<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 Furosemide and explain in detail? [/INST] Furosemide is a loop diuretic medication used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It may also be used for the treatment of high blood pressure. It can be taken by injection into a vein or by mouth. When taken by mouth, it typically begins working within an hour, while intravenously, it typically begins working within five minutes.Common side effects include feeling lightheaded with standing, ringing in the ears, and sensitivity to light. Potentially serious side effects include electrolyte abnormalities, low blood pressure, and hearing loss. Blood tests are recommended regularly for those on treatment. Furosemide is a type of loop diuretic that works by decreasing the reabsorption of sodium by the kidneys. Common side effects of furosemide injection include hypokalemia (low potassium level), hypotension (low blood pressure), and dizziness.Furosemide was patented in 1959 and approved for medical use in 1964. It is on the World Health Organizations List of Essential Medicines. In the United States, it is available as a generic medication. In 2020, it was the nineteenth most commonly prescribed medication in the United States, with more than 26 million prescriptions. In 2020/21 it was the twentieth most prescribed medication in England. It is on the World Anti-Doping Agencys banned drug list due to concerns that it may mask other drugs. It has also been used in race horses for the treatment and prevention of exercise-induced pulmonary hemorrhage.

Medical uses
Furosemide is primarily used  for the treatment of edema, but also in some cases of hypertension (where there is also kidney or heart impairment). It is often viewed as a first-line agent in most people with edema caused by congestive heart failure because of its anti-vasoconstrictor and diuretic effects. Compared with furosemide, however, torasemide (aka "torsemide") has been demonstrated to show improvements to heart failure symptoms, possibly lowering the rates of rehospitalisation associated with heart failure, with no difference in risk of death.  Torsemide may also be safer than furosemide.Furosemide is also used for liver cirrhosis, kidney impairment, nephrotic syndrome, in adjunct therapy for swelling of the brain or lungs where rapid diuresis is required (IV injection), and in the management of severe hypercalcemia in combination with adequate rehydration.

Kidney disease
In chronic kidney diseases with hypoalbuminemia, furosemide is used along with albumin to increase diuresis. It is also used along with albumin in nephrotic syndrome to reduce edema.

Other information
Furosemide is mainly excreted by tubular secretion in the kidney. In kidney impairment, clearance is reduced, increasing the risk of adverse effects.  Lower initial doses are recommended in older patients (to minimize side-effects) and high doses may be needed in kidney failure. It can also cause kidney damage; this is mainly by loss of excessive fluid (i.e., dehydration), and is usually reversible.Furosemide acts within 1 hour of oral administration (after IV injection, the peak effect is within 30 minutes). Diuresis is usually complete within 6–8 hours of oral administration, but there is significant variation between individuals.

Adverse effects
Furosemide also can lead to gout caused by hyperuricemia. Hyperglycemia is also a common side effect.
The tendency, as for all loop diuretics, to cause low serum potassium concentration (hypokalemia) has given rise to combination products, either with potassium or with the potassium-sparing diuretic amiloride (Co-amilofruse). Other electrolyte abnormalities that can result from furosemide use include hyponatremia, hypochloremia, hypomagnesemia, and hypocalcemia.In the treatment of heart failure, many studies have shown that the long-term use of furosemide can cause varying degrees of thiamine deficiency, so thiamine supplementation is also suggested.Furosemide is a known ototoxic agent generally causing transient hearing loss but can be permanent. Reported cases of furosemide induced hearing loss appeared to be associated with rapid intravenous administration, high dosages, concomitant renal disease and coadministration with other ototoxic medication. However, a recently reported longitudinal study showed that participants treated with loop diuretics over 10 years were 40% more likely to develop hearing loss and 33% more likely of progressive hearing loss compared to participants who did not use loop diuretics. This suggests the long-term consequences of loop diuretics on hearing could be a more significant than previously thought and further research is required in this area.
Other precautions include: nephrotoxicity, sulfonamide (sulfa) allergy, and increases free thyroid hormone effects with large doses.

Interactions
Furosemide has potential interactions with these medications:
Aspirin and other salicylates
Other diuretics (e.g. ethacrynic acid, hydrochlorothiazide)
Synergistic effects with other antihypertensives (e.g. doxazosin)
SucralfatePotentially hazardous interactions with other drugs:

Analgesics: increased risk of kidney damage (nephrotoxicity) with nonsteroidal anti-inflammatory drugs; antagonism of diuretic effect with NSAIDs
Antiarrhythmics: a risk of cardiac toxicity exists with antiarrhythmics if hypokalemia occurs; the effects of lidocaine and mexiletine are antagonized.
Antibacterials: increased risk of ototoxicity with aminoglycosides, polymyxins and vancomycin; avoid concomitant use with lymecycline
Antidepressants: increased risk of hypokalemia with reboxetine; enhanced hypotensive effect with MAOIs; increased risk of postural hypotension with tricyclic antidepressants
Antiepileptics: increased risk of hyponatremia with carbamazepine
Antifungals: increased risk of hypokalemia with amphotericin
Antihypertensives: enhanced hypotensive effect; increased risk of first dose hypotensive effect with alpha-blockers; increased risk of ventricular arrhythmias with sotalol if hypokalemia occurs
Antipsychotics: increased risk of ventricular arrhythmias with amisulpride, sertindole, or pimozide (avoid with pimozide) if hypokalemia occurs; enhanced hypotensive effect with phenothiazines
Atomoxetine: hypokalemia increases risk of ventricular arrhythmias
Cardiac glycosides: increased toxicity if hypokalemia occurs
Cyclosporine: variable reports of increased nephrotoxicity, ototoxicity and hepatotoxicity
Lithium: risk of toxicity.

Mechanism of action
Furosemide, like other loop diuretics, acts by inhibiting the luminal Na-K-Cl cotransporter in the thick ascending limb of the loop of Henle, by binding to the chloride transport channel, thus causing more sodium, chloride, and potassium to remain in the urine.The action on the distal tubules is independent of any inhibitory effect on carbonic anhydrase or aldosterone; it also abolishes the corticomedullary osmotic gradient and blocks negative, as well as positive, free water clearance. Because of the large NaCl absorptive capacity of the loop of Henle, diuresis is not limited by development of acidosis, as it is with the carbonic anhydrase inhibitors.
Additionally, furosemide is a noncompetitive subtype-specific blocker of GABA-A receptors. Furosemide has been reported to reversibly antagonize GABA-evoked currents of α6β2γ2 receptors at μM concentrations, but not α1β2γ2 receptors. During development, the α6β2γ2 receptor increases in expression in cerebellar granule neurons, corresponding to increased sensitivity to furosemide.

Pharmacokinetics
Molecular weight (daltons)             330.7
% Bioavailability    47-70%
Bioavailability with end-stage renal disease   43 - 46%
% Protein binding                      91–99
Volume of distribution (L/kg)          0.07 – 0.2Volume of distribution may be higher in patients with cirrhosis or nephrotic syndrome
Excretion
% Excreted in urine (% of total dose)   60 - 90
% Excreted unchanged in urine (% of total dose)         53.1 - 58.8
% Excreted in feces (% of total dose) 7 - 9
% Excreted in bile (% of total dose) 6 - 9
Approximately 10% is metabolized by the liver in healthy individuals, but this percentage may be greater in individuals with severe kidney failure
Renal clearance (mL/min/kg)  2.0
Elimination half-life (hrs)   2Prolonged in congestive heart failure (mean 3.4 hrs)
Prolonged in severe kidney failure (4 - 6 hrs) and anephric patients (1.5-9 hrs)
Time to peak concentration (hrs)
Intravenous administration    0.3
Oral solution    0.83
Oral tablet     1.45The pharmacokinetics of furosemide are apparently not significantly altered by food.No direct relationship has been found between furosemide concentration in the plasma and furosemide efficacy. Efficacy depends upon the concentration of furosemide in urine.

Names
Furosemide is the INN and BAN. The previous BAN was frusemide.
Brand names under which furosemide is marketed include: Aisemide, Apo-Furosemide, Beronald, Desdemin, Discoid, Diural, Diurapid, Dryptal, Durafurid, Edemid, Errolon, Eutensin, Flusapex, Frudix, Frusemide, Frusetic, Frusid, Fulsix, Fuluvamide, Furesis, Furix, Furo-Puren, Furon, Furosedon, Fusid.frusone, Hydro-rapid, Impugan, Katlex, Lasilix, Lasix, Lodix, Lowpston, Macasirool, Mirfat, Nicorol, Odemase, Oedemex, Profemin, Rosemide, Rusyde, Salix, Seguril, Teva-Furosemide, Trofurit, Uremide, and Urex.

Veterinary uses
The diuretic effects are put to use most commonly in horses to prevent bleeding during a race. Sometime in the early 1970s, furosemides ability to prevent, or at least greatly reduce, the incidence of bleeding (exercise-induced pulmonary hemorrhage) by horses during races was discovered accidentally.  In the United States of America, pursuant to the racing rules of most states, horses that bleed from the nostrils three times are permanently barred from racing. Clinical trials followed, and by decades end, racing commissions in some states in the USA began legalizing its use on race horses.  In 1995, New York became the last state in the United States to approve such use, after years of refusing to consider doing so. Some states allow its use for all racehorses; some allow it only for confirmed "bleeders".  Its use for this purpose is still prohibited in many other countries.
Furosemide is also used in horses for pulmonary edema, congestive heart failure (in combination with other drugs), and allergic reactions.  Although it increases circulation to the kidneys, it does not help kidney function, and is not recommended for kidney disease.It is also used to treat congestive heart failure (pulmonary edema, pleural effusion, and/or ascites) in cats and dogs. It can also be used in an attempt to promote urine production in anuric or oliguric acute kidney failure.

