<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Alitretinoin and explain in detail? [/INST] Alitretinoin, or 9-cis-retinoic acid, is a form of vitamin A. It is also used in medicine as an antineoplastic (anti-cancer) agent developed by Ligand Pharmaceuticals. It is a first generation retinoid. Ligand gained Food and Drug Administration (FDA) approval for alitretinoin in February 1999.

Medical uses
Kaposi’s sarcoma
In the United States, topical alitretinoin is indicated for the treatment of skin lesions in AIDS-related Kaposis sarcoma. Alitretinoin is not indicated when systemic therapy against Kaposis sarcoma is required. It has received EMA (11 October 2000) and FDA (2 March 1999) approval for this indication.

Chronic hand eczema
Alitretinoin has been granted prescription rights in the UK (08/09/2008) for in chronic hand eczema as used by mouth.
In May 2009 the National Institute for Health and Clinical Excellence (NICE) issued preliminary guidance on the use of alitretinoin for the treatment of severe chronic hand eczema in adults. The recommendation stated that only patients with severe chronic hand eczema who are unresponsive to potent topical corticosteroids, oral immunosuppressants or phototherapy should receive the drug. Final NICE guidance is expected in August 2009.

Adverse effects
Systemic use
Very common (>10% frequency):

Headache
Hypertriglyceridemia
High density lipoprotein decreased
HypercholesterolemiaCommon (1-10% frequency):

Uncommon (0.1-1% frequency):

Rare (<0.1% frequency):

Benign intracranial hypertension
VasculitisUnknown frequency:

Topical use
Very common (>10% frequency):

Rash (77%)
Pain (34%)
Itchiness (11%)Common (1-10% frequency):

Exfoliative dermatitis
Oedema
Skin changes
Paraesthesia

Contraindications
Pregnancy is an absolute contraindication as with most other vitamin A products, it should also be avoided when it comes to systemic use in any women that is of childbearing potential and not taking precautions to prevent pregnancy. Toctino (the oral capsule formulation of alitretinoin) contains soya oil and sorbitol. Patients who are allergic to peanut, soya or with rare hereditary fructose intolerance should not take this medicine </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Clonazepam and explain in detail? [/INST] Clonazepam, sold under the brand name Klonopin among others, is a medication used to prevent and treat seizures, panic disorder, anxiety, and the movement disorder known as akathisia. It is a tranquilizer of the benzodiazepine class. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. It is typically taken by mouth. Effects begin within one hour and last between six and twelve hours.Common side effects include sleepiness, poor coordination, and agitation. Long-term use may result in tolerance, dependence, and withdrawal symptoms if stopped abruptly. Dependence occurs in one-third of people who take clonazepam for longer than four weeks. There is an increased risk of suicide, particularly in people who are already depressed. If used during pregnancy it may result in harm to the fetus. Clonazepam binds to GABAA receptors, thus increasing the effect of the chief inhibitory neurotransmitter γ-aminobutyric acid (GABA).Clonazepam was patented in 1960 and went on sale in 1975 in the United States from Roche. It is available as a generic medication. In 2020, it was the 44th most commonly prescribed medication in the United States, with more than 14 million prescriptions. In many areas of the world it is commonly used as a recreational drug.

Medical uses
Clonazepam is prescribed for short term management of epilepsy, anxiety, and panic disorder with or without agoraphobia.

Seizures
Clonazepam, like other benzodiazepines, while being a first-line treatment for acute seizures, is not suitable for the long-term treatment of seizures due to the development of tolerance to the anticonvulsant effects.
Clonazepam has been found effective in treating epilepsy in children, and the inhibition of seizure activity seemed to be achieved at low plasma levels of clonazepam. As a result, clonazepam is sometimes used for certain rare childhood epilepsies; however, it has been found to be ineffective in the control of infantile spasms. Clonazepam is mainly prescribed for the acute management of epilepsies. Clonazepam has been found to be effective in the acute control of non-convulsive status epilepticus; however, the benefits tended to be transient in many people, and the addition of phenytoin for lasting control was required in these patients.It is also approved for treatment of typical and atypical absences (seizures), infantile myoclonic, myoclonic, and akinetic seizures. A subgroup of people with treatment resistant epilepsy may benefit from long-term use of clonazepam; the benzodiazepine clorazepate may be an alternative due to its slow onset of tolerance.

Anxiety disorders
Panic disorder with or without agoraphobia.
Clonazepam has also been found effective in treating other anxiety disorders, such as social phobia, but this is an off-label use.The effectiveness of clonazepam in the short-term treatment of panic disorder has been demonstrated in controlled clinical trials. Some long-term trials have suggested a benefit of clonazepam for up to three years without the development of tolerance but these trials were not placebo-controlled. Clonazepam is also effective in the management of acute mania.

Muscle disorders
Restless legs syndrome can be treated using clonazepam as a third-line treatment option as the use of clonazepam is still investigational. Bruxism also responds to clonazepam in the short-term. Rapid eye movement sleep behavior disorder responds well to low doses of clonazepam.
The treatment of acute and chronic akathisia induced by neuroleptics, also called antipsychotics.
Spasticity related to amyotrophic lateral sclerosis.
Alcohol withdrawal syndrome

Other
Benzodiazepines, such as clonazepam, are sometimes used for the treatment of mania or acute psychosis-induced aggression. In this context, benzodiazepines are given either alone, or in combination with other first-line drugs such as lithium, haloperidol or risperidone. The effectiveness of taking benzodiazepines along with antipsychotic medication is unknown, and more research is needed to determine if benzodiazepines are more effective than antipsychotics when urgent sedation is required.
Hyperekplexia
Many forms of parasomnia and other sleep disorders are treated with clonazepam.
It is not effective for preventing migraines.

Contraindications
Coma
Current alcohol use disorder
Current substance use disorder
Respiratory depression.

Adverse effects
In 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.

Common
Sedation
Euphoria
Motor impairment

Less common
Confusion
Irritability and aggression
Psychomotor agitation
Lack of motivation
Loss of libido
Impaired motor functionImpaired coordination
Impaired balance
Dizziness
Cognitive impairmentsHallucinations.
Short-term memory loss
Anterograde amnesia (common with higher doses)
Some users report hangover-like symptoms of drowsiness, headaches, sluggishness, and irritability upon waking up if the medication was taken before sleep. This is likely the result of the medications long half-life, which continues to affect the user after waking up. While benzodiazepines induce sleep, they tend to reduce the quality of sleep by suppressing or disrupting REM sleep. After regular use, rebound insomnia may occur when discontinuing clonazepam.
Benzodiazepines may cause or worsen depression.

Occasional
Dysphoria
Induction of seizures or increased frequency of seizures
Personality changes
Behavioural disturbances
Ataxia

Rare
Suicide through disinhibition
Psychosis
Incontinence
Liver damage
Paradoxical behavioural disinhibition (most frequently in children, the elderly, and in persons with developmental disabilities)
Rage
Excitement
ImpulsivityThe long-term effects of clonazepam can include depression, disinhibition, and sexual dysfunction.

Drowsiness
Clonazepam, like other benzodiazepines, may impair a persons ability to drive or operate machinery. The central nervous system depressing effects of the drug can be intensified by alcohol consumption, and therefore alcohol should be avoided while taking this medication. Benzodiazepines have been shown to cause dependence. Patients dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to reduce the intensity of withdrawal or rebound symptoms.

Withdrawal-related
Anxiety
Irritability
Insomnia
Tremors
Headaches
Stomach pain
Hallucinations
Suicidal thoughts or urges
Depression
Fatigue
Dizziness
Sweating
Confusion
Potential to exacerbate existing panic disorder upon discontinuation
Seizures similar to delirium tremens (with long-term use of excessive doses)Benzodiazepines such as clonazepam can be very effective in controlling status epilepticus, but, when used for longer periods of time, some potentially serious side-effects may develop, such as interference with cognitive functions and behavior. Many individuals treated on a long-term basis develop a dependence. Physiological dependence was demonstrated by flumazenil-precipitated withdrawal. Use of alcohol or other CNS depressants while taking clonazepam greatly intensifies the effects (and side effects) of the drug.
A recurrence of symptoms of the underlying disease should be separated from withdrawal symptoms.

Tolerance and withdrawal
Like all benzodiazepines, clonazepam is a GABA-positive allosteric modulator. One-third of individuals treated with benzodiazepines for longer than four weeks develop a dependence on the drug and experience a withdrawal syndrome upon dose reduction. High dosage and long-term use increase the risk and severity of dependence and withdrawal symptoms. Withdrawal seizures and psychosis can occur in severe cases of withdrawal, and anxiety and insomnia can occur in less severe cases of withdrawal. A gradual reduction in dosage reduces the severity of the benzodiazepine withdrawal syndrome. Due to the risks of tolerance and withdrawal seizures, clonazepam is generally not recommended for the long-term management of epilepsies. Increasing the dose can overcome the effects of tolerance, but tolerance to the higher dose may occur and adverse effects may intensify. The mechanism of tolerance includes receptor desensitization, down regulation, receptor decoupling, and alterations in subunit composition and in gene transcription coding.Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently. Chronic use of benzodiazepines can lead to the development of tolerance with a decrease of benzodiazepine binding sites. The degree of tolerance is more pronounced with clonazepam than with chlordiazepoxide. In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy. Many studies have found that tolerance develops to the anticonvulsant properties of clonazepam with chronic use, which limits its long-term effectiveness as an anticonvulsant.Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. Sudden withdrawal may also induce the potentially life-threatening condition, status epilepticus. Anti-epileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced in dose slowly and gradually when discontinuing the drug to mitigate withdrawal effects. Carbamazepine has been tested in the treatment of clonazepam withdrawal but was found to be ineffective in preventing clonazepam withdrawal-induced status epilepticus from occurring.

