<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 Methamphetamine and can you explain it in depth? [/INST] Methamphetamine (contracted from N-methylamphetamine) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamphetamine was discovered in 1893 and exists as two enantiomers: levo-methamphetamine and dextro-methamphetamine. Methamphetamine properly refers to a specific chemical substance, the racemic free base, which is an equal mixture of levomethamphetamine and dextromethamphetamine in their pure amine forms. It is rarely prescribed over concerns involving human neurotoxicity and potential for recreational use as an aphrodisiac and euphoriant, among other concerns, as well as the availability of safer substitute drugs with comparable treatment efficacy such as Adderall and Vyvanse. Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine.
Both racemic methamphetamine and dextromethamphetamine are illicitly trafficked and sold owing to their potential for recreational use. The highest prevalence of illegal methamphetamine use occurs in parts of Asia and Oceania, and in the United States, where racemic methamphetamine and dextromethamphetamine are classified as schedule II controlled substances. Levomethamphetamine is available as an over-the-counter (OTC) drug for use as an inhaled nasal decongestant in the United States. Internationally, the production, distribution, sale, and possession of methamphetamine is restricted or banned in many countries, due to its placement in schedule II of the United Nations Convention on Psychotropic Substances treaty. While dextromethamphetamine is a more potent drug, racemic methamphetamine is illicitly produced more often due to the relative ease of synthesis and regulatory limits of chemical precursor availability.
In low to moderate doses, methamphetamine can elevate mood, increase alertness, concentration and energy in fatigued individuals, reduce appetite, and promote weight loss. At very high doses, it can induce psychosis, breakdown of skeletal muscle, seizures and bleeding in the brain. Chronic high-dose use can precipitate unpredictable and rapid mood swings, stimulant psychosis (e.g., paranoia, hallucinations, delirium, and delusions) and violent behavior. Recreationally, methamphetamines ability to increase energy has been reported to lift mood and increase sexual desire to such an extent that users are able to engage in sexual activity continuously for several days while binging the drug. Methamphetamine is known to possess a high addiction liability (i.e., a high likelihood that long-term or high dose use will lead to compulsive drug use) and high dependence liability (i.e. a high likelihood that withdrawal symptoms will occur when methamphetamine use ceases). Withdrawal from methamphetamine after heavy use may lead to a post-acute-withdrawal syndrome, which can persist for months beyond the typical withdrawal period. Methamphetamine is neurotoxic to human midbrain dopaminergic neurons at high doses. Methamphetamine has been shown to have a higher affinity and, as a result, higher toxicity toward serotonergic neurons than amphetamine. Methamphetamine neurotoxicity causes adverse changes in brain structure and function, such as reductions in grey matter volume in several brain regions, as well as adverse changes in markers of metabolic integrity.
Methamphetamine belongs to the substituted phenethylamine and substituted amphetamine chemical classes. It is related to the other dimethylphenethylamines as a positional isomer of these compounds, which share the common chemical formula C10H15N.

Uses
Medical
In the United States, methamphetamine hydrochloride, under the trade name Desoxyn, has been approved by the FDA for treating ADHD and obesity in both adults and children; however, the FDA also indicates that the limited therapeutic usefulness of methamphetamine should be weighed against the inherent risks associated with its use. Methamphetamine is sometimes prescribed off label for narcolepsy and idiopathic hypersomnia. In the United States, methamphetamines levorotary form is available in some over-the-counter (OTC) nasal decongestant products.As methamphetamine is associated with a high potential for misuse, the drug is regulated under the Controlled Substances Act and is listed under Schedule II in the United States. Methamphetamine hydrochloride dispensed in the United States is required to include a boxed warning regarding its potential for recreational misuse and addiction liability.Desoxyn and Desoxyn Gradumet are both pharmaceutical forms of the drug. The latter is no longer produced and is a gradual-release form of the drug, flattening the curve of the effect of the drug while extending it.

Recreational
Methamphetamine is often used recreationally for its effects as a potent euphoriant and stimulant as well as aphrodisiac qualities.According to a National Geographic TV documentary on methamphetamine, an entire subculture known as party and play is based around sexual activity and methamphetamine use. Participants in this subculture, which consists almost entirely of homosexual male methamphetamine users, will typically meet up through internet dating sites and have sex. Due to its strong stimulant and aphrodisiac effects and inhibitory effect on ejaculation, with repeated use, these sexual encounters will sometimes occur continuously for several days on end. The crash following the use of methamphetamine in this manner is very often severe, with marked hypersomnia (excessive daytime sleepiness). The party and play subculture is prevalent in major US cities such as San Francisco and New York City.

Contraindications
Methamphetamine is contraindicated in individuals with a history of substance use disorder, heart disease, or severe agitation or anxiety, or in individuals currently experiencing arteriosclerosis, glaucoma, hyperthyroidism, or severe hypertension. The FDA states that individuals who have experienced hypersensitivity reactions to other stimulants in the past or are currently taking monoamine oxidase inhibitors should not take methamphetamine. The FDA also advises individuals with bipolar disorder, depression, elevated blood pressure, liver or kidney problems, mania, psychosis, Raynauds phenomenon, seizures, thyroid problems, tics, or Tourette syndrome to monitor their symptoms while taking methamphetamine. Due to the potential for stunted growth, the FDA advises monitoring the height and weight of growing children and adolescents during treatment.

Adverse effects
Physical
The physical effects of methamphetamine can include loss of appetite, hyperactivity, dilated pupils, flushed skin, excessive sweating, increased movement, dry mouth and teeth grinding (leading to "meth mouth"), headache, irregular heartbeat (usually as accelerated heartbeat or slowed heartbeat), rapid breathing, high blood pressure, low blood pressure, high body temperature, diarrhea, constipation, blurred vision, dizziness, twitching, numbness, tremors, dry skin, acne, and pale appearance. Long-term meth users may have sores on their skin; these may be caused by scratching due to itchiness or the belief that insects are crawling under their skin, and the damage is compounded by poor diet and hygiene. Numerous deaths related to methamphetamine overdoses have been reported.

Meth mouth
Methamphetamine users and addicts may lose their teeth abnormally quickly, regardless of the route of administration, from a condition informally known as meth mouth. The condition is generally most severe in users who inject the drug, rather than swallow, smoke, or inhale it. According to the American Dental Association, meth mouth "is probably caused by a combination of drug-induced psychological and physiological changes resulting in xerostomia (dry mouth), extended periods of poor oral hygiene, frequent consumption of high-calorie, carbonated beverages and bruxism (teeth grinding and clenching)". As dry mouth is also a common side effect of other stimulants, which are not known to contribute severe tooth decay, many researchers suggest that methamphetamine-associated tooth decay is more due to users other choices. They suggest the side effect has been exaggerated and stylized to create a stereotype of current users as a deterrence for new ones.

Sexually transmitted infection
Methamphetamine use was found to be related to higher frequencies of unprotected sexual intercourse in both HIV-positive and unknown casual partners, an association more pronounced in HIV-positive participants. These findings suggest that methamphetamine use and engagement in unprotected anal intercourse are co-occurring risk behaviors, behaviors that potentially heighten the risk of HIV transmission among gay and bisexual men. Methamphetamine use allows users of both sexes to engage in prolonged sexual activity, which may cause genital sores and abrasions as well as priapism in men. Methamphetamine may also cause sores and abrasions in the mouth via bruxism, increasing the risk of sexually transmitted infection.Besides the sexual transmission of HIV, it may also be transmitted between users who share a common needle. The level of needle sharing among methamphetamine users is similar to that among other drug injection users.

Fatal
Doses of 200 mg or more of methamphetamine are considered fatal.

Psychological
The psychological effects of methamphetamine can include euphoria, dysphoria, changes in libido, alertness, apprehension and concentration, decreased sense of fatigue, insomnia or wakefulness, self-confidence, sociability, irritability, restlessness, grandiosity and repetitive and obsessive behaviors. Peculiar to methamphetamine and related stimulants is "punding", persistent non-goal-directed repetitive activity. Methamphetamine use also has a high association with anxiety, depression, amphetamine psychosis, suicide, and violent behaviors.