Horses
Furosemide is injected either intramuscularly or intravenously, usually 0.5-1.0 mg/kg twice/day, although less before a horse is raced. As with many diuretics, it can cause dehydration and electrolyte imbalance, including loss of potassium, calcium, sodium, and magnesium. Excessive use of furosemide will most likely lead to a metabolic alkalosis due to hypochloremia and hypokalemia. The drug should, therefore, not be used in horses that are dehydrated or experiencing kidney failure. It should be used with caution in horses with liver problems or electrolyte abnormalities. Overdose may lead to dehydration, change in drinking patterns and urination, seizures, gastrointestinal problems, kidney damage, lethargy, collapse, and coma.
Furosemide should be used with caution when combined with corticosteroids (as this increases the risk of electrolyte imbalance), aminoglycoside antibiotics (increases risk of kidney or ear damage), and trimethoprim sulfa (causes decreased platelet count). It may also cause interactions with anesthetics, so its use should be related to the veterinarian if the animal is going into surgery, and it decreases the kidneys ability to excrete aspirin, so dosages will need to be adjusted if combined with that drug.
Furosemide may increase the risk of digoxin toxicity due to hypokalemia.
The drug is best not used during pregnancy or in a lactating mare, as it has been shown to be passed through the placenta and milk in studies with other species. It should not be used in horses with pituitary pars intermedia dysfunction (Cushings).
Furosemide is detectable in urine 36–72 hours following injection </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 Ethinylestradiol/norethisterone acetate 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 Benzyl alcohol and explain in detail? [/INST] Benzyl alcohol is an aromatic alcohol with the formula C6H5CH2OH. The benzyl group is often abbreviated "Bn" (not to be confused with "Bz" which is used for benzoyl), thus benzyl alcohol is denoted as BnOH.  Benzyl alcohol is a colorless liquid with a mild pleasant aromatic odor.  It is a useful solvent due to its polarity, low toxicity, and low vapor pressure. Benzyl alcohol has moderate solubility in water (4 g/100 mL) and is miscible in alcohols and diethyl ether.  The anion produced by deprotonation of the alcohol group is known as benzylate or benzyloxide.

Natural occurrences
Benzyl alcohol is produced naturally by many plants and is commonly found in fruits and teas.  It is also found in a variety of essential oils including jasmine, hyacinth and ylang-ylang. It is also found in castoreum from the castor sacs of beavers. Benzyl esters also occur naturally.

Preparation
Benzyl alcohol is produced industrially from toluene via benzyl chloride, which is hydrolyzed:

C6H5CH2Cl + H2O → C6H5CH2OH + HClAnother route entails hydrogenation of benzaldehyde, a by-product of the oxidation of toluene to benzoic acid.For laboratory use, Grignard reaction of phenylmagnesium bromide (C6H5MgBr) with formaldehyde and the Cannizzaro reaction of benzaldehyde also give benzyl alcohol.  The latter also gives benzoic acid, an example of an organic disproportionation reaction.

Reactions
Like most alcohols, it reacts with carboxylic acids to form esters. In organic synthesis, benzyl esters are popular protecting groups because they can be removed by mild hydrogenolysis.Benzyl alcohol reacts with acrylonitrile to give N-benzylacrylamide.  This is an example of a Ritter reaction:
C6H5CH2OH  +  NCCHCH2 →  C6H5CH2N(H)C(O)CHCH2

Applications
Benzyl alcohol is used as a general solvent for inks, waxes, shellacs, paints, lacquers, and epoxy resin coatings. Thus it can be used in paint strippers, especially when combined with compatible viscosity enhancers to encourage the mixture to cling to painted surfaces.It is a precursor to a variety of esters and ethers, used in the soap, perfume, and flavor industries.
E.g. benzyl benzoate, benzyl salicylate, benzyl cinnamate, dibenzyl ether, benzyl butyl phthalate.
It can be used as a local anesthetic, especially with epinephrine.As a dye solvent, it enhances the process of dying wool, nylon, and leather.

Use in health care
Benzyl alcohol is used as a bacteriostatic preservative at low concentration in intravenous medications, cosmetics, and topical drugs. Some caution is necessary if a high percent of Benzyl alcohol is used as benzaldehyde arises from benzyl alcohol when used as preservative in an injectable formulation solution.
Benzyl alcohol, sold under the brand name Ulesfia, was approved by the U.S </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 Intal 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 Estradiol acetate and explain in detail? [/INST] Estradiol acetate (EA), sold under the brand names Femtrace, Femring, and Menoring, is an estrogen medication which is used in hormone therapy for the treatment of menopausal symptoms in women. It is taken by mouth once daily or given as a vaginal ring once every three months.Side effects of estradiol acetate include breast tenderness, breast enlargement, nausea, headache, and fluid retention. Estradiol acetate is an estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol. It is an estrogen ester and a prodrug of estradiol in the body. Because of this, it is considered to be a natural and bioidentical form of estrogen.Estradiol acetate was introduced for medical use in 2001. It is available in the United States and the United Kingdom </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 Ixabepilone 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 Lurbinectedin and explain in detail? [/INST] Lurbinectedin, sold under the brand name Zepzelca, is a medication used for the treatment of small cell lung cancer.The most common side effects include leukopenia, lymphopenia, fatigue, anemia, neutropenia, increased creatinine, increased alanine aminotransferase, increased glucose, thrombocytopenia, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium and diarrhea.Lurbinectedin is a synthetic tetrahydropyrrolo [4,3,2-de]quinolin-8(1H)-one alkaloid analogue with potential antineoplastic activity. Lurbinectedin covalently binds to residues lying in the minor groove of DNA, which may result in delayed progression through S phase, cell cycle arrest in the G2/M phase and cell death.Lurbinectedin was approved for medical use in the United States in June 2020.

Medical uses
Lurbinectedin is indicated for the treatment of adults with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

Structure
Lurbinectedin is structurally similar to trabectedin, although the tetrahydroisoquinoline present in trabectedin is replaced with a tetrahydro β-carboline which enables lurbinectedin to exhibit increased antitumor activity compared with trabectedin.

Synthesis
Synthesis of lurbinectedin starts from small, common starting materials that require twenty-six individual steps to produce the drug with overall yield of 1.6%.

Mechanism of action
According to PharmaMar, lurbinectedin inhibits the active transcription of the encoding genes. This has two consequences.  It promotes tumor cell death and normalizes the tumor microenvironment. Active transcription is the process by which there are specific signal where information contained in the DNA sequence is transferred to an RNA molecule. This activity depends on the activity of an enzyme called RNA polymerase II. Lurbinectedin inhibits transcription through a very precise mechanism. Firstly, lurbinectedin binds to specific DNA sequences. It is at these precise spots that slides down the DNA to produce RNA polymerase II that is blocked and degraded by lurbinectedin. Lurbinectedin also has important role in tumor microenvironment. The tumor cells act upon macrophages to avoid them from behaving like an activator of the immune system.  Macrophages can contribute to tumor growth and progression by promoting tumor cell proliferation and invasion, fostering tumor angiogenesis and suppressing antitumor immune cells. Attracted to oxygen-starved (hypoxic) and necrotic tumor cells they promote chronic inflammation. So, not only that macrophages inhibit immune system avoiding the destruction of tumor cells, but they also create tumor tissue that allows tumor growth. However, macrophages associated with tumors are cells that are addicted to the transcription process. Lurbinectedin acts specifically on the macrophages associated with tumors in two ways: firstly, by inhibiting the transcription of macrophages that leads to cell death and secondly, inhibiting the production of tumor growth factors. In this way, lurbinectedin normalizes the tumor microenvironment.

History
Lurbinectedin was approved for medical use in the United States in June 2020.Efficacy was demonstrated in the PM1183-B-005-14 trial (Study B-005; NCT02454972), a multicenter open-label, multi-cohort study enrolling 105 participants with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. Participants received lurbinectedin 3.2 mg/m2 by intravenous infusion every 21 days until disease progression or unacceptable toxicity </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 Maprotiline and explain in detail? [/INST] Maprotiline, sold under the brand name Ludiomil among others, is a tetracyclic antidepressant (TeCA) that is used in the treatment of depression. It may alternatively be classified as a tricyclic antidepressant (TCA), specifically a secondary amine. In terms of its chemistry and pharmacology, maprotiline is closely related to other secondary amine TCAs like nortriptyline and protriptyline, and has similar effects to them.

Medical uses
Maprotiline is used in the treatment of depression, such as depression associated with agitation or anxiety and has similar efficacy to the antidepressant drug moclobemide.
Treatment of depression of all forms and severities (endogenous, psychotic, involutional, and neurotic) especially for depression associated with agitation or anxiety
Panic disorder
Neuropathic pain
Treatment of the depressive phase in bipolar depression
For the symptomatic relief of anxiety, tension or insomniaThe use of maprotiline in the treatment of enuresis in pediatric patients has so far not been systematically explored and its use is not recommended. Safety and effectiveness in the pediatric population in general have not been established. Anyone considering the use of maprotiline in a child or adolescent must balance the potential risks with the clinical need. In general, lower dosages are recommended for patients over 60 years of age. Dosages of 50 mg to 75 mg daily are usually satisfactory as maintenance therapy for elderly patients who do not tolerate higher amounts.

