<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 Alprazolam and can you explain it in depth? [/INST] Alprazolam, sold under the brand name Xanax, among others, is a fast-acting, potent tranquilizer of medium duration in the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring. It is most commonly used in short-term management of anxiety disorders, specifically panic disorder or generalized anxiety disorder (GAD). Other uses include the treatment of chemotherapy-induced nausea, together with other treatments. GAD improvement occurs generally within a week. Alprazolam is generally taken by mouth.Common side effects include sleepiness, depression, headaches, feeling tired, dry mouth, and memory problems. Some of the sedation and tiredness may improve within a few days. Due to concerns about misuse, some do not recommend alprazolam as an initial treatment for panic disorder. Withdrawal or rebound symptoms may occur if use is suddenly decreased; gradually decreasing the dose over weeks or months may be required. Other rare risks include suicide and a twofold increased risk of all-cause mortality. Alprazolam, like other benzodiazepines, acts through the GABAA receptor.Alprazolam was patented in 1971 and approved for medical use in the United States in 1981. Alprazolam is a Schedule IV controlled substance and is a common drug of abuse. It is available as a generic medication. In 2020, it was the 37th most-commonly-prescribed medication in the United States, with more than 16 million prescriptions.

Medical uses
Alprazolam is mostly used in short-term management of anxiety disorders, panic disorders, and nausea due to chemotherapy. Alprazolam is indicated for the treatment of generalized anxiety disorder and panic disorder with or without agoraphobia in adults. The FDA label advises that the physician should periodically reassess the usefulness of the drug.

Panic disorder
Alprazolam is effective in the relief of moderate to severe anxiety and panic attacks. However, it is not a first-line treatment since the development of selective serotonin reuptake inhibitors. Alprazolam is not recommended in Australia for the treatment of panic disorder because of concerns regarding tolerance, dependence, and abuse. Most evidence shows that the benefits of alprazolam in treating panic disorder last only four to ten weeks. However, people with panic disorder have been treated on an open basis for up to eight months without apparent loss of benefit.Alprazolam is recommended by the World Federation of Societies of Biological Psychiatry (WFSBP) for treatment-resistant cases of panic disorder where there is no history of tolerance or dependence.

Anxiety disorders
Anxiety associated with depression is responsive to alprazolam. Clinical studies have shown that the effectiveness is limited to 4 months for anxiety disorders. However, the research into antidepressant properties of alprazolam is poor and has only assessed its short-term effects against depression. In one study, some long term, high-dosage users of alprazolam developed reversible depression. In the US, alprazolam is FDA-approved for the management of anxiety disorders (a condition corresponding most closely to the APA Diagnostic and Statistical Manual DSM-IV-TR diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. In the UK, alprazolam is recommended for the short-term treatment (2–4 weeks) of severe acute anxiety.

Nausea due to chemotherapy
Alprazolam may be used in combination with other medications for chemotherapy-induced nausea and vomiting.

Contraindications
Benzodiazepines require special precaution if used in children and in alcohol- or drug-dependent individuals. Particular care should be taken in pregnant or elderly people, people with substance use disorder history (particularly alcohol dependence), and people with comorbid psychiatric disorders. The use of alprazolam should be avoided or carefully monitored by medical professionals in individuals with: myasthenia gravis, acute narrow-angle glaucoma, severe liver deficiencies (e.g., cirrhosis), severe sleep apnea, pre-existing respiratory depression, marked neuromuscular respiratory, acute pulmonary insufficiency, chronic psychosis, hypersensitivity or allergy to alprazolam or other benzodiazepines, and borderline personality disorder (where it may induce suicidality and dyscontrol).Like all central nervous system depressants, alprazolam in larger-than-normal doses can cause significant deterioration in alertness and increase drowsiness, especially in those unaccustomed to the drugs effects.Elderly individuals should be cautious in the use of alprazolam due to the possibility of increased susceptibility to side-effects, especially loss of coordination and drowsiness.

Side effects
Sedative drugs, including alprazolam, have been associated with an increased risk of death.Possible side effects include:

Anterograde amnesia and concentration problems
Ataxia, slurred speech
Disinhibition
Drowsiness, dizziness, lightheadedness, fatigue, unsteadiness, and impaired coordination, vertigo
Dry mouth (infrequent)
Hallucinations (rare)
Jaundice (very rare)
Seizures (less common)
Skin rash, respiratory depression, constipation
Suicidal ideation or suicide
Urinary retention (infrequent)
Muscle weaknessIn September 2020, the U.S. Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Paradoxical reactions
Although unusual, the following paradoxical reactions have been shown to occur:

Aggression
Mania, agitation, hyperactivity, and restlessness
Rage, hostility
Twitches and tremor

Food and drug interactions
Alprazolam is primarily metabolized via CYP3A4. Combining CYP3A4 inhibitors such as cimetidine, erythromycin, norfluoxetine, fluvoxamine, itraconazole, ketoconazole, nefazodone, propoxyphene, and ritonavir delay the hepatic clearance of alprazolam, which may result in its accumulation and increased severity of its side effects.Imipramine and desipramine have been reported to increase an average of 31% and 20% respectively by the concomitant administration of alprazolam tablets. Combined oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.Alcohol is one of the most common interactions; alcohol and alprazolam taken in combination have a synergistic effect on one another, which can cause severe sedation, behavioral changes, and intoxication. The more alcohol and alprazolam taken, the worse the interaction. Combination of alprazolam with the herb kava can result in the development of a semi-comatose state. Plants in the genus Hypericum (including St. Johns wort) conversely can lower the plasma levels of alprazolam and reduce its therapeutic effect.

Pregnancy and breastfeeding
Benzodiazepines cross the placenta, enter the fetus, and are also excreted in breast milk. Chronic administration of diazepam, another benzodiazepine, to nursing mothers has been reported to cause their infants to become lethargic and to lose weight.The use of alprazolam during pregnancy is associated with congenital abnormalities, and use in the last trimester may cause fetal drug dependence and withdrawal symptoms in the post-natal period as well as neonatal flaccidity and respiratory problems. However, in long-term users of benzodiazepines, abrupt discontinuation due to concerns of teratogenesis has a high risk of causing extreme withdrawal symptoms and a severe rebound effect of the underlying mental health disorder. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications, including benzodiazepines.

Overdose
The maximum recommended daily dose is 10 milligrams per day.Overdoses of alprazolam can be mild to severe depending on the quantity ingested and if other drugs are taken in combination.Alprazolam overdoses cause excess central nervous system (CNS) depression and may include one or more of the following symptoms:
Coma and death if alprazolam is combined with other substances.
Fainting
Hypotension (low blood pressure)
Hypoventilation (shallow breathing)
Impaired motor functions
Dizziness
Impaired balance
Impaired or absent reflexes
Muscle weakness
Orthostatic hypotension (fainting while standing up too quickly)
Somnolence (drowsiness)

Dependence and withdrawal
The potential for misuse among those taking it for medical reasons is controversial, with some expert reviews stating that the risk is low and similar to that of other benzodiazepine drugs. Others state that there is a substantial risk of misuse and dependence in both patients and non-medical users and that the short half-life and rapid onset of action may increase the risk of misuse. Compared to the large number of prescriptions, relatively few individuals increase their dose on their own initiative or engage in drug-seeking behavior.Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA (gamma-aminobutyric acid) receptor. When bound to these sites, which are referred to as benzodiazepine receptors, it modulates the effect of GABAA receptors and, thus, of GABAergic neurons. Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and thus making the drugs less potent.Withdrawal and rebound symptoms commonly occur and necessitate a gradual reduction in dosage to minimize withdrawal effects when discontinuing.Not all withdrawal effects are evidence of true dependence or withdrawal. Recurrence of symptoms such as anxiety may simply indicate that the drug was having its expected anti-anxiety effect and that, in the absence of the drug, the symptom has returned to pretreatment levels. If the symptoms are more severe or frequent, the person may be experiencing a rebound effect due to the removal of the drug. Either of these can occur without the person actually being drug dependent.Alprazolam and other benzodiazepines may also cause the development of physical dependence, tolerance, and benzodiazepine withdrawal symptoms during rapid dose reduction or cessation of therapy after long-term treatment. There is a higher chance of withdrawal reactions if the drug is administered in a higher dosage than recommended, or if a person stops taking the medication altogether without slowly allowing the body to adjust to a lower-dosage regimen.In 1992, Romach and colleagues reported that dose escalation is not a characteristic of long-term alprazolam users and that the majority of long-term alprazolam users change their initial pattern of regular use to one of symptom control only when required.Some common symptoms of alprazolam discontinuation include malaise, weakness, insomnia, tachycardia, lightheadedness, and dizziness.Those taking more than 4 mg per day have an increased potential for dependence. This medication may cause withdrawal symptoms upon abrupt withdrawal or rapid tapering, which in some cases have been known to cause seizures, as well as marked delirium similar to that produced by the anticholinergic tropane alkaloids of Datura (scopolamine and atropine). The discontinuation of this medication may also cause a reaction called rebound anxiety.
In a 1983 study, only 5% of patients who had abruptly stopped taking long-acting benzodiazepines after less than 8 months demonstrated withdrawal symptoms, but 43% of those who had been taking them for more than 8 months did. With alprazolam – a short-acting benzodiazepine – taken for 8 weeks, 65% of patients experienced significant rebound anxiety. To some degree, these older benzodiazepines are self-tapering.The benzodiazepines diazepam and oxazepam have been found to produce fewer withdrawal reactions than alprazolam, temazepam, or lorazepam. Factors that determine the risk of psychological dependence or physical dependence and the severity of the benzodiazepine withdrawal symptoms during dose reduction of alprazolam include: dosage used, length of use, frequency of dosing, personality characteristics of the individual, previous use of cross-dependent/cross-tolerant drugs (alcohol or other sedative-hypnotic drugs), current use of cross-dependent/-tolerant drugs, use of other short-acting, high-potency benzodiazepines, and method of discontinuation.