Overdose
Excess doses may result in:

Difficulty staying awake
Mental confusion
Impaired motor functions
Impaired reflexes
Impaired coordination
Impaired balance
Dizziness
Respiratory depression
Low blood pressure
ComaComa can be cyclic, with the individual alternating from a comatose state to a hyper-alert state of consciousness, which occurred in a four-year-old boy who overdosed on clonazepam. The combination of clonazepam and certain barbiturates (for example, amobarbital), at prescribed doses has resulted in a synergistic potentiation of the effects of each drug, leading to serious respiratory depression.Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.

Detection in biological fluids
Clonazepam and 7-aminoclonazepam may be quantified in plasma, serum, or whole blood in order to monitor compliance in those receiving the drug therapeutically. Results from such tests can be used to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Both the parent drug and 7-aminoclonazepam are unstable in biofluids, and therefore specimens should be preserved with sodium fluoride, stored at the lowest possible temperature and analyzed quickly to minimize losses.

Special precautions
The elderly metabolize benzodiazepines more slowly than younger people and are also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels. Doses for the elderly are recommended to be about half of that given to younger adults and are to be administered for no longer than two weeks. Long-acting benzodiazepines such as clonazepam are not generally recommended for the elderly due to the risk of drug accumulation.The elderly are especially susceptible to increased risk of harm from motor impairments and drug accumulation side effects. Benzodiazepines also require special precaution if used by individuals that may be pregnant, alcohol- or drug-dependent, or may have comorbid psychiatric disorders. Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.Clonazepam is not recommended for use in those under 18. Use in very young children may be especially hazardous. Of anticonvulsant drugs, behavioural disturbances occur most frequently with clonazepam and phenobarbital.Doses higher than 0.5–1 mg per day are associated with significant sedation.Clonazepam may aggravate hepatic porphyria.Clonazepam is not recommended for patients with chronic schizophrenia. A 1982 double-blinded, placebo-controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.Clonazepam has similar effectiveness to other benzodiazepines at often a lower dose.

Interactions
Clonazepam decreases the levels of carbamazepine, and, likewise, clonazepams level is reduced by carbamazepine. Azole antifungals, such as ketoconazole, may inhibit the metabolism of clonazepam. Clonazepam may affect levels of phenytoin (diphenylhydantoin). In turn, Phenytoin may lower clonazepam plasma levels by increasing the speed of clonazepam clearance by approximately 50% and decreasing its half-life by 31%.
Clonazepam increases the levels of primidone and phenobarbital.Combined use of clonazepam with certain antidepressants, anticonvulsants (such as phenobarbital, phenytoin, and carbamazepine), sedative antihistamines, opiates, and antipsychotics, nonbenzodiazepines (such as zolpidem), and alcohol may result in enhanced sedative effects.

Pregnancy
There is some medical evidence of various malformations (for example, cardiac or facial deformations when used in early pregnancy); however, the data is not conclusive. The data are also inconclusive on whether benzodiazepines such as clonazepam cause developmental deficits or decreases in IQ in the developing fetus when taken by the mother during pregnancy. Clonazepam, when used late in pregnancy, may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress.The safety profile of clonazepam during pregnancy is less clear than that of other benzodiazepines, and if benzodiazepines are indicated during pregnancy, chlordiazepoxide and diazepam may be a safer choice. The use of clonazepam during pregnancy should only occur if the clinical benefits are believed to outweigh the clinical risks to the fetus. Caution is also required if clonazepam is used during breastfeeding. Possible adverse effects of use of benzodiazepines such as clonazepam during pregnancy include: miscarriage, malformation, intrauterine growth retardation, functional deficits, carcinogenesis, and mutagenesis. Neonatal withdrawal syndrome associated with benzodiazepines include hypertonia, hyperreflexia, restlessness, irritability, abnormal sleep patterns, inconsolable crying, tremors, or jerking of the extremities, bradycardia, cyanosis, suckling difficulties, apnea, risk of aspiration of feeds, diarrhea and vomiting, and growth retardation. This syndrome can develop between three days to three weeks after birth and can have a duration of up to several months. The pathway by which clonazepam is metabolized is usually impaired in newborns. If clonazepam is used during pregnancy or breastfeeding, it is recommended that serum levels of clonazepam are monitored and that signs of central nervous system depression and apnea are also checked for. In many cases, non-pharmacological treatments, such as relaxation therapy, psychotherapy, and avoidance of caffeine, can be an effective and safer alternative to the use of benzodiazepines for anxiety in pregnant women.

Pharmacology
Mechanism of action
Clonazepam enhances the activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system to give its anticonvulsant, skeletal muscle relaxant, and anxiolytic effects. It acts by binding to the benzodiazepine site of the GABA receptors, which enhances the electric effect of GABA binding on neurons, resulting in an increased influx of chloride ions into the neurons. This further results in an inhibition of synaptic transmission across the central nervous system.Benzodiazepines do not have any effect on the levels of GABA in the brain. Clonazepam has no effect on GABA levels and has no effect on gamma-aminobutyric acid transaminase. Clonazepam does, however, affect glutamate decarboxylase activity. It differs from other anticonvulsant drugs it was compared to in a study.Clonazepams primary mechanism of action is the modulation of GABA function in the brain, by the benzodiazepine receptor, located on GABAA receptors, which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. Benzodiazepines do not replace GABA, but instead enhance the effect of GABA at the GABAA receptor by increasing the opening frequency of chloride ion channels, which leads to an increase in GABAs inhibitory effects and resultant central nervous system depression. In addition, clonazepam decreases the utilization of 5-HT (serotonin) by neurons and has been shown to bind tightly to central-type benzodiazepine receptors. Because clonazepam is effective in low milligram doses (0.5 mg clonazepam = 10 mg diazepam), it is said to be among the class of "highly potent" benzodiazepines. The anticonvulsant properties of benzodiazepines are due to the enhancement of synaptic GABA responses, and the inhibition of sustained, high-frequency repetitive firing.Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity. Clonazepam decreases release of acetylcholine in the feline brain and decreases prolactin release in rats. Benzodiazepines inhibit cold-induced thyroid-stimulating hormone (also known as TSH or thyrotropin) release. Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive calcium uptake in experimentation on rat brain cell components. This has been conjectured as a mechanism for high-dose effects on seizures in the study.Clonazepam is a 2-chlorinated derivative of nitrazepam, which increases its potency due to electron-attracting effect of the halogen in the ortho-position.

Pharmacokinetics
Clonazepam is lipid-soluble, rapidly crosses the blood–brain barrier, and penetrates the placenta. It is extensively metabolised into pharmacologically inactive metabolites, with only 2% of the unchanged drug excreted in the urine. Clonazepam is metabolized extensively via nitroreduction by cytochrome P450 enzymes, including CYP3A4. Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, cimetidine, and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of benzodiazepines. It has an elimination half-life of 19–60 hours. Peak blood concentrations of 6.5–13.5 ng/mL were usually reached within 1–2 hours following a single 2 mg oral dose of micronized clonazepam in healthy adults. In some individuals, however, peak blood concentrations were reached at 4–8 hours.Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.Clonazepam has plasma protein binding of 85%. Clonazepam passes through the blood–brain barrier easily, with blood and brain levels corresponding equally with each other </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Bempedoic acid/ezetimibe and explain in detail? [/INST] Bempedoic acid/ezetimibe, sold under the brand name Nexlizet among others, is a fixed-dose combination medication used for the treatment of high cholesterol. It is a combination of bempedoic acid and ezetimibe.The most common side effects are hyperuricemia (high blood levels of uric acid) and constipation.Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor and ezetimibe is a cholesterol absorption inhibitor. Bempedoic acid works by blocking an enzyme in the liver called adenosine triphosphate citrate lyase, which is involved in making cholesterol. Ezetimibe works by binding to a gut protein called Niemann-Pick C1 Like 1, preventing cholesterol from being absorbed into the blood from the gut.The combination was approved for medical use in the United States in February 2020, and in the European Union in March 2020.

Medical uses
In the US bempedoic acid/ezetimibe is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C.In the EU bempedoic acid/ezetimibe is indicated in adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet:
in combination with a statin in people unable to reach LDL-C goals with the maximum tolerated dose of a statin in addition to ezetimibe
alone in people who are either statin-intolerant or for whom a statin is contraindicated, and are unable to reach LDL-C goals with ezetimibe alone,
in people already being treated with the combination of bempedoic acid and ezetimibe as separate tablets with or without statin.

Contraindications
It the European Union it must not be used in pregnant or breast-feeding women. Use during pregnancy is not recommended in the US.

History
The European Medicines Agency (EMA) recommended approval of bempedoic acid/ezetimibe (Nustendi) in the EU in January 2020.Bempedoic acid/ezetimibe was approved in the United States in February 2020, and in the European Union in March 2020.Two studies showed that bempedoic acid and ezetimibe effectively reduced LDL cholesterol levels in participants with hypercholesterolemia and heart disease or who were at high risk of heart disease </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Minoxidil and explain in detail? [/INST] Minoxidil, sold under the brand name Rogaine among others, is a medication used for the treatment of high blood pressure and pattern hair loss. It is an antihypertensive vasodilator. It is available as a generic medication by prescription in oral tablet form and over the counter as a topical liquid or foam.

