<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Temazepam and can you explain it in depth? [/INST] Temazepam (sold under the brand names Restoril among others) is a medication of the benzodiazepine class which is now generally used to treat severe or debilitating insomnia. Such use should generally be for less than ten days. It is taken by mouth. Temazepam is rapidly absorbed, and significant hypnotic effects begin in less than 30 minutes and can last for up to eight hours. Many studies, some going as far back as the early 1980s out of Australia and the United Kingdom, both of which have had serious temazepam abuse epidemics and related mortality, have all mostly corroborated each other and proven that the potential for abuse and physical dependence is very high, even in comparison to many other benzodiazepines. As a result, prescriptions for hypnotics such as temazepam have seen a dramatic decrease since 2010, while anxiolytics such as alprazolam (Xanax), clonazepam (Rivitrol, Klonopin), and lorazepam (Ativan) have increased or remained stable. Temazepam and similar hypnotics, such as triazolam (Halcion) are generally reserved for severe and debilitating insomnia. They have largely been replaced by z-drugs (zopiclone, zolpidem) and atypical antidepressants (trazodone, mirtazapine) as first line treatment for insomnia. Even when a benzodiazepine is required, in many cases, smaller doses of anxiolytics such as diazepam (Valium) or alprazolam (Xanax) are recommended over hypnotic agents.Common side effects include drowsiness, motor and cognitive impairment, lethargy, confusion, euphoria, and dizziness. Serious side effects may include hallucinations, hypotension, respiratory depression, abuse, anaphylaxis, and suicide. Use is generally not recommended together with alcohol or opioids. If the dose is rapidly decreased withdrawal may occur. Use during pregnancy or breastfeeding is not recommended. Temazepam is a short-acting benzodiazepine and hypnotic. It works by affecting GABA within the brain.Temazepam was patented in 1962 and came into medical use in 1969. It is available as a generic medication. In 2019, it was the 214th most commonly prescribed medication in the United States, with more than 2 million prescriptions.

Medical uses
In sleep laboratory studies, temazepam significantly decreased the number of nightly awakenings, but has the drawback of distorting the normal sleep pattern.  It is officially indicated for severe insomnia and other severe or disabling sleep disorders. The prescribing guidelines in the UK limit the prescribing of hypnotics to two to four weeks due to concerns of tolerance and dependence.The American Academy of Sleep Medicines 2017 clinical practice guidelines recommended the use of temazepam in the treatment of sleep-onset and sleep-maintenance insomnia. It rated the recommendation as weak, the quality of evidence as moderate, and concluded that the potential benefits outweighed the potential harms. The guidelines found that temazepam at a dose of 15 mg reduces sleep latency by 37 minutes (95% CI 21 to 53 minutes), increases total sleep time by 99 minutes (95% CI 63 to 135 minutes), and provides a small improvement to sleep quality. The improvements in sleep latency and total sleep time were numerically much greater than any of the other included sleep medications, including eszopiclone, zopiclone, zolpidem, triazolam, estazolam, quazepam, flurazepam, trazodone, diphenhydramine, gabapentin, among others.The United States Air Force uses temazepam as one of the hypnotics approved as a "no-go pill" to help aviators and special-duty personnel sleep in support of mission readiness. "Ground tests" are necessary prior to required authorization being issued to use the medication in an operational situation, and a 12-hour restriction is imposed on subsequent flight operation. The other hypnotics used as "no-go pills" are zaleplon and zolpidem, which have shorter mandatory recovery periods.

Available forms
Temazepam is available in the form of 7.5, 15, 22.5, and 30 mg oral capsules in North America (Canada and United States). Although banned in some European countries (Norway, Sweden), it is available in most other European countries and the rest of the world, including in Australia and New Zealand, as 5, 10, 15 and 20 mg tablets or capsules.

Contraindications
Use of temazepam should be avoided, when possible, in individuals with these conditions:

Ataxia (gross lack of coordination of muscle movements)
Severe hypoventilation
Acute narrow-angle glaucoma
Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of two)
Severe renal deficiencies (e.g. patients on dialysis)
Sleep apnea
Severe depression, particularly when accompanied by suicidal tendencies
Acute intoxication with alcohol, narcotics, or other psychoactive substances
Myasthenia gravis (autoimmune disorder causing muscle weakness)
Hypersensitivity or allergy to any drug in the benzodiazepine class

Special caution needed
Temazepam should not be used in pregnancy, as it may cause harm to the fetus. The safety and effectiveness of temazepam has not been established in children; therefore, temazepam should generally not be given to individuals under 18 years of age, and should not be used at all in children under six months old. Benzodiazepines also require special caution if used in the elderly, alcohol- or drug-dependent individuals, and individuals with comorbid psychiatric disorders.Temazepam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial but incomplete tolerance develops to these impairments. The smallest possible effective dose should be used in elderly or very ill patients, as a risk of apnea and/or cardiac arrest exists. This risk is increased when temazepam is given concomitantly with other drugs that depress the central nervous system (CNS).

Misuse and dependence
Because benzodiazepines can be abused and lead to dependence, their use should be avoided in people in certain particularly high-risk groups. These groups include people with a history of alcohol or drug dependence, people significantly struggling with their mood or people with longstanding mental health difficulties. If temazepam must be prescribed to people in these groups, they should generally be monitored very closely for signs of misuse and development of dependence.

