit CYP46A1 at nanomolar concentrations. The clinical relevance of this effect is unknown.

Pharmacokinetics
Tranylcypromine reaches its maximum concentration (tmax) within 1–2 hours </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 Temozolomide and can you explain it in depth? [/INST] Temozolomide (TMZ), sold under the brand name Temodar among others, is a medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. It is taken by mouth or via intravenous infusion.The most common side effects with temozolomide are nausea, vomiting, constipation, loss of appetite, alopecia (hair loss), headache, fatigue, convulsions (seizures), rash, neutropenia or lymphopenia (low white-blood-cell counts), and thrombocytopenia (low blood platelet counts). People receiving the solution for infusion may also have injection-site reactions, such as pain, irritation, itching, warmth, swelling and redness, as well as bruising.Temozolomide is an alkylating agent used to treat serious brain cancers; most commonly as second-line treatments for astrocytoma and as the first-line treatment for glioblastoma. Olaparib in combination with temozolomide demonstrated substantial clinical activity in relapsed small cell lung cancer.

Medical uses
In the United States temozolomide is indicated for the treatment of adults with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment; or adults with refractory anaplastic astrocytoma who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.In the European Union temozolomide is indicated for adults with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment; or children from the age of three years, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.

Contraindications
Temozolomide is contraindicated in people with hypersensitivity to it or to the similar drug dacarbazine. The use of temozolomide is not recommended in people with severe myelosuppression.

Adverse effects
The most common side effect is bone marrow suppression. The most common non-hematological adverse effects associated with temozolomide are nausea and vomiting, which are either self-limiting or readily controlled with standard antiemetic therapy. These latter effects are usually mild to moderate (grade 1 to 2). The incidence of severe nausea and vomiting is around 4% each. Patients who have pre-existing or a history of severe vomiting may require antiemetic therapy before initiating temozolomide treatment. Temozolomide should be administered in the fasting state, at least one hour before a meal. Antiemetic therapy may be administered before, or following, administration of temozolomide.
Temozolomide is genotoxic, teratogenic and fetotoxic and should not be used during pregnancy.
Lactating women should discontinue nursing while receiving the drug because of the risk of secretion into breast milk.
One study indicated that women that have taken temozolomide without concomitant fertility preservation measures achieve pregnancy to a lesser rate later in life, but the study was too small to show statistical significance in the hypothesis that temozolomide would confer a risk of female infertility.
In male patients, temozolomide can have genotoxic effects. Men are advised not to father a child during or up to six months after treatment and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to temozolomide therapy.
Very rarely temozolomide can cause acute respiratory failure or liver damage.

Interactions
As temozolomide is not metabolized in the liver and has a low affinity to plasma proteins, it is expected to have a low potential for interactions. An analysis of patient data showed no interactions with a range of other drugs; the exception is valproic acid, which slightly slows down temozolomide elimination from the body. Combining the drug with other myelosuppressants may increase the risk of myelosuppression.

Pharmacology
Mechanism of action
The therapeutic benefit of temozolomide depends on its ability to alkylate/methylate DNA, which most often occurs at the N-7 or O-6 positions of guanine residues. This methylation damages the DNA and triggers the death of tumor cells. However, some tumor cells are able to repair this type of DNA damage, and therefore diminish the therapeutic efficacy of temozolomide, by expressing a protein O6-alkylguanine DNA alkyltransferase (AGT) encoded in humans by the O-6-methylguanine-DNA methyltransferase (MGMT) gene. In some tumors, epigenetic silencing of the MGMT gene prevents the synthesis of this enzyme, and as a consequence such tumors are more sensitive to killing by temozolomide. Conversely, the presence of AGT protein in brain tumors predicts poor response to temozolomide and these patients receive little benefit from chemotherapy with temozolomide.

Pharmacokinetics
Temozolomide is quickly and almost completely absorbed from the gut, and readily penetrates the blood–brain barrier; the concentration in the cerebrospinal fluid is 30% of the concentration in the blood plasma. Intake with food decreases maximal plasma concentrations by 33% and the area under the curve by 9%. Only 15% (10–20%) of the substance are bound to blood plasma proteins. Temozolomide is a prodrug; it is spontaneously hydrolyzed at physiological pH to 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC), which further splits into monomethylhydrazine, likely the active methylating agent, and 5-aminoimidazole-4-carboxamide (AIC). Other metabolites include temozolomide acid and unidentified hydrophilic substances.Plasma half-life is 1.8 hours. The substance and its metabolites are mainly excreted via the urine.

Chemical properties
Temozolomide is an imidazotetrazine derivative. It is slightly soluble in water and aqueous acids, and decomposes at 212 °C (414 °F). It was recently discovered that temozolomide is an explosive, tentatively assigned as UN Class 1.Mirroring its medicinal use as an alkylating antineoplastic agent, temozolomide has been reported to be a comparatively safe and stable in situ source of diazomethane in organic synthesis.  In particular, its use as a methylating and cyclopropanating reagent was demonstrated.

History
The agent was discovered by Simon Langdon, Niel Gibson and John Hickman at Aston University in Birmingham, England. The molecule was synthesised by PhD student Robert Stone, in a project directed by Malcolm Stevens to find anti-allergens. Its preclinical activity was reported in 1987 in Cancer Research. Stevens then directed its development with the late Edward Newlands at Charing Cross Hospital.It was approved for medical use in the European Union in January 1999, and in the United States in August 1999. The intravenous formulation was approved in the United States in February 2009.