Medical uses
Minoxidil, when used for hypertension, is generally reserved for use in severe hypertension patients who can not respond to at least two agents and a diuretic. Minoxidil is also generally administered with a loop diuretic to prevent the sodium and potassium retention. It may also cause a reflex tachycardia and thus is prescribed with a beta blocker.
Minoxidil, applied topically, is widely used for the treatment of hair loss. It is effective in helping promote hair growth in people with androgenic alopecia regardless of sex. Minoxidil must be used indefinitely for continued support of existing hair follicles and the maintenance of any experienced hair regrowth.Low-dose oral minoxidil is used off-label against hair loss.Its effect in people with alopecia areata is unclear. However, the association of oral minoxidil with Janus Kinase inhibitors (JAK inhibitors), termed oral adjuvant minoxidil, seems to increase hair regrowth in patients refractory to JAK inhibitor monotherapy.

Side effects
Topically applied minoxidil is generally well tolerated, but common side effects include itching of the eye, itching, redness or irritation at the treated area, and unwanted hair growth elsewhere on the body. Exacerbation of hair loss/alopecia has been reported. Other side effects may include rash, itching, difficulty breathing, swelling of the mouth, face, lips, or tongue, chest pain, dizziness, fainting, tachycardia, headache, sudden and unexplained weight gain, or swelling of the hands and feet. Rare side effects are erectile dysfunction, depression, anxiety, decreased libido, and skin disorders. Temporary hair loss is a common side effect of minoxidil treatment, a process referred to as "shedding."Alcohol and propylene glycol present in some topical preparations may dry the scalp, resulting in dandruff and contact dermatitis. Cases of allergic reactions to minoxidil or the non-active ingredient propylene glycol, which is found in some topical minoxidil formulations, have been reported.
Side effects of oral minoxidil may include swelling of the face and extremities, rapid heartbeat, or lightheadedness. Cardiac lesions, such as focal necrosis of the papillary muscle and subendocardial areas of the left ventricle, have been observed in laboratory animals treated with minoxidil. Pseudoacromegaly is an extremely rare side effect reported with large doses of oral minoxidil.In 2013 or 2014 a seven-year-old girl was admitted to a childrens hospital in Toulouse in France after accidentally ingesting a teaspoon of Alopexy (a brand name for minoxidil in France). The child vomited constantly after ingestion and showed hypotension and tachycardia for 40 hours.  The authors of the report on the incident stressed that the product should be kept out of reach of children, and urged manufacturers to consider more secure child-resistant packaging.Minoxidil may cause hirsutism, although it is exceedingly rare and reversible by discontinuation of the drug.

Pharmacology
Mechanism of action
The mechanism by which minoxidil promotes hair growth is not fully understood. Minoxidil is an adenosine 5-triphosphate-sensitive potassium channel opener, causing hyperpolarization of cell membranes. Theoretically, by widening blood vessels and opening potassium channels, it allows more oxygen, blood, and nutrients to the follicles. Moreover, minoxidil contains a nitric oxide moiety and may act as a nitric oxide agonist. This may cause follicles in the telogen phase to shed, which are then replaced by thicker hairs in a new anagen phase. Minoxidil is a prodrug that is converted by sulfation via the sulfotransferase enzyme SULT1A1 to its active form, minoxidil sulfate. The effect of minoxidil is mediated by adenosine, which triggers intracellular signal transduction via both adenosine A1 receptors and two sub-types of adenosine A2 receptors (A2A and A2B receptors). Minoxidil acts as an activator of the Kir6/SUR2 channel upon selective binding to SUR2. The expression of SUR2B in dermal papilla cells might play a role in the production of adenosine. Minoxidil induces cell growth factors such as VEGF, HGF, IGF-1 and potentiates HGF and IGF-1 actions by the activation of uncoupled sulfonylurea receptor on the plasma membrane of dermal papilla cells.A number of in vitro effects of minoxidil have been described in monocultures of various skin and hair follicle cell types including stimulation of cell proliferation, inhibition of collagen synthesis, and stimulation of vascular endothelial growth factor, prostaglandin synthesis and leukotriene B4 expression.Minoxidil causes a redistribution of cellular iron through its apparent capacity to bind this metal ion. By binding iron in a Fenton-reactive form, intracellular hydroxyl radical production would ensue, but hydroxyl would be immediately trapped and scavenged by the minoxidil to generate a nitroxyl radical. It is presumed that this nitroxyl radical will be capable of reduction by glutathione to reform minoxidil. Such a process would cycle until the minoxidil is otherwise metabolized and would result in rapid glutathione depletion with glutathione disulphide formation and therefore with concomitant consumption of NADPH/ NADH and other reducing equivalents. Minoxidil inhibited PHD by interfering with the normal function of ascorbate, a cofactor of the enzyme, leading to a stabilization of HIF-1α protein and a subsequent activation of HIF-1. In an in vivo angiogenesis assay, millimolar minoxidil increased blood vessel formation in a VEGF-dependent manner. Minoxidil inhibition of PHD occurs via interrupting ascorbate binding to iron. The structural feature of positioning amines adjacent to nitric oxide may confer the ability of millimolar minoxidil to chelate iron, thereby inhibiting PHD. Minoxidil is capable of tetrahydrobiopterin inhibition as a cofactor for nitric oxide synthase.Minoxidil stimulates prostaglandin E2 production by activating COX-1 and prostaglandin endoperoxide synthase-1 but inhibits prostacyclin production. Additionally, expression of the prostaglandin E2 receptor, the most upregulated target gene in the β-catenin pathway of DP cells, was enhanced by minoxidil, which may enable hair follicles to grow continuously and maintain the anagen phase.Due to anti-fibrotic activity of minoxidil inhibition of enzyme lysyl hydroxylase present in fibroblast may result in synthesis of a hydroxylysine-deficient collagen. Minoxidil can also potentially stimulate elastogenesis in aortic smooth muscle cells, and in skin fibroblasts in a dose-dependent manner. In hypertensive rats, minoxidil increases elastin level in the mesenteric, abdominal, and renal arteries by a decrease in "elastase" enzyme activity in these tissues. In rats, potassium channel openers decrease calcium influx which inhibits elastin gene transcription through extracellular signal-regulated kinase 1⁄2 (ERK 1/2)-activator protein 1 signaling pathway. ERK 1/2 increases, through elastin gene transcription, adequately cross-linked elastic fiber content synthetized by smooth muscle cells, and decreases the number of cells in the aorta.Minoxidil possesses alpha 2-adrenoceptor agonist activity, stimulates the peripheral sympathetic nervous system (SNS) by way of carotid and aortic baroreceptor reflexes. Minoxidil administration also brings an increase in plasma renin activity, largely due to the aforementioned activation of the SNS. This activation of the renin-angiotensin axis further prompts increased biosynthesis of aldosterone; whereas plasma and urinary aldosterone levels are increased early in the course of treatment with minoxidil, over time these values tend to normalize presumably because of accelerated metabolic clearance of aldosterone in association with hepatic vasodilation.Minoxidil may be involved in the inhibition of serotonergic (5-HT2) receptors.Minoxidil might increase blood-tumor barrier permeability in a time-dependent manner by down-regulating tight junction protein expression and this effect could be related to ROS/RhoA/PI3K/PKB signal pathway. Minoxidil significantly increases ROS concentration when compared to untreated cells.
In vitro Minoxidil treatment resulted in a 0.22 fold change for 5α-R2 (p < 0.0001). This antiandrogenic effect of minoxidil, shown by significant downregulation of 5α-R2 gene expression in HaCaT cells, may be one of its mechanisms of action in alopecia.Minoxidil is less effective when the area of hair loss is large. In addition, its effectiveness has largely been demonstrated in younger men who have experienced hair loss for less than 5 years. Minoxidil use is indicated for central (vertex) hair loss only. Two clinical studies are being conducted in the US for a medical device that may allow patients to determine if they are likely to benefit from minoxidil therapy.Conditions such as Cantú syndrome have been shown to mimic the pharmacological properties of minoxidil.

Chemistry
Minoxidil is an odorless, white to off-white, crystalline powder (crystals from methanol-acetonitrile). When heated to decomposition it emits toxic fumes of nitrogen oxides. It decomposes at 259-261 °C.Solubility (mg/ml): propylene glycol 75, methanol 44, ethanol 29, 2-propanol 6.7, dimethylsulfoxide 6.5, water 2.2, chloroform 0.5, acetone <0.5, ethyl acetate <0.5, diethyl ether <0.5, benzene <0.5, acetonitrile <0.5.

          p

          K

              a

        =

    {\displaystyle \mathrm {p} K_{{\ce {a}}}=}
   4.61
Commercially available minoxidil topical solution should be stored at a temperature of 20-25 °C. Extemporaneous formulations of minoxidil have been reported to have variable stability, depending on the vehicle and method of preparation, and the FDA requests that physicians and pharmacists refrain from preparing extemporaneous topical formulations using commercially available minoxidil tablets. Minoxidil tablets should be stored in well-closed containers at 15-30 °C.
Minoxidil, 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine, is synthesized from barbituric acid, the reaction of which with phosphorous oxychloride gives 2,4,6-trichloropyrimidine. Upon reaction with ammonium, this turns into 2,4-diamino-6-chloropyrimidine. Next, the resulting 2,4-diamino-6-chloropyrimidine undergoes reaction with 2,4-dichlorophenol in the presence of potassium hydroxide, giving 2,4-diamino-6-(2,4-dichlorophenoxy)-pyrimidine. Oxidation of this product with 3-chloroperbenzoic acid gives 2,4-diamino-6-(2,4-dichlorophenoxy)pyrimidine-3-oxide, the 2,4-dichlorophenoxyl group of which is replaced with a piperidine group at high temperature, giving minoxidil.Another synthesis approach is depicted here:

Compounds related to minoxidil include kopexil (diaminopyrimidine oxide).