Neurotoxic and neuroimmunological
Methamphetamine is directly neurotoxic to dopaminergic neurons in both lab animals and humans. Excitotoxicity, oxidative stress, metabolic compromise, UPS dysfunction, protein nitration, endoplasmic reticulum stress, p53 expression and other processes contributed to this neurotoxicity. In line with its dopaminergic neurotoxicity, methamphetamine use is associated with a higher risk of Parkinsons disease. In addition to its dopaminergic neurotoxicity, a review of evidence in humans indicated that high-dose methamphetamine use can also be neurotoxic to serotonergic neurons. It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine. Withdrawal of methamphetamine in dependent persons may lead to post-acute withdrawal which persists months beyond the typical withdrawal period.Magnetic resonance imaging studies on human methamphetamine users have also found evidence of neurodegeneration, or adverse neuroplastic changes in brain structure and function. In particular, methamphetamine appears to cause hyperintensity and hypertrophy of white matter, marked shrinkage of hippocampi, and reduced gray matter in the cingulate cortex, limbic cortex, and paralimbic cortex in recreational methamphetamine users. Moreover, evidence suggests that adverse changes in the level of biomarkers of metabolic integrity and synthesis occur in recreational users, such as a reduction in N-acetylaspartate and creatine levels and elevated levels of choline and myoinositol.Methamphetamine has been shown to activate TAAR1 in human astrocytes and generate cAMP as a result. Activation of astrocyte-localized TAAR1 appears to function as a mechanism by which methamphetamine attenuates membrane-bound EAAT2 (SLC1A2) levels and function in these cells.Methamphetamine binds to and activates both sigma receptor subtypes, σ1 and σ2, with micromolar affinity. Sigma receptor activation may promote methamphetamine-induced neurotoxicity by facilitating hyperthermia, increasing dopamine synthesis and release, influencing microglial activation, and modulating apoptotic signaling cascades and the formation of reactive oxygen species.

Addictive
Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens. The most important transcription factors that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB). ΔFosB plays a crucial role in the development of drug addictions, since its overexpression in D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for most of the behavioral and neural adaptations that arise from addiction. Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression. It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both directly oppose the induction of ΔFosB in the nucleus accumbens (i.e., they oppose increases in its expression). Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug use (i.e., the alterations mediated by ΔFosB). ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. Since both natural rewards and addictive drugs induce expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction. ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sex addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use. These sex addictions (i.e., drug-induced compulsive sexual behaviors) are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs, such as amphetamine or methamphetamine.

Epigenetic factors
Methamphetamine addiction is persistent for many individuals, with 61% of individuals treated for addiction relapsing within one year. About half of those with methamphetamine addiction continue with use over a ten-year period, while the other half reduce use starting at about one to four years after initial use.The frequent persistence of addiction suggests that long-lasting changes in gene expression may occur in particular regions of the brain, and may contribute importantly to the addiction phenotype. Recently a crucial role has been found for epigenetic mechanisms in driving lasting changes in gene expression in the brain.A review in 2015 summarized a number of studies involving chronic methamphetamine use in rodents. Epigenetic alterations were observed in the brain reward pathways, including areas like ventral tegmental area, nucleus accumbens, and dorsal striatum, the hippocampus, and the prefrontal cortex. Chronic methamphetamine use caused gene-specific histone acetylations, deacetylations and methylations. Gene-specific DNA methylations in particular regions of the brain were also observed. The various epigenetic alterations caused downregulations or upregulations of specific genes important in addiction. For instance, chronic methamphetamine use caused methylation of the lysine in position 4 of histone 3 located at the promoters of the c-fos and the C-C chemokine receptor 2 (ccr2) genes, activating those genes in the nucleus accumbens (NAc). c-fos is well known to be important in addiction. The ccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction.In methamphetamine addicted rats, epigenetic regulation through reduced acetylation of histones, in brain striatal neurons, caused reduced transcription of glutamate receptors. Glutamate receptors play an important role in regulating the reinforcing effects of misused illicit drugs.Administration of methamphetamine to rodents causes DNA damage in their brain, particularly in the nucleus accumbens region. During repair of such DNA damages, persistent chromatin alterations may occur such as in the methylation of DNA or the acetylation or methylation of histones at the sites of repair. These alterations can be epigenetic scars in the chromatin that contribute to the persistent epigenetic changes found in methamphetamine addiction.

Treatment and management
A 2018 systematic review and network meta-analysis of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate). Other treatment modalities examined in the analysis included monotherapy with contingency management or community reinforcement approach, cognitive behavioral therapy, 12-step programs, non-contingent reward-based therapies, psychodynamic therapy, and other combination therapies involving these.As of December 2019, there is no effective pharmacotherapy for methamphetamine addiction. A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in RCTs for amphetamine and methamphetamine addiction; it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration. There was low- to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion, mirtazapine, sertraline), antipsychotics (aripiprazole), anticonvulsants (topiramate, baclofen, gabapentin), naltrexone, varenicline, citicoline, ondansetron, prometa, riluzole, atomoxetine, dextroamphetamine, and modafinil.

Dependence and withdrawal
Tolerance is expected to develop with regular methamphetamine use and, when used recreationally, this tolerance develops rapidly. In dependent users, withdrawal symptoms are positively correlated with the level of drug tolerance. Depression from methamphetamine withdrawal lasts longer and is more severe than that of cocaine withdrawal.According to the current Cochrane review on drug dependence and withdrawal in recreational users of methamphetamine, "when chronic heavy users abruptly discontinue [methamphetamine] use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose". Withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for three to four weeks with a marked "crash" phase occurring during the first week. Methamphetamine withdrawal symptoms can include anxiety, drug craving, dysphoric mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and vivid or lucid dreams.Methamphetamine that is present in a mothers bloodstream can pass through the placenta to a fetus and be secreted into breast milk. Infants born to methamphetamine-abusing mothers may experience a neonatal withdrawal syndrome, with symptoms involving of abnormal sleep patterns, poor feeding, tremors, and hypertonia. This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.

Neonatal
Unlike other drugs, babies with prenatal exposure to methamphetamines dont show immediate signs of withdrawal. Instead, cognitive and behavioral problems start emerging when the children reach school age.A prospective cohort study of 330 children showed that at the age of 3, children with methamphetamine exposure showed increased emotional reactivity, as well as more signs of anxiety and depression; and at the age of 5, children showed higher rates of externalizing and attention deficit/hyperactivity disorders.

Overdose
A methamphetamine overdose may result in a wide range of symptoms. A moderate overdose of methamphetamine may induce symptoms such as: abnormal heart rhythm, confusion, difficult and/or painful urination, high or low blood pressure, high body temperature, over-active and/or over-responsive reflexes, muscle aches, severe agitation, rapid breathing, tremor, urinary hesitancy, and an inability to pass urine. An extremely large overdose may produce symptoms such as adrenergic storm, methamphetamine psychosis, substantially reduced or no urine output, cardiogenic shock, bleeding in the brain, circulatory collapse, hyperpyrexia (i.e., dangerously high body temperature), pulmonary hypertension, kidney failure, rapid muscle breakdown, serotonin syndrome, and a form of stereotypy ("tweaking"). A methamphetamine overdose will likely also result in mild brain damage due to dopaminergic and serotonergic neurotoxicity. Death from methamphetamine poisoning is typically preceded by convulsions and coma.

Psychosis
Use of methamphetamine can result in a stimulant psychosis which may present with a variety of symptoms (e.g., paranoia, hallucinations, delirium, and delusions). A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine use-induced psychosis states that about 5–15% of users fail to recover completely. The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis. Amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.