Pharmacology
Alprazolam is a positive allosteric modulator of the gamma-aminobutyric acid (GABA) type A receptor. When it binds to the receptor, effects of GABA are enhanced leading to inhibition of neurons in the brain. This results in effects including reduced anxiety, muscle relaxant, antidepressant and anticonvulsant activity. The activity of alprazolam in the central nervous system is dose dependent.

Mechanism of action
Alprazolam is classed as a high-potency triazolobenzodiazepine: a benzodiazepine with a triazole ring attached to its structure. As a benzodiazepine, alprazolam produces a variety of therapeutic and adverse effects by binding to the GABAA benzodiazepine receptor site and modulating its function; GABA receptors are the most prolific inhibitory receptor within the brain. The GABA chemical and receptor system mediates inhibitory or calming effects of alprazolam on the nervous system. Binding of alprazolam to the GABAA receptor, a chloride ion channel, enhances the effects of GABA, a neurotransmitter. When GABA binds the GABAA receptor the channel opens and chloride enters the cell which makes it more resistant to depolarisation. Therefore, alprazolam has a depressant effect on synaptic transmission to reduce anxiety.The GABAA receptor is made up of 5 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain, and, importantly, different activities with regard to benzodiazepines. Alprazolam and other triazolobenzodiazepines such as triazolam that have a triazole ring fused to their diazepine ring appear to have antidepressant properties. This is perhaps due to the similarities shared with tricyclic antidepressants, as they have two benzene rings fused to a diazepine ring. Alprazolam causes a marked suppression of the hypothalamic–pituitary–adrenal axis. The therapeutic properties of alprazolam are similar to other benzodiazepines and include anxiolytic, anticonvulsant, muscle relaxant, hypnotic and amnesic; however, it is used mainly as an anxiolytic.
Giving alprazolam, as compared to lorazepam, has been demonstrated to elicit a statistically significant increase in extracellular dopamine D1 and D2 concentrations in the striatum.

Pharmacokinetics
Alprazolam is taken orally, and is absorbed well – 80% of alprazolam binds to proteins in the serum (the majority binding to albumin). The concentration of alprazolam peaks after one to two hours.Alprazolam is metabolized in the liver, mostly by the enzyme cytochrome P450 3A4 (CYP3A4). Two major metabolites are produced: 4-hydroxyalprazolam and α-hydroxyalprazolam, as well as an inactive benzophenone. The low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they have little to no contribution to the effects of alprazolam.The metabolites, as well as some unmetabolized alprazolam, are filtered out by the kidneys and are excreted in the urine.

Chemistry
Physical properties
Alprazolam is a triazole and benzodiazepine derivative substituted with a phenyl group at position 6, with a chlorine atom at position 8 and with a methyl group at position 1. It is an analogue of triazolam, the difference between them being the absence of a chlorine atom in the ortho position of the phenyl ring. It is slightly soluble in chloroform, soluble in alcohol, slightly soluble in acetone and insoluble in water. It has a melting point of 228–229.5 °C (442.4–445.1 °F; 501.1–502.6 K).

Synthesis
For the synthesis of alprazolam the same method can be used as for triazolam, excepting that it starts from 2-amino-5-chlorobenzophenone. However, an alternative easier synthesis starting with 2,6-dichloro-4-phenylquinoline has been suggested, in which it reacts with hydrazine giving 6-chloro-2-hydrazino-4-phenylquinoline. Boiling the mixture with triethyl orthoacetate results in cyclization with the formation of the triazole ring. The product undergoes oxidative degradation in the presence of periodate and ruthenium dioxide in acetone solution, giving 2-[4-(3-methyl-1,2,4-triazolo)]-5-chlorobenzophenone. Oxy-methylation with formaldehyde results in a product that is treated with phosphorus tribromide, when 2-[4-(3-methyl-5-bromomethyl-1,2,4-triazolo)]-5-chlorobenzophenone is obtained. By substituting the bromine atom with an amino group conferred by ammonia, it forms alprazolam triazolobenzophenone, following which an intermolecular heterocyclization takes place to obtain alprazolam.

Detection
Quantification of alprazolam in blood and plasma samples may be necessary to confirm a diagnosis of intoxication in hospitalized patients, or to provide evidence in the case of crimes e.g., impaired driving arrest, or to assist in a thorough forensic investigation, e.g., in a medicolegal death investigation. Blood or plasma alprazolam concentrations are usually in a range of 10–100 μg/L in persons receiving the drug therapeutically, 100–300 μg/L in those arrested for impaired driving, and 300–2,000 μg/L in victims of acute overdosage. Most of the commercial immunoassays used for the benzodiazepine class of drugs cross-react with alprazolam, but confirmation and quantitative determination are usually done by chromatographic techniques.

Forms of alprazolam
Alprazolam regular release and orally disintegrating tablets are available as 0.25 mg, 0.5 mg, 1 mg, and 2 mg tablets, while extended release tablets are available as 0.5 mg, 1 mg, 2 mg, and 3 mg. Liquid alprazolam is available in a 1 mg/mL oral concentrate. Inactive ingredients in alprazolam tablets and solutions include microcrystalline cellulose, corn starch, docusate sodium, povidone, sodium starch glycolate, lactose monohydrate, magnesium stearate, colloidal silicon dioxide, and sodium benzoate. In addition, the 0.25 mg tablet contains D&C Yellow No. 10 and the 0.5 mg tablet contains FD&C Yellow No. 6 and D&C Yellow No. 10.

Society and culture
Patent
Alprazolam is covered under U.S. Patent 3,987,052, which was filed on 29 October 1969, granted on 19 October 1976, and expired in September 1993.

Recreational use
There is a risk of misuse and dependence in both patients and non-medical users of alprazolam; alprazolams high affinity binding, high potency, and rapid onset increase its abuse potential. The physical dependence and withdrawal syndrome of alprazolam also add to its addictive nature. In the small subgroup of individuals who escalate their doses there is usually a history of alcohol or other substance use disorders. Despite this, most prescribed alprazolam users do not use their medication recreationally, and the long-term use of benzodiazepines does not generally correlate with the need for dose escalation. However, based on US findings from the Treatment Episode Data Set (TEDS), an annual compilation of patient characteristics in substance abuse treatment facilities in the United States, admissions due to "primary tranquilizer" (including, but not limited to, benzodiazepine-type) drug use increased 79% from 1992 to 2002, suggesting that misuse of benzodiazepines may be on the rise. In 2011, The New York Times reported, "The Centers for Disease Control and Prevention last year reported an 89 percent increase in emergency room visits nationwide related to nonmedical benzodiazepine use between 2004 and 2008."Alprazolam is one of the most commonly prescribed and misused benzodiazepines in the United States. A large-scale nationwide U.S. government study conducted by SAMHSA found that, in the U.S., benzodiazepines are recreationally the most frequently used pharmaceuticals due to their widespread availability, accounting for 35% of all drug-related visits to hospital emergency and urgent care facilities. Men and women are equally likely to use benzodiazepines recreationally. The report found that alprazolam is the most common benzodiazepine for recreational use, followed by clonazepam, lorazepam, and diazepam. The number of emergency department visits due to benzodiazepines increased by 36% between 2004 and 2006.
Regarding the significant increases detected, it is worthwhile to consider that the number of pharmaceuticals dispensed for legitimate therapeutic uses may be increasing over time, and DAWN estimates are not adjusted to take such increases into account. Nor do DAWN estimates take into account the increases in the population or in ED use between 2004 and 2006.
Those at a particularly high risk for misuse and dependence are people with a history of alcoholism or drug abuse and/or dependence and people with borderline personality disorder.Alprazolam, along with other benzodiazepines, is often used with other recreational drugs. These uses include aids to relieve the panic or distress of dysphoric ("bad trip") reactions to psychedelic drugs, such as LSD, and the drug-induced agitation and insomnia in the "comedown" stages of stimulant use, such as amphetamine, cocaine, and MDMA allowing sleep. Alprazolam may also be used with other depressant drugs, such as ethanol, heroin, and other opioids, in an attempt to enhance their psychological effects. Alprazolam may be used in conjunction with cannabis, with users citing a synergistic effect achieved after consuming the combination.
The poly-drug use of powerful depressant drugs poses the highest level of health concerns due to a significant increase in the likelihood of experiencing an overdose, which may cause fatal respiratory depression.A 1990 study found that diazepam has a higher misuse potential relative to many other benzodiazepines and that some data suggest that alprazolam and lorazepam resemble diazepam in this respect.Anecdotally, injection of alprazolam has been reported, causing dangerous damage to blood vessels, closure of blood vessels (embolization) and decay of muscle tissue (rhabdomyolysis) </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 and can you explain it in depth? [/INST] Nitroglycerin (NG), (alternative spelling nitroglycerine) also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), Nobel Oil, or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating glycerol with white fuming nitric acid under conditions appropriate to the formation of the nitric acid ester. Chemically, the substance is an organic nitrate compound rather than a nitro compound, but the traditional name is retained. Invented in 1847 by Ascanio Sobrero, nitroglycerin has been used ever since as an active ingredient in the manufacture of explosives, namely dynamite, and as such it is employed in the construction, demolition, and mining industries. Since the 1880s, it has been used by the military as an active ingredient and gelatinizer for nitrocellulose in some solid propellants such as cordite and ballistite. It is a major component in double-based smokeless propellants used by reloaders. Combined with nitrocellulose, hundreds of powder combinations are used by rifle, pistol, and shotgun reloaders.
Nitroglycerin has been used for over 130 years in medicine as a potent vasodilator (dilation of the vascular system) to treat heart conditions, such as angina pectoris and chronic heart failure. Though it was previously known that these beneficial effects are due to nitroglycerin being converted to nitric oxide, a potent venodilator, the enzyme for this conversion was only discovered to be mitochondrial aldehyde dehydrogenase (ALDH2) in 2002. Nitroglycerin is available in sublingual tablets, sprays, ointments, and patches.