History
Initial application
Minoxidil was developed in the late 1950s by the Upjohn Company (later became part of Pfizer) to treat ulcers. In trials using dogs, the compound did not cure ulcers, but proved to be a powerful vasodilator. Upjohn synthesized over 200 variations of the compound, including the one it developed in 1963 and named minoxidil. These studies resulted in the U.S. Food and Drug Administration (FDA) approving minoxidil (with the brand name Loniten) in the form of oral tablets to treat high blood pressure in 1979.

Hair growth
When Upjohn received permission from the U.S. Food and Drug Administration (FDA) to test the new drug as medicine for hypertension they approached Charles A. Chidsey MD, Associate Professor of Medicine at the University of Colorado School of Medicine. He conducted two studies, the second study showing unexpected hair growth. Puzzled by this side-effect, Chidsey consulted Guinter Kahn (who while a dermatology resident at the University of Miami had been the first to observe and report hair development on patients using the minoxidil patch) and discussed the possibility of using minoxidil  for treating hair loss.
Kahn along with his colleague Paul J. Grant MD had obtained a certain amount of the drug and conducted their own research, since they were first to make the side effect observation.  Neither Upjohn or Chidsey at the time were aware of the side effect of hair growth. The two doctors had been experimenting with a 1% solution of minoxidil mixed with several alcohol-based liquids.   Both parties filed patents to use the drug for hair loss prevention, which resulted in a decade-long trial between Kahn and Upjohn, which ended with Kahns name included in a consolidated patent (U.S. #4,596,812 Charles A Chidsey, III and Guinter Kahn) in 1986 and royalties from the company to both Kahn and Grant.Meanwhile, the effect of minoxidil on hair loss prevention was so clear that in the 1980s physicians were prescribing Loniten off-label to their balding patients.In August 1988, the FDA approved the drug for treating baldness in men under the brand name "Rogaine" (FDA rejected Upjohns first choice, Regain, as misleading). The agency concluded that although "the product will not work for everyone", 39% of the men studied had "moderate to dense hair growth on the crown of the head".In 1991, Upjohn made the product available for women.On February 12, 1996, the FDA approved both the over-the-counter sale of the medication and the production of generic formulations of minoxidil </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Iron(II) sulfate and explain in detail? [/INST] Iron(II) sulfate (British English: iron(II) sulphate) or ferrous sulfate denotes a range of salts with the formula FeSO4·xH2O. These compounds exist most commonly as the heptahydrate (x = 7) but several values for x are known. The hydrated form is used medically to treat iron deficiency, and also for industrial applications. Known since ancient times as copperas and as green vitriol (vitriol is an archaic name for sulfate), the blue-green heptahydrate (hydrate with 7 molecules of water) is the most common form of this material. All the iron(II) sulfates dissolve in water to give the same aquo complex [Fe(H2O)6]2+, which has octahedral molecular geometry and is paramagnetic. The name copperas dates from times when the copper(II) sulfate was known as blue copperas, and perhaps in analogy, iron(II) and zinc sulfate were known respectively as green and white copperas.It is on the World Health Organizations List of Essential Medicines. In 2019, it was the 103rd most commonly prescribed medication in the United States, with more than 6 million prescriptions.

Uses
Industrially, ferrous sulfate is mainly used as a precursor to other iron compounds. It is a reducing agent, and as such is useful for the reduction of chromate in cement to less toxic Cr(III) compounds. Historically ferrous sulfate was used in the textile industry for centuries as a dye fixative. It is used historically to blacken leather and as a constituent of iron gall ink. The preparation of sulfuric acid (oil of vitriol) by the distillation of green vitriol (Iron(II) sulfate) has been known for at least 700 years.

Medical use
Plant growth
Iron(II) sulfate is sold as ferrous sulfate, a soil amendment for lowering the pH of a high alkaline soil so that plants can access the soils nutrients.In horticulture it is used for treating iron chlorosis. Although not as rapid-acting as ferric EDTA, its effects are longer-lasting. It can be mixed with compost and dug into the soil to create a store which can last for years. Ferrous sulfate can be used as a lawn conditioner. It can also be used to eliminate silvery thread moss in golf course putting greens.

Pigment and craft
Ferrous sulfate can be used to stain concrete and some limestones and sandstones a yellowish rust color.Woodworkers use ferrous sulfate solutions to color maple wood a silvery hue.
Green vitriol is also a useful reagent in the identification of mushrooms.

Historical uses
Ferrous sulfate was used in the manufacture of inks, most notably iron gall ink, which was used from the middle ages until the end of the 18th century. Chemical tests made on the Lachish letters (c. 588–586 BCE) showed the possible presence of iron. It is thought that oak galls and copperas may have been used in making the ink on those letters. It also finds use in wool dyeing as a mordant. Harewood, a material used in marquetry and parquetry since the 17th century, is also made using ferrous sulfate.
Two different methods for the direct application of indigo dye were developed in England in the 18th century and remained in use well into the 19th century. One of these, known as china blue, involved iron(II) sulfate. After printing an insoluble form of indigo onto the fabric, the indigo was reduced to leuco-indigo in a sequence of baths of ferrous sulfate (with reoxidation to indigo in air between immersions). The china blue process could make sharp designs, but it could not produce the dark hues of other methods.
In the second half of the 1850s ferrous sulfate was used as a photographic developer for collodion process images.

Hydrates
Iron(II) sulfate can be found in various states of hydration, and several of these forms exist in nature.

FeSO4·H2O (mineral: szomolnokite, relatively rare)
FeSO4·4H2O (mineral: rozenite, white, relatively common, may be dehydratation product of melanterite)
FeSO4·5H2O (mineral: siderotil, relatively rare)
FeSO4·6H2O (mineral: ferrohexahydrite, relatively rare)
FeSO4·7H2O (mineral: melanterite, blue-green, relatively common)
The tetrahydrate is stabilized when the temperature of aqueous solutions reaches 56.6 °C (133.9 °F). At 64.8 °C (148.6 °F) these solutions form both the tetrahydrate and monohydrate.Mineral forms are found in oxidation zones of iron-bearing ore beds, e.g. pyrite, marcasite, chalcopyrite, etc. They are also found in related environments, like coal fire sites. Many rapidly dehydrate and sometimes oxidize </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Iron(II) fumarate and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Disulfiram and explain in detail? [/INST] Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, causing many of the effects of a hangover to be felt immediately following alcohol consumption. Disulfiram plus alcohol, even small amounts, produces flushing, throbbing in the head and neck, a throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, fast heart rate, low blood pressure, fainting, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, abnormal heart rhythms, heart attack, acute congestive heart failure, unconsciousness, convulsions, and death.In the body, alcohol is converted to acetaldehyde, which is then broken down by acetaldehyde dehydrogenase. When the dehydrogenase enzyme is inhibited, acetaldehyde builds up, causing unpleasant side effects. Disulfiram should be used in conjunction with counseling and support.

Medical uses
Disulfiram is used as a second-line treatment, behind acamprosate and naltrexone, for alcohol dependence.Under normal metabolism, alcohol is broken down in the liver by the enzyme alcohol dehydrogenase to acetaldehyde, which is then converted by the enzyme acetaldehyde dehydrogenase to a harmless acetic acid derivative (acetyl coenzyme A).  Disulfiram blocks this reaction at the intermediate stage by blocking acetaldehyde dehydrogenase.  After alcohol intake under the influence of disulfiram, the concentration of acetaldehyde in the blood may be five to 10 times higher than that found during metabolism of the same amount of alcohol alone.  As acetaldehyde is one of the major causes of the symptoms of a "hangover", this produces immediate and severe negative reaction to alcohol intake. About 5 to 10 minutes after alcohol intake, the patient may experience the effects of a severe hangover for a period of 30 minutes up to several hours. Symptoms include flushing of the skin, accelerated heart rate, shortness of breath, nausea,  vomiting, throbbing headache, visual disturbance, mental confusion, postural syncope, and circulatory collapse.Disulfiram should not be taken if alcohol has been consumed in the last 12 hours. There is no tolerance to disulfiram: the longer it is taken, the stronger its effects. As disulfiram is absorbed slowly through the digestive tract and eliminated slowly by the body, the effects may last for up to two weeks after the initial intake; consequently, medical ethics dictate that patients must be fully informed about the disulfiram-alcohol reaction.Disulfiram does not reduce alcohol cravings, so a major problem associated with this drug is extremely poor compliance. Methods to improve compliance include subdermal implants, which release the drug continuously over a period of up to 12 weeks, and supervised administration practices, for example, having the drug regularly administered by ones spouse.Although disulfiram remained the most common pharmaceutical treatment of alcohol abuse until the end of the 20th century, today it is often replaced or accompanied with newer drugs, primarily the combination of naltrexone and acamprosate, which directly attempt to address physiological processes in the brain associated with alcohol abuse.

Side effects
The most common side effects in the absence of alcohol are headache, and a metallic or garlic taste in the mouth, though more severe side effects may occur. Tryptophol, a chemical compound that induces sleep in humans, is formed in the liver after disulfiram treatment. Less common side effects include decrease in libido, liver problems, skin rash, and nerve inflammation. Liver toxicity is an uncommon but potentially serious side effect, and risk groups e.g. those with already impaired liver function should be monitored closely. That said, the rate of disulfiram-induced hepatitis are estimated to be in between 1 per 25,000 to 1 in 30,000, and rarely the primary cause for treatment cessation.
Cases of disulfiram neurotoxicity have also occurred, causing extrapyramidal and other symptoms.  Disulfiram can produce neuropathy in daily doses of less than the usually recommended 500 mg. Nerve biopsies showed axonal degeneration and the neuropathy is difficult to distinguish from that associated with ethanol abuse. Disulfiram neuropathy occurs after a variable latent period (mean 5 to 6 months) and progresses steadily. Slow improvement may occur when the drugs use is stopped; often there is complete recovery eventually.Disulfiram disrupts metabolism of several other compounds, including paracetamol (acetaminophen), theophylline and caffeine. However, in most cases, this disruption is mild and presents itself as a 20–40% increase in the half-life of the compound at typical dosages of disulfiram.