Adverse effects
In September 2020, the U.S. Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Common
Side effects typical of hypnotic benzodiazepines are related to CNS depression, and include somnolence, sedation, dizziness, fatigue, ataxia, headache, lethargy, impairment of memory and learning, longer reaction time and impairment of motor functions (including coordination problems), slurred speech, decreased physical performance, numbed emotions, reduced alertness, muscle weakness, blurred vision (in higher doses), and inattention. Euphoria was rarely reported with its use. According to the U.S. Food and Drug Administration, temazepam had an incidence of euphoria of 1.5%, much more rarely reported than headaches and diarrhea. Anterograde amnesia may also develop, as may respiratory depression in higher doses.
A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking Temazepam or other hypnotic drugs compared to those taking a placebo.

Less common
Hyperhydrosis, hypotension, burning eyes, increased appetite, changes in libido, hallucinations, faintness, nystagmus, vomiting, pruritus, gastrointestinal disturbances, nightmares, palpitation and paradoxical reactions including restlessness, aggression, violence, overstimulation and agitation have been reported, but are rare (less than 0.5%).
Before taking temazepam, one should ensure that at least 8 hours are available to dedicate to sleep. Failing to do so can increase the side effects of the drug.
Like all benzodiazepines, the use of this drug in combination with alcohol potentiates the side effects, and can lead to toxicity and death.
Though rare, residual "hangover" effects after night-time administration of temazepam occasionally occur. These include sleepiness, impaired psychomotor and cognitive functions which may persist into the next day, impaired driving ability, and possible increased risks of falls and hip fractures, especially in the elderly.

Tolerance
Chronic or excessive use of temazepam may cause drug tolerance, which can develop rapidly, so this drug is not recommended for long-term use. In 1979, the Institute of Medicine (USA) and the National Institute on Drug Abuse stated that most hypnotics lose their sleep-inducing properties after about three to 14 days. In use longer than one to two weeks, tolerance will rapidly develop towards the ability of temazepam to maintain sleep, resulting in a loss of effectiveness. Some studies have observed tolerance to temazepam after as little as one weeks use. Another study examined the short-term effects of the accumulation of temazepam over seven days in elderly inpatients, and found little tolerance developed during the accumulation of the drug. Other studies examined the use of temazepam over six days and saw no evidence of tolerance. A study in 11 young male subjects showed significant tolerance occurs to temazepams thermoregulatory effects and sleep inducing properties after one week of use of 30-mg temazepam. Body temperature is well correlated with the sleep-inducing or insomnia-promoting properties of drugs.In one study, the drug sensitivity of people who had used temazepam for one to 20 years was no different from that of controls. An additional study, in which at least one of the authors is employed by multiple drug companies, examined the efficacy of temazepam treatment on chronic insomnia over three months, and saw no drug tolerance, with the authors even suggesting the drug might become more effective over time.Establishing continued efficacy beyond a few weeks can be complicated by the difficulty in distinguishing between the return of the original insomnia complaint and withdrawal or rebound related insomnia. Sleep EEG studies on hypnotic benzodiazepines show tolerance tends to occur completely after one to four weeks with sleep EEG returning to pretreatment levels. The paper concluded that due to concerns about long-term use involving toxicity, tolerance and dependence, as well as to controversy over long-term efficacy, wise prescribers should restrict benzodiazepines to a few weeks and avoid continuing prescriptions for months or years. A review of the literature found the nonpharmacological treatment options were a more effective treatment option for insomnia due to their sustained improvements in sleep quality.

Physical dependence
Temazepam, like other benzodiazepine drugs, can cause physical dependence and addiction. Withdrawal from temazepam or other benzodiazepines after regular use often leads to benzodiazepine withdrawal syndrome, which resembles symptoms during alcohol and barbiturate withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can also occur from standard dosages and after short-term use. Abrupt withdrawal from therapeutic doses of temazepam after long-term use may result in a severe benzodiazepine withdrawal syndrome. Gradual and careful reduction of the dosage, preferably with a long-acting benzodiazepine with long half-life active metabolites, such as chlordiazepoxide or diazepam, are recommended to prevent severe withdrawal syndromes from developing. Other hypnotic benzodiazepines are not recommended. A study in rats found temazepam is cross tolerant with barbiturates and is able to effectively substitute for barbiturates and suppress barbiturate withdrawal signs.
Rare cases are reported in the medical literature of psychotic states developing after abrupt withdrawal from benzodiazepines, even from therapeutic doses. Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions.
Patients who were treated in the hospital with temazepam or nitrazepam have continued taking these after leaving the hospital. Hypnotic uses in the hospital were recommended to be limited to five nights use only, to avoid the development of withdrawal symptoms such as insomnia.

Interactions
As with other benzodiazepines, temazepam produces additive CNS-depressant effects when coadministered with other medications which themselves produce CNS depression, such as barbiturates, alcohol, opiates, tricyclic antidepressants, nonselective MAO inhibitors, phenothiazines and other antipsychotics, skeletal muscle relaxants, antihistamines, and anaesthetics. Administration of theophylline or aminophylline has been shown to reduce the sedative effects of temazepam and other benzodiazepines.
Unlike many benzodiazepines, pharmacokinetic interactions involving the P450 system have not been observed with temazepam. Temazepam shows no significant interaction with CYP3A4 inhibitors (e.g. itraconazole, erythromycin). Oral contraceptives may decrease the effectiveness of temazepam and speed up its elimination half-life.