Available forms
Coated Tablets, 10 mg, 25 mg, 50 mg, and 75 mg
Injectable concentrate, 25 mg

Contraindications
Maprotiline may worsen psychotic conditions like schizophrenia and should be given with caution. The antipsychotic treatment should be continued. Patients with bipolar affective disorder should not receive antidepressants whilst in a manic phase, as antidepressants can worsen mania.

Absolute
Hypersensitivity to maprotiline or to other TCAs and TeCAs
Hypertrophy of the prostate gland with urine hesitancy
Closed angle glaucoma

Special caution needed
Concomitant treatment with a MAO inhibitor
Serious impairment of liver and kidney function
Epilepsy and other conditions that lower the seizure threshold (active brain tumors, alcohol withdrawal, other medications)
Serious cardiovascular conditions (arrhythmias, heart insufficience, state after myocardial infarction etc.)
Treatment of patients under age 18

Suicidal patients
Same as other antidepressants, maprotiline increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of maprotiline or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Maprotiline is not approved for use in pediatric patients.

Pregnancy and lactation
Reproduction studies have been performed in female laboratory rabbits, mice, and rats at doses up to 1.3, 7, and 9 times the maximum daily human dose respectively and have revealed no evidence of impaired fertility or harm to the fetus due to maprotiline. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Maprotiline is excreted in breast milk. At steady-state, the concentrations in milk correspond closely to the concentrations in whole blood. Caution should be exercised when maprotiline hydrochloride is administered to a nursing woman.

Side effects
The side-effect profile is comparable to other TCAs and TeCAS and many of the following are due to anticholinergic (which are less prominent than those of most TCAs) and antihistamine effects. Most often seen are:

Dizziness
Drowsiness
Somnolence
Fatigue
Dry mouth (and complications of long-term uncontrolled dry mouth such as dental caries)
Constipation
Vertigo
Nausea (rare, incidence of ~2%) and vomiting
Increased appetite and weight gain
Orthostatic hypotension, hypertension, sinus tachycardia, heart-block, arrhythmias and other cardiac effects
Sexual dysfunction in men: impotence, priapism, delayed ejaculation, anejaculation, decreased libido
Sexual dysfunction in women: decreased libido, vaginal dryness, painful sexual intercourse, anorgasmia
Allergic skin reactions such as rash or urticaria (more often than with other antidepressants). Rarely, severe skin reactions such as erythema multiforme can occur.
Photosensitivity
Agitation, confusion
Induction of hypomania or mania in patients with underlying bipolar affective disorder
Psychotic symptoms
Tremor
Extrapyramidal symptoms
Headache
Seizures (at high doses)
Rare haematological complications: leukopenia and agranulocytosis (dangerous fall in white blood cells)
Fever
Urinary retentionMaprotiline causes a strong initial sedation (first 2 to 3 weeks of therapy) and is therefore indicated to treat agitated patients or those with suicidal risks. It causes anticholinergic side effects (dry mouth, constipation, confusion, tachycardia) with a lower incidence than amitriptyline. Originally, the manufacturer claimed that maprotiline is better tolerated than other TCAs and TeCAs. However, seizures, leukopenia and skin reactions occur more often with maprotiline than with comparable drugs like amitriptyline.
Maprotiline has no known potential for abuse and psychological dependence.

Withdrawal
Withdrawal symptoms frequently seen when treatment with maprotiline is stopped abruptly (agitation, anxiety, insomnia, sometimes activation of mania or rebound depression) are not indicative of addiction and can be avoided by reducing the daily dose of maprotiline gradually by approximately 25% each week. If treatment has to be stopped at once due to medical reasons, the use of a benzodiazepine (e.g. lorazepam, clonazepam, or alprazolam) for a maximum of 4 weeks as needed will usually suppress withdrawal symptoms.

Interactions
Maprotiline has a wide range of possible interactions. Some are typical for TCAs and TeCAs, others are caused by specific metabolic effects (e.g. high plasma-protein-binding) of maprotiline:

Irreversible MAO-inhibitors: agitation, delirium, coma, hyperpyrexia (high fever), seizures and severe changes in blood pressure. Treatment-resistant and hospitalized patients may be treated concomitantly with an MAO-inhibitor, if they are closely monitored and if the initial dose of the MAO-Inhibitor is low.Increased drug actions:

Other antidepressants, barbiturates, narcotics, sedating antihistamines, anticonvulsive drugs, alcohol - resulting in increased central depression
Anticholinergics (antiparkinsonian agents, TCAs and TeCAs) - resulting in increased anticholinergic action (dry mouth, constipation etc.)
Sympathomimetics (also those used in local anesthetics like noradrenaline) : sympathomimetic effects increased (increased blood pressure, pulse rate, paleness of skin etc.)
Nitrates and antihypertensives (e.g. beta-blockers) - increased antihypertensive action with pronounced fall in blood pressureDecreased drug actions:

Guanethidine, Reserpine, Guanfacine : antihypertensive effects decreased
Clonidine : antihypertensive effects decreased and risk of (massive) rebound hypertension.Other types of interaction:

Drugs, which induce certain enzymes in the liver, e.g. barbiturates, phenytoin, carbamazepine and oral anticonceptive drugs, enhance the elimination of maprotiline and decrease its antidepressant effects. Additionally the blood-concentrations of phenytoin or carbamazepine may be increased, leading to a higher incidents of side effects.
The concomitant use of maprotiline and neuroleptics can lead to increased maprotiline blood-levels and to seizures. Combining maprotiline and thioridazine could induce severe arrhythmias.
Additionally, increased blood-levels of Maprotiline are possible, if certain beta-blocking agents (e.g. Propranolol) are given concomitantly.
Maprotiline may amplify the actions of coumarin-type anticoagulants (e.g. warfarin, phenprocoumon). The plasma-prothrombin-activity must be assessed closely in order to avoid overt bleedings.
Maprotiline can increase the actions of oral antidiabetic drugs (sulfonylureas) and Insulin. Diabetic patients should have regular assessments of their blood-glucose-levels.
The concomitant application with fluoxetine or fluvoxamine may lead to significantly increased plasma-levels of maprotiline with a high incidence of maprotiline side effects. Due to the long half-lives of fluoxetine and fluvoxamine this effect may persist.

Pharmacology
Pharmacodynamics
Maprotiline exhibits strong effects as a norepinephrine reuptake inhibitor with only weak actions the reuptake of serotonin and dopamine. It is also a strong antagonist of the H1 receptor, a moderate antagonist of the 5-HT2 and α1-adrenergic receptors, and a weak antagonist of the D2 and muscarinic acetylcholine receptors. Maprotiline has also more recently been identified as a potent antagonist of the 5-HT7 receptor, with this action potentially playing an important role in its antidepressant effectiveness. The drug is a strong antihistamine, but unlike most TCAs, has minimal anticholinergic effects.The pharmacological profile of maprotiline explains its antidepressant, sedative, anxiolytic, and sympathomimetic activities. In accordance to the pharmacological characteristics it is used in the treatment of depression, such as depression associated with agitation or anxiety. Additionally, it shows strong antagonism against reserpine-induced effects in animal studies, as do the other classical antidepressants. Although maprotiline behaves in most regards as a first-generation antidepressant it is commonly referred to as second-generation antidepressant.
The postulated mechanism of maprotiline is that it acts primarily by potentiation of central adrenergic synapses by blocking reuptake of norepinephrine at nerve endings. This pharmacological action is thought to be primarily responsible for the drugs antidepressant and anxiolytic effects. It is a strong norepinephrine reuptake inhibitor with only weak effects on serotonin and dopamine reuptake. At higher doses however, maprotiline increases serotonergic transmission and increases the level of serotonin available.

Pharmacokinetics
After oral use absorption is good. It binds to plasma proteins 80–90%. Maximal plasma concentration is reached 6 hours after use. The mean time to peak is 12 hours. The terminal half-life of averages 51 hours.

Chemistry
Maprotiline is a tetracyclic compound and is grouped with the TeCAs. Its chemical name is N-methyl-9,10-ethanoanthracen-9(10H)-propylamine. The drug has a dibenzobicyclo[2.2.2]octadiene (9,10-dihydro-9,10-ethanoanthracene) ring system; that is, a tricyclic anthracene ring system with an ethylene bridge across the central ring. This results in it having a unique three-dimensional central ring (a bicyclo[2.2.2]octane or 1,4-endoethylenecyclohexane ring) and being a tetracyclic rather than a tricyclic compound. However, it could also or alternatively be considered to be a tricyclic and hence a TCA. In addition to its heterocyclic ring system, maprotiline has an alkylamine side chain attached similarly to other TCAs (but notably unlike other TeCAs). In terms of the side chain, it is a secondary amine, and its chemical structure, aside from the ethylene link in the central ring, is similar to that of secondary amine TCAs like nortriptyline and protriptyline </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 Crisaborole and explain in detail? [/INST] Crisaborole, sold under the brand name Eucrisa among others, is a nonsteroidal topical medication used for the treatment of mild-to-moderate atopic dermatitis (eczema) in adults and children.The most common side effects are reactions at the application site (including burning or stinging).Crisaborole is a phosphodiesterase 4 (PDE-4) inhibitor, although its specific mechanism of action in atopic dermatitis is not known.