Emergency treatment
Acute methamphetamine intoxication is largely managed by treating the symptoms and treatments may initially include administration of activated charcoal and sedation. There is not enough evidence on hemodialysis or peritoneal dialysis in cases of methamphetamine intoxication to determine their usefulness. Forced acid diuresis (e.g., with vitamin C) will increase methamphetamine excretion but is not recommended as it may increase the risk of aggravating acidosis, or cause seizures or rhabdomyolysis. Hypertension presents a risk for intracranial hemorrhage (i.e., bleeding in the brain) and, if severe, is typically treated with intravenous phentolamine or nitroprusside. Blood pressure often drops gradually following sufficient sedation with a benzodiazepine and providing a calming environment.Antipsychotics such as haloperidol are useful in treating agitation and psychosis from methamphetamine overdose. Beta blockers with lipophilic properties and CNS penetration such as metoprolol and labetalol may be useful for treating CNS and cardiovascular toxicity. The mixed alpha- and beta-blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine. The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta-blockers for treatment of methamphetamine toxicity.

Interactions
Methamphetamine is metabolized by the liver enzyme CYP2D6, so CYP2D6 inhibitors will prolong the elimination half-life of methamphetamine. Methamphetamine also interacts with monoamine oxidase inhibitors (MAOIs), since both MAOIs and methamphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous. Methamphetamine may decrease the effects of sedatives and depressants and increase the effects of antidepressants and other stimulants as well. Methamphetamine may counteract the effects of antihypertensives and antipsychotics due to its effects on the cardiovascular system and cognition respectively. The pH of gastrointestinal content and urine affects the absorption and excretion of methamphetamine. Specifically, acidic substances will reduce the absorption of methamphetamine and increase urinary excretion, while alkaline substances do the opposite. Due to the effect pH has on absorption, proton pump inhibitors, which reduce gastric acid, are known to interact with methamphetamine.

Pharmacology
Pharmacodynamics
Methamphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor (GPCR) that regulates brain catecholamine systems. Activation of TAAR1 increases cyclic adenosine monophosphate (cAMP) production and either completely inhibits or reverses the transport direction of the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT). When methamphetamine binds to TAAR1, it triggers transporter phosphorylation via protein kinase A (PKA) and protein kinase C (PKC) signaling, ultimately resulting in the internalization or reverse function of monoamine transporters. Methamphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent signaling pathway, in turn producing dopamine efflux. TAAR1 has been shown to reduce the firing rate of neurons through direct activation of G protein-coupled inwardly-rectifying potassium channels. TAAR1 activation by methamphetamine in astrocytes appears to negatively modulate the membrane expression and function of EAAT2, a type of glutamate transporter.In addition to its effect on the plasma membrane monoamine transporters, methamphetamine inhibits synaptic vesicle function by inhibiting VMAT2, which prevents monoamine uptake into the vesicles and promotes their release. This results in the outflow of monoamines from synaptic vesicles into the cytosol (intracellular fluid) of the presynaptic neuron, and their subsequent release into the synaptic cleft by the phosphorylated transporters. Other transporters that methamphetamine is known to inhibit are SLC22A3 and SLC22A5. SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter.Methamphetamine is also an agonist of the alpha-2 adrenergic receptors and sigma receptors with a greater affinity for σ1 than σ2, and inhibits monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). Sigma receptor activation by methamphetamine may facilitate its central nervous system stimulant effects and promote neurotoxicity within the brain. Dextromethamphetamine is a stronger psychostimulant, but levomethamphetamine has stronger peripheral effects, a longer half-life, and longer perceived effects among addicts. At high doses, both enantiomers of methamphetamine can induce similar stereotypy and methamphetamine psychosis, but levomethamphetamine has shorter psychodynamic effects.

Pharmacokinetics
The bioavailability of methamphetamine is 67% orally, 79% intranasally, 67 to 90% via inhalation (smoking), and 100% intravenously. Following oral administration, methamphetamine is well-absorbed into the bloodstream, with peak plasma methamphetamine concentrations achieved in approximately 3.13–6.3 hours post ingestion. Methamphetamine is also well absorbed following inhalation and following intranasal administration. Due to the high lipophilicity of methamphetamine, it can readily move through the blood–brain barrier faster than other stimulants, where it is more resistant to degradation by monoamine oxidase. The amphetamine metabolite peaks at 10–24 hours. Methamphetamine is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH. When taken orally, 30–54% of the dose is excreted in urine as methamphetamine and 10–23% as amphetamine. Following IV doses, about 45% is excreted as methamphetamine and 7% as amphetamine. The elimination half-life of methamphetamine varies with a range of 5–30 hours, however it is on average 9 to 12 hours in most studies. The elimination half-life of methamphetamine does not vary by route of administration, but is subject to substantial interindividual variability.CYP2D6, dopamine β-hydroxylase, flavin-containing monooxygenase 3, butyrate-CoA ligase, and glycine N-acyltransferase are the enzymes known to metabolize methamphetamine or its metabolites in humans. The primary metabolites are amphetamine and 4-hydroxymethamphetamine; other minor metabolites include: 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone, the metabolites of amphetamine. Among these metabolites, the active sympathomimetics are amphetamine, 4‑hydroxyamphetamine, 4‑hydroxynorephedrine, 4-hydroxymethamphetamine, and norephedrine. Methamphetamine is a CYP2D6 inhibitor.The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination. The known metabolic pathways include:

Detection in biological fluids
Methamphetamine and amphetamine are often measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics. Chiral techniques may be employed to help distinguish the source of the drug to determine whether it was obtained illicitly or legally via prescription or prodrug. Chiral separation is needed to assess the possible contribution of levomethamphetamine, which is an active ingredients in some OTC nasal decongestants, toward a positive test result. Dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine.

Chemistry
Methamphetamine is a chiral compound with two enantiomers, dextromethamphetamine and levomethamphetamine. At room temperature, the free base of methamphetamine is a clear and colorless liquid with an odor characteristic of geranium leaves. It is soluble in diethyl ether and ethanol as well as miscible with chloroform.In contrast, the methamphetamine hydrochloride salt is odorless with a bitter taste. It has a melting point between 170 and 175 °C (338 and 347 °F) and, at room temperature, occurs as white crystals or a white crystalline powder. The hydrochloride salt is also freely soluble in ethanol and water. Its crystal structure is monoclinic with P21 space group; at 90 K (−183.2 °C; −297.7 °F), it has lattice parameters a = 7.10 Å, b = 7.29 Å, c = 10.81 Å, and β = 97.29°.

Degradation
A 2011 study into the destruction of methamphetamine using bleach showed that effectiveness is correlated with exposure time and concentration. A year-long study (also from 2011) showed that methamphetamine in soils is a persistent pollutant. In a 2013 study of bioreactors in wastewater, methamphetamine was found to be largely degraded within 30 days under exposure to light.

Synthesis
Racemic methamphetamine may be prepared starting from phenylacetone by either the Leuckart or reductive amination methods. In the Leuckart reaction, one equivalent of phenylacetone is reacted with two equivalents of N-methylformamide to produce the formyl amide of methamphetamine plus carbon dioxide and methylamine as side products. In this reaction, an iminium cation is formed as an intermediate which is reduced by the second equivalent of N-methylformamide. The intermediate formyl amide is then hydrolyzed under acidic aqueous conditions to yield methamphetamine as the final product. Alternatively, phenylacetone can be reacted with methylamine under reducing conditions to yield methamphetamine.