Research
Laboratory studies and clinical trials have started investigating the possibility of increasing the anticancer potency of temozolomide by combining it with other pharmacologic agents. For example, clinical trials have indicated that the addition of chloroquine might be beneficial for the treatment of glioma patients. Laboratory studies found that temozolomide killed brain tumor cells more efficiently when epigallocatechin gallate (EGCG), a component of green tea, was added; however, the efficacy of this effect has not yet been confirmed in brain-tumor patients. Preclinical studies reported in 2010 on investigations into the use of the novel oxygen diffusion-enhancing compound trans sodium crocetinate (TSC) when combined with temozolomide and radiation therapy and a clinical trial was underway as of August  2015.While the above-mentioned approaches have investigated whether the combination of temozolomide with other agents might improve therapeutic outcome, efforts have also started to study whether altering the temozolomide molecule itself can increase its activity. One such approach permanently fused perillyl alcohol, a natural compound with demonstrated therapeutic activity in brain cancer patients, to the temozolomide molecule. The resultant novel compound, called NEO212 or TMZ-POH, revealed anticancer activity that was significantly greater than that of either of its two parent molecules, temozolomide and perillyl alcohol. Although as of 2016, NEO212 has not been tested in humans, it has shown superior cancer therapeutic activity in animal models of glioma, melanoma, and brain metastasis of triple-negative breast cancer.Because tumor cells that express the MGMT gene are more resistant to the effects of temozolomide, researchers investigated whether the inclusion of O6-benzylguanine (O6-BG), an AGT inhibitor, could overcome this resistance and improve the drugs therapeutic effectiveness. In the laboratory, this combination indeed showed increased temozolomide activity in tumor-cell culture in vitro and in animal models in vivo. However, a recently completed phase-II clinical trial with brain-tumor patients yielded mixed outcomes; while there was some improved therapeutic activity when O6-BG and temozolomide were given to patients with temozolomide-resistant anaplastic glioma, there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant glioblastoma multiforme.Some efforts focus on engineering hematopoietic stem cells expressing the MGMT gene prior to transplanting them into brain-tumor patients. This would allow for the patients to receive stronger doses of temozolomide, since the patients hematopoietic cells would be resistant to the drug.High doses of temozolomide in high-grade gliomas have low toxicity, but the results are comparable to the standard doses.Two mechanisms of resistance to temozolomide effects have now been described: 1) intrinsic resistance conferred by MGMT deficiency (MGMTd) and 2) intrinsic or acquired resistance through MMR deficiency (MMRd). The MGMT enzyme is the first line of repair of mismatched bases created by TMZ. Cells are normally MGMT proficient (MGMTp) as they have an unmethylated MGMT promoter allowing the gene to be expressed normally. In this state, TMZ induced DNA damage is able to be efficiently repaired in tumor cells (and normal cells) by the active MGMT enzyme. Cells may grow and pass through the cell cycle normally without arrest or death. However, some tumors cells are MGMT deficient (MGMTd). This is most commonly due to abnormal methylation of the MGMT gene promoter and suppression of gene expression. MGMTd has also been described to occur by promoter rearrangement </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 Nitroglycerin (medication) and can you explain it in depth? [/INST] Nitroglycerin, also known as glyceryl trinitrate (GTN), is a medication used for heart failure, high blood pressure, anal fissures, painful periods, and to treat and prevent chest pain caused by decreased blood flow to the heart (angina) or due to the recreational use of cocaine. This includes chest pain from a heart attack. It is taken by mouth, under the tongue, applied to the skin, or by injection into a vein.Common side effects include headache and low blood pressure. The low blood pressure can be severe. It is unclear if use in pregnancy is safe for the baby. It should not be used together with medications within the sildenafil (PDE5 inhibitor) family due to the risk of low blood pressure. Nitroglycerin is in the nitrate family of medications. While it is not entirely clear how it works, it is believed to function by dilating blood vessels.Nitroglycerin was written about as early as 1846 and came into medical use in 1878. It is on the World Health Organizations List of Essential Medicines.  The drug nitroglycerin (GTN) is a dilute form of the same chemical used as the explosive, nitroglycerin. Dilution makes it non-explosive. In 2019, it was the 184th most commonly prescribed medication in the United States, with more than 3 million prescriptions.

Medical uses
Nitroglycerin is used for the treatment of angina, acute myocardial infarction, severe hypertension, and acute coronary artery spasms. It may be administered intravenously, as a sublingual spray, or as a patch applied to the skin.

Angina
GTN is useful in decreasing angina attacks, perhaps more so than reversing angina once started, by supplementing blood concentrations of NO, also called endothelium-derived relaxing factor, before the structure of NO as the responsible agent was known. This led to the development of transdermal patches of glyceryl trinitrate, providing 24-hour release. However, the effectiveness of glyceryl trinitrate is limited by development of tolerance/tachyphylaxis within 2–3 weeks of sustained use. Continuous administration and absorption (such as provided by daily pills and especially skin patches) accelerate onset of tolerance and limit the usefulness of the agent. Thus, glyceryl trinitrate works best when used only in short-term, pulse dosing. Glyceryl trinitrate is useful for myocardial infarction (heart attack) and pulmonary edema, again working best if used quickly, within a few minutes of symptom onset, as a pulse dose.It may also be given as a sublingual or buccal dose in the form of a tablet placed under the tongue or a spray into the mouth for the treatment of an angina attack.

Other uses
Tentative evidence indicates efficacy of glyceryl trinitrate in the treatment of various tendinopathies, both in pain management and acceleration of soft tissue repair.GTN is also used in the treatment of anal fissures, though usually at a much lower concentration than that used for angina treatment.GTN has been used to decrease pain associated with dysmenorrhea.GTN was once researched for the prevention and treatment of osteoporosis; however, the researcher Sophie Jamal was found to have falsified the findings, sparking one of the largest scientific misconduct cases in Canada.