Side effects
At the site of application, crisaborole may cause burning or stinging. Rarely, there may be an allergic reaction.

Medical uses
In the US, crisaborole is indicated for topical treatment of mild to moderate atopic dermatitis in people three months of age and older.In the EU, crisaborole was authorized for treatment of mild to moderate atopic dermatitis in people two years of age and older with ≤ 40% body surface area (BSA) affected.

Pharmacology
Pharmacodynamics
Crisaborole is a phosphodiesterase-4 inhibitor, mainly acting on phosphodiesterase 4B (PDE4B), which causes inflammation. Chemically, crisaborole is a phenoxybenzoxaborole. Inhibition of PDE4B appears to suppress the release of tumor necrosis factor alpha (TNFα), interleukin-12 (IL-12), IL-23 and other cytokines, proteins believed to be involved in the immune response and inflammation.People with atopic dermatitis produce high levels of proteins called cytokines, which can cause the inflammation of the skin seen in dermatitis. Crisaborole blocks the release of certain cytokines involved in the inflammation process such as tumor necrosis factor alpha, interleukins (IL‑2, IL-4, IL-5), and interferon gamma. By blocking their release, crisaborole is expected to ease the inflammation and therefore relieve symptoms of the disease.

Chemistry
Crisaborole (chemical name: 4-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile) is a member of the class of benzoxaboroles characterized by the presence of a boronic acid hemiester with a phenolic ether and a nitrile. Crisaborole crystallizes into two polymorphs that differ in the conformation of the oxaborole ring. A cocrystal with 4,4-bipyridine has been prepared and studied by X-ray crystallography.

History
Crisaborole was developed by Anacor Pharmaceuticals for the topical treatment of psoriasis </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 Mogamulizumab and explain in detail? [/INST] Mogamulizumab, sold under the brand name Poteligeo, is a humanized, afucosylated monoclonal antibody targeting CC chemokine receptor 4 (CCR4). The  U.S. Food and Drug Administration (FDA) approved it in August 2018 for treatment of relapsed or refractory mycosis fungoides and Sézary disease.  It was approved in Japan in 2012, for the treatment of relapsed or refractory CCR4+ adult T-cell leukemia/lymphoma (ATCLL) and in 2014, for relapsed or refractory CCR4+ cutaneous T cell lymphoma (CTCL).  The latter approval was based on study with 28 subjects.The precursor to mogamulizumab was a mouse anti-human CCR4 IgG1 mAb (KM2160), that was made in 1996 in a collaboration between Kouji Matsushima of University of Tokyo and Kyowa Hakko Kirin.  Kyowa humanized it, and expressed the humanized gene in a CHO cell line in which FUT8 had been knocked out, which produced antibodies with no fucose in the Fc region.  This is thought to enhance its antibody-dependent cell-mediated cytotoxicity.  It was first tested in humans in 2007.Kyowa licensed rights for use outside of cancer to Amgen in 2008, for $100 million up front and $420 million in biodollars. Amgen ran a Phase I study to explore its use in asthma.  Amgen terminated the agreement in 2014.As of 2014, there were reports that mogamulizimab can cause serious skin rashes and some cases of Stevens–Johnson syndrome.In 2017, the US FDA granted it a priority review for CTCL.  Full approval was granted in August 2018. The U.S </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 Arylsulfatase B and explain in detail? [/INST] Arylsulfatase B (N-acetylgalactosamine-4-sulfatase, chondroitinsulfatase, chondroitinase, acetylgalactosamine 4-sulfatase, N-acetylgalactosamine 4-sulfate sulfohydrolase, EC 3.1.6.12) is an enzyme associated with mucopolysaccharidosis VI (Maroteaux–Lamy syndrome).
Arylsulfatase B is among a group of arylsulfatase enzymes present in the lysosomes of the liver, pancreas, and kidneys of animals. The purpose of the enzyme is to hydrolyze sulfates in the body. ARSB does this by breaking down glycosaminoglycans (GAGs), which are large sugar molecules in the body. ARSB targets two GAGs in particular: dermatan sulfate and chondroitin sulfate.Over 130 mutations to ARSB have been found, each leading to a deficiency in the body. In most cases, the mutation occurs on a single nucleotide in the sequence. An arylsulfatase B deficiency can lead to an accumulation of GAGs in lysosomes, which in turn can lead to mucopolysaccharidosis VI.
Used as a pharmaceutical drug, the enzyme is known under the International Nonproprietary Name galsulfase and is sold under the brand name Naglazyme. Galsulfase was approved for medical use in the United States in May 2005 and in  European Union in January 2006. Galsulfase is indicated for long-term enzyme-replacement therapy in people with a confirmed diagnosis of mucopolysaccharidosis VI (MPS VI; N-acetylgalactosamine-4-sulfatase deficiency; Maroteaux-Lamy syndrome).

Structure
The primary structure of Escherichia coli  arylsulfatase B contains a primary sequence of 502 amino acids. Its secondary structure is quite complex, containing numerous alpha helices (20 total containing 138 residues) and beta sheets (21 strands total containing 87 residues).  The functional enzyme is believed to be a homo tetramer. Due to the complexity of arylsulfatase Bs secondary structure, many hydrophobic and hydrophilic regions are present, as demonstrated by the Kyte-Doolittle hydropathy plot:

Medical uses
Galsulfase is used to treat adults and children who have mucopolysaccharidosis VI (MPS VI or Maroteaux-Lamy syndrome). This disease is caused by the lack of an enzyme called N-acetylgalactosamine 4-sulfatase, which is needed to break down substances in the body called glycosaminoglycans (GAGs). If the enzyme is not present, GAGs cannot be broken down and they build up in the cells. This causes the signs of the disease, the most noticeable being a short body, a large head and difficulty moving about. The disease is usually diagnosed in infants between one and five years of age. Galsulfase has been shown to improve walking and stair-climbing capacity.The most common adverse reactions (≥10%) are: rash, pain, urticaria, pyrexia, pruritus, chills, headache, nausea, vomiting, abdominal pain and dyspnea. The most common adverse reactions requiring interventions are infusion-related reactions.Galsulfase (N-acetylgalactosamine-4-sulfatase, recombinant human) was granted orphan drug designation by both the European Commission and the U.S. Food and Drug Administration (FDA).

Role in cystic fibrosis
Expression and activity of ARSB were found to be related to the function of cystic fibrosis transmembrane conductance regulator (CFTR), the membrane channel deficient in cystic fibrosis. Measurements in cystic fibrosis cell line IB3 and its derivative cell line C38, which has a functional CFTR, showed increased ARSB activity and expression in the C38 line. CFTR potentiator VRT-532 increased ARSB expression and activity in cystic fibrosis cells to the level in the normal bronchial epithelial cells.

Role in malignancy
ARSB has been studied in a variety of cancers. Cultured normal mammary epithelial and myoepithelial cells had significantly higher ARSB activity than cultured malignant mammary cells. Immunohistochemistry  in the colon showed decreased membrane ARSB staining in colon cancer compared to normal colon, as well as in higher grade malignancies. ARSB activity was lower in malignant than normal prostate tissue, and immunostaining of prostate tissue microarrays showed not only decreasing ARSB staining in prostate cancer tissue of a higher Gleason score, but also lower staining in patients with recurrent compared to non-recurrent cancer. ARSB staining was a greater predictor of recurrence than Prostate-specific antigen (PSA) test, indicating possible future role of ARSB as a prognostic biomarker of prostate cancer. Further evidence of ARSB as a tumor suppressor was determined by molecular studies in cell cultures where ARSB was silenced by siRNA. The studies showed that decrease of ARSB leads to increase in free galectin-3, which attaches more strongly to less sulfated chondroitin 4-sulfate. Galectin-3 then acts on transcription factors AP-1 to increase expression of chondroitin sulfate proteoglycan versican and SP-1 to increase expression of WNT9A. Another mechanism by which reduced ARSB is associated with carcinogenesis is through increased binding of SHP2 to more sulfated chondroitin 4-sulfate, which leads to increased phosphorylation of p38 and MITF with subsequently increased expression of GPNMB.

Role in metabolism
Reduced sulfate availability due to impaired activity of ARSB has been linked to increased aerobic glycolysis, as shown by an increase in NADH and NADPH, reduced oxygen consumption, increased extracellular acidification and serum lactate, and a decline in mitochondrial membrane potential in ARSB-silenced cells and ARSB-null mouse tissues.

Extra-lysosomal localization
Although primarily a lysosomal enzyme, ARSB was also found to localize at the cell membrane of hepatocytes, sinusoidal endothelial cells, and Kupffer cells in the liver, as well as in the apical membranes of normal and malignant colonic and prostatic epithelial cells, by immunohistochemistry and immunofluorescence studies. Membrane immunostaining in the colon and prostate was lower in malignant than in normal tissue and also was lower in higher grade malignancies. ARSB activity assay in the membrane and cytosol fractions of cultured bronchial epithelial cells showed that the activity was several-fold greater in the membrane fraction.