History
Nitroglycerin was the first practical explosive produced that was stronger than black powder. It was first synthesized by the Italian chemist Ascanio Sobrero in 1847, working under Théophile-Jules Pelouze at the University of Turin. Sobrero initially called his discovery pyroglycerine and warned vigorously against its use as an explosive.Nitroglycerin was later adopted as a commercially useful explosive by Alfred Nobel, who experimented with safer ways to handle the dangerous compound after his younger brother, Emil Oskar Nobel, and several factory workers were killed in an explosion at the Nobels armaments factory in 1864 in Heleneborg, Sweden.

One year later, Nobel founded Alfred Nobel and Company in Germany and built an isolated factory in the Krümmel hills of Geesthacht near Hamburg. This business exported a liquid combination of nitroglycerin and gunpowder called "Blasting Oil", but this was extremely unstable and difficult to handle, as evidenced in numerous catastrophes. The buildings of the Krümmel factory were destroyed twice.In April 1866, three crates of nitroglycerin were shipped to California for the Central Pacific Railroad, which planned to experiment with it as a blasting explosive to expedite the construction of the 1,659-foot-long (506 m) Summit Tunnel through the Sierra Nevada Mountains. One of the crates exploded, destroying a Wells Fargo company office in San Francisco and killing 15 people. This led to a complete ban on the transportation of liquid nitroglycerin in California. The on-site manufacture of nitroglycerin was thus required for the remaining hard-rock drilling and blasting required for the completion of the First Transcontinental Railroad in North America.In June 1869, two one-ton wagons loaded with nitroglycerin, then known locally as Powder-Oil, exploded in the road at the North Wales village of Cwm-y-glo. The explosion led to the loss of six lives, many injuries and much damage to the village. Little trace was found of the two horses. The UK Government was so alarmed at the damage caused and what could have happened in a city location (these two tons were part of a larger load coming from Germany via Liverpool) that they soon passed The Nitro-Glycerine Act of 1869. Liquid nitroglycerin was widely banned elsewhere, as well, and these legal restrictions led to Alfred Nobel and his companys developing dynamite in 1867. This was made by mixing nitroglycerin with diatomaceous earth ("Kieselguhr" in German) found in the Krümmel hills. Similar mixtures, such as "dualine" (1867), "lithofracteur" (1869), and "gelignite" (1875), were formed by mixing nitroglycerin with other inert absorbents, and many combinations were tried by other companies in attempts to get around Nobels tightly held patents for dynamite.
Dynamite mixtures containing nitrocellulose, which increases the viscosity of the mix, are commonly known as "gelatins".
Following the discovery that amyl nitrite helped alleviate chest pain, the physician William Murrell experimented with the use of nitroglycerin to alleviate angina pectoris and to reduce the blood pressure. He began treating his patients with small diluted doses of nitroglycerin in 1878, and this treatment was soon adopted into widespread use after Murrell published his results in the journal The Lancet in 1879. A few months before his death in 1896, Alfred Nobel was prescribed nitroglycerin for this heart condition, writing to a friend: "Isnt it the irony of fate that I have been prescribed nitro-glycerin, to be taken internally! They call it Trinitrin, so as not to scare the chemist and the public." The medical establishment also used the name "glyceryl trinitrate" for the same reason.

Wartime production rates
Large quantities of nitroglycerin were manufactured during World War I and World War II for use as military propellants and in military engineering work. During World War I, HM Factory, Gretna, the largest propellant factory in the United Kingdom, produced about 800 tonnes of cordite RDB per week. This amount required at least 336 tonnes of nitroglycerin per week (assuming no losses in production). The Royal Navy had its own factory at the Royal Navy Cordite Factory, Holton Heath, in Dorset, England. A large cordite factory was also built in Canada during World War I. The Canadian Explosives Limited cordite factory at Nobel, Ontario, was designed to produce 1,500,000 lb (680 t) of cordite per month, requiring about 286 tonnes of nitroglycerin per month.

Instability and desensitization
In its undiluted form, nitroglycerin is a contact explosive, with physical shock causing it to explode. If it has not been adequately purified during manufacture it can degrade over time to even more unstable forms. This makes nitroglycerin highly dangerous to transport or use. In its undiluted form, it is one of the worlds most powerful explosives, comparable to the more recently developed RDX and PETN.
Early in its history,  liquid nitroglycerin was found to be  "desensitized" by freezing it at a temperature below 45 to 55 °F (7 to 13 °C) depending on its purity. Its sensitivity to shock while frozen is somewhat unpredictable: "It is more insensitive to the shock from a fulminate cap or a rifle ball when in that condition but on the other hand it appears to be more liable to explode on breaking, crushing, tamping, etc." Frozen nitroglycerine is much less energetic than liquid, and so must be thawed before use. Thawing it out can be extremely sensitizing, especially if impurities are present or the warming is too rapid. Ethylene glycol dinitrate or another polynitrate may be added to lower the melting point and thereby avoid the necessity of thawing frozen explosive.Chemically "desensitizing" nitroglycerin is possible to a point where it can be considered about as "safe" as modern high explosives, such as by the addition of ethanol, acetone, or dinitrotoluene. The nitroglycerin may have to be extracted from the desensitizer chemical to restore its effectiveness before use, for example by adding water to draw off ethanol used as a desensitizer.

Detonation
Nitroglycerin and any diluents can deflagrate (burn). The explosive power of nitroglycerin derives from detonation: energy from the initial decomposition causes a strong pressure wave that detonates the surrounding fuel. This is a self-sustained shock wave that propagates through the explosive medium at 30 times the speed of sound as a near-instantaneous pressure-induced decomposition of the fuel into a white-hot gas. Detonation of nitroglycerin generates gases that would occupy more than 1,200 times the original volume at ordinary room temperature and pressure. The heat liberated raises the temperature to about 5,000 °C (9,000 °F). This is entirely different from deflagration, which depends solely upon available fuel regardless of pressure or shock. The decomposition results in a much higher ratio of energy to gas moles released compared to other explosives, making it one of the hottest detonating high explosives.

Manufacturing
Nitroglycerin can be produced by acid-catalyzed nitration of glycerol (glycerin).

The industrial manufacturing process often reacts glycerol with a nearly 1:1 mixture of concentrated sulfuric acid and concentrated nitric acid. This can be produced by mixing white fuming nitric acid—a quite expensive pure nitric acid in which the oxides of nitrogen have been removed, as opposed to red fuming nitric acid, which contains nitrogen oxides—and concentrated sulfuric acid. More often, this mixture is attained by the cheaper method of mixing fuming sulfuric acid, also known as oleum—sulfuric acid containing excess sulfur trioxide—and azeotropic nitric acid (consisting of about 70% nitric acid, with the rest being water).
The sulfuric acid produces protonated nitric acid species, which are attacked by glycerols nucleophilic oxygen atoms. The nitro group is thus added as an ester C−O−NO2 and water is produced. This is different from an electrophilic aromatic substitution reaction in which nitronium ions are the electrophile.
The addition of glycerol results in an exothermic reaction (i.e., heat is produced), as usual for mixed-acid nitrations. If the mixture becomes too hot, it results in a runaway reaction, a state of accelerated nitration accompanied by the destructive oxidation of organic materials by the hot nitric acid and the release of poisonous nitrogen dioxide gas at high risk of an explosion. Thus, the glycerin mixture is added slowly to the reaction vessel containing the mixed acid (not acid to glycerin). The nitrator is cooled with cold water or some other coolant mixture and maintained throughout the glycerin addition at about 22 °C (72 °F), hot enough for esterification to occur at a fast rate but cold enough to avoid runaway reaction. The nitrator vessel, often constructed of iron or lead and generally stirred with compressed air, has an emergency trap door at its base, which hangs over a large pool of very cold water and into which the whole reaction mixture (called the charge) can be dumped to prevent an explosion, a process referred to as drowning. If the temperature of the charge exceeds about 30 °C (86 °F) (actual value varying by country) or brown fumes are seen in the nitrators vent, then it is immediately drowned.

Use as an explosive and a propellant
The main use of nitroglycerin, by tonnage, is in explosives such as dynamite and in propellants.
Nitroglycerin is an oily liquid that may explode when subjected to heat, shock, or flame.
Alfred Nobel developed the use of nitroglycerin as a blasting explosive by mixing nitroglycerin with inert absorbents, particularly "Kieselgur", or diatomaceous earth. He named this explosive dynamite and patented it in 1867. It was supplied ready for use in the form of sticks, individually wrapped in greased waterproof paper. Dynamite and similar explosives were widely adopted for civil engineering tasks, such as in drilling highway and railroad tunnels, for mining, for clearing farmland of stumps, in quarrying, and in demolition work. Likewise, military engineers have used dynamite for construction and demolition work.
Nitroglycerin was also used as an ingredient in military propellants for use in firearms.
Nitroglycerin has been used in conjunction with hydraulic fracturing, a process used to recover oil and gas from shale formations. The technique involves displacing and detonating nitroglycerin in natural or hydraulically induced fracture systems, or displacing and detonating nitroglycerin in hydraulically induced fractures followed by wellbore shots using pelletized TNT.Nitroglycerin has an advantage over some other high explosives that on detonation it produces practically no visible smoke. Therefore, it is useful as an ingredient in the formulation of various kinds of smokeless powder.Its sensitivity has limited the usefulness of nitroglycerin as a military explosive, and less sensitive explosives such as TNT, RDX, and HMX have largely replaced it in munitions. It remains important in military engineering, and combat engineers still use dynamite.
Alfred Nobel then developed ballistite, by combining nitroglycerin and guncotton. He patented it in 1887. Ballistite was adopted by a number of European governments, as a military propellant. Italy was the first to adopt it. The British government and the Commonwealth governments adopted cordite instead, which had been developed by Sir Frederick Abel and Sir James Dewar of the United Kingdom in 1889. The original Cordite Mk I consisted of 58% nitroglycerin, 37% guncotton, and 5.0% petroleum jelly. Ballistite and cordite were both manufactured in the form of "cords".
Smokeless powders were originally developed using nitrocellulose as the sole explosive ingredient. Therefore, they were known as single-base propellants. A range of smokeless powders that contains both nitrocellulose and nitroglycerin, known as double-base propellants, were also developed. Smokeless powders were originally supplied only for military use, but they were also soon developed for civilian use and were quickly adopted for sports. Some are known as sporting powders. Triple-base propellants contain nitrocellulose, nitroglycerin, and nitroguanidine, but are reserved mainly for extremely high-caliber ammunition rounds such as those used in tank cannons and naval artillery. Blasting gelatin, also known as gelignite, was invented by Nobel in 1875, using nitroglycerin, wood pulp, and sodium or potassium nitrate. This was an early, low-cost, flexible explosive.