Overdose
Overdosage of temazepam results in increasing CNS effects, including:

Somnolence (difficulty staying awake)
Mental confusion
Respiratory depression
Hypotension
Impaired motor functions
Impaired or absent reflexes
Impaired coordination
Impaired balance
Dizziness, sedation
Coma
DeathTemazepam had the highest rate of drug intoxication, including overdose, among common benzodiazepines in cases with and without combination with alcohol in a 1985 study. Temazepam and nitrazepam were the two benzodiazepines most commonly detected in overdose-related deaths in an Australian study of drug deaths. A 1993 British study found temazepam to have the highest number of deaths per million prescriptions among medications commonly prescribed in the 1980s (11.9, versus 5.9 for benzodiazepines overall, taken with or without alcohol).A 1995 Australian study of patients admitted to hospital after benzodiazepine overdose corroborated these results, and found temazepam overdose much more likely to lead to coma than other benzodiazepines (odds ratio 1.86). The authors noted several factors, such as differences in potency, receptor affinity, and rate of absorption between benzodiazepines, could explain this higher toxicity.  Although benzodiazepines have a high therapeutic index, temazepam is one of the more dangerous of this class of drugs. The combination of alcohol and temazepam makes death by alcohol poisoning more likely.

Pharmacology
Pharmacodynamics
The main pharmacological action of temazepam is to increase the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor. This causes sedation, motor impairment, ataxia, anxiolysis, an anticonvulsant effect, muscle relaxation, and a reinforcing effect.As a medication before surgery, temazepam decreased cortisol in elderly patients. In rats, it triggered the release of vasopressin into paraventricular nucleus of the hypothalamus and decreased the release of ACTH under stress.

Pharmacokinetics
Oral administration of 15 to 45 mg of temazepam in humans resulted in rapid absorption with significant blood levels achieved in fewer than 30 minutes and peak levels at two to three hours.In a single- and multiple-dose absorption, distribution, metabolism, and excretion (ADME) study, using tritium-labelled drug, temazepam was well absorbed and found to have minimal (8%) first-pass drug metabolism. No active metabolites were formed and the only significant metabolite present in blood was the O-conjugate.  The unchanged drug was 96% bound to plasma proteins. The blood-level decline of the parent drug was biphasic, with the short half-life ranging from 0.4 to 0.6 hours and the terminal half-life from 3.5 to 18.4 hours (mean 8.8 hours), depending on the study population and method of determination.Temazepam has very good bioavailability, with almost 100% being absorbed following being taken by mouth. The drug is metabolized through conjugation and demethylation prior to excretion. Most of the drug is excreted in the urine, with about 20% appearing in the faeces. The major metabolite was the O-conjugate of temazepam (90%); the O-conjugate of N-desmethyl temazepam was a minor metabolite (7%).

Chemistry
Temazepam is a benzodiazepine. It is a white, crystalline substance, very slightly soluble in water, and sparingly soluble in alcohol.

Synthesis
Pharmacologically active metabolite of diazepam, q.v.

N-oxides are prone to undergo the Polonovski rearrangement when treated with acetic anhydride, and this was illustrated by the synthesis of oxazepam. It is not surprising that the N-methyl analogue (1) also undergoes this process, and hydrolysis of the resulting acetate gives temazepam (2). Care must be exacted with the conditions, or the inactive rearrangement product (3) results.

History
Temazepam was synthesized in 1964, but it came into use in 1981 when its ability to counter insomnia was realized. By the late 1980s, temazepam was one of the most popular and widely prescribed hypnotics on the market and it became one of the most widely prescribed drugs.

Society and culture
Recreational use
Temazepam is a drug with a high potential for misuse.Benzodiazepines have been abused orally and intravenously. Different benzodiazepines have different abuse potential; the more rapid the increase in the plasma level following ingestion, the greater the intoxicating effect and the more open to abuse the drug becomes. The speed of onset of action of a particular benzodiazepine correlates well with the popularity of that drug for abuse. The two most common reasons for preference were that a benzodiazepine was strong and that it gave a good high.A 1995 study found that temazepam is more rapidly absorbed and oxazepam is more slowly absorbed than most other benzodiazepines.A 1985 study found that temazepam and triazolam maintained significantly higher rates of self-injection than a variety of other benzodiazepines. The study tested and compared the abuse liability of temazepam, triazolam, diazepam, lorazepam, oxazepam, flurazepam, alprazolam, chlordiazepoxide, clonazepam, nitrazepam, flunitrazepam, bromazepam, and clorazepate. The study tested self-injection rates on human, baboon, and rat subjects. All test subjects consistently showed a strong preference for temazepam and triazolam over all the rest of the benzodiazepines included in the study.

North America
In North America, temazepam misuse is not widespread. Other benzodiazepines are more commonly prescribed for insomnia. In the United States, temazepam is the fifth-most prescribed benzodiazepine, however there is a major drop off from the top four most prescribed (alprazolam, lorazepam, diazepam, and clonazepam in that order). Individuals abusing benzodiazepines obtain the drug by getting prescriptions from several doctors, forging prescriptions, or buying diverted pharmaceutical products on the illicit market.  North America has never had a serious problem with temazepam misuse, but is becoming increasingly vulnerable to the illicit trade of temazepam.