See also
Aryl
Sulfatase

References
Further reading
Brunelli MJ, Atallah ÁN, da Silva EM (September 2021). "Enzyme replacement therapy with galsulfase for mucopolysaccharidosis type VI". Cochrane Database Syst Rev. 2021 (9): CD009806. doi:10.1002/14651858.CD009806.pub3. PMC 8447860. PMID 34533215.
"Galsulfase (Naglazyme)". Common Drug Review. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health (CADTH). November 2016 </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 Etelcalcetide and explain in detail? [/INST] Etelcalcetide (formerly velcalcetide, trade name Parsabiv) is a calcimimetic drug for the treatment of secondary hyperparathyroidism in patients undergoing hemodialysis. It is administered intravenously at the end of each dialysis session. Etelcalcetide functions by binding to and activating the calcium-sensing receptor in the parathyroid gland. Parsabiv is currently owned by Amgen and Ono Pharmaceuticals in Japan.

Medical uses
Etelcalcetide is used for the treatment of secondary hyperparathyroidism in people with chronic kidney disease (CKD) on hemodialysis. Hyperparathyroidism is the condition of elevated parathyroid hormone (PTH) levels and is often observed in people with CKD.

Pharmacodynamics
Mechanism of action
Etelcalcetide functions by binding to and activating the calcium-sensing receptor (CaSR) in the parathyroid gland as an allosteric activator, resulting in PTH reduction and suppression.

Pharmacokinetics
Etelcalcetide functions in a first order elimination, with a half life of 19 hours.No interaction studies in humans were conducted </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 Timolol and explain in detail? [/INST] Timolol  is a beta blocker medication used either by mouth or as eye drops. As eye drops it is used to treat increased pressure inside the eye such as in ocular hypertension and glaucoma. By mouth it is used for high blood pressure, chest pain due to insufficient blood flow to the heart, to prevent further complications after a heart attack, and to prevent migraines.Common side effects with the drops is irritation of the eye. Common side effects by mouth include tiredness, slow heart beat, itchiness, and shortness of breath. Other side effects include masking the symptoms of low blood sugar in those with diabetes. Use is not recommended in those with asthma, uncompensated heart failure, or COPD. It is unclear if use during pregnancy is safe for the baby. Timolol is a non-selective beta blocker.Timolol was patented in 1968, and came into medical use in 1978. It is on the World Health Organizations List of Essential Medicines. Timolol is available as a generic medication. In 2019, it was the 160th most commonly prescribed medication in the United States, with more than 3 million prescriptions.

Medical uses
By mouth
In its by mouth or oral form, it is used:

to treat high blood pressure
to prevent heart attacks
to prevent migraine headachesThe combination of timolol and the alpha-1 blocker prazosin has sedative effects.

Eye drops
In its eye drop form it is used to treat open-angle and, occasionally, secondary glaucoma. The mechanism of action of timolol is probably the reduction of the formation of aqueous humor in the ciliary body in the eye. It was the first beta blocker approved for topical use in treatment of glaucoma in the United States (1978). When used by itself, it depresses intraocular pressure (IOP) 18–34% below baseline within first few treatments. However, there are short-term escape and long-term drift effects in some people. That is, tolerance develops. It may reduce the extent of the diurnal IOP curve up to 50%. The IOP is higher during sleep. Efficacy of timolol in lowering IOP during the sleep period may be limited. It is a 5–10× more potent β-blocker than propranolol. Timolol is light-sensitive; it is usually preserved with 0.01% benzalkonium chloride (BAC), but also comes BAC-free. It can also be used in combination with pilocarpine, carbonic anhydrase inhibitors or prostaglandin analogs.A Cochrane review compared the effect of timolol versus brimonidine in slowing the progression of open angle glaucoma in adults but found insufficient evidence to come to conclusions.

On the skin
In its gel form it is used on the skin to treat infantile hemangiomas.

Contraindications
The medication should not be taken by individuals with:
An allergy to timolol or any other beta-blockers
Asthma or severe chronic obstructive bronchitis
A slow heart rate (bradycardia), or a heart block
Heart failure

Side effects
The most serious possible side effects include cardiac arrhythmias and severe bronchospasms. Timolol can also lead to fainting, congestive heart failure, depression, confusion, worsening of Raynauds syndrome and impotence.Side effects when given in the eye include: burning sensation, eye redness, superficial punctate keratopathy, corneal numbness.

Formulations
It is available in tablet and liquid formulations.For ophthalmic use, timolol is also available combined:

with carbonic anhydrase inhibitors:
timolol and brinzolamide
timolol and dorzolamide
with α2 agonists:
timolol and brimonidine
with prostaglandin analogs:
timolol and latanoprost
timolol and travoprost

Brand names
Timolol is marketed under many trade names worldwide. Timolol eye drops are marketed under the brand name Istalol among others.

References
External links
"Timolol" </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 Mupirocin and explain in detail? [/INST] Mupirocin, sold under the brand name Bactroban among others, is a topical antibiotic useful against superficial skin infections such as impetigo or folliculitis. It may also be used to get rid of methicillin-resistant S. aureus (MRSA) when present in the nose without symptoms. Due to concerns of developing resistance, use for greater than ten days is not recommended. It is used as a cream or ointment applied to the skin.Common side effects include itchiness and rash at the site of application, headache, and nausea. Long term use may result in increased growth of fungi. Use during pregnancy and breastfeeding appears to be safe. Mupirocin is in the carboxylic acid class of medications. It works by blocking a bacterias ability to make protein, which usually results in bacterial death.Mupirocin was initially isolated in 1971 from Pseudomonas fluorescens. It is on the World Health Organizations List of Essential Medicines. In 2019, it was the 190th most commonly prescribed medication in the United States, with more than 3 million prescriptions.

Medical uses
Mupirocin is used as a topical treatment for bacterial skin infections, for example, furuncle, impetigo, open wounds, which are typically due to infection by Staphylococcus aureus or Streptococcus pyogenes. It is also useful in the treatment of superficial methicillin-resistant Staphylococcus aureus (MRSA) infections. Mupirocin is inactive for most anaerobic bacteria, mycobacteria, mycoplasma, chlamydia, yeast and fungi.Intranasal mupirocin before surgery is effective for prevention of post-operative wound infection with Staphylcoccus aureus and preventative intranasal or catheter-site treatment is effective for reducing the risk of catheter site infection in persons treated with chronic peritoneal dialysis.

Resistance
Shortly after the clinical use of mupirocin began, strains of Staphylococcus aureus that were resistant to mupirocin emerged, with nares clearance rates of less than 30% success. Two distinct populations of mupirocin-resistant S. aureus were isolated. One strain possessed low-level resistance, MuL, (MIC = 8–256 mg/L) and another possessed high-level resistance, MuH, (MIC > 256 mg/L). Resistance in the MuL strains is probably due to mutations in the organisms wild-type isoleucyl-tRNA synthetase. In E. coli IleRS, a single amino acid mutation was shown to alter mupirocin resistance. MuH is linked to the acquisition of a separate Ile synthetase gene, MupA. Mupirocin is not a viable antibiotic against MuH strains. Other antibiotic agents, such as azelaic acid, nitrofurazone, silver sulfadiazine, and ramoplanin have been shown to be effective against MuH strains.Most strains of Cutibacterium acnes, a causative agent in the skin disease acne vulgaris, are naturally resistant to mupirocin.The mechanism of action of mupirocin differs from other clinical antibiotics, rendering cross-resistance to other antibiotics unlikely. However, the MupA gene may co-transfer with other antibacterial resistance genes. This has been observed already with resistance genes for triclosan, tetracycline, and trimethoprim.  It may also result in overgrowth of non-susceptible organisms.

Mechanism of action
Pseudomonic acid inhibits isoleucine tRNA synthetase in bacteria, leading to depletion of isoleucyl-tRNA and accumulation of the corresponding uncharged tRNA.  Depletion of isoleucyl-tRNA results in inhibition of protein synthesis. The uncharged form of the tRNA binds to the aminoacyl-tRNA binding site of ribosomes, triggering the formation of (p)ppGpp, which in turn inhibits RNA synthesis. The combined inhibition of protein synthesis and RNA synthesis results in bacteriostasis.  This mechanism of action is shared with furanomycin, an analog of isoleucine.

Biosynthesis
Mupirocin is a mixture of several pseudomonic acids, with pseudomonic acid A (PA-A) constituting greater than 90% of the mixture. Also present in mupirocin are pseudomonic acid B with an additional hydroxyl group at C8, pseudomonic acid C with a double bond between C10 and C11, instead of the epoxide of PA-A, and pseudomonic acid D with a double bond at C4` and C5` in the 9-hydroxy-nonanoic acid portion of mupirocin.