Medical use
Nitroglycerin belongs to a group of drugs called nitrates, which includes many other nitrates like isosorbide dinitrate (Isordil) and isosorbide mononitrate (Imdur, Ismo, Monoket). These agents all exert their effect by being converted to nitric oxide in the body by mitochondrial aldehyde dehydrogenase (ALDH2), and nitric oxide is a potent natural vasodilator.

In medicine, nitroglycerin is probably most commonly prescribed for angina pectoris, a painful symptom of ischemic heart disease caused by inadequate flow of blood and oxygen to the heart and as a potent antihypertensive agent. Nitroglycerin corrects the imbalance between the flow of oxygen and blood to the heart and the heart’s energy demand. There are plenty of formulations on the market at different doses. At low doses, nitroglycerin dilates veins more than arteries, thereby reducing preload (volume of blood in the heart after filling); this is thought to be its primary mechanism of action. By decreasing preload, the heart has less blood to pump, which decreases oxygen requirement since the heart does not have to work as hard. Additionally, having a smaller preload reduces the ventricular transmural pressure (pressure exerted on the walls of the heart), which decreases the compression of heart arteries to allow more blood to flow through the heart. At higher doses, it also dilates arteries, thereby reducing afterload (decreasing the pressure against which the heart must pump). An improved ratio of myocardial oxygen demand to supply leads to the following therapeutic effects during episodes of angina pectoris: subsiding of chest pain, decrease of blood pressure, increase of heart rate, and orthostatic hypotension. Patients experiencing angina when doing certain physical activities can often prevent symptoms by taking nitroglycerin 5 to 10 minutes before the activity. Overdoses may generate methemoglobinemia.Nitroglycerin is available in tablets, ointment, solution for intravenous use, transdermal patches, or sprays administered sublingually. Some forms of nitroglycerin last much longer in the body than others.  Nitroglycerin as well as the onset and duration of action of each form is different. The sublingual or tablet spray of nitroglycerin has a two minute onset and twenty five minute duration of action. The oral formulation of nitroglycerin has a thirty five minute onset and a duration of action of 4-8 hours. The transdermal patch has an onset of thirty minutes and a duration of action of ten to twelve hours. Continuous exposure to nitrates has been shown to cause the body to stop responding normally to this medicine. Experts recommend that the patches be removed at night, allowing the body a few hours to restore its responsiveness to nitrates. Shorter-acting preparations of nitroglycerin can be used several times a day with less risk of developing tolerance. Nitroglycerin was first used by William Murrell to treat angina attacks in 1878, with the discovery published that same year.

Industrial exposure
Infrequent exposure to high doses of nitroglycerin can cause severe headaches known as "NG head" or "bang head". These headaches can be severe enough to incapacitate some people; however, humans develop a tolerance to and dependence on nitroglycerin after long-term exposure. Although rare, withdrawal can be fatal </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 Topiramate and can you explain it in depth? [/INST] Topiramate, sold under the brand name Topamax among others, is a carbonic anhydrase inhibitor medication used to treat epilepsy and prevent migraines. It has also been used in alcohol dependence. For epilepsy this includes treatment for generalized or focal seizures. It is taken by mouth.Common side effects include tingling, feeling tired, loss of appetite, abdominal pain, weight loss, and decreased cognitive function such as trouble concentrating. Serious side effects may include suicide, increased ammonia levels resulting in encephalopathy, and kidney stones. Use in pregnancy may result in harm to the baby and use during breastfeeding is not recommended. How it works is unclear.Topiramate was approved for medical use in the United States in 1996. It is available as a generic medication. In 2020, it was the 57th most commonly prescribed medication in the United States, with more than 11 million prescriptions.

Medical uses
Topiramate is used to treat epilepsy in children and adults, and it was originally used as an anticonvulsant. In children, it is indicated for the treatment of Lennox-Gastaut syndrome, a disorder that causes seizures and developmental delay. It is most frequently prescribed for the prevention of migraines as it decreases the frequency of attacks. Topiramate is used to treat medication overuse headache and is recommended by the European Federation of Neurological Societies as one of the few medications showing effectiveness for this indication.

Pain
A 2018 review found topiramate of no use in chronic low back pain. Topiramate has not been shown to work as a pain medicine in diabetic neuropathy, the only neuropathic condition in which it has been adequately tested.

Other
One common off-label use for topiramate is in the treatment of bipolar disorder. A review published in 2010 suggested a benefit of topiramate in the treatment of symptoms of borderline personality disorder, however the authors noted that this was based only on one randomized controlled trial and requires replication.Topiramate has been used as a treatment for alcoholism. The Veterans Affairs and the Department of Defense 2015 guideline on substance use disorders lists topiramate as a "strong for" in its recommendations for alcohol use disorder.Other uses include treatment of obesity, binge eating disorder, and off-setting weight gain induced by taking antipsychotic medications. In 2012, the combination of phentermine/topiramate was approved in the United States for weight loss.
It is being studied as a potential treatment for post traumatic stress disorder.There is some evidence for the use of topiramate in the management of cravings related to withdrawal from Dextromethorphan.

Adverse effects
People taking topiramate should be aware of the following risks:

Avoid activities requiring mental alertness and coordination until drug effects are realized.
Topiramate may impair heat regulation, especially in children. Use caution with activities leading to an increased core temperature, such as strenuous exercise, exposure to extreme heat, or dehydration.
Topiramate may cause visual field defects.
Topiramate may decrease effectiveness of oestrogen-containing oral contraceptives.
Taking topiramate in the first trimester of pregnancy may increase risk of cleft lip/cleft palate in infant.
As is the case for all antiepileptic drugs, it is advisable not to suddenly discontinue topiramate as there is a theoretical risk of rebound seizures.

Frequency
Adverse effects by incidence:Very common (>10% incidence) adverse effects include:

Common (1-10% incidence) adverse effects include:

Rarely, the inhibition of carbonic anhydrase may be strong enough to cause metabolic acidosis of clinical importance.The U.S. Food and Drug Administration (FDA) has notified prescribers that topiramate can cause acute myopia and secondary angle closure glaucoma in a small subset of people who take topiramate regularly. The symptoms, which typically begin in the first month of use, include blurred vision and eye pain. Discontinuation of topiramate may halt the progression of the ocular damage and may reverse the visual impairment.
Preliminary data suggests that, as with several other anti-epileptic drugs, topiramate carries an increased risk of congenital malformations. This might be particularly important for women who take topiramate to prevent migraine attacks. In March 2011, the FDA notified healthcare professionals and patients of an increased risk of development of cleft lip and/or cleft palate (oral clefts) in infants born to women treated with Topamax (topiramate) during pregnancy and placed it in Pregnancy Category D.Topiramate has been associated with a statistically significant increase in suicidality, and "suicidal thoughts or actions" is now listed as one of the possible side effects of the drug "in a very small number of people, about 1 in 500."

Overdose
Symptoms of acute and acute on chronic exposure to topiramate range from asymptomatic to status epilepticus, including in patients with no seizure history. In children, overdose may also result in hallucinations. Topiramate has been deemed the primary substance that led to fatal overdoses in cases that were complicated by polydrug exposure. The most common signs of overdose are dilated pupils, somnolence, dizziness, psychomotor agitation, and abnormal, uncoordinated body movements.Symptoms of overdose may include but are not limited to:

A specific antidote is not available. Treatment is entirely supportive.

Interactions
Topiramate has many drug-drug interactions. Some of the most common are listed below:

As topiramate inhibits carbonic anhydrase, use with other inhibitors of carbonic anhydrase (e.g. acetazolamide) increases the risk of kidney stones.
Enzyme inducers (e.g. carbamazepine) can increase the elimination of topiramate, possibly necessitating dose escalations of topiramate.
Topiramate may increase the plasma-levels of phenytoin.
Topiramate itself is a weak inhibitor of CYP2C19 and induces CYP3A4; a decrease in plasma levels of estrogens and digoxin has been noted during topiramate therapy. This can reduce the effectiveness of oral contraceptives (birth control  pills); use of alternative birth control methods is recommended. Neither intrauterine devices (IUDs) nor Depo-Provera are affected by topiramate.
Alcohol may cause increased sedation or drowsiness, and increase the risk of having a seizure.
As topiramate may result in acidosis other treatments that also do so may worsen this effect.
Oligohidrosis and hyperthermia were reported in post-marketing reports about topiramate; antimuscarinic drugs (like trospium) can aggravate these disorders.