Tolerance
After long-term use for chronic conditions, nitrate tolerance—tolerance to agents such as GTN— may develop in a patient, reducing its effectiveness. Tolerance is defined as the loss of symptomatic and hemodynamic effects of GTN and/or the need for higher doses of the drug to achieve the same effects, and was first described soon after the introduction of GTN in cardiovascular therapy. Studies have shown that nitrate tolerance is associated with vascular abnormalities which have the potential to worsen patients prognosis </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 Pegaspargase and can you explain it in depth? [/INST] Pegaspargase, sold under the brand name Oncaspar, is a medication used in the treatment of acute lymphoblastic leukemia (ALL). Often it is used together with anthracycline, vincristine, and corticosteroids (for example prednisone and dexamethasone). Pegaspargase can be administered either via an intravenous infusion or a intramuscular injection.Known side effects include allergic reactions, coagulopathy, high blood sugar, affected liver function, pancreas inflammation, and blood clots in the brain. There is no data regarding the usage of pegaspargase during pregnancy. Therefor caution should be observed and pegaspargase should only be used during pregnancy when the benefits outweigh the possible risks </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 Candesartan and can you explain it in depth? [/INST] Candesartan is an angiotensin receptor blocker used mainly for the treatment of high blood pressure and congestive heart failure. Candesartan has a very low maintenance dose. The metabolism for the drug is unique as it is a cascading pro-drug. Candesartan has good bioavailibility and is more potent among the AT-1 receptor antagonists.
It was patented in 1990 and approved for medical use in 1997.

Medical uses
Hypertension
As with other angiotensin II receptor antagonists, candesartan is indicated for the treatment of hypertension. Candesartan has an additive antihypertensive effect when combined with a diuretic, such as chlorthalidone. It is available in a fixed-combination formulation with a low dose of the thiazide diuretic hydrochlorothiazide. Candesartan/hydrochlorothiazide combination preparations are marketed under various trade names including Atacand Plus, Hytacand, Blopress Plus, Advantec and Ratacand Plus.

Congestive heart failure
Angiotensin receptor blockers such as candesartan and valsartan have been demonstrated in randomised controlled trials to reduce heart failure hospitalisations and cardiovascular deaths for chronic heart failure patients with reduced left ventricular ejection fraction (LVEF ≤40%) and are intolerant to angiotensin-converting enzyme inhibitors.

Prehypertension
In a four-year randomized controlled trial, candesartan was compared to placebo to see whether it could prevent or postpone the development of full-blown hypertension in people with so-called prehypertension. During the first two years of the trial, half of participants were given candesartan while the other half received placebo; candesartan reduced the risk of developing hypertension by nearly two-thirds during this period. In the last two years of the study, all participants were switched to placebo. By the end of the study, candesartan had significantly reduced the risk of hypertension, by more than 15%. Serious adverse effects were more common among participants receiving placebo than in those given candesartan.

Prevention of atrial fibrillation
Results from a meta-analysis completed in 2005 demonstrated a reduction in atrial fibrillation in patients with systolic left ventricular dysfunction treated with candesartan, another angiotensin receptor blocker or an angiotensin converting enzyme inhibitor. Evidence for the use of candesartan specifically is also supported by an analysis of the CHARM study which demonstrated a reduction in atrial fibrillation in patients with systolic left ventricular dysfunction. While these studies have demonstrated a potential additional benefit for candesartan when used in patients with systolic left ventricular dysfunction, additional studies are required to further elucidate the role of candesartan in the prevention of atrial fibrillation in other population groups.

Diabetic retinopathy
Use of antihypertensive drugs has been demonstrated to slow the progression of diabetic retinopathy; the role of candesartan specifically in reducing progression in type 1 and type 2 diabetes is still up for debate. Results from a 2008 study on patients with type 1 diabetes showed there was no benefit in using candesartan to reduce progression of diabetic retinopathy when compared to placebo. Candesartan has been demonstrated to reverse the severity (cause regression) of mild to moderate diabetic retinopathy in patients with type 2 diabetes. The patient populations investigated in these studies were limited to mostly Caucasians and those younger than 75 years of age, so generalization of these findings to other population groups should be done with caution.

Migraine prophylaxis
In two small randomised, controlled cross-over studies, candesartan was shown to be effective for the prophylaxis of migraine; however, further studies would enhance confidence in its use for this indication.

Adverse effects
As with other drugs that inhibit the renin–angiotensin system, if candesartan is taken by pregnant women during the second or third trimester, it can cause injury and in some cases, death of the developing fetus. Symptomatic hypotension may occur in people who take candesartan and are volume-depleted or salt-depleted, as can also occur when diuretics are coadministered. Reduction in renal glomerular filtration rate may occur; people with renal artery stenosis may be at higher risk. Hyperkalemia may occur; people who are also taking spironolactone or eplerenone may be at higher risk.Anemia may occur, due to inhibition of the renin–angiotensin system.As with other angiotensin receptor blockers, candesartan can rarely cause severe liver injury.