Biosynthesis of pseudomonic acid A
The 74 kb mupirocin gene cluster contains six multi-domain enzymes and twenty-six other peptides (Table 1). Four large multi-domain type I polyketide synthase (PKS) proteins are encoded, as well as several single function enzymes with sequence similarity to type II PKSs. Therefore, it is believed that mupirocin is constructed by a mixed type I and type II PKS system. The mupirocin cluster exhibits an atypical acyltransferase (AT) organization, in that there are only two AT domains, and both are found on the same protein, MmpC. These AT domains are the only domains present on MmpC, while the other three type I PKS proteins contain no AT domains. The mupirocin pathway also contains several tandem acyl carrier protein doublets or triplets. This may be an adaptation to increase the throughput rate or to bind multiple substrates simultaneously.Pseudomonic acid A is the product of an esterification between the 17C polyketide monic acid and the 9C fatty acid 9-hydroxy-nonanoic acid. The possibility that the entire molecule is assembled as a single polyketide with a Baeyer-Villiger oxidation inserting an oxygen into the carbon backbone has been ruled out because C1 of monic acid and C9 of 9-hydroxy-nonanoic acid are both derived from C1 of acetate.

Monic acid biosynthesis
Biosynthesis of the 17C monic acid unit begins on MmpD (Figure 1). One of the AT domains from MmpC may transfer an activated acetyl group from acetyl-Coenzyme A (CoA) to the first ACP domain. The chain is extended by malonyl-CoA, followed by a SAM-dependent methylation at C12 (see Figure 2 for PA-A numbering) and reduction of the B-keto group to an alcohol. The dehydration (DH) domain in module 1 is predicted to be non-functional due to a mutation in the conserved active site region. Module 2 adds another two carbons by the malonyl-CoA extender unit, followed by ketoreduction (KR) and dehydration. Module three adds a malonyl-CoA extender unit, followed by SAM-dependent methylation at C8, ketoreduction, and dehydration. Module 4 extends the molecule with a malonyl-CoA unit followed by ketoreduction.
Assembly of monic acid is continued by the transfer of the 12C product of MmpD to MmpA. Two more rounds of extension with malonyl-CoA units are achieved by module 5 and 6. Module 5 also contains a KR domain.

Post-PKS tailoring
The keto group at C3 is replaced with a methyl group in a multi-step reaction (Figure 3). MupG begins by decarboxylating a malonyl-ACP. The alpha carbon of the resulting acetyl-ACP is linked to C3 of the polyketide chain by MupH. This intermediate is dehydrated and decarboxylated by MupJ and MupK, respectively.The formation of the pyran ring requires many enzyme-mediated steps (Figure 4). The double bond between C8 and C9 is proposed to migrate to between C8 and C16. Gene knockout experiments of mupO, mupU, mupV, and macpE have eliminated PA-A production. PA-B production is not removed by these knockouts, demonstrating that PA-B is not created by hydroxylating PA-A. A knockout of mupW eliminated the pyran ring, identifying MupW as being involved in ring formation. It is not known whether this occurs before or after the esterification of monic acid to 9-hydroxy-nonanoic acid.
The epoxide of PA-A at C10-11 is believed to be inserted after pyran formation by a cytochrome P450 such as MupO. A gene knockout of mupO abolished PA-A production but PA-B, which also contains the C10-C11 epoxide, remained. This indicates that MupO is either not involved or is not essential for this epoxidation step.

9-Hydroxy-nonanoic acid biosynthesis
The nine-carbon fatty acid 9-hydroxy-nonanoic acid (9-HN) is derived as a separate compound and later esterified to monic acid to form pseudomonic acid. 13C labeled acetate feeding has shown that C1-C6 are constructed with acetate in the canonical fashion of fatty acid synthesis. C7 shows only C1 labeling of acetate, while C8 and C9 show a reversed pattern of 13C labeled acetate </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 Haloperidol and explain in detail? [/INST] Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosis, and hallucinations from alcohol withdrawal. It may be used by mouth or injection into a muscle or a vein. Haloperidol typically works within 30 to 60 minutes. A long-acting formulation may be used as an injection every four weeks by people with schizophrenia or related illnesses, who either forget or refuse to take the medication by mouth.Haloperidol may result in a movement disorder known as tardive dyskinesia which may be permanent. Neuroleptic malignant syndrome and QT interval prolongation may occur. In older people with psychosis due to dementia it results in an increased risk of death. When taken during pregnancy it may result in problems in the infant. It should not be used by people with Parkinsons disease.Haloperidol was discovered in 1958 by Paul Janssen, prepared as part of a structure-activity relationship investigation into analogs of pethidine (meperidine). It is on the World Health Organizations List of Essential Medicines. It is the most commonly used typical antipsychotic. In 2017, it was the 296th most commonly prescribed medication in the United States, with more than one million prescriptions.

Medical uses
Haloperidol is used in the control of the symptoms of:

Acute psychosis, such as drug-induced psychosis caused by, amphetamines, ketamine, and phencyclidine, and psychosis associated with high fever or metabolic disease. Some evidence, however, has found haloperidol to worsen psychosis due to psilocybin.
Adjunctive treatment of alcohol and opioid withdrawal
Agitation and confusion associated with cerebral sclerosis
Alcohol-induced psychosis
Hallucinations in alcohol withdrawal
Hyperactive delirium (to control the agitation component of delirium)
Hyperactivity, aggression
Otherwise uncontrollable, severe behavioral disorders in children and adolescents
Schizophrenia
Therapeutic trial in personality disorders, such as borderline personality disorder
Treatment of intractable hiccups
Treatment of neurological disorders, such as tic disorders such as Tourette syndrome, and chorea
Treatment of severe nausea and emesis in postoperative and palliative care, especially for palliating adverse effects of radiation therapy and chemotherapy in oncology. Also used as a first line antiemetic for acute Cannabis Hyperemesis Syndrome.Haloperidol was considered indispensable for treating psychiatric emergency situations, although the newer atypical drugs have gained a greater role in a number of situations as outlined in a series of consensus reviews published between 2001 and 2005.In a 2013 comparison of 15 antipsychotics in schizophrenia, haloperidol demonstrated standard effectiveness. It was 13–16% more effective than ziprasidone, chlorpromazine, and asenapine, approximately as effective as quetiapine and aripiprazole, and 10% less effective than paliperidone. A 2013 systematic review compared haloperidol to placebo in schizophrenia:

Pregnancy and lactation
Data from animal experiments indicate haloperidol is not teratogenic, but is embryotoxic in high doses.  In humans, no controlled studies exist.  Reports in pregnant women revealed possible damage to the fetus, although most of the women were exposed to multiple drugs during pregnancy. In addition,  reports indicate neonates exposed to antipsychotic drugs are at risk for extrapyramidal and/or withdrawal symptoms following delivery, such as agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder. Following accepted general principles, haloperidol should be given during pregnancy only if the benefit to the mother clearly outweighs the potential fetal risk.Haloperidol is excreted in breast milk. A few studies have examined the impact of haloperidol exposure on breastfed infants and in most cases, there were no adverse effects on infant growth and development.

Other considerations
During long-term treatment of chronic psychiatric disorders, the daily dose should be reduced to the lowest level needed for maintenance of remission.  Sometimes, it may be indicated to terminate haloperidol treatment gradually. In addition, during long-term use, routine monitoring including measurement of BMI, blood pressure, fasting blood sugar, and lipids, is recommended due to the risk of side effects.Other forms of therapy (psychotherapy, occupational therapy/ergotherapy, or social rehabilitation) should be instituted properly.
PET imaging studies have suggested low doses are preferable. Clinical response was associated with at least 65% occupancy of D2 receptors, while greater than 72% was likely to cause hyperprolactinaemia and over 78% associated with extrapyramidal side effects. Doses of haloperidol greater than 5 mg increased the risk of side effects without improving efficacy. Patients responded with doses under even 2 mg in first-episode psychosis. For maintenance treatment of schizophrenia, an international consensus conference recommended a reduction dosage by about 20% every 6 months until a minimal maintenance dose is established.
Depot forms are also available; these are injected deeply intramuscularly at regular intervals. The depot forms are not suitable for initial treatment, but are suitable for patients who have demonstrated inconsistency with oral dosages.The decanoate ester of haloperidol (haloperidol decanoate, trade names Haldol decanoate, Halomonth, Neoperidole) has a much longer duration of action, so is often used in people known to be noncompliant with oral medication. A dose is given by intramuscular injection once every two to four weeks. The IUPAC name of haloperidol decanoate is [4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl] decanoate.
Topical formulations of haloperidol should not be used as treatment for nausea because research does not indicate this therapy is more effective than alternatives.