History, society, and culture
Amphetamine, discovered before methamphetamine, was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine. Shortly after, methamphetamine was synthesized from ephedrine in 1893 by Japanese chemist Nagai Nagayoshi. Three decades later, in 1919, methamphetamine hydrochloride was synthesized by pharmacologist Akira Ogata via reduction of ephedrine using red phosphorus and iodine.
Since 1938, methamphetamine was marketed on a large scale in Germany as a nonprescription drug under the brand name Pervitin, produced by the Berlin-based Temmler pharmaceutical company. It was used by all branches of the combined armed forces of the Third Reich, for its stimulant effects and to induce extended wakefulness. Pervitin became colloquially known among the German troops as "Stuka-Tablets" (Stuka-Tabletten) and "Herman-Göring-Pills" (Hermann-Göring-Pillen), as a snide allusion to Görings widely-known addiction to drugs. However, the side effects, particularly the withdrawal symptoms, were so serious that the army sharply cut back its usage in 1940. By 1941, usage was restricted to a doctors prescription, and the military tightly controlled its distribution. Soldiers would only receive a couple of tablets at a time, and were discouraged from using them in combat. Historian Łukasz Kamieński says, "A soldier going to battle on Pervitin usually found himself unable to perform effectively for the next day or two. Suffering from a drug hangover and looking more like a zombie than a great warrior, he had to recover from the side effects." Some soldiers turned violent, committing war crimes against civilians; others attacked their own officers.At the end of the war, it was used as part of a new drug: D-IX.
Obetrol, patented by Obetrol Pharmaceuticals in the 1950s and indicated for treatment of obesity, was one of the first brands of pharmaceutical methamphetamine products. Due to the psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in America in the 1950s and 1960s. Eventually, as the addictive properties of the drug became known, governments began to strictly regulate the production and distribution of methamphetamine. For example, during the early 1970s in the United States, methamphetamine became a schedule II controlled substance under the Controlled Substances Act. Currently, methamphetamine is sold under the trade name Desoxyn, trademarked by the Danish pharmaceutical company Lundbeck. As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.

Trafficking
The Golden Triangle (Southeast Asia), specifically Shan State, Myanmar, is the worlds leading producer of methamphetamine as production has shifted to Yaba and crystalline methamphetamine, including for export to the United States and across East and Southeast Asia and the Pacific.Concerning the accelerating synthetic drug production in the region, the Cantonese Chinese syndicate Sam Gor, also known as The Company, is understood to be the main international crime syndicate responsible for this shift. It is made up of members of five different triads. Sam Gor is primarily involved in drug trafficking, earning at least $8 billion per year. Sam Gor is alleged to control 40% of the Asia-Pacific methamphetamine market, while also trafficking heroin and ketamine. The organization is active in a variety of countries, including Myanmar, Thailand, New Zealand, Australia, Japan, China, and Taiwan. Sam Gor previously produced meth in Southern China and is now believed to manufacture mainly in the Golden Triangle, specifically Shan State, Myanmar, responsible for much of the massive surge of crystal meth in recent years. The group is understood to be headed by Tse Chi Lop, a gangster born in Guangzhou, China who also holds a Canadian passport.
Liu Zhaohua was another individual involved in the production and trafficking of methamphetamine until his arrest in 2005. It was estimated over 18 tonnes of methamphetamine were produced under his watch.

Legal status
The production, distribution, sale, and possession of methamphetamine is restricted or illegal in many jurisdictions. Methamphetamine has been placed in schedule II of the United Nations Convention on Psychotropic Substances treaty.

Research
It has been suggested, based on animal research, that calcitriol, the active metabolite of vitamin D, can provide significant protection against the DA- and 5-HT-depleting effects of neurotoxic doses of methamphetamine.

See also
18-MC
Breaking Bad, a TV drama series centered on illicit methamphetamine synthesis
Drug checking
Faces of Meth, a drug prevention project
Harm reduction
Methamphetamine in Australia
Methamphetamine in Bangladesh
Methamphetamine in the Philippines
Methamphetamine in the United States
Montana Meth Project, a Montana-based organization aiming to reduce meth use among teenagers
Recreational drug use
Rolling meth lab, a transportable laboratory that is used to illegally produce methamphetamine
Ya ba, Southeast Asian tablets containing a mixture of methamphetamine and caffeine

Explanatory notes
Image legend

Reference notes
References
Further reading
Szalavitz M. "Why the Myth of the Meth-Damaged Brain May Hinder Recovery". Time.com </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 Fexofenadine/pseudoephedrine and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Sacituzumab govitecan and can you explain it in depth? [/INST] Sacituzumab govitecan, sold under the brand name Trodelvy, is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate used for the treatment of metastatic triple-negative breast cancer and metastatic urothelial cancer.The most common side effects include nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia (hair loss), constipation, decreased appetite, rash and abdominal pain. Sacituzumab govitecan has a boxed warning about the risk of severe neutropenia (abnormally low levels of white blood cells) and severe diarrhea. Sacituzumab govitecan may cause harm to a developing fetus or newborn baby. Women are advised not to breastfeed while on sacituzumab govitecan and one month after the last dose is administered.The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) consider it to be a first-in-class medication. Sacituzumab govitecan was approved for medical use in the European Union in November 2021.

Medical uses
Sacituzumab govitecan is indicated for the treatment of adults with metastatic triple-negative breast cancer who received at least two prior therapies for metastatic disease; people with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease; and for people with locally advanced or metastatic urothelial cancer (mUC) who previously received a platinum-containing chemotherapy and either a programmed death receptor-1 (PD-1) or a programmed death-ligand 1 (PD-L1) inhibitor.

Administration
Sacituzumab govitecan is given in a 21-day treatment cycle in which an injection is only given a few days of the cycle. It is given slowly from one to three hours under the supervision of a physician.

Mechanism
Sacituzumab govitecan is a conjugate of the humanized anti-Trop-2 monoclonal antibody linked with SN-38, the active metabolite of irinotecan. Each antibody having on average 7.6 molecules of SN-38 attached. SN-38 is too toxic to administer directly to patients, but linkage to an antibody allows the drug to specifically target cells containing Trop-2.Sacituzumab govitecan is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate, meaning that the drug targets the Trop-2 receptor that helps the cancer grow, divide and spread, and is linked to topoisomerase inhibitor, which is a chemical compound that is toxic to cancer cells. Approximately two of every ten breast cancer diagnoses worldwide are triple-negative. Triple-negative breast cancer is a type of breast cancer that tests negative for estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2) protein. Therefore, triple-negative breast cancer does not respond to hormonal therapy medicines or medicines that target HER2.

Development
Immunomedics announced in 2013, that it had received fast track designation from the US Food and Drug Administration (FDA) for the compound as a potential treatment for non-small cell lung cancer, small cell lung cancer, and metastatic triple-negative breast cancer. Orphan drug status was granted for small cell lung cancer and pancreatic cancer. In February 2016, Immunomedics announced that sacituzumab govitecan had received an FDA breakthrough therapy designation (a classification designed to expedite the development and review of drugs that are intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition) for the treatment of people with triple-negative breast cancer who have failed at least two other prior therapies for metastatic disease.

History
Sacituzumab govitecan was added to the proposed International nonproprietary name (INN) list in 2015, and to the recommended list in 2016.Sacituzumab govitecan-hziy was approved for medical use in the United States in April 2020.Sacituzumab govitecan-hziy was approved based on the results of IMMU-132-01, a multicenter, single-arm clinical trial (NCT01631552) of 108 participants with metastatic triple-negative breast cancer who had received at least two prior treatments for metastatic disease. Of the 108 participants involved within the study, 107 were female and 1 was male. Participants received sacituzumab govitecan-hziy at a dose of 10 milligrams per kilogram of body weight intravenously on days one and eight every 21 days. Treatment with sacituzumab govitecan-hziy was continued until disease progression or unacceptable toxicity. Tumor imaging was obtained every eight weeks. The efficacy of sacituzumab govitecan-hziy was based on the overall response rate (ORR) – which reflects the percentage of participants that had a certain amount of tumor shrinkage. The ORR was 33.3% (95% confidence interval [CI], 24.6 to 43.1). Additionally, with the 33.3% of study participants who achieved a response, 2.8% of participants experienced complete responses. The median time to response in participants was 2.0 months (range, 1.6 to 13.5), the median duration of response was 7.7 months (95% confidence interval [CI], 4.9 to 10.8), the median progression free survival was 5.5 months, and the median overall survival was 13.0 months. Of the participants that achieved an objective response to sacituzumab govitecan-hziy, 55.6% maintained their response for six or more months and 16.7% maintained their response for twelve or more months.Sacituzumab govitecan-hziy was granted accelerated approval along with priority review, breakthrough therapy, and fast track designations. The U.S. Food and Drug Administration (FDA) granted approval of Trodelvy to Immunomedics, Inc.In April 2021, the FDA granted regular approval to sacituzumab govitecan for people with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. Efficacy and safety were evaluated in a multicenter, open-label, randomized trial (ASCENT; NCT02574455) conducted in 529 participants with unresectable locally advanced or mTNBC who had relapsed after at least two prior chemotherapies, one of which could be in the neoadjuvant or adjuvant setting, if progression occurred within twelve months. Participants were randomized (1:1) to receive sacituzumab govitecan, 10 mg/kg as an intravenous infusion, on days 1 and 8 of a 21-day (n=267) cycle or physicians choice of single agent chemotherapy (n=262).In April 2021, the FDA granted accelerated approval to sacituzumab govitecan for people with locally advanced or metastatic urothelial cancer (mUC) who previously received a platinum-containing chemotherapy and either a programmed death receptor-1 (PD-1) or a programmed death-ligand 1 (PD-L1) inhibitor. Efficacy and safety were evaluated in TROPHY (IMMU-132-06; NCT03547973), a single-arm, multicenter trial that enrolled 112 participants with locally advanced or mUC who received prior treatment with a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor.