Chemistry and pharmacokinetics
Candesartan is marketed as the cyclohexyl 1-hydroxyethyl carbonate (cilexetil) ester, known as candesartan cilexetil. Candesartan cilexetil is metabolised completely by esterases in the intestinal wall during absorption to the active candesartan moiety </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 Potassium chloride and can you explain it in depth? [/INST] Potassium chloride (KCl, or potassium salt) is a metal halide salt composed of potassium and chlorine. It is odorless and has a white or colorless vitreous crystal appearance. The solid dissolves readily in water, and its solutions have a salt-like taste. Potassium chloride can be obtained from ancient dried lake deposits. KCl is used as a fertilizer, in medicine, in scientific applications, domestic water softeners (as a substitute for sodium chloride salt), and in food processing, where it may be known as E number additive E508.
It occurs naturally as the mineral sylvite, and in combination with sodium chloride as sylvinite.

Uses
Fertilizer
The majority of the potassium chloride produced is used for making fertilizer, called potash, since the growth of many plants is limited by potassium availability.  Potassium chloride sold as fertilizer is known as muriate of potash (MOP). The vast majority of potash fertilizer worldwide is sold as MOP.

Medical use
Potassium is vital in the human body, and potassium chloride by mouth is the common means to treat low blood potassium, although it can also be given intravenously. It is on the World Health Organizations List of Essential Medicines. Overdose causes hyperkalemia which can disrupt cell signaling to the extent that the heart will stop, reversibly in the case of some open heart surgeries.

Culinary use
It can be used as a salt substitute for food, but due to its weak, bitter, unsalty flavor, it is often mixed with ordinary table salt (sodium chloride) to improve the taste to form low sodium salt. The addition of 1 ppm of thaumatin considerably reduces this bitterness.  Complaints of bitterness or a chemical or metallic taste are also reported with potassium chloride used in food.

Industrial
As a chemical feedstock, it is used for the manufacture of potassium hydroxide and potassium metal. It is also used in medicine, lethal injections, scientific applications, food processing, soaps, and as a sodium-free substitute for table salt for people concerned about the health effects of sodium.
It is used as a supplement in animal feed to boost the potassium level in the feed. As an added benefit, it is known to increase milk production.
It is sometimes used in solution as a completion fluid in petroleum and natural gas operations, as well as being an alternative to sodium chloride in household water softener units.
Glass manufacturers use granular potash as a flux, lowering the temperature at which a mixture melts. Because potash imparts excellent clarity to glass, it is commonly used in eyeglasses, glassware, televisions, and computer monitors.
KCl is useful as a beta radiation source for calibration of radiation monitoring equipment, because natural potassium contains 0.0118% of the isotope 40K. One kilogram of KCl yields 16350 becquerels of radiation, consisting of 89.28% beta and 10.72% gamma, with 1.46083 MeV. In order to use off-the-shelf materials, it needs to be crystallized sequentially, using controlled temperature, in order to extract KCl, which is the subject of ongoing research. It also emits a relatively low level of 511 keV gamma rays from positron annihilation, which can be used to calibrate medical scanners.
Potassium chloride is used in some de-icing products designed to be safer for pets and plants, though these are inferior in melting quality to calcium chloride [lowest usable temperature 12 °F (−11 °C) v. −25 °F (−32 °C)]. It is also used in various brands of bottled water.
Potassium chloride was once used as a fire extinguishing agent, and in portable and wheeled fire extinguishers. Known as Super-K dry chemical, it was more effective than sodium bicarbonate-based dry chemicals and was compatible with protein foam. This agent fell out of favor with the introduction of potassium bicarbonate (Purple-K) dry chemical in the late 1960s, which was much less corrosive, as well as more effective. It is rated for B and C fires.
Along with sodium chloride and lithium chloride, potassium chloride is used as a flux for the gas welding of aluminium.
Potassium chloride is also an optical crystal with a wide transmission range from 210 nm to 20 µm. While cheap, KCl crystals are hygroscopic. This limits its application to protected environments or short-term uses such as prototyping. Exposed to free air, KCl optics will "rot". Whereas KCl components were formerly used for infrared optics, it has been entirely replaced by much tougher crystals such as zinc selenide.
Potassium chloride is used as a scotophor with designation P10 in dark-trace CRTs, e.g. in the Skiatron.

Toxicity
The typical amounts of potassium chloride found in the diet appear to be generally safe. In larger quantities, however, potassium chloride is toxic. The LD50 of orally ingested potassium chloride is approximately 2.5 g/kg, or 190 grams (6.7 oz) for a body mass of 75 kilograms (165 lb). In comparison, the LD50 of sodium chloride (table salt) is 3.75 g/kg.
Intravenously, the LD50 of potassium chloride is far smaller, at about 57.2 mg/kg to 66.7 mg/kg; this is found by dividing the lethal concentration of positive potassium ions (about 30 to 35 mg/kg) by the proportion by mass of potassium ions in potassium chloride (about 0.52445 mg K+/mg KCl).

Chemical properties
Solubility
KCl is soluble in a variety of polar solvents.

Solutions of KCl are common standards, for example for calibration of the electrical conductivity of (ionic) solutions, since KCl solutions are stable, allowing for reproducible measurements.  In aqueous solution, it is essentially fully ionized into solvated K+ and Cl− ions.

Redox and the conversion to potassium metal
Although potassium is more electropositive than sodium, KCl can be reduced to the metal by reaction with metallic sodium at 850 °C because the more volatile potassium can be removed by distillation (see Le Chateliers principle):

            KCl

                (
                l
                )

          +

            Na

                (
                l
                )

                      ↽

                      −

                      −

                      ⇀

            NaCl

                (
                l
                )

          +

            K

                (
                g
                )

    {\displaystyle {\ce {KCl_{(l)}{}+ Na_{(l)}<=> NaCl_{(l)}{}+ K_{(g)}}}}
  This method is the main method for producing metallic potassium. Electrolysis (used for sodium) fails because of the high solubility of potassium in molten KCl.