Adverse effects
Sources for the following lists of adverse effects:As haloperidol is a high-potency typical antipsychotic, it tends to produce significant extrapyramidal side effects. According to a 2013 meta-analysis of the comparative efficacy and tolerability of 15 antipsychotic drugs it was the most prone of the 15 for causing extrapyramidal side effects.With more than 6 months of use 14 percent of users gain weight. Haloperidol may be neurotoxic.Common (>1% incidence)

Extrapyramidal side effects including:
Akathisia (motor restlessness)
Dystonia (continuous spasms and muscle contractions)
Muscle rigidity
Parkinsonism (characteristic symptoms such as rigidity)
Hypotension
Anticholinergic side effects such as: (These adverse effects are less common than with lower-potency typical antipsychotics, such as chlorpromazine and thioridazine.)
Blurred vision
Constipation
Dry mouth
Somnolence (which is not a particularly prominent side effect, as is supported by the results of the aforementioned meta-analysis.)Unknown frequency

Anemia
Headache
Increased respiratory rate
Orthostatic hypotension
Prolonged QT interval
Visual disturbancesRare (<1% incidence)

Contraindications
Pre-existing coma, acute stroke
Severe intoxication with alcohol or other central depressant drugs
Known allergy against haloperidol or other butyrophenones or other drug ingredients
Known heart disease, when combined will tend towards cardiac arrest

Special cautions
A multiple-year study suggested this drug and other neuroleptic antipsychotic drugs commonly given to people with Alzheimers with mild behavioral problems often make their condition worse and its withdrawal was even beneficial for some cognitive and functional measures.
Elderly patients with dementia-related psychosis: analysis of 17 trials showed the risk of death in this group of patients was 1.6 to 1.7 times that of placebo-treated patients. Most of the causes of death were either cardiovascular or infectious in nature. It is not clear to what extent this observation is attributed to antipsychotic drugs rather than the characteristics of the patients. The drug bears a boxed warning about this risk.
Impaired liver function, as haloperidol is metabolized and eliminated mainly by the liver
In patients with hyperthyroidism, the action of haloperidol is intensified and side effects are more likely.
IV injections: risk of hypotension or orthostatic collapse
Patients at special risk for the development of QT prolongation (hypokalemia, concomitant use of other drugs causing QT prolongation)
Patients with a history of leukopenia: a complete blood count should be monitored frequently during the first few months of therapy and discontinuation of the drug should be considered at the first sign of a clinically significant decline in white blood cells.
Pre-existing Parkinsons disease or dementia with Lewy bodies

Interactions
Amiodarone: Q-Tc interval prolongation (potentially dangerous change in heart rhythm).
Amphetamine and methylphenidate: counteracts increased action of norepinephrine and dopamine in patients with narcolepsy or ADD/ADHD
Epinephrine:  action antagonized, paradoxical decrease in blood pressure may result
Guanethidine:  antihypertensive action antagonized
Levodopa:  decreased action of levodopa
Lithium:  rare cases of the following symptoms have been noted: encephalopathy, early and late extrapyramidal side effects, other neurologic symptoms, and coma.
Methyldopa:  increased risk of extrapyramidal side effects and other unwanted central effects
Other central depressants (alcohol, tranquilizers, narcotics):  actions and side effects of these drugs (sedation, respiratory depression) are increased. In particular, the doses of concomitantly used opioids for chronic pain can be reduced by 50%.
Other drugs metabolized by the CYP3A4 enzyme system: inducers such as carbamazepine, phenobarbital, and rifampicin decrease plasma levels and inhibitors such as quinidine, buspirone, and fluoxetine increase plasma levels
Tricyclic antidepressants:  metabolism and elimination of tricyclics significantly decreased, increased toxicity noted (anticholinergic and cardiovascular side effects, lowering of seizure threshold)

Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Overdose
Symptoms
Symptoms are usually due to side effects. Most often encountered are:

Anticholinergic side effects (dry mouth, constipation, paralytic ileus, difficulties in urinating, decreased perspiration)
Coma in severe cases, accompanied by respiratory depression and massive hypotension, shock
Hypotension or hypertension
Rarely, serious ventricular arrhythmia (torsades de pointes), with or without prolonged QT-time
Sedation
Severe extrapyramidal side effects with muscle rigidity and tremors, akathisia, etc.

Treatment
Treatment is mostly symptomatic and involves intensive care with stabilization of vital functions. In early detected cases of oral overdose, induction of emesis, gastric lavage, and the use of activated charcoal can be tried. In the case of a severe overdose, antidotes such as bromocriptine or ropinirole may be used to treat the extrapyramidal effects caused by haloperidol, acting as dopamine receptor agonists. ECG and vital signs should be monitored especially for QT prolongation and severe arrhythmias should be treated with antiarrhythmic measures.

Prognosis
An overdose of haloperidol can be fatal, but in general the prognosis after overdose is good, provided the person has survived the initial phase.

Pharmacology
Haloperidol is a typical butyrophenone type antipsychotic that exhibits high affinity dopamine D2 receptor antagonism and slow receptor dissociation kinetics. It has effects similar to the phenothiazines. The drug binds preferentially to D2 and α1 receptors at low dose (ED50 = 0.13 and 0.42 mg/kg, respectively), and 5-HT2 receptors at a higher dose (ED50 = 2.6 mg/kg). Given that antagonism of D2 receptors is more beneficial on the positive symptoms of schizophrenia and antagonism of 5-HT2 receptors on the negative symptoms, this characteristic underlies haloperidols greater effect on delusions, hallucinations and other manifestations of psychosis. Haloperidols negligible affinity for histamine H1 receptors and muscarinic M1 acetylcholine receptors yields an antipsychotic with a lower incidence of sedation, weight gain, and orthostatic hypotension though having higher rates of treatment emergent extrapyramidal symptoms.
Haloperidol acts on these receptors: (Ki)

D1 (silent antagonist) – Unknown efficiency
D5 (silent antagonist) – Unknown efficiency
D2 (inverse agonist) – 0.7 nM
D3 (inverse agonist) – 0.2 nM
D4 (inverse agonist) – 5–9 nM
σ1 (irreversible inactivation by haloperidol metabolite HPP+) –  3 nM
σ2 (agonist): 54 nM
5HT1A receptor agonist –  1927 nM
5HT2A (silent antagonist) –  53 nM
5HT2C (silent antagonist) – 10,000 nM
5HT6 (silent antagonist) – 3666 nM
5HT7 (irreversible silent antagonist) – 377.2 nM
H1 (silent antagonist) – 1,800 nM
M1 (silent antagonist) – 10,000 nM
α1A (silent antagonist) – 12 nM
α2A (silent antagonist) – 1130 nM
α2B (silent antagonist) – 480 nM
α2C (silent antagonist) – 550 nM
NR1/NR2B subunit containing NMDA receptor (antagonist; ifenprodil site): IC50 – 2,000 nM

Pharmacokinetics
By mouth
The bioavailability of oral haloperidol ranges from 60 to 70%. However, there is a wide variance in reported mean Tmax and T1/2 in different studies, ranging from 1.7 to 6.1 hours and 14.5 to 36.7 hours respectively.

Intramuscular injections
The drug is well and rapidly absorbed with a high bioavailability when injected intramuscularly. The Tmax is 20 minutes in healthy individuals and 33.8 minutes in patients with schizophrenia. The mean T1/2 is 20.7 hours. The decanoate injectable formulation is for intramuscular administration only and is not intended to be used intravenously. The plasma concentrations of haloperidol decanoate reach a peak at about six days after the injection, falling thereafter, with an approximate half-life of three weeks.

Intravenous injections
The bioavailability is 100% in intravenous (IV) injection, and the very rapid onset of action is seen within seconds. The T1/2 is 14.1 to 26.2 hours. The apparent volume of distribution is between 9.5 and 21.7 L/kg.  The duration of action is four to six hours.

Therapeutic concentrations
Plasma levels of five to 15 micrograms per liter are typically seen for therapeutic response (Ulrich S, et al. Clin Pharmacokinet. 1998) </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 Vigabatrin and explain in detail? [/INST] Vigabatrin, brand name Sabril, is a medication used to treat epilepsy. It became available as a generic medication in 2019.It works by inhibiting the breakdown of γ-aminobutyric acid (GABA). It is also known as γ-vinyl-GABA, and is a structural analogue of GABA, but does not bind to GABA receptors.

Medical uses
Epilepsy
In Canada, vigabatrin is approved for use as an adjunctive treatment (with other drugs) in treatment resistant epilepsy, complex partial seizures, secondary generalized seizures, and for monotherapy use in infantile spasms in West syndrome.As of 2003, vigabatrin is approved in Mexico for the treatment of epilepsy that is not satisfactorily controlled by conventional therapy (adjunctive or monotherapy) or in recently diagnosed patients who have not tried other agents (monotherapy).Vigabatrin is also indicated for monotherapy use in secondarily generalized tonic-clonic seizures, partial seizures, and in infantile spasms due to West syndrome.On August 21, 2009, Lundbeck announced that the U.S. Food and Drug Administration had granted two New Drug Application approvals for vigabatrin. The drug is indicated as monotherapy for pediatric patients one month to two years of age with infantile spasms for whom  the potential benefits outweigh the potential risk of vision loss, and as adjunctive (add-on) therapy for adult patients with refractory complex partial seizures (CPS) who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss.In 1994, Feucht and Brantner-Inthaler reported that vigabatrin reduced seizures by 50-100% in 85% of children with Lennox-Gastaut syndrome who had poor results with sodium valproate.

Others
Vigabatrin reduced cholecystokinin tetrapeptide-induced symptoms of panic disorder, in addition to elevated cortisol and ACTH levels, in healthy volunteers.Vigabatrin is also used to treat seizures in succinic semialdehyde dehydrogenase deficiency (SSADHD), which is an inborn GABA metabolism defect that causes intellectual disability, hypotonia, seizures, speech disturbance, and ataxia through the accumulation of γ-Hydroxybutyric acid (GHB). Vigabatrin helps lower GHB levels through GABA transaminase inhibition. However, this is in the brain only; it has no effect on peripheral GABA transaminase, so the GHB keeps building up and eventually reaches the brain.