Australia
Temazepam is a Schedule 4 drug and requires a prescription. The drug accounts for most benzodiazepine sought by forgery of prescriptions and through pharmacy burglary in Victoria. Due to rife intravenous abuse, the Australian government decided to put it under a more restrictive schedule than it had been, and since March 2004 temazepam capsules have been withdrawn from the Australian market, leaving only 10 mg tablets available.Benzodiazepines are commonly detected by Customs at different ports and airports, arriving by mail, also found occasionally in the baggage of air passengers, mostly small or medium quantities (up to 200–300 tablets) for personal use. From 2003 to 2006, customs detected about 500 illegal importations of benzodiazepines per year, most frequently diazepam. Quantities varied from single tablets to 2,000 tablets.

United Kingdom
In 1987, temazepam was the most widely abused legal prescription drug in the United Kingdom. The use of benzodiazepines by street-drug abusers was part of a polydrug abuse pattern, but many of those entering treatment facilities were declaring temazepam as their main drug of abuse. Temazepam was the most commonly used benzodiazepine in a study, published 1994, of injecting drug users in seven cities, and had been injected from preparations of capsules, tablets, and syrup. The increase in use of heroin, often mixed with other drugs, which most often included temazepam, diazepam, and alcohol, was a major factor in the increase in drug-related deaths in Glasgow and Edinburgh in 1990–1992. Temazepam use was particularly associated with violent or disorderly behaviours and contact with the police in a 1997 study of young single homeless people in Scotland. The BBC series Panorama featured an episode titled "Temazepam Wars", dealing with the epidemic of temazepam abuse and directly related crime in Paisley, Scotland. The trend was mocked in the 1995 Black Grape song "Temazi Party" (also called "Tramazi Party").

Medical research issues
The Journal of Clinical Sleep Medicine published a paper expressing concerns about benzodiazepine receptor agonist drugs, the benzodiazepines and the Z-drugs used as hypnotics in humans. The paper cites a systematic review of the medical literature concerning insomnia medications and states almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry, while this is not the case in general medicine or psychiatry. It cites another study that "found that the odds ratio for finding results favorable to industry in industry-sponsored trials was 3.6 times as high as in non–industry-sponsored studies". Issues discussed regarding industry-sponsored studies include: comparison of a drug to a placebo, but not to an alternative treatment; unpublished studies with unfavorable outcomes; and trials organized around a placebo baseline followed by drug treatment, but not counterbalanced with parallel-placebo-controlled studies. Quoting a 1979 report that too little research into hypnotics was independent of the drug manufacturers, the authors conclude, "the public desperately needs an equipoised assessment of hypnotic benefits and risks" and the NIH and VA should provide leadership to that end.

Street terms
Street terms for temazepam include king kong pills (formerly referred to barbiturates, now more commonly refers to temazepam), jellies, jelly, Edinburgh eccies, tams, terms, mazzies, temazies, tammies, temmies, beans, eggs, green eggs, wobbly eggs, knockouts, hardball, norries, oranges (common term in Australia and New Zealand), rugby balls, ruggers, terminators, red and blue, no-gos, num nums, blackout, green devils, drunk pills, brainwash, mind erasers, neurotrashers, tem-tems (combined with buprenorphine), mommys big helper, vitamin T, big T, TZ, the mazepam, resties (North America) and others.

Availability
Temazepam is available in English-speaking countries under the following brand names:

Euhypnos
Normison
Norkotral
Nortem
Remestan
Restoril
Temaze
Temtabs
In Spain, the drug is sold as temzpem. In Hungary the drug is sold as Signopam.