Similarly acting substances
In medicine, the term "disulfiram effect" refers to an adverse effect of a particular medication in causing an unpleasant hypersensitivity to alcohol, similar to the effect caused by disulfiram administration.Examples:
Antibiotics (nitroimidazoles), e.g. metronidazole
First-generation sulfonylureas, e.g. tolbutamide and chlorpropamide
Several cephalosporin drugs, including cefoperazone, cefamandole and cefotetan, that have a N-methylthio-tetrazole moiety
Griseofulvin, an oral antifungal drug
Procarbazine
Temposil, or citrated calcium carbimide, has the same function as disulfiram, but is weaker and safer.
Coprine, which metabolizes to 1-aminocyclopropanol, a chemical having the same metabolic effects as disulfiram.  It occurs naturally in the otherwise edible common ink cap mushroom (Coprinopsis atramentaria), hence its colloquial name "tipplers bane". Similar reactions have been recorded with Clitocybe clavipes and Suillellus luridus, although the agent in those species is unknown.

History
The synthesis of disulfiram, originally known as tetraethylthiuram disulfide, was first reported in 1881. By around 1900, it was introduced to the industrial process of sulfur vulcanization of rubber and became widely used.  In 1937 a rubber factory doctor in the US published a paper noting that workers exposed to disulfiram had negative reactions to alcohol and could be used as a drug for alcoholism; the effects were also noticed in workers at Swedish rubber boot factory.In the early 1940s it had been tested as a treatment for scabies, a parasitic skin infection, as well as intestinal worms.Around that time, during the German occupation of Denmark, Erik Jacobsen and Jens Hald at the Danish drug company Medicinalco picked up on that research and began exploring the use of disulfiram to treat intestinal parasites.  The company had a group of enthusiastic self-experimenters that called itself the "Death Battalion", and in the course of testing the drug on themselves, accidentally discovered that drinking alcohol while the drug was still in their bodies  made them mildly sick.: 98–105 They made that discovery in 1945, and did nothing with it until two years later, when Jacobsen gave an impromptu talk and mentioned that work, which was discussed afterwards in newspapers at the time, leading them to further explore the use of the drug for that purpose.: 98–105  That work included small clinical trials with Oluf Martensen-Larsen, a doctor who worked with alcoholics.  They published their work starting in 1948.The chemists at Medicinalco discovered a new form of disulfiram while trying to purify a batch that had been contaminated with copper. This form turned out to have better pharmacological properties, and the company patented it and used that form for the product that was introduced as Antabus (later anglicized to Antabuse).This work led to renewed study of the human metabolism of ethanol.  It was already known that ethanol was mostly metabolized in the liver, with it being converted first to acetaldehyde and then acetaldehyde to acetic acid and carbon dioxide, but the enzymes involved were not known.  By 1950 the work led to the knowledge that ethanol is oxidized to acetaldehyde by alcohol dehydrogenase and acetaldehyde is oxidized to acetic acid by aldehyde dehydrogenase (ALDH), and that disulfiram works by inhibiting ALDH, leading to a buildup of acetaldehyde, which is what causes the negative effects in the body.The drug was first marketed in Denmark and as of 2008, Denmark is the country where it is most widely prescribed. It was approved by the FDA in 1951 </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Ciclopirox and explain in detail? [/INST] Ciclopirox (sometimes known by the abbreviation CPX) is a synthetic antifungal agent for topical dermatologic treatment of superficial mycoses. It is most useful against tinea versicolor. It is sold under many brand names worldwide.

Medical uses
Ciclopirox is indicated for the treatment of tinea pedis and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes and Epidermophyton floccosum, as well as seborrheic dermatitis. It is not to be used in the eyes or vagina, and nursing women should consult their doctors before use, since it is not known whether ciclopirox passes into human milk. A burning sensation may be felt when first applying ciclopirox on the skin.

Nail infections
In addition to other formulations, ciclopirox is used in lacquers for topical treatment of onychomycosis (fungal infections of the nails) </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Hydrocortisone valerate and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Tetrahydrobiopterin and explain in detail? [/INST] Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide synthases. Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (quinonoid dihydrobiopterin).

Medical use
Tetrahydrobiopterin is available as a tablet for oral administration in the form of sapropterin dihydrochloride (BH4*2HCL). It was approved for use in the United States as a tablet in December 2007 and as a powder in December 2013. It was approved for use in the European Union in December 2008, Canada in April 2010, and Japan in July 2008.  It is sold under the brand names Kuvan and Biopten. The typical cost of treating a patient with Kuvan is US$100,000 per year. BioMarin holds the patent for Kuvan until at least 2024, but Par Pharmaceutical has a right to produce a generic version by 2020.Sapropterin is indicated in tetrahydrobiopterin deficiency caused by GTP cyclohydrolase I (GTPCH) deficiency, or 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency. Also, BH4*2HCL is FDA approved for use in phenylketonuria (PKU), along with dietary measures. However, most people with PKU have little or no benefit from BH4*2HCL.

Adverse effects
The most common adverse effects, observed in more than 10% of people, include headache and a running or obstructed nose. Diarrhea and vomiting are also relatively common, seen in at least 1% of people.

Interactions
No interaction studies have been conducted. Because of its mechanism, tetrahydrobiopterin might interact with dihydrofolate reductase inhibitors like methotrexate and trimethoprim, and NO-enhancing drugs like nitroglycerin, molsidomine, minoxidil, and PDE5 inhibitors. Combination of tetrahydrobiopterin with levodopa can lead to increased excitability.

Functions
Tetrahydrobiopterin has multiple roles in human biochemistry. The major one is to convert amino acids such as phenylalanine, tyrosine, and tryptophan to precursors of dopamine and serotonin, major monoamine neurotransmitters. It works as a cofactor, being required for an enzymes activity as a catalyst, mainly hydroxylases.

Cofactor for tryptophan hydroxylases
Tetrahydrobiopterin is a cofactor for tryptophan hydroxylase (TPH) for the conversion of L-tryptophan (TRP) to 5-hydroxytryptophan (5-HTP).

Cofactor for phenylalanine hydroxylase
Phenylalanine hydroxylase (PAH) catalyses the conversion of L-phenylalanine (PHE) to L-tyrosine (TYR). Therefore, a deficiency in tetrahydrobiopterin can cause a toxic buildup of L-phenylalanine, which manifests as the severe neurological issues seen in phenylketonuria.

Cofactor for tyrosine hydroxylase
Tyrosine hydroxylase (TH) catalyses the conversion of L-tyrosine to L-DOPA (DOPA), which is the precursor for dopamine. Dopamine is a vital neurotransmitter, and is the precursor of norepinephrine and epinephrine. Thus, a deficiency of BH4 can lead to systemic deficiencies of dopamine, norepinephrine, and epinephrine. In fact, one of the primary conditions that can result from GTPCH-related BH4 deficiency is dopamine-responsive dystonia; currently, this condition is typically treated with carbidopa/levodopa, which directly restores dopamine levels within the brain.

Cofactor for nitric oxide synthase
Nitric oxide synthase (NOS) catalyses the conversion of a guanidino nitrogen of L-arginine (L-Arg) to nitric oxide (NO). Among other things, nitric oxide is involved in vasodilation, which improves systematic blood flow. The role of BH4 in this enzymatic process is so critical that some research points to a deficiency of BH4 – and thus, of nitric oxide – as being a core cause of the neurovascular dysfunction that is the hallmark of circulation-related diseases such as diabetes.

Cofactor for ether lipid oxidase
Ether lipid oxidase (alkylglycerol monooxygenase, AGMO) catalyses the conversion of 1-alkyl-sn-glycerol to 1-hydroxyalkyl-sn-glycerol.

History
Tetrahydrobiopterin was discovered to play a role as an enzymatic cofactor. The first enzyme found to use tetrahydrobiopterin is phenylalanine hydroxylase (PAH).

Biosynthesis and recycling
Tetrahydrobiopterin is biosynthesized from guanosine triphosphate (GTP) by three chemical reactions mediated by the enzymes GTP cyclohydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), and sepiapterin reductase (SR).BH4 can be oxidized by one or two electron reactions, to generate BH4 or BH3 radical and BH2, respectively. Research shows that ascorbic acid (also known as ascorbate or vitamin C) can reduce BH3 radical into BH4, preventing the BH3 radical from reacting with other free radicals (superoxide and peroxynitrite specifically). Without this recycling process, uncoupling of the endothelial nitric oxide synthase (eNOS) enzyme and reduced bioavailability of the vasodilator nitric oxide occur, creating a form of endothelial dysfunction. Ascorbic acid is oxidized to dehydroascorbic acid during this process, although it can be recycled back to ascorbic acid.
Folic acid and its metabolites seem to be particularly important in the recycling of BH4 and NOS coupling.

Research
Other than PKU studies, tetrahydrobiopterin has participated in clinical trials studying other approaches to solving conditions resultant from a deficiency of tetrahydrobiopterin. These include autism, depression, ADHD, hypertension, endothelial dysfunction, and chronic kidney disease. Experimental studies suggest that tetrahydrobiopterin regulates deficient production of nitric oxide in cardiovascular disease states, and contributes to the response to inflammation and injury, for example in pain due to nerve injury. A 2015 BioMarin-funded study of PKU patients found that those who responded to tetrahydrobiopterin also showed a reduction of ADHD symptoms.