Society and culture
Legal status
On 14 October 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 Trodelvy, intended for the treatment of unresectable or metastatic triple-negative breast cancer. The applicant for this medicinal product is Gilead Sciences Ireland UC. Sacituzumab govitecan was approved for medical use in the European Union in November 2021.

References
Further reading
Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR,  et al. (February 2019). "Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer". N. Engl. J. Med. 380 (8): 741–751. doi:10.1056/NEJMoa1814213. PMID 30786188.
Weiss J, Glode A, Messersmith WA, Diamond J (August 2019). "Sacituzumab govitecan: breakthrough targeted therapy for triple-negative breast cancer" </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 Alosetron and can you explain it in depth? [/INST] Alosetron, sold under the brand name Lotronex among others, is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in women only.
It was patented in 1987 and approved for medical use in 2002. It is currently marketed by Prometheus Laboratories Inc. (San Diego). Alosetron was withdrawn from the market in 2000 owing to the occurrence of serious life-threatening gastrointestinal adverse effects, but was reintroduced in 2002 with availability and use restricted.

Medical uses
Alosetron is indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS-D) who have:

chronic IBS symptoms (generally lasting 6 months or longer),
had anatomic or biochemical abnormalities of the gastrointestinal tract excluded, and
not responded adequately to conventional therapy.Severe IBS-D includes: diarrhea and 1 or more of the following:

frequent and severe abdominal pain/discomfort,
frequent bowel urgency or fecal incontinence,
disability or restriction of daily activities due to IBS.

Efficacy
The phase III trial for approval was published in 2000 as an industry-funded randomised, placebo-controlled trial (PCT). Its authors found 1 mg alosetron, taken orally twice daily for 12 weeks, was associated with a 12% (CI 4.7-19.2) improvement in relief from abdominal pain and discomfort associated with diarrhoea-predominant patients. The prescription of alosetron is currently approved in the U.S. at 0.5 and 1 mg.The FDA Medical Officers Review, dated November 4, 1999, noted: "Patients considered by investigators to fit the diarrhea-predominant subtype had at baseline... stool consistency values that were neither loose nor watery". The FDAs Gastrointestinal Drugs Advisory Committee referred to the drugs efficacy as "modest", highlighting that the placebo brought relief on the primary outcome measure to 40–50% of women.

Contraindications
Lotronexs prescribing information brochure states that alosetron should not be initiated in patients with constipation. Other contraindications are: history of chronic or severe constipation or sequelae from constipation; intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions, ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state; Crohns disease or ulcerative colitis; diverticulitis; severe hepatic impairment. Concomitant use of fluvoxamine is also contraindicated.

Adverse effects
Alosetron was withdrawn in 2000 following the association of alosetron with serious life-threatening gastrointestinal adverse effects. The cumulative incidence of ischaemic colitis was 2 in 1000, while serious complications arising from constipation (obstruction, perforation, impaction, toxic megacolon, secondary colonic ischaemia, death) was 1 in 1000. A 1999 review performed by FDA medical officer John Senior, indicated that 27% of patients experienced constipation. The phase III trial reported constipation occurred in 30% and 3% of patients in the alosetron and placebo groups, respectively. It was cited as the most important reason for patients dropping out of the study.

Mechanism of action
Alosetron has an antagonist action on the 5-HT3 receptors of the enteric nervous system of the gastrointestinal tract. While being a 5-HT3 antagonist like ondansetron, it is not classified or approved as an antiemetic. Since stimulation of 5-HT3 receptors is positively correlated with gastrointestinal motility, alosetrons 5-HT3 antagonism slows the movement of fecal matter through the large intestine, increasing the extent to which water is absorbed, and decreasing the moisture and volume of the remaining waste products.

History
Alosetron was originally approved by the U.S. Food and Drug Administration (FDA) on February 9, 2000, after a seven-month review. At the time of the initial approval U.S. Food and Drug Administration (FDA) reviewers found that alosetron improved symptoms in 10% to 20% of patients.Shipment to pharmacies started in March, 2000 </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 Rabies vaccine and can you explain it in depth? [/INST] The rabies vaccine is a vaccine used to prevent rabies. There are a number of rabies vaccines available that are both safe and effective. They can be used to prevent rabies before, and, for a period of time, after exposure to the rabies virus, which is commonly caused by a dog bite or a bat bite.Doses are usually given by injection into the skin or muscle. After exposure, the vaccination is typically used along with rabies immunoglobulin. It is recommended that those who are at high risk of exposure be vaccinated before potential exposure. Rabies vaccines are effective in humans and other animals, and vaccinating dogs is very effective in preventing the spread of rabies to humans. A long-lasting immunity to the virus develops after a full course of treatment.Rabies vaccines may be used safely by all age groups. About 35 to 45 percent of people develop a brief period of redness and pain at the injection site, and 5 to 15 percent of people may experience fever, headaches, or nausea. After exposure to rabies, there is no contraindication to its use, because the untreated virus is overwhelmingly fatal.The first rabies vaccine was introduced in 1885 and was followed by an improved version in 1908. Millions of people globally are vaccinated against the virus. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Before exposure
The World Health Organization (WHO) recommends vaccinating those who are at high risk of the disease, such as children who live in areas where it is common. Other groups may include veterinarians, researchers, or people planning to travel to regions where rabies is common. Three doses of the vaccine are given over a one-month period on days zero, seven, and either twenty-one or twenty-eight.

After exposure
For individuals who have been potentially exposed to the virus, four doses over two weeks are recommended, as well as an injection of rabies immunoglobulin with the first dose. This is known as post-exposure vaccination. For people who have previously been vaccinated, only a single dose of the rabies vaccine is required. However, vaccination after exposure is neither a treatment nor a cure for rabies; it can only prevent the development of rabies in a person if given before the virus reaches the brain.  Because the rabies virus has a relatively long incubation period, post-exposure vaccinations are typically highly effective.

Additional doses
Immunity following a course of doses is typically long lasting, and additional doses are usually not needed unless the person has a high risk of contracting the virus. Those at risk may have tests done to measure the amount of rabies antibodies in the blood, and then get rabies boosters as needed. Following administration of a booster dose, one study found 97% of immunocompetent individuals demonstrated protective levels of neutralizing antibodies after ten years.

Safety
Rabies vaccines are safe in all age groups. About 35 to 45 percent of people develop a brief period of redness and pain at the injection site, and 5 to 15 percent of people may experience fever, headaches, or nausea. Because of the certain fatality of the virus, receiving the vaccine is always advisable.Vaccines made from nerve tissue are used in a few countries, mainly in Asia and Latin America, but are less effective and have greater side effects. Their use is thus not recommended by the World Health Organization.

Types
The human diploid cell rabies vaccine (H.D.C.V.) was started in 1967. Human diploid cell rabies vaccines are inactivated vaccines made using the attenuated Pitman-Moore L503 strain of the virus.In addition to these developments, newer and less expensive purified chicken embryo cell vaccines (CCEEV) and purified Vero cell rabies vaccines are now available and are recommended for use by the WHO.   The purified Vero cell rabies vaccine uses the attenuated Wistar strain of the rabies virus, and uses the Vero cell line as its host.  CCEEVs can be used in both pre- and post-exposure vaccinations.  CCEEVs use inactivated rabies virus grown from either embryonated eggs or in cell cultures and are safe for use in humans and animals.The vaccine was attenuated and prepared in the H.D.C. strain WI-38 which was gifted to Dr. Hilary Koprowski at the Wistar Institute by Dr. Leonard Hayflick, an Associate Member, who developed this normal human diploid cell strain.