Pharmacology
The topiramate molecule is a sulfamate modified sugar, more specifically, fructose diacetonide, an unusual chemical structure for a pharmaceutical.
Topiramate is quickly absorbed after oral use. It has a half life of 21 hours and a steady state of the drug is reached in 4 days in patients with normal renal function. Most of the drug (70%) is excreted in the urine unchanged. The remainder is extensively metabolized by hydroxylation, hydrolysis, and glucuronidation. Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose.
Several cellular targets have been proposed to be relevant to the therapeutic activity of topiramate. These include (1) voltage-gated sodium channels; (2) high-voltage-activated calcium channels; (3) GABA-A receptors; (4) AMPA/kainate receptors; and (5) carbonic anhydrase isoenzymes. There is evidence that topiramate may alter the activity of its targets by modifying their phosphorylation state instead of by a direct action. The effect on sodium channels could be of particular relevance for seizure protection. Although topiramate does inhibit high-voltage-activated calcium channels, the relevance to clinical activity is uncertain. Effects on specific GABA-A receptor isoforms could also contribute to the antiseizure activity of the drug. Topiramate selectively inhibits cytosolic (type II) and membrane associated (type IV) forms of carbonic anhydrase. The action on carbonic anhydrase isoenzymes may contribute to the drugs side-effects, including its propensity to cause metabolic acidosis and calcium phosphate kidney stones.
Topiramate inhibits maximal seizure activity in electroconvulsive therapy and in pentylenetetrazol-induced seizures as well as partial and secondarily generalized tonic-clonic seizures in the kindling model, findings predictive of a broad spectrum of activities clinically. Its action on mitochondrial permeability transition pores has been proposed as a mechanism.While many anticonvulsants have been associated with apoptosis in young animals, animal experiments have found that topiramate is one of the very few anticonvulsants [see: levetiracetam, carbamazepine, lamotrigine] that do not induce apoptosis in young animals at doses needed to produce an anticonvulsant effect.

Detection in body fluids
Blood, serum, or plasma topiramate concentrations may be measured using immunoassay or chromatographic methods to monitor therapy, confirm a diagnosis of poisoning in hospitalized patients, or to assist in a medicolegal death investigation </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 Eravacycline and can you explain it in depth? [/INST] Eravacycline (TP-434, Xerava) is a synthetic halogenated tetracycline class antibiotic by Tetraphase Pharmaceuticals. It is closely related to tigecycline. It has a broad spectrum of activity including many multi-drug resistant strains of bacteria. Phase III studies in complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI) were recently completed with mixed results. Eravacycline was granted fast track designation by the FDA and is currently available in USA.

Medical uses
Eravacycline has shown broad spectrum of activity against a variety of Gram-positive and Gram-negative bacteria, including multi-drug resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Enterobacteriaceae. It is currently being formulated as for intravenous and oral administration.

Spectrum of activity
Gram-positive organisms
Staphylococcus aureus (both methicillin-resistant and sensitive strains)
Streptococcus pneumoniae
Enterococcus faecalis
Enterococcus faecium (including vancomycin resistant strains)

Gram-negative organisms
Acinetobacter baumannii
Stenotrophomonas maltophilia
Haemophilus influenzae
Moraxella catarrhalis
Neisseria gonorrhoeae
Enterobacteriaceae
Escherichia coli (including ESBL-producing strains)
Klebsiella pneumoniae (including carbapenem resistant strains)
Klebsiella oxytoca
Enterobacter species
Citrobacter species
Proteus mirabilis
Serratia marcescensSimilar to other tetracycline derivatives, eravacycline is poorly active against Pseudomonas aeruginosa with a MIC90 = 16 mcg/mL (range 0.06-64 mcg/mL). Eravacycline maintains in-vitro activity against Enterobacteriaceae carrying the mcr-1 gene responsible for polymyxin b/colistin resistance.

Clinical trials
Current and past clinical trial information:
https://clinicaltrials.gov/ct2/results?cond=&term=eravacycline&cntry1=&state1=&recrs=

Phase 3 trials
Complicated Intra-abdominal infections (IGNITE 1)
The IGNITE 1 trial compared twice-daily IV eravacycline to once-daily ertapenem for the treatment of cIAI. A total of 541 patients were included and eravacycline demonstrated noninferiority to ertapenem. An additional pivotal phase 3 study (IGNITE 4) is planned for late 2016 with initial results likely available in the fourth quarter of 2017.

Complicated Intra-abdominal Infections (IGNITE 4)
IGNITE 4 assessed twice-daily intravenous eravacycline(1.0 mg/kg every 12 hours) compared to those receiving meropenem (1g every 8 hours). The study enrolled 500 adult patients with the primary endpoint being clinical response at the test-of-cure visit which is 25–31 days after initial dosing.  Primary efficiency analysis was conducted using a 12.5% non-inferiority margin in the microbiological intent-to-treat (micro-ITT) population.
On July 25, 2017, Tetraphase pharmaceuticals released top line data via press showing clinical cure rates in the micro-ITT population to be 90.8% and 91.2% for eravacycline (n=195) and meropenem (n=205), respectively (95% CI: -6.3%,5.3%).  Primary analysis was conducted using a 12.5% non-inferiority margin of the modified intent-to-treat (MITT) and clinically evaluable (CE) patient populations.  Clinical cure rates in the MITT population were 92.4% and 91.6% for eravacycline (n=250) and meropenem (n=249), respectively (95% CI: -4.1%,5.8%).  Clinical cure rates in the CE population were 96.9% and 96.1% for eravacycline (n=225) and meropenem (n=231), respectively (95% CI: -2.9%,4.5%). Eravacycline met the primary efficacy endpoints according to the FDA and EMA guidelines. The secondary analyses were consistent with, and supportive of, the primary outcome according to Tetraphase. There were no treatment-related serious adverse events (SAEs) in the trial </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 Factor VIII (medication) and can you explain it in depth? [/INST] Factor VIII is a medication used to treat and prevent bleeding in people with hemophilia A and other causes of low factor VIII. Certain preparations may also be used in those with von Willebrands disease. It is given by slow injection into a vein.Side effects include skin flushing, shortness of breath, fever, and red blood cell breakdown. Allergic reactions including anaphylaxis may occur. It is unclear if use during pregnancy is safe for the baby. A purified factor VIII concentrate is made from human blood plasma. A recombinant version is also available. People may develop antibodies to factor VIII such that this medication becomes less effective.Factor VIII was first identified in the 1940s and became available as a medication in the 1960s. Recombinant factor VIII was first made in 1984 and approved for medical use in the United States in 1992. It is on the World Health Organizations List of Essential Medicines.

Available forms
Factor VIII is delivered by intravenous infusion.

History
This transfer of a plasma byproduct into the blood stream of a hemophiliac often led to the transmission of diseases such as HIV and hepatitis before purification methods were improved. In the early 1990s, pharmaceutical companies began to produce recombinant synthesized factor products, which now prevent nearly all forms of disease transmission during replacement therapy.

Society and culture
Economics
The cost of Factor VIII and similar clotting factors has been described as "highly expensive".  The cost of the clotting factors is 80% of all medical costs for people with hemophilia.  They are so expensive that gene therapy for haemophilia might be less expensive, especially for people with severe hemophilia.

See also
Damoctocog alfa pegol, a recombinant antihemophilic factor VIII
Efmoroctocog alfa, a recombinant antihemophilic factor VIII
Moroctocog alfa, a recombinant antihemophilic factor VIII
Susoctocog alfa, a recombinant antihemophilic factor VIII
Turoctocog alfa, a recombinant antihemophilic factor VIII

References
External links
"Blood-coagulation factor VIII, procoagulant" </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 Satralizumab and can you explain it in depth? [/INST] Satralizumab, sold under the brand name Enspryng, is a humanized monoclonal antibody medication that is used for the treatment of neuromyelitis optica spectrum disorder (NMOSD), a rare autoimmune disease. The drug is being developed by Chugai Pharmaceutical, a subsidiary of Roche.The most common side effects include the common cold (nasopharyngitis), headache, upper respiratory tract infection, inflammation of the lining of the stomach, rash, joint pain, extremity pain, fatigue and nausea.Satralizumab regulates inflammation by inhibiting the interleukin-6 (IL-6) receptor, a key mediator of the immune response.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.

Medical uses
Satralizumab is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with a particular antibody – people who are anti-aquaporin-4 or AQP4 antibody-positive.NMOSD is a rare autoimmune disease of the central nervous system that mainly affects the optic nerves and spinal cord. In people with NMOSD, the bodys immune system mistakenly attacks healthy cells and proteins in the body, most often those in the optic nerves and spinal cord. Individuals with NMOSD typically have attacks of optic neuritis, which causes eye pain and vision loss. Approximately 50% of people with NMOSD have permanent visual impairment and paralysis caused by NMOSD attacks. Estimates vary, but NMOSD is thought to impact approximately 4,000 to 8,000 Americans.NMOSD can be associated with antibodies that bind to a protein called aquaporin-4 (AQP4). Binding of the anti-AQP4 antibody appears to activate other components of the immune system, causing inflammation and damage to the central nervous system.

Contraindications
Vaccination with live-attenuated or live vaccines is not recommended during treatment and should be administered at least four weeks before starting satralizumab.

Side effects
The most common side effects observed were the common cold (nasopharyngitis), headache, upper respiratory tract infection, inflammation of the lining of the stomach, rash, joint pain, extremity pain, fatigue and nausea.The FDA label for satralizumab includes a warning for increased risk of infection, including serious and potentially fatal infections – such as potential reactivation of hepatitis B and tuberculosis. Other warnings and precautions for satralizumab include elevated liver enzymes, decreased neutrophil counts and hypersensitivity reactions.

Pharmacology
Mechanism of action
Satralizumab is a humanized IgG2 monoclonal antibody that binds to soluble and membrane-bound human interleukin-6 (IL-6) receptors and thereby prevents IL-6-mediated signal transmission through these receptors.IL-6 is a pleiotropic cytokine that is produced by a large number of cell types and is involved in a variety of inflammatory processes. Patients with NMO and NMOSD have elevated levels of IL-6 in cerebro-spinal fluid and serum during periods of active disease. Some of the pro-inflammatory processes involved in NMOSD are thought to involve IL-6, including the formation of pathological autoantibodies against aquaporin-4 (AQP4), and the permeability of the blood-brain barrier to mediators of inflammation.