Depression
In psychiatry, tetrahydrobiopterin has been hypothesized to be involved in the pathophysiology of depression, although evidence is inconclusive to date.

Autism
In 1997, a small pilot study was published on the efficacy of tetrahydrobiopterin (BH4) on relieving the symptoms of autism, which concluded that it "might be useful for a subgroup of children with autism" and that double-blind trials are needed, as are trials which measure outcomes over a longer period of time. In 2010, Frye et al. published a paper which concluded that it was safe, and also noted that "several clinical trials have suggested that treatment with BH4 improves ASD symptomatology in some individuals."

Cardiovascular disease
Since nitric oxide production is important in regulation of blood pressure and blood flow, thereby playing a significant role in cardiovascular diseases, tetrahydrobiopterin is a potential therapeutic target. In the endothelial cell lining of blood vessels, endothelial nitric oxide synthase is dependent on tetrahydrobiopterin availability </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Ledipasvir/sofosbuvir and explain in detail? [/INST] Ledipasvir/sofosbuvir, sold under the trade name Harvoni among others, is a medication used to treat hepatitis C. It is a fixed-dose combination of ledipasvir and sofosbuvir. Cure rates are 94% to 99% in people infected with hepatitis C virus (HCV) genotype 1. Some evidence also supports use in HCV genotype 3 and 4. It is taken daily by mouth for 8–24 weeks.It is generally well tolerated. Common side effects include muscle pains, headache, nausea, rash, and cough. It is unclear if use in pregnancy is safe for the baby. Ledipasvir works by decreasing the activity of NS5A and sofosbuvir works by decreasing the activity of NS5B polymerase.Ledipasvir/sofosbuvir was approved for medical use in the United States, in the European Union, and in Canada in 2014. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Cure rates are 94% to 99% in people infected with genotype 1 (46% of HCV cases). It has also been evaluated for the treatment of infection with other hepatitis C genotypes, and has shown promising results in genotypes 3 and 4 (making up 30% and less than 22% of HCV cases respectively).

Resistance
NS5A mutations
Multiple mutations of HCV replicons are necessary to cause a significant effect in resistance due to multiple mechanisms of action. In general, HCV genotype 1a is less resistant to mutation than genotype 1b.For genotype 1b a single amino acid substitution (e.g. L31V) in the replicon had less than a 100 fold increase in resistance to the ledipasvir in Harvoni, while a two amino acid substitution had over a 1000 fold increase in resistance. Genotype 1a had a similar but more substantial increase in resistance with each respective increase in amino acid substitution with resistance associated substitutions at K24R, M28T/V, Q30R/H/K/L, L31M, and or Y93H/N.NS5A polymorphisms also have an effect on viral resistance with the most common resistance-associated amino acid substitutions detected at Q30R, Y93H or N, and L31M in patients with a rapid virological response (RVR). The specific baseline NS5A resistance-associated polymorphisms observed in clinical trials were M28T/V, Q30H, Q30R, L31M, H58P, Y93H, and Y93N in genotype 1a and L28M, A92T, and Y93H in genotype 1b. Patients with multiple baseline NS5A polymorphisms tend to have higher relapse rates when using ledipasvir/sofosbuvir. The difference in relapse rates between treatment naive and treatment experience groups with baseline NS5A polymorphisms ranges from 1% after a 12-week regimen and 0% after a 24-week regimen respectively.

NS5B mutations
A single amino acid substitution S282T contributes to viral resistance and decreases the activity of sofosbuvir in ledipasvir/sofosbuvir by approximately 2 to 18 fold.

Cross resistance
No cross resistance was seen in the combination of ledipasvir and sofosbuvir in ION phase 1,2 and, 3 clinical trials as ledipasvir was fully active against sofosbuvir-resistance-associated substitutions and vice versa.

Side effects
More than 10% of people taking ledipasvir/sofosbuvir have headaches or fatigue; rashes, nausea, diarrhea, and insomnia occur in between 1% and 10% of people taking it.More severe reactions are connected with allergic reactions to the medications and cardiovascular problems. Harvoni side effects are considered relatively mild compared to older interferon-based treatment.
Ledipasvir/sofosbuvir could cause hepatitis B re-activation in people co-infected with hepatitis B and C viruses. The European Medicines Agency recommended screening all people for hepatitis B before starting ledipasvir/sofosbuvir for hepatitis C in order to minimize the risk of hepatitis B reactivation.

Drug interactions
Ledipasvir/sofosbuvir is a substrate for the drug transporters P-Glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Intestinal absorption of these drug transporter substrates may be decreased by inducers such as rifampin and St </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pyrantel and explain in detail? [/INST] Pyrantel is a medication used to treat a number of parasitic worm infections. This includes ascariasis, hookworm infections, enterobiasis (pinworm infection), trichostrongyliasis, and trichinellosis. It is taken by mouth.Side effects include nausea, headache, dizziness, trouble sleeping, and rash. A lower dose should be used in people with liver disease. While it does not appear to be harmful during pregnancy, it has not been studied for this use. It is unclear if it is safe for use during breastfeeding. It is in the antihelmintic family of medications. It works by paralyzing worms.Pyrantel was initially described in 1965. It is on the World Health Organizations List of Essential Medicines. Pyrantel is available as a generic medication. It costs less than US$25 per course of treatment in the United States </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Codeine/paracetamol and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Foscarnet and explain in detail? [/INST] Foscarnet (phosphonomethanoic acid), known by its brand name Foscavir, is an antiviral medication which is primarily used to treat viral infections involving the Herpesviridae family. It is classified as a pyrophosphate analog DNA polymerase inhibitor. Foscarnet is the conjugate base of a chemical compound with the formula HO2CPO3H2 (Trisodium phosphonoformate).Foscarnet was approved for medical use in 1991.

Medical use
This phosphonic acid derivative (marketed by Clinigen as foscarnet sodium under the trade name Foscavir) is an antiviral medication used to treat herpes viruses, including drug-resistant cytomegalovirus (CMV) and herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2). It is particularly used to treat CMV retinitis. Foscarnet can be used to treat highly treatment-experienced patients with HIV as part of salvage therapy.

Mechanism of action
Foscarnet is a structural mimic of the anion pyrophosphate that selectively inhibits the pyrophosphate binding site on viral DNA polymerases at concentrations that do not affect human DNA polymerases.In individuals treated with the DNA polymerase inhibitors acyclovir or ganciclovir, HSV or CMV particles can develop mutant protein kinases (thymidine kinase or UL97 protein kinase, respectively) that make them resistant to these antiviral drugs. However, unlike acyclovir and ganciclovir, foscarnet is not activated by viral protein kinases, making it useful in acyclovir- or ganciclovir-resistant HSV and CMV infections.However, acyclovir- or ganciclovir-resistant mutants with alterations in viral DNA polymerase may also be resistant to foscarnet.

Administration
Foscarnet is administered by intravenous infusion or intravitreous injection.

Side effects
Nephrotoxicity — increase in serum creatinine levels and renal injury can occur in patients receiving foscarnet. Other nephrotoxic drugs should be avoided. Nephrotoxicity is usually reversible and can be reduced by dosage adjustment and adequate hydration.
Electrolyte disturbances — hypocalcemia and hypomagnesemia can occur and regular monitoring of electrolytes is necessary to avoid clinical toxicity.
Genital ulceration — a less common reported side effect which occurs more in men and usually during induction use of foscarnet. It is most likely a contact dermatitis due to high concentrations of foscarnet in urine </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is My Way and explain in detail? [/INST] "My Way" is a song popularized in 1969 by Frank Sinatra set to the music of the French song "Comme dhabitude" composed by Jacques Revaux with lyrics by Gilles Thibaut and Claude François and first performed in 1967 by Claude François. Its English lyrics were written by Paul Anka and are unrelated to the original French song.
The song was a success for a variety of performers including Sinatra, Elvis Presley, and Sid Vicious. Sinatras version of "My Way" spent 75 weeks in the UK Top 40, which is 2nd place all-time.

Background
In 1967, Jacques Revaux wrote a ballad named "For Me", with English lyrics about a couple falling out of love. According to Revaux, the demo was then sent to Petula Clark, Dalida, and Claude François, to no avail. Revaux rejected a version by Hervé Villard and reworked the track into Comme dhabitude ("As usual") with the help of Claude François. It was released in November 1967 and was at the top of the French pop chart for one week in February 1968.Paul Anka heard the French original, while on holiday in the south of France. He flew to Paris to negotiate the rights to the song. He acquired adaptation, recording, and publishing rights for the nominal but formal consideration of one dollar, subject to the provision that the melodys composers would retain their original share of royalty rights with respect to whatever versions Anka or his designates created or produced.  Some time later, Anka had a dinner in Florida with Frank Sinatra and "a couple of Mob guys" during which Sinatra said: "Im quitting the business. Im sick of it; Im getting the hell out."
Back in New York, Anka re-wrote the original French song for Sinatra, subtly altering the melodic structure and changing the lyrics: At one oclock in the morning, I sat down at an old IBM electric typewriter and said, If Frank were writing this, what would he say? And I started, metaphorically, And now the end is near. I read a lot of periodicals, and I noticed everything was my this and my that. We were in the me generation and Frank became the guy for me to use to say that. I used words I would never use: I ate it up and spit it out. But thats the way he talked. I used to be around steam rooms with the Rat Pack guys—they liked to talk like Mob guys, even though they would have been scared of their own shadows. Anka finished the song at 5 in the morning: "I called Frank up in Nevada—he was at Caesars Palace – and said, Ive got something really special for you." Anka asserted: "When my record company caught wind of it, they were very pissed that I didnt keep it for myself. I said, Hey, I can write it, but Im not the guy to sing it. It was for Frank, no one else."Despite this, Anka would record the song in 1969 very shortly after Sinatras recording was released. Anka recorded it four other times as well: in 1996 (as a duet with Gabriel Byrne, performed in the movie Mad Dog Time); in 1998 in Spanish as "A Mi Manera" (duet with Julio Iglesias); in 2007 (as a duet with Jon Bon Jovi); and in 2013 (as a duet with Garou).On December 30, 1968, Frank Sinatra recorded his version of the song in one take, featuring session drummer Buddy Saltzman among the band.
“My Way” was released in early 1969 on the My Way LP and as a single. It reached No. 27 on the Billboard Hot 100 chart and No. 2 on the Easy Listening chart in the US. In the UK, the single achieved a still unmatched record, becoming the recording with the most weeks inside the Top 40, spending 75 weeks from April 1969 to September 1971. It spent a further 49 weeks in the Top 75 but never bettered the No. 5 slot achieved upon its first chart run.Although this work became Frank Sinatras signature song, his daughter Tina says the singer came to hate the song: "He didnt like it. That song stuck and he couldnt get it off his shoe. He always thought that song was self-serving and self-indulgent."