History
Virtually all infections with rabies resulted in death until two French scientists, Louis Pasteur and Émile Roux, developed the first rabies vaccination in 1885. Nine-year-old Joseph Meister (1876–1940), who had been mauled by a rabid dog, was the first human to receive this vaccine. The treatment started with a subcutaneous injection on 6 July 1885, at 8:00 pm, which was followed with 12 additional doses administered over the following 10 days. The first injection was derived from the spinal cord of an inoculated rabbit which had died of rabies 15 days earlier. All the doses were obtained by attenuation, but later ones were progressively more virulent.The Pasteur-Roux vaccine attenuated the harvested virus samples by allowing them to dry for five to ten days. Similar nerve tissue-derived vaccines are still used in some countries, and while they are much cheaper than modern cell culture vaccines, they are not as effective. Neural tissue vaccines also carry a certain risk of neurological complications.

Cost
When the modern cell-culture rabies vaccine was first introduced in the early 1980s, it cost $45 per dose, and was considered to be too expensive.  The cost of the rabies vaccine continues to be a limitation to acquiring pre-exposure rabies immunization for travelers from developed countries. In 2015 in the United States, a course of three doses could cost over $1,000, while in Europe a course costs around €100. It is possible and more cost-effective to split one intramuscular dose of the vaccine into several intradermal doses. This method is recommended by the World Health Organisation in areas that are constrained by cost or with supply issues. The route is as safe and effective as intramuscular according to the WHO.

Veterinary use
Pre-exposure immunization has been used on domesticated and wild populations. In many jurisdictions, domestic dogs, cats, ferrets, and rabbits are required to be vaccinated.There are two main types of vaccines used for domesticated animals and pets (including pets from wildlife species):

Inactivated rabies virus (similar technology to that given to humans) administered by injection
Modified live viruses administered orally (by mouth): Live rabies virus from attenuated strains. Attenuated means strains that have developed mutations that cause them to be weaker and do not cause disease.Imrab is an example of a veterinary rabies vaccine containing the Pasteur strain of killed rabies virus. Several different types of Imrab exist, including Imrab, Imrab 3, and Imrab Large Animal. Imrab 3 has been approved for ferrets and, in some areas, pet skunks.

Dogs
Aside from vaccinating humans, another approach was also developed by vaccinating dogs to prevent the spread of the virus. In 1979, the Van Houweling Research Laboratory of the Silliman University Medical Center in Dumaguete in the Philippines developed and produced a dog vaccine that gave a three-year immunity from rabies. The development of the vaccine resulted in the elimination of rabies in many parts of the Visayas and Mindanao Islands. The successful program in the Philippines was later used as a model by other countries, such as Ecuador and the Yucatan State of Mexico, in their fight against rabies conducted in collaboration with the World Health Organization.In Tunisia, a rabies control program was initiated to give dog owners free vaccination to promote mass vaccination which was sponsored by their government. The vaccine is known as Rabisin (Mérial), which is a cell based rabies vaccine only used countrywide. Vaccinations are often administered when owners take in their dogs for check-ups and visits at the vet.Oral rabies vaccines (see below for details) have been trialled on feral/stray dogs in some areas with high rabies incidence, as it could potentially be more efficient than catching and injecting them. However these have not been deployed for dogs at large scale yet.

Wild animals
Wildlife species, primarily bats, raccoons, skunks, and foxes, act as reservoir species for different variants of the rabies virus. This results in the general occurrence of rabies as well as outbreaks in animal populations.  Approximately 90% of all reported rabies cases in the US are from wildlife.

Oral rabies vaccine
Oral rabies vaccines in pellet form are intended to be given to wild animals to produce a herd immunity effect. The development of safe and effective rabies virus vaccines applied in attractive baits resulted in the first field trials in Switzerland in 1978 to immunize red foxes.There are currently two different types of oral wildlife rabies vaccine in use:

Modified live virus: Attenuated vaccine strains of rabies virus such as SAG2 and SAD B19
Recombinant vaccinia virus expressing rabies glycoprotein: This is a strain of the vaccinia virus (originally a smallpox vaccine) that has been engineed to encode the gene for the rabies glycoprotein. It is mostly used in the USA (raccoons, foxes, and coyotes) and in western Europe (red foxes)Other oral rabies experimental vaccines in development include recombinant adenovirus vaccines.
Oral rabies vaccination (ORV) programs have been used in many countries in an effort to control the spread of rabies and limit the risk of human contact with the rabies virus. ORV programs were initiated in Europe in the 1980s, Canada in 1985, and in the United States in 1990. ORV is a preventive measure to eradicate rabies in wild animal vectors of disease, mainly foxes, raccoons, raccoon dogs, coyotes and jackals, but also can be used for dogs in developing countries. ORV programs typically use edible baits to deliver the vaccine to targeted animals. ORV baits consist of a small packet containing the oral vaccine which is then either coated in a fishmeal paste or encased in a fishmeal-polymer block. When an animal bites into the bait, the packets burst and the vaccine is administered.  Current research suggests that if adequate amounts of the vaccine is ingested, immunity to the virus should last for upwards of one year.  By immunizing wild or stray animals, ORV programs work to create a buffer zone between the rabies virus and potential contact with humans, pets, or livestock.  The effectiveness of ORV campaigns in specific areas is determined through trap-and-release methods. Titer tests are performed on the blood drawn from the sample animals in order to measure rabies antibody levels in the blood.  Baits are usually distributed by aircraft to more efficiently cover large, rural regions.  In order to place baits more precisely and to minimize human and pet contact with baits, however, they are distributed by hand in suburban or urban regions.ORV programs have seen success in preventing the westward spread of raccoon variant rabies in the United States and even eradicating rabies in red foxes in Switzerland.The oral vaccine does not contain the whole rabies virus and has been proven safe in over 60 animal species including cats and dogs. The idea of wildlife vaccination was conceived during the 1960s, and modified-live rabies viruses were used for the experimental oral vaccination of carnivores by the 1970s. The potential for human contact with baits is a present concern for ORV programs, but the inactivated rabies vaccine cannot cause rabies, and the recombinant poxvirus vaccine is based on an attenuated poxvirus which is unlikely to cause serious disease in humans anyway. In the USA between 1990 and 2000, over 22 million doses of vaccinia-rabies were distributed, but there were only 160 incidents of people touching a vaccine bait, and only one resulted in a serious infection. The person in this case had been bitten by her dog while removing a bait from its mouth.

References
External links
"Rabies Vaccine Information Statement". U.S </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 Endo International and can you explain it in depth? [/INST] Endo International plc is an American Irish-domiciled generics and specialty branded pharmaceutical company that generated over 93% of its 2017 sales from the U.S. healthcare system.  While Endos management, operations, and customers are almost exclusively U.S.–based, in 2013 Endo executed a corporate tax inversion to Ireland to avoid U.S. corporate taxes on their U.S. drug sales, and to avail of Irelands corporate tax system.

History and Acquisitions
Endo was created as a result of a management buyout from DuPont Merck in 1997 led by Carol Ammon.In 2009, Endo bought Indevus Pharmaceuticals to diversify into endocrinology and oncology </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 Allopurinol and can you explain it in depth? [/INST] Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken by mouth or injected into a vein.Common side effects when used by mouth include itchiness and rash. Common side effects when used by injection include vomiting and kidney problems. While not recommended historically, starting allopurinol during an attack of gout appears to be safe. In those already on the medication, it should be continued even during an acute gout attack. While use during pregnancy does not appear to result in harm, this use has not been well studied. Allopurinol is in the xanthine oxidase inhibitor family of medications.Allopurinol was approved for medical use in the United States in 1966. It is on the World Health Organizations List of Essential Medicines. Allopurinol is available as a generic medication.  In 2020, it was the 42nd most commonly prescribed medication in the United States, with more than 15 million prescriptions.