Legal status
In Austria, temazepam is listed in UN71 Schedule III under the Psychotropic Substances Decree of 1997. The drug is considered to have a high potential for abuse and addiction, but has accepted medical use for the treatment of severe insomnia.In Australia, temazepam is a Schedule 4 - Prescription Only medicine. It is primarily used for the treatment of insomnia, and is also seen as pre-anaesthetic medication.In Canada, temazepam is a Schedule IV controlled substance requiring a registered doctors prescription.In Denmark, temazepam is listed as a Class D substance under the Executive Order 698 of 1993 on Euphoric Substances which means it has a high potential for abuse, but is used for medical and scientific purposes.In Finland, temazepam is more tightly controlled than other benzodiazepines. The temazepam product Normison was pulled out of shelves and banned because the liquid inside gelatin capsules had caused a large increase in intravenous temazepam use. The other temazepam product, Tenox, was not affected and remains as prescription medicine. Temazepam intravenous use has not decreased to the level before Normison came to the market.In France, temazepam is listed as a psychotropic substance as are other similar drugs. It is prescribed with a nonrenewable prescription (a new doctor visit every time), available only in 7 or 14-pill packaging for one or two weeks. One brand was withdrawn from the market in 2013.In Hong Kong, temazepam is regulated under Schedule 1 of Hong Kongs Chapter 134 Dangerous Drugs Ordinance. Temazepam can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined HKD$10,000. The penalty for trafficking or manufacturing the substance is a $5,000,000-fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000-fine and/or seven years of jail time.In Ireland, temazepam is a Schedule 3 controlled substance with strict restrictions.In the Netherlands, temazepam is available for prescription as 10- or 20-mg tablets and capsules. Formulations of temazepam containing less than 20 mg are included in List 2 of the Opium Law, while formulations containing 20 mg or more of the drug (along with the gel-capsules) are a List 1 substance of the Opium Law, thus subject to more stringent regulation. Besides being used for insomnia, it is also occasionally used as a preanesthetic medication.In Norway, temazepam is not available as a prescription drug. It is regulated as a Class A substance under Norways Narcotics Act.In Portugal, temazepam is a Schedule IV controlled drug under Decree-Law 15/93.In Singapore, temazepam is a Class A controlled drug (Schedule I), making it illegal to possess and requiring a private prescription from a licensed physician to be dispensed.
In Slovenia, it is regulated as a Group II (Schedule 2) controlled substance under the Production and Trade in Illicit Drugs Act.In South Africa, temazepam is a Schedule 5 drug, requiring a special prescription, and is restricted to 10– to 30-mg doses.In Sweden, temazepam is classed as a "narcotic" drug listed as both a List II (Schedule II) which denotes it is a drug with limited medicinal use and a high risk of addiction, and is also listed as a List V (Schedule V) substance which denotes the drug is prohibited in Sweden under the Narcotics Drugs Act (1968) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Acetazolamide and can you explain it in depth? [/INST] Acetazolamide, sold under the trade name Diamox among others, is a medication used to treat glaucoma, epilepsy, altitude sickness, periodic paralysis, idiopathic intracranial hypertension (raised brain pressure of unclear cause), urine alkalinization, and heart failure. It may be used long term for the treatment of open angle glaucoma and short term for acute angle closure glaucoma until surgery can be carried out. It is taken by mouth or injection into a vein. Acetazolamide is a first generation carbonic anhydrase inhibitor and it decreases the ocular fluid and osmolality in the eye to decrease intraocular pressure.Common side effects include numbness, ringing in the ears, loss of appetite, vomiting, and sleepiness. It is not recommended in those with significant kidney problems, liver problems, or who are allergic to sulfonamides. Acetazolamide is in the diuretic and carbonic anhydrase inhibitor families of medication. It works by decreasing the formation of hydrogen ions and bicarbonate from carbon dioxide and water.Acetazolamide came into medical use in 1952. It is on the World Health Organizations List of Essential Medicines. Acetazolamide is available as a generic medication.

Medical uses
It is used in the treatment of glaucoma, drug-induced edema, heart failure-induced edema, epilepsy and in reducing intraocular pressure after surgery. It has also been used in the treatment of altitude sickness, Ménières disease, increased intracranial pressure and neuromuscular disorders.In epilepsy, the main use of acetazolamide is in menstrual-related epilepsy and as an add on to other treatments in refractory epilepsy. Though various websites on the internet report that acetazolamide can be used to treat dural ectasia in individuals with Marfan Syndrome, the only supporting evidence for this assertion exists from a small study of 14 patients which was not peer-reviewed or submitted for publication. Several published cases of intracranial hypotension related to Marfan syndrome would warrant caution in using acetazolamide in these patients unless there is a clear indication, as it could lower intracranial pressure further. A 2012 review and meta-analysis found that there was "limited supporting evidence" but that acetazolamide "may be considered" for the treatment of central (as opposed to obstructive) sleep apnea.It has also been used to prevent methotrexate-induced kidney damage by alkalinizing the urine, hence speeding up methotrexate excretion by increasing its solubility in urine. There is some evidence to support its use to prevent hemiplegic migraine.

Open-Angle Glaucoma
Acetazolamide is used in the treatment of open-angle glaucoma. The carbonic anhydrase inhibitor is able to decrease ocular fluid and osmolality of the fluid in the humor of the eye and decrease intraocular pressure in the eye. The medication comes in the form of an oral tablet used for this indication.

High altitude sickness
Acetazolamide is also used for the treatment of acute mountain sickness. In the prevention or treatment of mountain sickness, acetazolamide inhibits the ability of the kidneys to reabsorb bicarbonate, the conjugate base of carbonic acid. Increasing the amount of bicarbonate excreted in the urine leads to acidification of the blood. Because the body senses CO2 concentration indirectly via blood pH (increase in CO2 causes a decrease in pH), acidifying the blood through decreased renal reabsorption of bicarbonate is sensed as an increase in CO2. This, in turn, causes the body to increase minute ventilation (the amount of air breathed per minute) in order to "breathe off" CO2, which in turn increases the amount of oxygen in the blood. Acetazolamide is not an immediate cure for acute mountain sickness; rather, it speeds up (or, when taking before traveling, forces the body to early start) part of the acclimatization process which in turn helps to relieve symptoms. Acetazolamide is still effective if started early in the course of mountain sickness. As prevention, it is started one day before travel to altitude and continued for the first 2 days at altitude.

Pregnancy and lactation
Acetazolamide is pregnancy category B3 in Australia, which means that studies in rats, mice and rabbits in which acetazolamide was given intravenously or orally caused an increased risk of fetal malformations, including defects of the limbs. Despite this, there is insufficient evidence from studies in humans to either support or discount this evidence.Limited data are available on the effects of nursing mothers taking acetazolamide. Therapeutic doses create low levels in breast milk and are not expected to cause problems in infants.