Physical properties
The crystal structure of potassium chloride is like that of NaCl. It adopts a face-centered cubic structure. Its lattice constant is roughly 6.3 Å.   Crystals cleave easily in three directions.
Some other properties are

Transmission range: 210 nm to 20 µm
Transmittivity = 92% at 450 nm and rises linearly to 94% at 16 µm
Refractive index = 1.456 at 10 µm
Reflection loss = 6.8% at 10 µm (two surfaces)
dN/dT (expansion coefficient)= −33.2×10−6/°C
dL/dT (refractive index gradient)= 40×10−6/°C
Thermal conductivity = 0.036 W/(cm·K)
Damage threshold (Newman and Novak): 4 GW/cm2 or 2 J/cm2 (0.5 or 1 ns pulse rate); 4.2 J/cm2 (1.7 ns pulse rate Kovalev and Faizullov)As with other compounds containing potassium, KCl in powdered form gives a lilac flame.

Production
Potassium chloride is extracted from minerals sylvite, carnallite, and potash. It is also extracted from salt water and can be manufactured by crystallization from solution, flotation or electrostatic separation from suitable minerals. It is a by-product of the production of nitric acid from potassium nitrate and hydrochloric acid.
The vast majority of potassium chloride is produced as agricultural and industrial grade potash in Saskatchewan, Canada, as well as Russia and Belarus. Saskatchewan alone accounted for over 25% of the worlds potash production in 2017.

Laboratory methods
Potassium chloride is inexpensively available and is rarely prepared intentionally in the laboratory.  It can be generated by treating potassium hydroxide (or other potassium bases) with hydrochloric acid:

          KOH
          +
          HCl
          ⟶
          KCl
          +

            H

              2

          O

    {\displaystyle {\ce {KOH + HCl -> KCl + H2O}}}
  This conversion is an acid-base neutralization reaction. The resulting salt can then be purified by recrystallization. Another method would be to allow potassium to burn in the presence of chlorine gas, also a very exothermic reaction:

          2

          K
          +

            Cl

              2

          ⟶
          2

          KCl

    {\displaystyle {\ce {2 K + Cl2 -> 2 KCl}}}

References
Further reading
Lide, D. R., ed </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 Celecoxib/tramadol 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 Guaifenesin and can you explain it in depth? [/INST] Guaifenesin, sold under the brand name Mucinex, among others, is a medication used as an expectorant, intended to help cough out phlegm from the airways. Chemically it is an ether of guaiacol and glycerine. It is unclear if it decreases coughing. Use is not recommended in children less than six years old. It is often used in combination with other medications. It is taken by mouth.Side effects may include dizziness, sleepiness, skin rash, and nausea. While it has not been properly studied in pregnancy, it appears to be safe. It is believed to work by making airway secretions more liquid.Guaifenesin has been used medically since at least 1933. It is available as a generic medication and over the counter. In 2018, it was the 172nd most commonly prescribed medication in the United States, with more than 3 million prescriptions.

Medical use
Guaifenesin is used to try to help with coughing up thick mucus and is sometimes combined with dextromethorphan, an antitussive (cough suppressant), such as in Mucinex DM or Robitussin DM. It is also combined with ephedrine to produce Primatene and Bronkaid tablets for symptomatic relief of asthma.

Side effects
Side-effects of guaifenesin include nausea, vomiting, formation of kidney stones, diarrhea, and constipation.  Nausea and vomiting can be reduced by taking guaifenesin with meals.  The risk of forming kidney stones during prolonged use can be reduced by maintaining good hydration and increasing the pH of urine. Rarely, severe allergic reactions may occur, including a rash or swelling of the lips or gums, which may require urgent medical assistance.  Mild dry mouth or chapped lips may also occur when taking this medication. Drinking a glass of water is recommended with each dose of guaifenesin.

Pharmacology
Mechanism of action
Guaifenesin is thought to act as an expectorant by increasing the volume and reducing the viscosity of secretions in the trachea and bronchi. It may aid in the flow of respiratory tract secretions, allowing ciliary movement to carry the loosened secretions upward toward the pharynx. Thus, it may increase the efficiency of the cough reflex and facilitate removal of the secretions.
Guaifenesin has muscle relaxant and anticonvulsant properties and may act as an NMDA receptor antagonist.

History
Similar medicines derived from the guaiac tree were in use as a generic remedy by American indigenous peoples when explorers reached North America in the 16th century. The Spanish encountered guaiacum wood "when they conquered Santo Domingo; it was soon brought back to Europe, where it acquired an immense reputation in the sixteenth century as a cure for syphilis and certain other diseases..."The 1955 edition of the Textbook of Pharmacognosy states: "Guaiacum has a local stimulant action which is sometimes useful in sore throat. The resin is used in chronic gout and rheumatism, whilst the wood is an ingredient in the compound concentrated solution of sarsaparilla, which was formerly much used as an alternative in syphilis."In the US, guaifenesin was first approved by the Food and Drug Administration (FDA) in 1952. Although previously deemed "Generally Regarded as Safe" in its original approval, the drug received a New Drug Application for the extended-release version, which received approval on 12 July 2002.  Because of this, the FDA then issued letters to other manufacturers of timed-release guaifenesin to stop marketing their unapproved versions, leaving Adams Respiratory Therapeutics in control of the market. In 2007, Adams was acquired by Reckitt Benckiser. The drug is now sold over-the-counter by many companies, alone and in combination.