Medical uses
Gout
Allopurinol is used to reduce urate formation in conditions where urate deposition has already occurred or is predictable.  The specific diseases and conditions where it is used include gouty arthritis, skin tophi, kidney stones, idiopathic gout; uric acid lithiasis; acute uric acid nephropathy; neoplastic disease and myeloproliferative disease with high cell turnover rates, in which high urate levels occur either spontaneously, or after cytotoxic therapy; certain enzyme disorders which lead to overproduction of urate, for example: hypoxanthine-guanine phosphoribosyltransferase, including Lesch–Nyhan syndrome; glucose 6-phosphatase including glycogen storage disease; phosphoribosyl pyrophosphate synthetase, phosphoribosyl pyrophosphate amidotransferase; adenine phosphoribosyltransferase.
It is also used to treat kidney stones caused by deficient activity of adenine phosphoribosyltransferase.

Tumor lysis syndrome
Allopurinol was also commonly used to treat tumor lysis syndrome in chemotherapeutic treatments, as these regimens can rapidly produce severe acute hyperuricemia; however, it has gradually been replaced by urate oxidase therapy. Intravenous formulations are used in this indication when people cannot take medicine by mouth.

Inflammatory bowel disease
Allopurinol cotherapy is used to improve outcomes for people with inflammatory bowel disease and Crohns disease who do not respond to thiopurine monotherapy. Cotherapy has also been shown to greatly improve hepatoxicity side effects in treatment of IBD. Cotherapy invariably requires dose reduction of the thiopurine, usually to one-third of the standard dose depending upon the patients genetic status for thiopurine methyltransferase.

Psychiatric disorders
Allopurinol has been tested as an augmentation strategy for the treatment of mania in bipolar disorder. Meta-analytic evidence showed that adjunctive allopurinol was superior to placebo for acute mania (both with and without mixed features). Its efficacy was not influenced by dosage, follow-up duration, or concurrent standard treatment.

Cardiovascular disease
There is a correlation between uric acid levels and cardiovascular disease and mortality, and so allopurinol has been explored as a potential treatment to reduce risk of cardiac disease. However, the data is inconsistent and conflicting, and the use of allopurinol for use in cardiovascular disease is controversial. Independently of its effects on uric acid, it may also have effects on oxidative stress and inflammation.

Side effects
Because allopurinol is not a uricosuric, it can be used in people with poor kidney function.  However, for people with impaired kidney function, allopurinol has two disadvantages. First, its dosing is complex. Second, some people are hypersensitive to the drug; therefore, its use requires careful monitoring.Allopurinol has rare but potentially fatal adverse effects involving the skin. The most serious adverse effect is a hypersensitivity syndrome consisting of fever, skin rash, eosinophilia, hepatitis, and worsened renal function, collectively referred to as DRESS syndrome. Allopurinol is one of the drugs commonly known to cause Stevens–Johnson syndrome and toxic epidermal necrolysis, two life-threatening dermatological conditions. More common is a less-serious rash that leads to discontinuing this drug.More rarely, allopurinol can also result in the depression of bone marrow elements, leading to cytopenias, as well as aplastic anemia. Moreover, allopurinol can also cause peripheral neuritis in some patients, although this is a rare side effect. Another side effect of allopurinol is interstitial nephritis.

Drug interactions
Drug interactions are extensive, and are as follows:
Azathioprine and 6-mercaptopurine: Azathioprine is metabolised to 6-mercaptopurine which in turn is inactivated by the action of xanthine oxidase - the target of allopurinol.  Giving allopurinol with either of these drugs at their normal dose will lead to overdose of either drug;  only one-quarter of the usual dose of 6-mercaptopurine or azathioprine should be given;
Didanosine: plasma didanosine Cmax and AUC values were approximately doubled with concomitant allopurinol treatment; it should not be co-administered with allopurinol and if it must be, the dose of should be reduced and the person should be closely monitored.Allopurinol may also increase the activity or half-life of the following drugs, in order of seriousness and certainty of the interaction:
Ciclosporin
Coumarin anticoagulants, such as warfarin (reported rarely, but is serious when it occurs)
Vidarabine
Chlorpropamide
Phenytoin
Theophylline
Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechlorethamineCo-administration of the following drugs may make allopurinol less active or decrease its half-life:
Salicylates and medicines that increase the secretion of uric acid
furosemide (see more on diuretics below)Co-administration of the following drugs may cause hypersensitivity or skin rash:
Ampicillin and amoxicillin
Diuretics, in particular thiazides, especially in renal impairment
Angiotensin-converting-enzyme inhibitors (ACE inhibitors)

Pharmacology
A common misconception is that allopurinol is metabolized by its target, xanthine oxidase, but this action is principally carried out by aldehyde oxidase. The active metabolite of allopurinol is oxipurinol, which is also an inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxipurinol within two hours of oral administration, whereas oxipurinol is slowly excreted by the kidneys over 18–30 hours. For this reason, oxipurinol is believed responsible for the majority of allopurinols effect.

Mechanism of action
Allopurinol is a purine analog; it is a structural isomer of hypoxanthine (a naturally occurring purine in the body) and is an inhibitor of the enzyme xanthine oxidase. Xanthine oxidase is responsible for the successive oxidation of hypoxanthine and xanthine, resulting in the production of uric acid, the product of human purine metabolism. In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purine ribotides, hypoxanthine can be salvaged to the purine ribotides adenosine and guanosine monophosphates. Increased levels of these ribotides may cause feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis.

Pharmacogenetics
The HLA-B*5801 allele is a genetic marker for allopurinol-induced severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The frequency of the HLA-B*5801 allele varies between ethnicities: Han Chinese and Thai populations have HLA-B*5801 allele frequencies of around 8%, as compared to European and Japanese populations, who have allele frequencies of around 1.0% and 0.5%, respectively. The increase in risk for developing allopurinol-induced SJS or TEN in individuals with the HLA-B*5801 allele (as compared to those who do not have this allele) is very high, ranging from a 40-fold to a 580-fold increase in risk, depending on ethnicity. As of 2011 the FDA-approved drug label for allopurinol did not contain any information regarding the HLA-B*5801 allele, though FDA scientists did publish a study in 2011 which reported a strong, reproducible and consistent association between the allele and allopurinol-induced SJS and TEN. However, the American College of Rheumatology recommends screening for HLA-B*5801 in high-risk populations (e.g. Koreans with stage 3 or worse chronic kidney disease and those of Han Chinese and Thai descent), and prescribing patients who are positive for the allele an alternative drug. The Clinical Pharmacogenetics Implementation Consortium guidelines state that allopurinol is contraindicated in known carriers of the HLA-B*5801 allele.

History
Allopurinol was first synthesized and reported in 1956 by Roland K. Robins (1926-1992), in a search for antineoplastic agents.   Because allopurinol inhibits the breakdown (catabolism) of the thiopurine drug mercaptopurine, and it was later tested by Wayne Rundles, in collaboration with Gertrude Elions lab at Wellcome Research Laboratories to see if it could improve treatment of acute lymphoblastic leukemia by enhancing the action of mercaptopurine.  However, no improvement in leukemia response was noted with mercaptopurine-allopurinol co-therapy, so that work turned to other compounds and the team then started testing allopurinol as a potential therapeutic for gout.  Allopurinol was first marketed as a treatment for gout in 1966.

Society and culture
Formulations
Allopurinol is sold as an injection for intravenous use and as a tablet.

Brands
Allopurinol has been marketed in the United States since 19 August 1966, when it was first approved by FDA under the trade name Zyloprim.  Allopurinol was marketed at the time by Burroughs Wellcome.  Allopurinol is a generic drug sold under a variety of brand names, including Allohexal, Allosig, Milurit, Alloril, Progout, Ürikoliz, Zyloprim, Zyloric, Zyrik, and Aluron.