Side effects
Common adverse effects of acetazolamide include the following: paraesthesia, fatigue, drowsiness, depression, decreased libido, bitter or metallic taste, nausea, vomiting, abdominal cramps, diarrhea, black stool, polyuria, kidney stones, metabolic acidosis and electrolyte changes (hypokalemia, hyponatremia). Whereas less common adverse effects include Stevens–Johnson syndrome, anaphylaxis and blood dyscrasias.

Contraindications
Contraindications include:
Hyperchloremic acidosis
Hypokalemia (low blood potassium)
Hyponatremia (low blood sodium)
Adrenal insufficiency
Impaired kidney function
Hypersensitivity to acetazolamide or other sulphonamides.
Marked liver disease or impairment of liver function, including cirrhosis because of the risk of development of hepatic encephalopathy. Acetazolamide decreases ammonia clearance.

Interactions
It is possible that it might interact with:
Amphetamines, because it increases the pH of the renal tubular urine, hence reducing the clearance of amphetamines.
Other carbonic anhydrase inhibitors — potential for additive inhibitory effects on carbonic anhydrase and hence potential for toxicity.
Ciclosporin, may increase plasma levels of ciclosporin.
Antifolates such as trimethoprim, methotrexate, pemetrexed and raltitrexed.
Hypoglycemics, acetazolamide can both increase or decrease blood glucose levels.
Lithium, increases excretion, hence reducing therapeutic effect.
Methenamine compounds, reduces the urinary excretion of methenamines.
Phenytoin, reduces phenytoin excretion, hence increasing the potential for toxicity.
Primidone, reduces plasma levels of primidone. Hence reducing anticonvulsant effect.
Quinidine, reduces urinary excretion of quinidine, hence increasing the potential for toxicity.
Salicylates, potential for severe toxicity.
Sodium bicarbonate, potential for kidney stone formation.
Anticoagulants, cardiac glycosides, may have their effects potentiated by acetazolamide.

Mechanism of action
Acetazolamide is a carbonic anhydrase inhibitor, hence causing the accumulation of carbonic acid. Carbonic anhydrase is an enzyme found in red blood cells and many other tissues that catalyses the following reaction:
H2CO3 ⇌ H2O + CO2hence lowering blood pH, by means of the following reaction that carbonic acid undergoes:
H2CO3 ⇌ HCO3− + H+which has a pKa of 6.3.The mechanism of diuresis involves the proximal tubule of the kidney. The enzyme carbonic anhydrase is found here, allowing the reabsorption of bicarbonate, sodium, and chloride. By inhibiting this enzyme, these ions are excreted, along with excess water, lowering blood pressure, intracranial pressure, and intraocular pressure. A general side effect of carbonic anhydrase inhibitors is loss of potassium due to this function. By excreting bicarbonate, the blood becomes acidic, causing compensatory hyperventilation with deep respiration (Kussmaul breathing), increasing levels of oxygen and decreasing levels of carbon dioxide in the blood.In the eye this results in a reduction in aqueous humour.Bicarbonate (HCO3−) has a pKa of 10.3 with carbonate (CO32−), far further from physiologic pH (7.35–7.45), and so it is more likely to accept a proton than to donate one, but it is also far less likely for it to do either, thus bicarbonate will be the major species at physiological pH.
Under normal conditions in the proximal convoluted tubule of the kidney, most of the carbonic acid (H2CO3) produced intracellularly by the action of carbonic anhydrase quickly dissociates in the cell to bicarbonate (HCO3−) and an H+ ion (a proton), as previously mentioned. The bicarbonate (HCO3−) exits at the basal portion of the cell via sodium (Na+) symport and chloride (Cl−) antiport and re-enters circulation, where it may accept a proton if blood pH decreases, thus acting as a weak, basic buffer. The remaining H+ left over from the intracellular production of carbonic acid (H2CO3) exits the apical (urinary lumen) portion of the cell by Na+ antiport, acidifying the urine </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Simeticone and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Adoxa and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Abacavir/lamivudine/zidovudine and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Pentosan polysulfate and can you explain it in depth? [/INST] Pentosan polysulfate (PPS) is a medication used for interstitial cystitis. It is a semi-synthetic polysulfated xylan.

Medical uses
Interstitial cystitis/painful bladder syndrome
Pentosan polysulfate may be used either by mouth or in the bladder to treat interstitial cystitis/painful bladder syndrome (IC/PBS). An older review found improvements in pain (36%), urgency (28%), and frequency (54%), but that it does not change the frequency of urination at night. More recent trials, however, found it to be of no benefit.

Osteoarthritis
PPS has been studied in knee osteoarthritis, though evidence to support such use is poor as of 2003. There is some theoretical evidence that it should help.

Adverse effects
Patients who have taken PPS orally report a variety of side effects, primarily gastrointestinal complaints such as diarrhea, heartburn, and stomach pain. Hair loss, headache, rash, and insomnia have also been reported. Due to Elmirons anticoagulant effects, some patients report bruising more easily. In some cases, patients are asked to stop taking the medication before any major surgical procedures to reduce the likelihood of bleeding. Recent report based on clinical observation hypothesizes that chronic exposure to PPS can cause retinal toxicity, mimicking pigmentary pattern dystrophy.