Availability
Guaifenesin is taken by mouth as pills or syrups. It is available under many brand names, as either the lone active ingredient or as one part of a combination drug. Drugs combined with guaifenesin in over-the-counter preparations include the cough-suppressant dextromethorphan, analgesics such as paracetamol/acetaminophen, and decongestants such as ephedrine, pseudoephedrine, or phenylephrine.

Veterinary use
Guaifenesins neurological properties first became known in the late 1940s </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 Ibutilide and can you explain it in depth? [/INST] Ibutilide is a Class III antiarrhythmic agent that is indicated for acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm. It exerts its antiarrhythmic effect by induction of slow inward sodium current, which prolongs action potential and refractory period (physiology) of myocardial cells. Because of its Class III antiarrhythmic activity, there should not be concomitant administration of Class Ia and Class III agents.
Ibutilide is marketed as Corvert by Pfizer. Administration resulted in successful heart rhythm control in 31-44% of patients within 90 minutes, with sustained polymorphic ventricular tachycardia in 0.9-2.5% of patients. It appears to show better results in atrial flutter as compared to atrial fibrillation.

Mechanism of action
Ibutilide, like other class III antiarrhythmic drugs, blocks delayed rectified potassium current.It does have action on the slow sodium channel and promotes the influx of sodium through these slow channels.
Although potassium current seems to play a role, their interactions are complex and not well understood. Ibutilides unique mechanism works by an activation of a specific inward sodium current, thus producing its therapeutic response in which a prolonged action potential increases myocytes’ cardiac refractoriness in case of atrial fibrillation and flutter.

Pharmacokinetics
Absorption
Ibutilide is intravenously administered. It has a high first-pass metabolism, which results in a poor bioavailability when taken orally. Individual pharmacokinetic properties are highly viable during the clinical trial.

Distribution
Ibutilide has a relatively large volume of distribution among individual subjects, which is about 11L/kg. Approximately 40% of the drug is bound with plasma albumin of healthy volunteers in a trial. This is also approximately close to patients with atrial fibrillation and flutter.

Metabolism
Ibutilide has a high systemic plasma clearance that closes to the hepatic blood flow  (29mL/min/kg) </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 Ephedrine and can you explain it in depth? [/INST] Ephedrine is a central nervous system (CNS) stimulant that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in nasal congestion. It can be taken by mouth or by injection into a muscle, vein, or just under the skin. Onset with intravenous use is fast, while injection into a muscle can take 20 minutes, and by mouth can take an hour for effect. When given by injection it lasts about an hour and when taken by mouth it can last up to four hours.Common side effects include trouble sleeping, anxiety, headache, hallucinations, high blood pressure, fast heart rate, loss of appetite, and inability to urinate. Serious side effects include stroke and heart attack. While likely safe in pregnancy, its use in this population is poorly studied. Use during breastfeeding is not recommended. Ephedrine works by increasing the activity of the α and β adrenergic receptors.Ephedrine was first isolated in 1885 and came into commercial use in 1926. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication.  It can normally be found in plants of the Ephedra genus. Dietary supplements containing ephedrine are illegal in the United States, with the exception of those used in traditional Chinese medicine, where its presence is noted by má huáng.

Medical use
Both ephedrine and pseudoephedrine increase blood pressure and act as bronchodilators, with pseudoephedrine having considerably less effect.Ephedrine may decrease motion sickness, but it has mainly been used to decrease the sedating effects of other medications used for motion sickness.Ephedrine is also found to have quick and long-lasting responsiveness in congenital myasthenic syndrome in early childhood and also even in the adults with a novel COLQ mutation.

Weight loss
Ephedrine promotes modest short-term weight loss, specifically fat loss, but its long-term effects are unknown. In mice, ephedrine is known to stimulate thermogenesis in the brown adipose tissue, but because adult humans have only small amounts of brown fat, thermogenesis is assumed  to take place mostly in the skeletal muscle. Ephedrine also decreases gastric emptying. Methylxanthines such as caffeine and theophylline have a synergistic effect with ephedrine with respect to weight loss.  This led to creation and marketing of compound products.  One of them, known as the ECA stack, contains ephedrine with caffeine and aspirin. It is a popular supplement taken by bodybuilders seeking to cut body fat before a competition.

Recreational use
As a phenethylamine, ephedrine has a similar chemical structure to amphetamines and is a methamphetamine analogue having the methamphetamine structure with a hydroxyl group at the β position. Because of ephedrines structural similarity to methamphetamine, it can be used to create methamphetamine using chemical reduction in which ephedrines hydroxyl group is removed; this has made ephedrine a highly sought-after chemical precursor in the illicit manufacture of methamphetamine.
The most popular method for reducing ephedrine to methamphetamine is similar to the Birch reduction, in that it uses anhydrous ammonia and lithium metal in the reaction. The second-most popular method uses red phosphorus and iodine in the reaction with ephedrine. Moreover, ephedrine can be synthesized into methcathinone via simple oxidation. As such, ephedrine is listed as a table-I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.

Detection of use
Ephedrine may be quantified in blood, plasma, or urine to monitor possible abuse by athletes, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Many commercial immunoassay screening tests directed at the amphetamines cross-react appreciably with ephedrine, but chromatographic techniques can easily distinguish ephedrine from other phenethylamine derivatives. Blood or plasma ephedrine concentrations are typically in the 20–200 µg/L range in persons taking the drug therapeutically, 300–3000 µg/L in abusers or poisoned patients and 3–20 mg/L in cases of acute fatal overdosage. The current World Anti-Doping Agency (WADA) limit for ephedrine in an athletes urine is 10 µg/mL.