Efficacy
The effectiveness and safety of satralizumab for the treatment of neuromyelitis optica spectrum disorder (NMOSD) were demonstrated in two 96-week clinical studies.A study of satralizumab as monotherapy for NMOSD included 95 adult participants, 64 of whom had antibodies against AQP4 (i.e. were anti-AQP4 positive). During this study, treatment with satralizumab reduced the number of NMOSD relapses by 74% in participants who were anti-AQP4 positive compared to treatment with a placebo (inactive treatment).A study of satralizumab as an adjuvant to immunosuppressant treatment for NMOSD included 76 adult participants; 52 were anti-AQP4 positive. Immunosuppressant treatment in combination with satralizumab reduced the rate of relapses in participants who were anti-AQP4 positive by four-fifths compared to immunosuppressant treatment alone.The U.S. Food and Drug Administration (FDA) approved satralizumab based on evidence from two clinical trials (Trial 1/ NCT02073279 and Trial 2/NCT02028884) of 116 participants with NMOSD who were anti-aquaporin-4 (AQP4) antibody positive. The trials were conducted at 62 sites in the United States, Canada, Europe and Asia. Participants received at random either satralizumab or placebo injections according to the schedule </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 Safinamide and can you explain it in depth? [/INST] Safinamide (INN; brand name Xadago) is a drug used as an add-on treatment for Parkinsons disease with "off" episodes; it has multiple modes of action, including the inhibition of monoamine oxidase B.It was approved in the European Union in February 2015, in the United States in March 2017, and in Canada in January 2019.

Medical uses
Safinamide is used to treat idiopathic Parkinsons disease as add-on for people taking a stable dose of levodopa (L-dopa) alone or in combination with other Parkinson drugs, to help with "off" episodes when levodopa stops working.

Contraindications
Safinamide is contraindicated in people with severe liver impairment, with albinism, retinitis pigmentosa, severe diabetic neuropathy, uveitis and other disorders of the retina. Combination with other monoamine oxidase (MAO) inhibitors and pethidine is also contraindicated.It is not safe for women to take during pregnancy. It is excreted in breast milk and the effects on infants are unknown.

Adverse effects
Common adverse events in clinical trials (in more than 1% of people) included nausea, dizziness, tiredness, sleeplessness, orthostatic hypotension (low blood pressure), and headache. There was no significant difference in the occurrence of these effects between safinamide and placebo.In experiments with rats (but not in those with monkeys), retinopathies have been observed.

Overdose
Expected overdose effects are hypertension (high blood pressure), orthostatic hypotension, hallucinations, psychomotor agitation, nausea, vomiting, and dyskinesia. In studies, a single person was suspected to have overdosed for a month; symptoms were confusion, drowsiness and mydriasis (dilation of the pupils) and subsided completely after the drug was discontinued. No specific antidote is available.

Interactions
As a MAO inhibitor, safinamide can theoretically cause hypertensive crises, serotonin syndrome and other severe side effects when combined with other MAO inhibitors or with drugs that are known to interact with MAO inhibitors, such as pethidine, dextromethorphan, selective serotonin reuptake inhibitors (SSRIs), serotonin–noradrenaline reuptake inhibitors (SNRIs), tricyclic and tetracyclic antidepressants. An interaction with tyramine, a substance found in various foods, could be expected by the same reasoning but has been excluded in studies.Safinamide should not be given with opioids; some fatal reactions have occurred.Another theoretical interaction is with drugs with affinity to the transporter protein ABCG2 (also known as BCRP), such as pitavastatin, pravastatin, ciprofloxacin, methotrexate, and diclofenac; a study with the latter has shown no clinical relevance. A study testing possible interactions with amidase inhibitors is part of the post-authorisation development plan. There are no relevant interactions related to cytochrome P450 (CYP) liver enzymes, although one inactivation pathway of safinamide seems to be mediated by CYP3A4.

Pharmacology
Mechanisms of action
Like the older antiparkinson drugs selegiline and rasagiline, safinamide is a selective monoamine oxidase B inhibitor, reducing degradation of dopamine; in contrast to the other two, its action is reversible. Safinamide also inhibits glutamate release and dopamine and serotonin reuptake. It binds to the sigma receptors as well, with IC50 values for binding inhibition of 19 nM for σ1 and 1,590 nM for σ2. Additionally, it blocks sodium and calcium channels, the relevance of which for its antiparkinson action is however unknown.

Pharmacokinetics
Safinamide is absorbed quickly and nearly completely from the gut and reaches highest blood plasma concentrations after 1.8 to 2.8 hours. There is no relevant first-pass metabolism; total bioavailability is 95%. The substance is bound to plasma proteins to 88–90%.The metabolism is not well understood. The principal step is mediated by amidases which have not been identified, and produces safinamide acid (NW-1153). Other relevant metabolites are O-debenzylated safinamide (NW-1199), the N-dealkylated amine which is then oxidized to a carboxylic acid (NW-1689), and the glucuronide of the latter. In tests with liver microsomes, dealkylation seemed to be mediated by CYP3A4, but other CYP enzymes appear to be involved as well. Safinamide acid binds to the organic anion transporter 3 (OAT3), but this has probably no clinical relevance. Safinamide itself transiently binds to ABCG2. No other transporter affinities have been found in preliminary studies.Safinamide is eliminated, mainly (>90%) in form of its metabolites, via the kidney, with an elimination half-life of 20 to 30 hours. Only 1.5% are found in the stool.

History
The compound was originally discovered at Farmitalia-Carlo Erba, which was acquired by Pharmacia in 1993. In 1995, Pharmacia merged with Upjohn. Safinamide was first disclosed in 1998. In the course of a major restructuring in the same year, all rights for safinamide were transferred to the newly formed company Newron Pharmaceuticals, which developed the drug until it was sold to Merck KGaA in 2006.In 2007, a Phase III clinical trial was started, scheduled to run until 2011. In October 2011 Merck, now Merck-Serono, announced that they would give all rights to develop the compound back to Newron because they wanted to prioritise other projects and had corrected their estimates for safinamides market potential downwards.The US Food and Drug Administration (FDA) refused to file Newrons application in 2014 on formal grounds. Newron re-applied in December 2014. In spring 2015, following a commercial agreement between Newron and the Italian pharmaceutical company Zambon, the European Medicines Agency (EMA) approved the drug. In the following years, the drug has been launched in several European countries </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 Antacid and can you explain it in depth? [/INST] An antacid is a substance which neutralizes stomach acidity and is used to relieve heartburn, indigestion or an upset stomach. Some antacids have been used in the treatment of constipation and diarrhea. Marketed antacids contain salts of aluminum, calcium, magnesium, or sodium. Some preparations contain a combination of two salts, such as magnesium carbonate and aluminium hydroxide (e.g. hydrotalcite).

Medical uses
Antacids are available over the counter and are taken by mouth to quickly relieve occasional heartburn, the major symptom of gastroesophageal reflux disease and indigestion. Treatment with antacids alone is symptomatic and only justified for minor symptoms. Alternative uses for antacids include constipation, diarrhea,  hyperphosphatemia, and urinary alkalization. Some antacids are also used as an adjunct to pancreatic enzyme replacement therapy in the treatment of pancreatic insufficiency.Non-particulate antacids (sodium citrate, magnesium trisilicate) increase gastric pH with little or no effect on gastric volume, and therefore may see some limited use in pre-operative procedures. Sodium citrate should be given within 1 hour of surgery to be the most effective.

Side effects
Conventional effervescent tablets contain a significant amount of sodium and are associated with increased odds of adverse cardiovascular events according to an 2013 study. Alternative sodium-free formulations containing magnesium salts may cause diarrhea, whereas those containing calcium or aluminum may cause constipation. Rarely, long-term use of calcium carbonate may cause kidney stones. Long-term use of antacids containing aluminum may increase the risk of developing osteoporosis. In vitro studies have found a potential for acid rebound to occur due to antacid overuse, however the significance of this finding has been called into question.

Properties of antacids
When an excess amount of acid is produced in the stomach, the natural mucous barrier that protects the lining of the stomach can degrade, leading to pain and irritation. There is also potential for the development of acid reflux, which can cause pain and damage to the esophagus. Antacids contain alkaline ions that chemically neutralize stomach gastric acid, reducing damage to the stomach lining and esophagus, and relieving pain. Some antacids also inhibit pepsin, an enzyme that can damage the esophagus in acid reflux.Antacids do not directly inhibit acid secretion, and thus are distinct from acid-reducing drugs like H2-receptor antagonists or proton pump inhibitors. Antacids do not kill the bacteria Helicobacter pylori, which causes most ulcers.

Interactions
Antacids are known to interact with several oral medications, including fluoroquinolone and tetracycline antibiotics, iron, itraconazole, and prednisone. Metal chelation is responsible for some of these interactions (e.g </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 Mitoxantrone 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 Ibuprofen/famotidine and can you explain it in depth? [/INST] Ibuprofen/famotidine, sold under the brand name Duexis, is a fixed-dose combination medication used for the treatment of rheumatoid arthritis and osteoarthritis. It contains ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID) and famotidine, a histamine H2-receptor antagonist.

References
Further reading
Deeks ED (September 2013). "Fixed-dose ibuprofen/famotidine: a review of its use to reduce the risk of gastric and duodenal ulcers in patients requiring NSAID therapy". Clin Drug Investig. 33 (9): 689–97. doi:10.1007/s40261-013-0113-x. PMID 23881568 </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 Histrelin and can you explain it in depth? [/INST] Histrelin acetate, sold under the brand names Vantas and Supprelin LA among others, is a nonapeptide analogue of gonadotropin-releasing hormone (GnRH) with added potency </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 Levorphanol and can you explain it in depth? [/INST] Levorphanol (brand name Levo-Dromoran) is an opioid medication used to treat moderate to severe pain. It is one of two enantiomers of the compound racemorphan.
It was first described in Germany in 1946. The drug has been in medical use in the United States since 1953.