Mechanism of action
In IC, PPS is believed to work by providing a protective coating to the damaged bladder wall. PPS is similar in structure to the natural glycosaminoglycan coating of the inner lining of the bladder, and may replace or repair the lining, reducing its permeability.

History
The calcium salt of PPS was one of the first reported disease-modifying osteoarthritis drugs (DMOAD).

Names
The IUPAC name for pentosan polysulfate is [(2R,3R,4S,5R)-2-hydroxy-5-[(2S,3R,4S,5R)-5-hydroxy-3,4-disulfooxyoxan-2-yl]oxy-3-sulfooxyoxan-4-yl] hydrogen sulfate.There are 40 synonyms listed for pentosan polysulfate on PubChem including BAY-946, HOE-946, pentosan sulfuric polyester, polypentose sulfate, polysulfated xylan, PZ-68, SP-54, xylan SP54 and xylan sulfate.Various brand names include Elmiron (as sodium salt), Hemoclar, Anarthron, Fibrase, Fibrocid, Thrombocid and SP54. PPS capsules are sold in India under the brand names Comfora, Pentossan-100, Cystopen and For-IC </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Lopid and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Olanzapine and can you explain it in depth? [/INST] Olanzapine (sold under the trade name Zyprexa among others) is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is taken by mouth or by injection into a muscle.Common side effects include weight gain, movement disorders, dizziness, feeling tired, constipation, and dry mouth. Other side effects include low blood pressure with standing, allergic reactions, neuroleptic malignant syndrome, high blood sugar, seizures, and tardive dyskinesia. In older people with dementia, its use increases the risk of death. Use in the later part of pregnancy may result in a movement disorder in the baby for some time after birth. Although how it works is not entirely clear, it blocks dopamine and serotonin receptors.Olanzapine was patented in 1991 and approved for medical use in the United States in 1996. It is available as a generic medication. In 2019, it was the 185th most commonly prescribed medication in the United States, with more than 3 million prescriptions. Lilly also markets olanzapine in a fixed-dose combination with fluoxetine as olanzapine/fluoxetine (Symbyax).

Medical uses
Schizophrenia
The first-line psychiatric treatment for schizophrenia is antipsychotic medication, with olanzapine being one such medication. Olanzapine appears to be effective in reducing symptoms of schizophrenia, treating acute exacerbations, and treating early-onset schizophrenia. The usefulness of maintenance therapy, however, is difficult to determine, as more than half of people in trials quit before the 6-week completion date. Treatment with olanzapine (like clozapine) may result in increased weight gain and increased glucose and cholesterol levels when compared to most other second-generation antipsychotic drugs used to treat schizophrenia.

Comparison
The National Institute for Health and Care Excellence, the British Association for Psychopharmacology, and the World Federation of Societies for Biological Psychiatry suggest that little difference in effectiveness is seen between antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on a persons preference and the drugs side-effect profile. The U.S. Agency for Healthcare Research and Quality concludes that olanzapine is not different from haloperidol in the treatment of positive symptoms and general psychopathology, or in overall assessment, but that it is superior for the treatment of negative and depressive symptoms. It has a lower risk of causing movement disorders than typical antipsychotics.In a 2013 comparison of fifteen antipsychotic drugs in schizophrenia, olanzapine was ranked third in efficacy. It was 5% more effective than risperidone (fourth), 24-27% more effective than haloperidol, quetiapine, and aripiprazole, and 33% less effective than clozapine (first). A 2013 review of first-episode schizophrenia concluded that olanzapine is superior to haloperidol in providing a lower discontinuation rate, and in short-term symptom reduction, response rate, negative symptoms, depression, cognitive function, discontinuation due to poor efficacy, and long-term relapse, but not in positive symptoms or on the clinical global impressions (CGI) score. In contrast, pooled second-generation antipsychotics showed superiority to first-generation antipsychotics only against the discontinuation, negative symptoms (with a much larger effect seen among industry- compared to government-sponsored studies), and cognition scores. Olanzapine caused less extrapyramidal side effects and less akathisia, but caused significantly more weight gain, serum cholesterol increase, and triglyceride increase than haloperidol.A 2012 review concluded that among ten atypical antipsychotics, only clozapine, olanzapine, and risperidone were better than first-generation antipsychotics. A 2011 review concluded that neither first- nor second-generation antipsychotics produce clinically meaningful changes in CGI scores, but found that olanzapine and amisulpride produce larger effects on the PANSS and BPRS batteries than five other second-generation antipsychotics or pooled first-generation antipsychotics. A 2010 Cochrane systematic review found that olanzapine may have a slight advantage in effectiveness when compared to aripiprazole, quetiapine, risperidone, and ziprasidone. No differences in effectiveness were detected when comparing olanzapine to amisulpride and clozapine. A 2014 meta-analysis of nine published trials having minimum duration six months and median duration 52 weeks concluded that olanzapine, quetiapine, and risperidone had better effects on cognitive function than amisulpride and haloperidol.