Contraindications
Ephedrine should not be used in conjunction with certain antidepressants, namely norepinephrine-dopamine reuptake inhibitors (NDRIs), as this increases the risk of symptoms due to excessive serum levels of norepinephrine.
Bupropion is an example of an antidepressant with an amphetamine-like structure similar to ephedrine, and it is an NDRI. Its action bears more resemblance to amphetamine than to fluoxetine in that its primary mode of therapeutic action involves norepinephrine and to a lesser degree dopamine, but it also releases some serotonin from presynaptic clefts. It should not be used with ephedrine, as it may increase the likelihood of side effects.
Ephedrine should be used with caution in patients with inadequate fluid replacement, impaired adrenal function, hypoxia, hypercapnia, acidosis, hypertension, hyperthyroidism, prostatic hypertrophy, diabetes mellitus, cardiovascular disease, during delivery if maternal blood pressure is >130/80 mmHg, and during lactation.Contraindications for the use of ephedrine include: closed-angle glaucoma, phaeochromocytoma, asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis), concomitant or recent (previous 14 days) monoamine oxidase inhibitor (MAOI) therapy, general anaesthesia with halogenated hydrocarbons (particularly halothane), tachyarrhythmias or ventricular fibrillation, or hypersensitivity to ephedrine or other stimulants.
Ephedrine should not be used at any time during pregnancy unless specifically indicated by a qualified physician and only when other options are unavailable.

Adverse effects
Ephedrine is a potentially dangerous natural compound; as of 2004 the US Food and Drug Administration had received over 18,000 reports of adverse effects in people using it.Adverse drug reactions (ADRs) are more common with systemic administration (e.g. injection or oral administration) compared to topical administration (e.g. nasal instillations). ADRs associated with ephedrine therapy include:
Cardiovascular: tachycardia, cardiac arrhythmias, angina pectoris, vasoconstriction with hypertension
Dermatological: flushing, sweating, acne vulgaris
Gastrointestinal: nausea
Genitourinary: decreased urination due to vasoconstriction of renal arteries, difficulty urinating is not uncommon, as alpha-agonists such as ephedrine constrict the internal urethral sphincter, mimicking the effects of sympathetic nervous system stimulation
Nervous system: restlessness, confusion, insomnia, mild euphoria, mania/hallucinations (rare except in previously existing psychiatric conditions), delusions, formication (may be possible, but lacks documented evidence) paranoia, hostility, panic, agitation
Respiratory: dyspnea, pulmonary edema
Miscellaneous: dizziness, headache, tremor, hyperglycemic reactions, dry mouthThe neurotoxicity of l-ephedrine is disputed.

Other uses
In chemical synthesis, ephedrine is used in bulk quantities as a chiral auxiliary group.
In saquinavir synthesis, the half-acid is resolved as its salt with l-ephedrine.

Chemistry and nomenclature
Ephedrine is a sympathomimetic amine and substituted amphetamine. It is similar in molecular structure to phenylpropanolamine, methamphetamine, and epinephrine (adrenaline). Chemically, it is an alkaloid with a phenethylamine skeleton found in various plants in the genus Ephedra (family Ephedraceae). It works mainly by increasing the activity of norepinephrine (noradrenaline) on adrenergic receptors. It is most usually marketed as the hydrochloride or sulfate salt.
Ephedrine exhibits optical isomerism and has two chiral centres, giving rise to four stereoisomers. By convention, the pair of enantiomers with the stereochemistry (1R,2S) and (1S,2R) is designated ephedrine, while the pair of enantiomers with the stereochemistry (1R,2R) and (1S,2S) is called pseudoephedrine.
Ephedrine is a substituted amphetamine and a structural methamphetamine analogue. It differs from methamphetamine only by the presence of a hydroxyl group (—OH).
The isomer which is marketed is (−)-(1R,2S)-ephedrine.Ephedrine hydrochloride has a melting point of 187−188 °C.In the outdated D/L system (+)-ephedrine is also referred to as D-ephedrine and (−)-ephedrine as L-ephedrine (in which case, in the Fisher projection, the phenyl ring is drawn at the bottom).Often, the D/L system (with small caps) and the d/l system (with lower-case) are confused. The result is that the levorotary l-ephedrine is wrongly named L-ephedrine and the dextrorotary d-pseudoephedrine (the diastereomer) wrongly D-pseudoephedrine.
The IUPAC names of the two enantiomers are (1R,2S)- respectively (1S,2R)-2-methylamino-1-phenylpropan-1-ol. A synonym is erythro-ephedrine.

Sources
Agricultural
Ephedrine is obtained from the plant Ephedra sinica and other members of the genus Ephedra, from which the name of the substance is derived. Raw materials for the manufacture of ephedrine and traditional Chinese medicines are produced in China on a large scale. As of 2007, companies produced for export US$13 million worth of ephedrine from 30,000 tons of ephedra annually, or about ten times the amount used in traditional Chinese medicine.

Synthetic
Most of the l-ephedrine produced today for official medical use is made synthetically as the extraction and isolation process from E. sinica is tedious and no longer cost effective.

Biosynthetic
Ephedrine was long thought to come from modifying the amino acid L-phenylalanine. L-Phenylalanine would be decarboxylated and subsequently attacked with ω-aminoacetophenone. Methylation of this product would then produce ephedrine. This pathway has since been disproven. A new pathway proposed suggests that phenylalanine first forms cinnamoyl-CoA via the enzymes phenylalanine ammonia-lyase and acyl CoA ligase. The cinnamoyl-CoA is then reacted with a hydratase to attach the alcohol functional group. The product is then reacted with a retro-aldolase, forming benzaldehyde. Benzaldehyde reacts with pyruvic acid to attach a 2 carbon unit. This product then undergoes transamination and methylation to form ephedrine and its stereoisomer, pseudoephedrine.