Adverse effects
Central nervous system
Sleepiness (12.5%), headache (3.8%), dizziness (3.8%), nervousness (2.7%), depression (2.5%), memory disturbances (2.3%), diplopia (2.2%), aggression (2.0%), ataxia (1.9%), vertigo (1.9%), hyperactivity (1.8%), vision loss (1.6%) (See below), confusion (1.4%), insomnia (1.3%), impaired concentration (1.2%), personality issues (1.1%). Out of 299 children, 33 (11%) became hyperactive.Some patients develop psychosis during the course of vigabatrin therapy, which is more common in adults than in children. This can happen even in patients with no prior history of psychosis. Other rare CNS side effects include anxiety, emotional lability, irritability, tremor, abnormal gait, and speech disorder.

Gastrointestinal
Abdominal pain (1.6%), constipation (1.4%), vomiting (1.4%), and nausea (1.4%). Dyspepsia and increased appetite occurred in less than 1% of subjects in clinical trials.

Body as a whole
Fatigue (9.2%), weight gain (5.0%), asthenia (1.1%).

Teratogenicity
A teratology study conducted in rabbits found that a dose of 150 mg/kg/day caused cleft palate in 2% of pups and a dose of 200 mg/kg/day caused it in 9%. This may be due to a decrease in methionine levels, according to a study published in March 2001. In 2005, a study conducted at the University of Catania was published stating that rats whose mothers had consumed 250–1000 mg/kg/day had poorer performance in the water maze and open-field tasks, rats in the 750-mg group were underweight at birth and did not catch up to the control group, and rats in the 1000 mg group did not survive pregnancy.There is no controlled teratology data in humans to date.

Sensory
In 2003, vigabatrin was shown by Frisén and Malmgren to cause irreversible diffuse atrophy of the retinal nerve fiber layer in a retrospective study of 25 patients. This has the most effect on the outer area (as opposed to the macular, or central area) of the retina.
Visual field defects had been reported as early as 1997 by Tom Eke and others, in the UK. Some authors, including Comaish et al. believe that visual field loss and electrophysiological changes may be demonstrable in up to 50% of Vigabatrin users.
The retinal toxicity of vigabatrin can be attributed to a taurine depletion.Due to safety issues, the Vigabatrin REMS Program is required by the FDA to ensure informed decisions before initiating and to ensure appropriate use of this drug.

Interactions
A study published in 2002 found that vigabatrin causes a statistically significant increase in plasma clearance of carbamazepine.In 1984, Drs Rimmer and Richens at the University of Wales reported that administering vigabatrin with phenytoin lowered the serum phenytoin concentration in patients with treatment-resistant epilepsy. Five years later, the same two scientists reported a fall in concentration of phenytoin of 23% within five weeks in a paper describing their failed attempt at elucidating the mechanism behind this interaction.

Pharmacology
Vigabatrin is an irreversible mechanism-based inhibitor of gamma-aminobutyric acid aminotransferase (GABA-AT), the enzyme responsible for the catabolism of GABA. Inhibition of GABA-AT results in increased levels of GABA in the brain. Vigabatrin is a racemic compound, and its [S]-enantiomer is pharmacologically active.,

Pharmacokinetics
With most drugs, elimination half-life is a useful predictor of dosing schedules and the time needed to reach steady state concentrations. In the case of vigabatrin, however, it has been found that the half-life of biologic activity is far longer than the elimination half-life.For vigabatrin, there is no range of target concentrations because researchers found no difference between the serum concentration levels of responders and those of non-responders. Instead, the duration of action is believed to be more a function of the GABA-T resynthesis rate; levels of GABA-T do not usually return to their normal state until six days after stopping the medication.

History
Vigabatrin was developed in the 1980s with the specific goal of increasing GABA concentrations in the brain in order to stop an epileptic seizure. To do this, the drug was designed to irreversibly inhibit the GABA transaminase, which degrades the GABA substrate </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 Fluvoxamine and explain in detail? [/INST] Fluvoxamine, sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and obsessive–compulsive disorder (OCD), but is also used to treat anxiety disorders such as panic disorder, social anxiety disorder, and post-traumatic stress disorder.Fluvoxamines side-effect profile is very similar to other SSRIs: constipation, gastrointestinal problems, headache, anxiety, irritation, sexual problems, dry mouth, sleep problems and a risk of suicide at the start of treatment by lifting the psychomotor inhibition, but these effects appear to be significantly weaker than with other SSRIs (except gastrointestinal side-effects). The tolerance profile is superior in some respects to other SSRIs, particularly with respect to cardiovascular complications, despite its age.It is on the World Health Organizations List of Essential Medicines.

Medical uses
In many countries (e.g., Australia, the UK, and Russia) it is commonly used for major depressive disorder. Fluvoxamine is also approved in the United States for OCD, and social anxiety disorder. In Japan it is also approved to treat OCD, social anxiety disorder and MDD. Fluvoxamine is indicated for children and adolescents with OCD. The drug works long-term, and retains its therapeutic efficacy for at least one year. It has also been found to possess some analgesic properties in line with other SSRIs and tricyclic antidepressants.There is tentative evidence that fluvoxamine is effective for social phobia in adults. Fluvoxamine is also effective for GAD, social anxiety disorder, panic disorder and separation anxiety disorder in children and adolescents. There is tentative evidence that fluvoxamine may help some people with negative symptoms of chronic schizophrenia.

Adverse effects
Gastrointestinal side effects are more common in those receiving fluvoxamine than with other SSRIs. Otherwise, fluvoxamines side-effect profile is very similar to other SSRIs.

Common (1–10% incidence) adverse effects
Uncommon (0.1–1% incidence) adverse effects
Rare (0.01–0.1% incidence) adverse effects
Unknown frequency adverse effects
Interactions
Fluvoxamine inhibits the following cytochrome P450 enzymes:
CYP1A2 (strongly) which metabolizes agomelatine, amitriptyline, caffeine, clomipramine, clozapine, duloxetine, haloperidol, imipramine, phenacetin, tacrine, tamoxifen, theophylline, olanzapine, etc.
CYP3A4 (moderately) which metabolizes alprazolam, aripiprazole, clozapine, haloperidol, quetiapine, pimozide, ziprasidone, etc.
CYP2D6 (weakly) which metabolizes aripiprazole, chlorpromazine, clozapine, codeine, fluoxetine, haloperidol, olanzapine, oxycodone, paroxetine, perphenazine, pethidine, risperidone, sertraline, thioridazine, zuclopenthixol, etc.
CYP2C9 (moderately) which metabolizes nonsteroidal anti-inflammatory drugs, phenytoin, sulfonylureas, etc.
CYP2C19 (strongly) which metabolizes clonazepam, diazepam, phenytoin, etc.
CYP2B6 (weakly) which metabolizes bupropion, cyclophosphamide, sertraline, tamoxifen, valproate, etc.By so doing, fluvoxamine can increase serum concentration of the substrates of these enzymes.The plasma levels of oxidatively metabolized benzodiazepines (e.g., triazolam, midazolam, alprazolam and diazepam) are likely to be increased when co-administered with fluvoxamine. However the clearance of benzodiazepines metabolized by glucuronidation (e.g., lorazepam, oxazepam, temazepam) is unlikely to be affected by fluvoxamine. It appears that benzodiazepines metabolized by nitro-reduction (clonazepam, nitrazepam) are unlikely to be affected by fluvoxamine. Using fluvoxamine and alprazolam together can increase alprazolam plasma concentrations. If alprazolam is coadministered with fluvoxamine, the initial alprazolam dose should be reduced to the lowest effective dose.Fluvoxamine and ramelteon coadministration is not indicated.Fluvoxamine has been observed to increase serum concentrations of mirtazapine, which is mainly metabolized by CYP1A2, CYP2D6, and CYP3A4, by three- to four-fold in humans. Caution and adjustment of dosage as necessary are warranted when combining fluvoxamine and mirtazapine.Fluvoxamine seriously affects the pharmacokinetics of tizanidine and increases the intensity and duration of its effects. Because of the potentially hazardous consequences, the concomitant use of tizanidine with fluvoxamine, or other potent inhibitors of CYP1A2, should be avoided.

Pharmacology
Fluvoxamine is a potent selective serotonin reuptake inhibitor with around 100-fold affinity for the serotonin transporter over the norepinephrine transporter. It has negligible affinity for the dopamine transporter or any other site, with the sole exception of the σ1 receptor. It behaves as a potent agonist at this receptor and has the highest affinity (36 nM) of any SSRI for doing so. This may contribute to its antidepressant and anxiolytic effects and may also afford it some efficacy in treating the cognitive symptoms of depression. Unlike some other SSRI, fluvoxamines metabolites are pharmacologically neutral.

History
Fluvoxamine was developed by Kali-Duphar, part of Solvay Pharmaceuticals, Belgium, now Abbott Laboratories, and introduced as Floxyfral in Switzerland in 1983. It was approved by the U.S. Food and Drug Administration (FDA) in 1994, and introduced as Luvox in the US. In India, it is available, among several other brands, as Uvox by Abbott. It was one of the first SSRI antidepressants to be launched, and is prescribed in many countries to patients with major depression. It was the first SSRI, a non-TCA drug, approved by the U.S. FDA specifically for the treatment of OCD. At the end of 1995, more than ten million patients worldwide had been treated with fluvoxamine. Fluvoxamine was the first SSRI to be registered for the treatment of obsessive compulsive disorder in children by the FDA in 1997 </s>