Pharmacology
Levorphanol acts predominantly as an agonist of the μ-opioid receptor (MOR), but is also an agonist of the δ-opioid receptor (DOR), κ-opioid receptor (KOR), and the nociceptin receptor (NOP), as well as an NMDA receptor antagonist and a serotonin-norepinephrine reuptake inhibitor (SNRI). Levorphanol, similarly to certain other opioids, also acts as a glycine receptor antagonist and GABA receptor antagonist at very high concentrations. Levorphanol is 6 to 8 times as potent as morphine at the MOR.Relative to morphine, levorphanol lacks complete cross-tolerance and possesses greater intrinsic activity at the MOR. The duration of action is generally long compared to other comparable analgesics and varies from 4 hours to as much as 15 hours. For this reason levorphanol is useful in palliation of chronic pain and similar conditions. Levorphanol has an oral to parenteral effectiveness ratio of 2:1, one of the most favorable of the strong narcotics </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 Paricalcitol 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 Dimethyl sulfoxide and can you explain it in depth? [/INST] Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula (CH3)2SO.  This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water.  It has a relatively high boiling point.  DMSO has the unusual property that many individuals perceive a garlic-like taste in the mouth after DMSO makes contact with their skin.In terms of chemical structure, the molecule has idealized Cs symmetry. It has a trigonal pyramidal molecular geometry consistent with other three-coordinate S(IV) compounds, with a nonbonded electron pair on the approximately tetrahedral sulfur atom.

Synthesis and production
Dimethyl sulfoxide was first synthesized in 1866 by the Russian scientist Alexander Zaytsev, who reported his findings in 1867.  Dimethyl sulfoxide is produced industrially from dimethyl sulfide, a by-product of the Kraft process, by oxidation with oxygen or nitrogen dioxide.

Reactions
Reactions with electrophiles
The sulfur center in DMSO is nucleophilic toward soft electrophiles and the oxygen is nucleophilic toward hard electrophiles.  With methyl iodide it forms trimethylsulfoxonium iodide, [(CH3)3SO]I:

(CH3)2SO  +  CH3I  →  [(CH3)3SO]IThis salt can be deprotonated with sodium hydride to form the sulfur ylide:

[(CH3)3SO]I  +  NaH  → (CH3)2S(CH2)O  +  NaI  +  H2

Acidity
The methyl groups of DMSO are only weakly acidic, with a pKa = 35.  For this reason, the basicities of many weakly basic organic compounds have been examined in this solvent.
Deprotonation of DMSO requires strong bases like lithium diisopropylamide and sodium hydride.  Stabilization of the resultant carbanion is provided by the S(O)R group.  The sodium derivative of DMSO formed in this way is referred to as dimsyl sodium.  It is a base, e.g., for the deprotonation of ketones to form sodium enolates, phosphonium salts to form Wittig reagents, and formamidinium salts to form diaminocarbenes.  It is also a potent nucleophile.

Oxidant
In organic synthesis, DMSO is used as a mild oxidant. It forms the basis of several selective sulfonium-based oxidation reactions include the Pfitzner–Moffatt oxidation, Corey–Kim oxidation and the Swern oxidation.
The Kornblum oxidation is conceptually similar. These all involve formation an intermediate sulfonium species (R2S+X where X is a heteroatom)

Ligand and Lewis base
Related to its ability to dissolve many salts, DMSO is a common ligand in coordination chemistry. Illustrative is the complex dichlorotetrakis(dimethyl sulfoxide)ruthenium(II) (RuCl2(dmso)4). In this complex, three DMSO ligands are bonded to ruthenium through sulfur. The fourth DMSO is bonded through oxygen. In general, the oxygen-bonded mode is more common.
In carbon tetrachloride solutions DMSO functions as a Lewis base with a variety of Lewis acids such as I2, phenols, trimethyltin chloride, metalloporphyrins, and the dimer Rh2Cl2(CO)4. The donor properties are discussed in the ECW model. The relative donor strength of DMSO toward a series of acids, versus other Lewis bases, can be illustrated by C-B plots.

Applications
Solvent
DMSO is a polar aprotic solvent and is less toxic than other members of this class, such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, and hexamethylphosphoramide (HMPA). DMSO is frequently used as a solvent for chemical reactions involving salts, most notably Finkelstein reactions and other nucleophilic substitutions. It is also extensively used as an extractant in biochemistry and cell biology. Because DMSO is only weakly acidic, it tolerates relatively strong bases and as such has been extensively used in the study of carbanions.  A set of non-aqueous pKa values (C-H, O-H, S-H and N-H acidities) for thousands of organic compounds have been determined in DMSO solution.Because of its high boiling point, 189 °C (372 °F), DMSO evaporates slowly at normal atmospheric pressure. Samples dissolved in DMSO cannot be as easily recovered compared to other solvents, as it is very difficult to remove all traces of DMSO by conventional rotary evaporation. One technique to fully recover samples is removal of the organic solvent by evaporation followed by addition of water (to dissolve DMSO) and cryodesiccation to remove both DMSO and water. Reactions conducted in DMSO are often diluted with water to precipitate or phase-separate products. The relatively high freezing point of DMSO, 18.5 °C (65.3 °F), means that at, or just below, room temperature it is a solid, which can limit its utility in some chemical processes (e.g. crystallization with cooling).
In its deuterated form (DMSO-d6), it is a useful solvent for NMR spectroscopy, again due to its ability to dissolve a wide range of analytes, the simplicity of its own spectrum, and its suitability for high-temperature NMR spectroscopic studies. Disadvantages to the use of DMSO-d6 are its high viscosity, which broadens signals, and its hygroscopicity, which leads to an overwhelming H2O resonance in the 1H-NMR spectrum. It is often mixed with CDCl3 or CD2Cl2 for lower viscosity and melting points.

DMSO is also used to dissolve test compounds in in vitro drug discovery and drug design screening programs, including high-throughput screening programs.  This is because it is able to dissolve both polar and nonpolar compounds, can be used to maintain stock solutions of test compounds (important when working with a large chemical library), is readily miscible with water and cell culture media, and has a high boiling point (this improves the accuracy of test compound concentrations by reducing room temperature evaporation).  One limitation with DMSO is that it can affect cell line growth and viability, with low DMSO concentrations sometimes stimulating cell growth, and high DMSO concentrations sometimes inhibiting or killing cells.DMSO is used as a vehicle in in vivo studies of test compounds too.  It has, for example, been employed as a co-solvent to assist absorption of the flavonol glycoside Icariin in the nematode worm Caenorhabditis elegans.  As with its use in in vitro studies, DMSO has some limitations in animal models. Pleiotropic effects can occur and, if DMSO control groups are not carefully planned, then solvent effects can falsely be attributed to the prospective drug. For example, even a very low dose of DMSO has a powerful protective effect against paracetamol (acetaminophen)-induced liver injury in mice.In addition to the above, DMSO is finding increased use in manufacturing processes to produce microelectronic devices. It is widely used to strip photoresist in TFT-LCD flat panel displays and advanced packaging applications (such as wafer-level packaging / solder bump patterning). DMSO is an effective paint stripper too, being safer than many of the others such as nitromethane and dichloromethane.

Biology
DMSO is used in polymerase chain reaction (PCR) to inhibit secondary structures in the DNA template or the DNA primers. It is added to the PCR mix before reacting, where it interferes with the self-complementarity of the DNA, minimizing interfering reactions.DMSO in a PCR is applicable for supercoiled plasmids (to relax before amplification) or DNA templates with high GC-content (to decrease thermostability). For example, 10% final concentration of DMSO in the PCR mixture with Phusion decreases primer annealing temperature (i.e. primer melting temperature) by 5.5–6.0 °C (9.9–10.8 °F).It is well known as a reversible cell cycle arrester at phase G1 of human lymphoid cells.DMSO may also be used as a cryoprotectant, added to cell media to reduce ice formation and thereby prevent cell death during the freezing process. Approximately 10% may be used with a slow-freeze method, and the cells may be frozen at −80 °C (−112 °F) or stored in liquid nitrogen safely.
In cell culture, DMSO is used to induce differentiation of P19 embryonic carcinoma cells into cardiomyocytes and skeletal muscle cells.

Medicine
Use of DMSO in medicine dates from around 1963, when an Oregon Health & Science University Medical School team, headed by Stanley Jacob, discovered it could penetrate the skin and other membranes without damaging them and could carry other compounds into a biological system. In medicine, DMSO is predominantly used as a topical analgesic, a vehicle for topical application of pharmaceuticals, as an anti-inflammatory, and an antioxidant. Because DMSO increases the rate of absorption of some compounds through biological tissues, including skin, it is used in some transdermal drug delivery systems.  Its effect may be enhanced with the addition of EDTA. It is frequently compounded with antifungal medications, enabling them to penetrate not just skin but also toenails and fingernails.DMSO has been examined for the treatment of numerous conditions and ailments, but the U.S. Food and Drug Administration (FDA) has approved its use only for the symptomatic relief of patients with interstitial cystitis. A 1978 study concluded that DMSO brought significant relief to the majority of the 213 patients with inflammatory genitourinary disorders that were studied. The authors recommended DMSO for genitourinary inflammatory conditions not caused by infection or tumor in which symptoms were severe or patients failed to respond to conventional therapy.
In interventional radiology, DMSO is used as a solvent for ethylene vinyl alcohol in the Onyx liquid embolic agent, which is used in embolization, the therapeutic occlusion of blood vessels.
In cryobiology DMSO has been used as a cryoprotectant and is still an important constituent of cryoprotectant vitrification mixtures used to preserve organs, tissues, and cell suspensions. Without it, up to 90% of frozen cells will become inactive. It is particularly important in the freezing and long-term storage of embryonic stem cells and hematopoietic stem cells, which are often frozen in a mixture of 10% DMSO, a freezing medium, and 30% fetal bovine serum. In the cryogenic freezing of heteroploid cell lines (MDCK, VERO, etc.) a mixture of 10% DMSO with 90% EMEM (70% EMEM + 30% fetal bovine serum + antibiotic mixture) is used. As part of an autologous bone marrow transplant the DMSO is re-infused along with the patients own hematopoietic stem cells.
DMSO is metabolized by disproportionation to dimethyl sulfide and dimethyl sulfone. It is subject to renal and pulmonary excretion. A possible side effect of DMSO is therefore elevated blood dimethyl sulfide, which may cause a blood borne halitosis symptom.