Mechanism of action
Ephedrine, a sympathomimetic amine, acts on part of the sympathetic nervous system (SNS). The principal mechanism of action relies on its indirect stimulation of the adrenergic receptor system by increasing the activity of norepinephrine at the postsynaptic α  and β receptors. The presence of direct interactions with α receptors is unlikely, but still controversial. L-ephedrine, and particularly its stereoisomer norpseudoephedrine (which is also present in Catha edulis) has indirect sympathomimetic effects and due to its ability to cross the blood-brain barrier, it is a CNS stimulant similar to amphetamines, but less pronounced, as it releases noradrenaline and dopamine in the substantia nigra.The presence of an N-methyl group decreases binding affinities at α receptors, compared with norephedrine. Ephedrine, though, binds better than N-methylephedrine, which has an additional methyl group at the nitrogen atom. Also the steric orientation of the hydroxyl group is important for receptor binding and functional activity.
Compounds with decreasing α-receptor affinity

History
Asia
Ephedrine in its natural form, known as máhuáng (麻黄) in traditional Chinese medicine, has been documented in China since the Han dynasty (206 BC – 220 AD) as an antiasthmatic and stimulant. In traditional Chinese medicine, máhuáng has been used as a treatment for asthma and bronchitis for centuries.In 1885, the chemical synthesis of ephedrine was first accomplished by Japanese organic chemist Nagai Nagayoshi based on his research on  traditional Japanese and Chinese herbal medicines.
The industrial manufacture of ephedrine in China began in the 1920s, when Merck began marketing and selling the drug as ephetonin. Ephedrine exports from China to the West grew from 4 to 216 tonnes between 1926 and 1928.

Western medicine
Introduced in 1948 Vicks Vatronol nose drops (now discontinued) contained ephedrine sulfate as the active ingredient for rapid nasal decongestion.

Legality
Canada
In January 2002, Health Canada issued a voluntary recall of all ephedrine products containing more than 8 mg per dose, all combinations of ephedrine with other stimulants such as caffeine, and all ephedrine products marketed for weight-loss or bodybuilding indications, citing a serious risk to health. Ephedrine is still sold as an oral nasal decongestant in 8 mg pills as a natural health product, with a limit of 0.4g per package, the limit established by the Controlled Drugs and Substances Act as it is considered as Class A Precursor.

United States
In 1997, the FDA proposed a regulation on ephedra (the herb from which ephedrine is obtained), which limited an ephedra dose to 8 mg (of active ephedrine) with no more than 24 mg per day. This proposed rule was withdrawn, in part, in 2000 because of "concerns regarding the agencys basis for proposing a certain dietary ingredient level and a duration of use limit for these products." In 2004, the FDA created a ban on ephedrine alkaloids marketed for reasons other than asthma, colds, allergies, other disease, or traditional Asian use. On April 14, 2005, the U.S. District Court for the District of Utah ruled the FDA did not have proper evidence that low dosages of ephedrine alkaloids are actually unsafe, but on August 17, 2006, the U.S. Court of Appeals for the Tenth Circuit in Denver upheld the FDAs final rule declaring all dietary supplements containing ephedrine alkaloids adulterated, and therefore illegal for marketing in the United States. Furthermore, ephedrine is banned by the NCAA, MLB, NFL, and PGA. Ephedrine is, however, still legal in many applications outside of dietary supplements. Purchasing is currently limited and monitored, with specifics varying from state to state.
The House passed the Combat Methamphetamine Epidemic Act of 2005 as an amendment to the renewal of the USA PATRIOT Act. Signed into law by President George W. Bush on March 6, 2006, the act amended the US Code (21 USC 830) concerning the sale of products containing ephedrine and the closely related drug pseudoephedrine. Both substances are used as precursors in the illicit production of methamphetamine, and to discourage that use the federal statute included the following requirements for merchants who sell these products:

A retrievable record of all purchases identifying the name and address of each party to be kept for two years
Required verification of proof of identity of all purchasers
Required protection and disclosure methods in the collection of personal information
Reports to the Attorney General of any suspicious payments or disappearances of the regulated products
Non-liquid dose form of regulated product may only be sold in unit-dose blister packs
Regulated products are to be sold behind the counter or in a locked cabinet in such a way as to restrict access
Daily sales of regulated products not to exceed 3.6 g to a single purchaser, without regard to the number of transactions
Monthly sales to a single purchaser not to exceed 9 g of pseudoephedrine base in regulated productsThe law gives similar regulations to mail-order purchases, except the monthly sales limit is 7.5 g.
As a pure herb or tea, má huáng, containing ephedrine, is still sold legally in the US.  The law restricts/prohibits its being sold as a dietary supplement (pill) or as an ingredient/additive to other products, like diet pills.

Australia
Ephedrine and all Ephedra species which contain it are considered Schedule 4 substances under the Poisons Standard (October 2015). A Schedule 4 drug is considered a Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription under the Poisons Standard (October 2015).

South Africa
In South Africa, ephedrine was moved to schedule 6 on 27 May 2008, which makes pure ephedrine tablets prescription only. Pills containing ephedrine up to 30mg per tablet in combination with other medications are still available OTC, schedule 1 and 2, for sinus, head colds and influenza.

Germany
Ephedrine was freely available in pharmacies in Germany until 2001.  Afterwards, access was restricted since it was mostly bought for unindicated uses. Similarly, ephedra can only be bought with a prescription </s>