Charts
Certifications
Versions
David Bowie reportedly wrote the first English language lyrics to Claude Françoiss original tune, though the lyrics and performance were only informally recorded and never commercially published.

Dorothy Squires
In the midst of Sinatras multiple runs on the UK Singles Chart, Welsh singer Dorothy Squires also released a rendition of "My Way" in Summer 1970. Her recording reached number 25 on the UK Singles Chart and re-entered the chart twice more during that year.

Elvis Presley
Elvis Presley began performing the song in concert during the mid-1970s, despite Ankas suggestions that the song did not suit him. Nevertheless, on January 12 and 14, 1973, Presley sang the song during his satellite show Aloha from Hawaii Via Satellite, beamed live and on deferred basis (for European audiences, who also saw it in prime time), to 43 countries via Intelsat.
On October 3, 1977, several weeks after Presleys death, his live recording of "My Way" (recorded for the Elvis In Concert CBS-TV special on June 21, 1977) was released as a single. In the U.S., it reached number 22 on the Billboard Hot 100 pop singles chart in late 1977/early 1978 (higher than Frank Sinatras peak position), number 6 on the Billboard Adult Contemporary chart, and went gold for its successful sales of over a million copies. The following year the single reached number 2 on the Billboard Country singles chart but went all the way to number 1 on the rival Cash Box Country Singles chart. In the UK, it reached number 9 on the UK Singles Chart.
Presleys version is featured in the climax of the 2001 film 3000 Miles to Graceland with Kurt Russell and Kevin Costner. (Paul Anka appears in a cameo as a casino pit boss who loathes Presley.)
Presleys studio version of the song, recorded in 1971, was included on the fourth disc of "Walk a Mile in My Shoes: The Essential 70s Masters".

Certifications
Sid Vicious
Sex Pistols bassist Sid Vicious did a punk rock version of the song, in which a large body of the words were changed and the arrangement was sped up. The orchestral backing was arranged by Simon Jeffes.
Interviewed in 2007, Paul Anka said he had been "somewhat destabilized by the Sex Pistols version. It was kind of curious, but I felt he [Sid Vicious] was sincere about it."Vicious and his girlfriend, Nancy Spungen, changed many of the words when it was recorded, including use of the swear words "cunt" and "fuck" as well as the word "queer" (slang for a gay man). Viciouss reference to a "prat who wears hats" was an in-joke directed towards Viciouss friend and Sex Pistols bandmate Johnny Rotten, who was fond of wearing different kinds of hats he would pick up at rummage sales.
Leonard Cohen said of the song: I never liked this song except when Sid Vicious did it. Sung straight, it somehow deprives the appetite of a certain taste we’d like to have on our lips. When Sid Vicious did it, he provided that other side to the song; the certainty, the self-congratulation, the daily heroism of Sinatra’s version is completely exploded by this desperate, mad, humorous voice. I can’t go round in a raincoat and fedora looking over my life saying I did it my way — well, for 10 minutes in some American bar over a gin and tonic you might be able to get away with it. But Sid Vicious’s rendition takes in everybody; everybody is messed up like that, everybody is the mad hero of his own drama </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Rabeprazole and explain in detail? [/INST] Rabeprazole, sold under the brand name Aciphex, among others, is a medication that decreases stomach acid. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and excess stomach acid production such as in Zollinger–Ellison syndrome. It may also be used in combination with other medications to treat Helicobacter pylori. Effectiveness is similar to other proton pump inhibitors (PPIs). It is taken by mouth.Common side effects include constipation, feeling weak, and throat inflammation. Serious side effects may include osteoporosis, low blood magnesium, Clostridium difficile infection, and pneumonia. Use in pregnancy and breastfeeding is of unclear safety. It works by blocking H+/K+-ATPase in the parietal cells of the stomach.Rabeprazole was patented in 1986, and approved for medical use in 1997. It is available as a generic medication. In 2017, it was the 279th most commonly prescribed medication in the United States, with more than one million prescriptions.

Medical uses
Rabeprazole, like other proton pump inhibitors such as omeprazole, is used for the purposes of gastric acid suppression. This effect is beneficial for the treatment and prevention of conditions in which gastric acid directly worsens symptoms, such as duodenal and gastric ulcers. In the setting of gastroesophageal reflux disease (GERD), whose pathophysiology is characterized by prolonged exposure to gastric acid in the esophagus (often due to changes in stomach and/or esophagus anatomy, such as those induced by abdominal obesity), acid suppression can provide symptomatic relief. Acid suppression is also useful when gastric production of acid is increased, including conditions with excess gastric acid secretion (hypersecretory conditions) like Zollinger-Ellison syndrome, multiple endocrine adenomas, and systemic mastocytosis.Rabeprazole is also useful alongside antibiotic therapy for the treatment of the pathogen Helicobacter pylori, which otherwise thrives in acidic environments. Notably, H. pylori eradication with antibiotics and rabeprazole was also shown to prevent development of second gastric cancer in a randomized trial in high-risk South Korean patients with early stomach cancer treated by endoscopy.Thus, rabeprazole is US Food and Drug Administration (FDA) approved for the treatment of symptomatic GERD in adolescents and adults, healing duodenal ulcers in adults, eradication of Helicobacter pylori, and pathologic hypersecretory conditions.

Available forms
Rabeprazole is available in 10 and 20 mg, delayed-release tablets (pictured below). Rabeprazole-based products, like other proton pump inhibitor products, have to be formulated in delayed-release tablets to protect the active medication from being degraded by the acid of the stomach before being absorbed.

Specific populations
Pediatrics
Rabeprazoles only pediatric indication is for the treatment of symptomatic GERD in adolescents (12 years-old and up).

Pregnancy
Studies using animals models to investigate the likelihood for rabeprazole to cause harm to fetuses have not yet shown evidence of harm, though avoidance of rabeprazole during pregnancy (especially during the critical development period of the first trimester) is considered to be the safest possible route until human studies clarify the exact risk.

Lactation
It is expected that rabeprazole will be secreted into human breast milk, though the clinical impact of this is still unknown. Avoiding rabeprazole during breastfeeding confers to lowest possible risk.

Geriatrics
Advanced age does not appear to clinically impact rabeprazoles metabolism. However, elevations in the maximum plasma concentration and the total drug exposure (area under the curve, AUC) have occurred.

Japanese ancestry
In a study on rabeprazoles pharmacokinetics, the AUC was elevated by approximately 50–60% in men of Japanese ancestry compared to men in the United States. See the pharmacogenetics section below for a pharmacogenetic explanation of these findings.

Kidney or liver problems
In people that have kidney or liver problems, these problems do not appear to affect rabeprazoles metabolism in a clinically meaningful way. This includes individuals on dialysis for kidney problems. Severe liver problems like cirrhosis of the liver do affect rabeprazoles elimination half-life, but not to a degree of dangerous accumulation. In a review of patients taking rabeprazole while having end-stage kidney disease and mild-to-moderate severity, chronic compensated cirrhosis of the liver, the alteration in rabeprazoles metabolism was not clinically meaningful.

Contraindications
Rabeprazole is contraindicated in the following populations and situations:
people with a known hypersensitivity to rabeprazole, substituted benzimidazoles (which are chemically similar to rabeprazole, like omeprazole), or any other component of the capsule formulation (e.g. certain dyes)
concurrent use of rilpivirine, a medication used to treat HIV infection

Hypersensitivity
Syndrome
An allergy to a PPI like rabeprazole may take the form of type I hypersensitivity or delayed hypersensitivity reactions. A selective (pattern C—see below for a discussion of cross-reactivity patterns) type I hypersensitivity reaction to rabeprazole resulting in anaphylaxis has been reported, as well as several whole group hypersentivities.

Cross-reactivity
Hypersensitivity to PPIs can take the form of whole group hypersensitivity, pattern A, B, or C. Whole group hypersentivity occurs when a person is cross-reactive to all PPIs; that is, all PPIs will induce the allergy. In pattern A, a person may be allergic to omeprazole, esomeprazole, and pantoprazole, but not to lansoprazole and rabeprazole. This is thought to be due to the structural similarities between omeprazole, esomeprazole, and pantoprazole, contrasted with lansoprazole and rabeprazole. Pattern B is the opposite, reflecting people that are allergic to lansoprazole and rabeprazole, but not to omeprazole, esomeprazole, and pantoprazole. Pattern C, in the context of rabeprazole, would reflect a person that is allergic to only rabeprazole, but not to other PPIs (omeprazole, esomeprazole, pantoprazole, and lansoprazole).