Alternative medicine
DMSO is marketed as an alternative medicine. Its popularity as an alternative cure is stated to stem from a 60 Minutes documentary in 1980 featuring an early proponent. However, DMSO is an ingredient in some products listed by the U.S. FDA as fake cancer cures and the FDA has had a running battle with distributors. One such distributor is Mildred Miller, who promoted DMSO for a variety of disorders and was consequently convicted of Medicare fraud.The use of DMSO as an alternative treatment for cancer is of particular concern, as it has been shown to interfere with a variety of chemotherapy drugs, including cisplatin, carboplatin, and oxaliplatin. There is insufficient evidence to support the hypothesis that DMSO has any effect, and most sources agree that its history of side effects when tested warrants caution when using it as a dietary supplement, for which it is marketed heavily with the usual disclaimer.

Veterinary medicine
DMSO is commonly used in veterinary medicine as a liniment for horses, alone or in combination with other ingredients.  In the latter case, often, the intended function of the DMSO is as a solvent, to carry the other ingredients across the skin.  Also in horses, DMSO is used intravenously, again alone or in combination with other drugs.  It is used alone for the treatment of increased intracranial pressure and/or cerebral edema in horses.

Taste
The perceived garlic taste upon skin contact with DMSO may be due to nonolfactory activation of TRPA1 receptors in trigeminal ganglia.  Unlike dimethyl and diallyl disulfides (which have odors resembling garlic), mono- and tri- sulfides (which typically have foul odors), and similar odiferous sulfur compounds, the pure chemical DMSO is odorless.

Safety
Toxicity
DMSO is a non-toxic solvent with a median lethal dose higher than ethanol (DMSO: LD50, oral, rat, 14,500 mg/kg; ethanol: LD50, oral, rat, 7,060 mg/kg).
Early clinical trials with DMSO were stopped because of questions about its safety, especially its ability to harm the eye. The most commonly reported side effects include headaches and burning and itching on contact with the skin. Strong allergic reactions have been reported. DMSO can cause contaminants, toxins, and medicines to be absorbed through the skin, which may cause unexpected effects. DMSO is thought to increase the effects of blood thinners, steroids, heart medicines, sedatives, and other drugs. In some cases this could be harmful or dangerous.In Australia, it is listed as a Schedule 4 (S4) Drug, and a company has been prosecuted for adding it to products as a preservative.Because DMSO easily penetrates the skin, substances dissolved in DMSO may be quickly absorbed. Glove selection is important when working with DMSO. Butyl rubber, fluoroelastomer, neoprene, or thick (15 mil / 0.4  mm) latex gloves are recommended. Nitrile gloves, which are very commonly used in chemical laboratories, may protect from brief contact but have been found to degrade rapidly with exposure to DMSO.On September 9, 1965, The Wall Street Journal reported that a manufacturer of the chemical warned that the death of an Irish woman after undergoing DMSO treatment for a sprained wrist may have been due to the treatment, although no autopsy was done, nor was a causal relationship established </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 Olmesartan/amlodipine/hydrochlorothiazide 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 Pantoprazole and can you explain it in depth? [/INST] Pantoprazole, sold under the brand name Protonix, among others, is a proton pump inhibitor used for the treatment of stomach ulcers, short-term treatment of erosive esophagitis due to gastroesophageal reflux disease (GERD), maintenance of healing of erosive esophagitis, and pathological hypersecretory conditions including Zollinger–Ellison syndrome. It may also be used along with other medications to eliminate Helicobacter pylori. Effectiveness is similar to other proton pump inhibitors (PPIs). It is available by mouth and by injection into a vein.Common side effects include headaches, diarrhea, vomiting, abdominal pain, and joint pain. More serious side effects may include severe allergic reactions, a type of chronic inflammation known as atrophic gastritis, Clostridium difficile colitis, low magnesium, and vitamin B12 deficiency. Use in pregnancy appears to be safe. Pantoprazole is a proton pump inhibitor that decreases gastric acid secretion. It works by inactivating (H+/K+)-ATPase function in the stomach.Study of pantoprazole began in 1985, and it came into medical use in Germany in 1994. It is available as a generic medication. In 2020, it was the twentieth most commonly prescribed medication in the United States, with more than 26 million prescriptions.

Medical uses
Pantoprazole is used for short-term treatment of erosion and ulceration of the esophagus for adults and children five years of age and older caused by gastroesophageal reflux disease. It can be used as a maintenance therapy for long-term use after initial response is obtained, but there have not been any controlled studies about the use of pantoprazole past a duration of 12 months. Pantoprazole may also be used in combination with antibiotics to treat ulcers caused by Helicobacter pylori. It can also be used for long-term treatment of Zollinger-Ellison syndrome. It may be used to prevent gastric ulcers in those taking NSAIDs.For improved efficacy of pantoprazole, the oral tablet formulation is taken half an hour prior to ingestion of food. In the hospital, intravenous administration is indicated when patients are unable to take the medication by mouth.

Children
Pantoprazole is only indicated for the short-term treatment of erosive esophagitis in children ages seven and older; and the safety and effectiveness of pantoprazole have only been established in the treatment of erosive esophagitis in children.

Elderly
The incidence of adverse effects occurring in people aged 65 years and older was similar to that in people aged 65 years and less.

Pregnancy
In reproductive studies using doses largely greater than the recommended doses performed on rats and rabbits, there was no evident harm on the development of the baby.

Breast feeding
Pantoprazole has been found to pass through the breast milk. However, in rodent cancer studies, pantoprazole has been shown to potentially cause tumor growth. The clinical relevance of the finding is unknown, but risks and benefits are recommended for consideration in determining the use of therapy for the mother and child.

Adverse effects
Infection: Stomach acid plays a role in killing ingested bacteria. Use of pantoprazole may increase the chance of developing infections such as pneumonia, particularly in hospitalized patients.

Common
Gastrointestinal: abdominal pain (6%), diarrhea (9%), flatulence (4%), nausea (7%), vomiting (4%)
Neurologic: headache (12%), dizziness (3%)
Neuromuscular and skeletal: arthralgia (3%)

Rare
Gastrointestinal: constipation, dry mouth, hepatitis
Blood problems: low white blood cell count, thrombocytopenia
Immunologic: Stevens–Johnson syndrome, toxic epidermal necrolysis
Metabolic: elevated creatine kinase, elevated cholesterol levels, elevated liver enzymes (AST/ALT), swelling
Musculoskeletal: Muscle disorders, bone fracture and infection, Clostridium difficile infection, osteoporosis-related hip fracture, rhabdomyolysis
Kidneys: interstitial nephritis
Nutrition:  may reduce the absorption of important nutrients, vitamins, and minerals, including certain medications, leaving users at increased risk for pneumonia.

Long-term use
Osteoporosis and bone fracture have been observed in people on high-dose and/or long-term (over one year) prescription proton pump inhibitors.
Hypomagnesia has been observed in people on medications like pantoprazole when taken for longer periods of time (generally one year or more, although cases have been reported with regimens as short as three months).
Deficiencies such as vitamin B12 deficiency, iron deficiency, and calcium deficiency may be seen with long term use. Vitamin B12 deficiency is due to the change in the acidic environment within the stomach with the use of pantoprazole which prevents peptidases from being activated. This prevents the cleaving of R-factor from vitamin B12 and prevents its absorption.
Rebound hypergastrinemia may be seen when stopping the medication after long term use.

Discontinuation
In people taking PPIs for longer than six months, a dose taper should be considered prior to discontinuation. For those on a moderate to high dose, this can be done by 50 percent every week until on the lowest dose. After a week it can then be stopped.

Interactions
Due to its effect of reducing stomach acidity, use of pantoprazole can affect absorption of drugs that are pH-sensitive, such as ampicillin esters, ketoconazole, atazanavir, iron salts, amphetamine and mycophenolate mofetil.Additional medications that are affected include bisphosphonate derivatives, fluconazole, clopidogrel, and methotrexate.

Pharmacology
The mechanism of action of pantoprazole is to inhibit the final step in gastric acid production. In the gastric parietal cell of the stomach, pantoprazole covalently binds to the H+/K+ ATP pump to inhibit gastric acid and basal acid secretion. The covalent binding prevents acid secretion for up to 24 hours and longer.Pantoprazole is metabolized in the liver by the cytochrome P450 system. Metabolism mainly consists of demethylation by CYP2C19 followed by sulfation. Another metabolic pathway is oxidation by CYP3A4. Pantoprazole metabolites are not thought to have any pharmacological significance. It is usually given with a prokinetic drug because of inactivity in the acidic environment of the stomach. Pantoprazole binds irreversibly to H+K+ATPase (proton pumps) to suppress the secretion of acid. Due to irreversible binding of the pumps, new pumps have to be made before acid production can be resumed. The drugs plasma half-life is about two hours. After administration, the time for the drug to reach peak plasma concentrations is 2 to 3 hours. The percentage of the drug that is protein bound is 98%.In veterinary medicine, pantoprazole appears to be safe to use in several large animal species. The pharmacokinetics of pantoprazole have been explored in several veterinary species, including calves, alpacas and foals with half lives reported as 2.81, 0.47, and 1.43 hours, respectively </s>