See also
Lesinurad/allopurinol, a fixed-dose combination drug
Hydroxychavicol, potent xanthine oxidase inhibitor

References
Further reading
Dean L (March 2016). "Allopurinol Therapy and HLA-B*58:01 Genotype".  In Pratt VM, McLeod HL, Rubinstein WS,  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 Linaclotide and can you explain it in depth? [/INST] Linaclotide, (sold under the brand name Linzess in the US and Mexico, and as Constella elsewhere) is a drug used to treat irritable bowel syndrome with constipation and chronic constipation with no known cause.
It has a black box warning about the risk of serious dehydration in children in the US; the most common adverse effects in others are gastrointestinal.It is an oligo-peptide agonist of guanylate cyclase 2C and remains in the GI tract after it is taken orally.  It was approved in the US and Europe in 2012.It is marketed by Allergan in most of the world and by Astellas in Asia; Ironwood Pharmaceuticals was the originator. In 2017, it was the 257th most commonly prescribed medication in the United States, with more than one million prescriptions.

Medical use
Linaclotide is used to treat irritable bowel syndrome with constipation and chronic constipation with no known cause.It has not been tested in pregnant women and it is unknown if it is excreted in breast milk.

Adverse effects
The US label has a black box warning to not use linaclotide in children less than 6 years old and to avoid in people from 6 to 18 years old, due to the risk of serious dehydration.More than 10% of people taking linaclotide have diarrhea.  Between 1% and 10% of people have decreased appetite, dehydration, low potassium, dizziness when standing up too quickly, nausea, vomiting, urgent need to defecate, fecal incontinence, and bleeding in their colon, rectum, and anus.

Pharmacology
Systemic absorption of the globular tetradecapeptide is minimal.Linaclotide, like the endogenous guanylin and uroguanylin it mimics, is an agonist that activates the cell surface receptor of guanylate cyclase 2C (GC-C). The medication binds to the surface of the intestinal epithelial cells. Linaclotide is minimally absorbed and it is undetectable in the systemic circulation at therapeutic doses. Activation of GC-C increases cyclic guanosine monophosphate (cGMP) </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 Pentobarbital and can you explain it in depth? [/INST] Pentobarbital (previously known as pentobarbitone in Britain and Australia) is a short-acting barbiturate typically used as a sedative, a preanesthetic, and to control convulsions in emergencies. It can also be used for short-term treatment of insomnia but has been largely replaced by the benzodiazepine family of drugs.
In high doses, pentobarbital causes death by respiratory arrest. It is used for veterinary euthanasia and is used by some U.S. states and the U.S. federal government for executions of convicted criminals. In some countries and states, it is also used for physician-assisted suicide.Pentobarbital was widely abused and sometimes known as "yellow jackets" due to the yellow capsule of the Nembutal brand. Pentobarbital in oral (pill) form is no longer commercially available.

Uses
Medical
Typical applications for pentobarbital are sedative, short term hypnotic, preanesthetic, insomnia treatment, and control of convulsions in emergencies. Abbott Pharmaceutical discontinued manufacture of their Nembutal brand of Pentobarbital capsules in 1999, largely replaced by the benzodiazepine family of drugs. Pentobarbital was also widely abused, known on the street as "yellow jackets". They were available as 30, 50, and 100-milligram capsules of yellow, white-orange, and yellow colors, respectively.It is also used as a veterinary anesthetic agent.Pentobarbital can reduce intracranial pressure in Reyes syndrome, treat traumatic brain injury and induce coma in cerebral ischemia patients. Pentobarbital-induced coma has been advocated in patients with acute liver failure refractory to mannitol.

Euthanasia
Pentobarbital can cause death when used in high doses. It is used for euthanasia for humans as well as animals. It is taken alone, or in combination with complementary agents such as phenytoin, in commercial animal euthanasia injectable solutions.

In the Netherlands, it is part of the standard protocol for physician-assisted suicide for self-administration by the patient.It is taken by mouth for physician-assisted death in the United States states of Oregon, Washington, Vermont, and California (as of January, 2016).The oral dosage of pentobarbital indicated for physician-assisted suicide in Oregon is typically 10 g of liquid.In Switzerland, sodium pentobarbital is administered to the patient intravenously. Once administered, sleep is induced within 30 seconds, and the heart stops beating within 3 minutes.

Execution
Pentobarbital has been used or considered as a substitute for other drugs previously used for capital punishment in the United States when those drugs are unavailable. Such use however is illegal under Danish law, and when this was discovered, after public outcry in Danish media, Lundbeck, the owner of the drug, stopped selling it to US states that impose the death penalty. US distributors of the drug are forbidden by the owner to sell it to any customers, such as state authorities, that practice or participate in executions of humans.Texas began using pentobarbital for executing death-row inmates by lethal injection on July 18, 2012. The use of pentobarbital has been considered by several states, including Ohio, Arizona, Idaho, and Washington; those states made the decision to switch following shortages of pancuronium bromide, a muscle paralytic previously used as one component in a three-drug cocktail.In October 2013, Missouri changed its protocol to allow for compounded pentobarbital to be used in a lethal dose for executions. It was first used in November 2013.According to a December 2019 ProPublica article, by 2017 the Bureau of Prisons (BOP), in discussion with then Attorney General Jeff Sessions, had begun to search for suppliers of pentobarbital to be used in lethal injections. The BOP was aware that the use of pentobarbital as their "new drug choice" would be challenged in the courts because some lawyers had said that "pentobarbital would flood prisoners’ lungs with froth and foam, inflicting pain and terror akin to a death by drowning." BOP claimed that these concerns were unjustified and that their two expert witnesses asserted that the use of pentobarbital was "humane". On July 25, 2019, US Attorney General William Barr directed the federal government to resume capital punishment after 16 years </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 Daratumumab/hyaluronidase and can you explain it in depth? [/INST] Daratumumab/hyaluronidase, sold under the brand name Darzalex Faspro, is a fixed-dose combination medication for the treatment of adults with newly diagnosed or relapsed/refractory multiple myeloma. It is a combination of daratumumab and hyaluronidase. It is administered via subcutaneous injection.The most common adverse reaction using daratumumab/hyaluronidase as monotherapy is upper respiratory tracts infection. The most common adverse reactions (≥20%) in people with amyloid light-chain amyloidosis who received daratumumab/hyaluronidase in combination with bortezomib, cyclophosphamide, and dexamethasone are upper respiratory tract infection, diarrhea, peripheral edema, constipation peripheral sensory neuropathy, fatigue, nausea, insomnia, dyspnea and cough. The most common adverse reactions (≥20%) occurring in people treated with daratumumab/hyaluronidase, carfilzomib, and dexamethasone were upper respiratory tract infections, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral.

Medical uses
Daratumumab/hyaluronidase is indicated for the treatment of adults with multiple myeloma:
in combination with bortezomib, melphalan and prednisone (D-VMP) in newly diagnosed adults who are ineligible for autologous stem cell transplant
in combination with lenalidomide and dexamethasone (D-Rd) in newly diagnosed adults who are ineligible for autologous stem cell transplant and in people with relapsed or refractory multiple myeloma who have received at least one prior therapy
in combination with bortezomib and dexamethasone (D-Vd) in adults who have received at least one prior therapy
as monotherapy, in adults who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.In January 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval to daratumumab/hyaluronidase in combination with bortezomib, cyclophosphamide, and dexamethasone for newly diagnosed amyloid light-chain amyloidosis.In November 2021, the FDA granted  approval to daratumumab/hyaluronidase in combination with carfilzomib plus dexamethasone to treat relapsed or refractory multiple myeloma in adults who have received one to three prior lines of therapy.

History
It was approved for use in the United States in May 2020.Efficacy of daratumumab and hyaluronidase-fihji (monotherapy) was evaluated in the COLUMBA trial (NCT03277105), an open-label non-inferiority trial randomizing 263 participants to daratumumab and hyaluronidase-fihj and 259 to intravenous daratumumab (daratumumab IV). The trials co-primary endpoints were overall response rate (ORR) and pharmacokinetic (PK) endpoint of the maximum Ctrough on cycle 3, day 1 pre-dose </s>