Rilpivirine
Rilpivirine, a non-nucleoside reverse transcriptase inhibitor used in the treatment of HIV, is contraindicated with all PPIs because of their acid-suppressing effect. PPIs suppress acid, thereby raising the pH of (alkalizing) the stomachs contents. Rilpivirine is best absorbed under acidic conditions. Therefore, rabeprazole would be expected to decrease the absorption of rilpivirine, decrease the concentration of rilpivirine in the blood, and possibly lead to therapeutic failure and resistance to the medication/class.

Adverse effects
In general, rabeprazole is fairly well tolerated, even up to five years after clinical trial follow-up. The side effect profile is similar to that of omeprazole. The most common side effects include headache, nausea, and diarrhea. Rare side effects include rashes, flu-like symptoms, and infections (including by the gastrointestinal pathogen Clostridium difficile). Rare instances of rabeprazole-induced liver injury (also known as hepatotoxicity) have been reported. Characteristic proton-pump inhibitor hepatoxicity usually occurs within the first four weeks of starting the medication.Rabeprazole is associated with elevated serum gastrin levels, which are thought to be dependent upon the degree of CYP2C19 metabolism the drug undergoes. In comparison, rabeprazole is not as significantly metabolized by this enzyme compared to other medications in the same class, like omeprazole. Elevated serum gastrin may be associated with gastric cancer.Acid suppression via rabeprazole can decrease the absorption of vitamin B12 and magnesium, leading to deficiency.Very serious side effects have been reported in people taking rabeprazole, but these effects have not been "correlated directly" with the use of rabeprazole. These include Stevens–Johnson syndrome, serious hematological abnormalities, coma, and death. Other possible side effects, common to other PPIs medications in the same class, include bone fractures due to osteoporosis and serious infections with Clostridium difficile.

Overdose
No signs and symptoms have been reported in overdoses of rabeprazole up to 80 mg, but case examples are limited. Notably, rabeprazole has been used in higher doses for the treatment of hypersecretory conditions like Zollinger-Ellison syndrome (up to 120 mg daily).Animal experiments with ultra-high doses of rabeprazole have demonstrated lethality through unknown mechanisms. The lethal overdose syndrome in animals is characterized by convulsion and coma.

Interactions
Drug-drug interactions
Rabeprazole does not interfere with the plasma concentration of drugs that are also metabolized by the same enzymes (i.e. CYP2C19) that it is metabolized by. Therefore, it is not expected to react with CYP2C19 substrates like theophylline, warfarin, diazepam, and phenytoin.  However, the acid-suppression effects of rabeprazole, like other PPIs, may interfere with the absorption of drugs that require acid, such as ketoconazole and digoxin.There is some evidence that omeprazole and esomeprazole, two medications in the same class as rabeprazole, can disturb the conversion of an anticoagulant medication called clopidogrel to its active metabolite. However, because this is thought to be mediated by the effect of omeprazole and esomeprazole on CYP2C19, the enzyme that activates clopidogrel, this drug interaction is not expected to occur as strongly with rabeprazole. However, whether the effect of omeprazole and esomeprazole on clopidogrels metabolism actually leads to poor clinical outcomes is still a matter of intense debate among healthcare professionals.Clinically serious drug-drug interactions may involve the acid-suppression effects of rabeprazole. For example, rabeprazole should not be used concomitantly with rilpivirine, an anti-HIV therapy, which requires acid for absorption. Lowered plasma concentrations of rilpivirine could lead to progression of HIV infection. Other drugs that require acid for absorption include antifungal drugs like ketoconazole and itraconazole, digoxin, iron, mycophenolate, and tyrosine kinase inhibitors like erlotinib, dasatinib, and nilotinib. There is no clinically relevant drug interaction between rabeprazole and antacids.

Food-drug interactions
Food does not affect the amount of rabeprazole that enters the body, but it does delay its onset of effect by about 1.7 hours.

Pharmacology
Mechanism of action
Rabeprazoles mechanism of action first involves getting absorbed into the parietal cells of the stomach, which are the cells that are responsible for secreting hydrochloric acid (HCl). At this point, rabeprazole is inactive. However, rabeprazole is then secreted into the secretory canaliculus of the parietal cells, which is the space from which acid secretion occurs. Here, acid secretion is mediated by the energy-dependent acid pumps, called hydrogen potassium adenosine triphosphatase (H+/K+ ATPase) pumps. These enzymatic pumps have cysteine amino acid residues. After being activated by gastric (stomach) acid to a reactive sulfenamide intermediate, rabeprazole permanently binds the cysteine residues, forming covalent, disulfide bonds. This action fundamentally alters the configuration of the acid pump, thereby inhibiting its activity. Thus, acid can no longer be secreted into the gastric lumen (the empty space of the stomach), and the pH of the stomach increases (decrease in the concentration of hydrogen ions, H+). Due to the permanent inhibition of the individual proton pump that each molecule of rabeprazole has bound to, acid secretion is effectively suppressed until new proton pumps are produced by the parietal cells.Rabeprazole, like other medications in the same class, cannot inhibit the H+/K+ ATPase pumps found in lysosomes, a cellular organelle that degrades biological molecules, because the pumps found in these organelles lack the cysteine residues involved in rabeprazoles mechanism of action.A unique feature of rabeprazoles mechanism of action in inhibiting acid secretion involves its activation. The pKa (the pH at which 50% of the drug becomes positively charged) of rabeprazole is around 5.0, meaning that it doesnt take a lot of acid to activate it. While this theoretically translates into a faster onset of action for rabeprazoles acid-inhibiting effect, the clinical implications of this fact have yet to be elucidated.

Pharmacokinetics
Rabeprazoles bioavailability is approximately 52%, meaning that 52% of orally administered dose is expected to enter systemic circulation (the bloodstream). Once in the blood, rabeprazole is approximately 96.3%-97% bound to plasma proteins. The biological half-life of rabeprazole in humans is approximately one hour. It takes about 3.5 hours for rabeprazole to reach the maximum concentration in human plasma after a single orally administered dose. Oral absorption is independent of the dose administered.Rabeprazole is extensively metabolized by the liver. 90% of the drug is rendered into metabolites by the liver, which are then excreted by the kidneys. 10% of the dose is excreted in the feces. The drug metabolizing enzymes primarily responsible for rabeprazoles metabolism are CYP2C19 and CYP3A4. However, rabeprazole is mainly metabolized through non-enzymatic reduction to a thioether metabolite. Some of rabeprazoles metabolites include the following: a thioether carboxylic acid metabolite, a thioether glucuronide metabolite, and a sulfone metabolite. The most common metabolites excreted in the urine are the mercapturic acid conjugate and carboxylic acid. A diagram of rabeprazoles phase I metabolism is shown below.

Pharmacogenetics
The effect of rabeprazole may vary based upon the genetics of the individual taking the medication. People may have differences in their capacity to metabolize rabeprazole to an inactive metabolite. This may be mediated through genetic differences in the gene that encodes for the metabolic enzyme CYP2C19. For example, people that are poor CYP2C19 metabolizers (i.e. their version of CYP2C19 is less effective than average) will have trouble metabolizing rabeprazole, allowing the active rabeprazole to stay in the body, where it can exert its effect, longer than intended. Conversely, extensive CYP2C19 metabolizers (i.e. the average metabolic capacity of CYP2C19) will extensively metabolize rabeprazole, as expected. The poor metabolizing CYP2C19 phenotype is found in roughly 3–5% of Caucasian people, and in 17–20% of people of Asian ancestry. In a study on men of Japanese ancestry, this has translated to an average increase of total drug exposure by 50–60% compared to men in the United States.However, rabeprazoles metabolism is primarily non-enzymatic (it is often inactivated chemically, without the participation of the bodys natural drug metabolizing enzymes). Therefore, while a persons CYP2C19 phenotype will affect rabeprazoles metabolism, it is not expected to dramatically affect the efficacy of the medication.

Chemistry
Rabeprazole is classified as a substituted benzimidazole, like omeprazole, lansoprazole, and pantoprazole. Rabeprazole possess properties of both acids and bases, making it an amphotere. The acid dissociation constant (pKa) of the pyridine nitrogen is about equal to 5.

Synthesis
The above synthesis pathway begins with 2,3-dimethypyridine N-oxide (1). Nitration of 2,3-dimethylpyridine N-oxide affords the nitro derivative (the addition of NO2) (2) The newly introduced nitro group is then displaced by the alkoxide from 3-methoxypropanol to yield the corresponding ether (3). Treatment with acetic anhydride results in the Polonovski reaction. Saponification followed by treatment with thionyl chloride then chlorinates the primary alcohol (5). Reaction with benzimidazole-2-thiol (6) followed by oxidation of the resulting thioether to the sulfoxide yields the final product: rabeprazole (8).

Physiochemical properties
Rabeprazole is characterized as a white to yellowish-white solid in its pure form. It is soluble in a number of solvents. Rabeprazole is very soluble in water and methanol, freely soluble in ethanol, chloroform, and ethyl acetate, and is insoluble in ether and n-hexane. It is unstable under humid conditions.

History
Rabeprazole was first marketed in Europe in 1998. In 1999, one year later, rabeprazole was approved for use in the United States.

Development
Developed by Eisai Medical Research by the research names E3810 and LY307640, the pre-investigational new drug application was submitted on October 28, 1998. The final investigational new drug application was submitted August 6, 1999 </s>