Bipolar disorder
Olanzapine is recommended by the National Institute for Health and Care Excellence as a first-line therapy for the treatment of acute mania in bipolar disorder. Other recommended first-line treatments are haloperidol, quetiapine, and risperidone. It is recommended in combination with fluoxetine as a first-line therapy for acute bipolar depression, and as a second-line treatment by itself for the maintenance treatment of bipolar disorder.The Network for Mood and Anxiety Treatments recommends olanzapine as a first-line maintenance treatment in bipolar disorder and the combination of olanzapine with fluoxetine as second-line treatment for bipolar depression.A review on the efficacy of olanzapine as maintenance therapy in patients with bipolar disorder was published by Dando & Tohen in 2006. A 2014 meta-analysis concluded that olanzapine with fluoxetine was the most effective among nine treatments for bipolar depression included in the analysis.

Other uses
Olanzapine may be useful in promoting weight gain in underweight adult outpatients with anorexia nervosa. However, no improvement of psychological symptoms was noted.Olanzapine has been shown to be helpful in addressing a range of anxiety and depressive symptoms in individuals with schizophrenia and schizoaffective disorders, and has since been used in the treatment of a range of mood and anxiety disorders. Olanzapine is no less effective than lithium or valproate and more effective than placebo in treating bipolar disorder. It has also been used for Tourette syndrome and stuttering.Olanzapine has been studied for the treatment of hyperactivity, aggressive behavior, and repetitive behaviors in autism.Olanzapine is frequently prescribed off-label for the treatment of insomnia, including difficulty falling asleep and staying asleep, even though such use is not recommended. The daytime sedation experienced with olanzapine is generally comparable to quetiapine and lurasidone, which is a frequent complaint in clinical trials. In some cases, the sedation due to olanzapine impaired the ability of people to wake up at a consistent time every day. Some evidence of efficacy for treating insomnia is seen; however, side effects such as dyslipidemia and neutropenia, which may possibly be observed even at low doses, outweigh any potential benefits for insomnia that is not due to an underlying mental health condition.Olanzapine has been recommended to be used in antiemetic regimens in people receiving chemotherapy that has a high risk for vomiting.

Specific populations
Pregnancy and lactation
Olanzapine is associated with the highest placental exposure of any atypical antipsychotic. Despite this, the available evidence suggests it is safe during pregnancy, although the evidence is insufficiently strong to say anything with a high degree of confidence. Olanzapine is associated with weight gain, which according to recent studies, may put olanzapine-treated patients offspring at a heightened risk for neural tube defects (e.g. spina bifida). Breastfeeding in women taking olanzapine is advised against because olanzapine is secreted in breast milk, with one study finding that the exposure to the infant is about 1.8% that of the mother.

Elderly
Citing an increased risk of stroke, in 2004, the Committee on the Safety of Medicines in the UK issued a warning that olanzapine and risperidone, both atypical antipsychotic medications, should not be given to elderly patients with dementia. In the U.S., olanzapine comes with a black box warning for increased risk of death in elderly patients. It is not approved for use in patients with dementia-related psychosis. A BBC investigation in June 2008 found that this advice was being widely ignored by British doctors. Evidence suggested that the elderly are more likely to experience weight gain on olanzapine compared to aripiprazole and risperidone.

Adverse effects
The principal side effect of olanzapine is weight gain, which may be profound in some cases and/or associated with derangement in blood-lipid and blood-sugar profiles (see section metabolic effects). A 2013 meta-analysis of the efficacy and tolerance of 15 antipsychotic drugs (APDs) found that it had the highest propensity for causing weight gain out of the 15 APDs compared with an SMD of 0.74. Extrapyramidal side effects, although potentially serious, are infrequent to rare from olanzapine, but may include tremors and muscle rigidity.
Aripiprazole, asenapine, clozapine, quetiapine and olanzapine, in comparison to other antipsychotic drugs, are less frequently associated with hyperprolactinaemia. Although these drugs can cause transient or sustained hyperprolactinaemia, the risk is much lower. Owing to its partial dopaminergic agonist effect, aripiprazole is likely to reduce prolactin levels and, in some patients, can cause hypoprolactinaemia. Although olanzapine causes an early dose-related rise in prolactin, this is less frequent and less marked than that seen with haloperidol, and is usually transient. A rise in prolactin is seen in about half of patients on olanzapine compared to over 90% of those taking risperidone, and enduring increases were less frequent in those taking olanzapine.It is not recommended to be used by IM injection in acute myocardial infarction, bradycardia, recent heart surgery, severe hypotension, sick sinus syndrome, and unstable angina.Several patient groups are at a heightened risk of side effects from olanzapine and antipsychotics in general. Olanzapine may produce nontrivial high blood sugar in people with diabetes mellitus. Likewise, the elderly are at a greater risk of falls and accidental injury. Young males appear to be at heightened risk of dystonic reactions, although these are relatively rare with olanzapine. Most antipsychotics, including olanzapine, may disrupt the bodys natural thermoregulatory systems, thus permitting excursions to dangerous levels when situations (exposure to heat, strenuous exercise) occur.Other side effects include galactorrhea, amenorrhea, gynecomastia, and erectile dysfunction (impotence).

Paradoxical effects
Olanzapine is used therapeutically to treat serious mental illness. Occasionally, it can have the opposite effect and provoke serious paradoxical reactions in a small subgroup of people, causing unusual changes in personality, thoughts, or behavior; hallucinations and excessive thoughts about suicide have also been linked to olanzapine use.

Drug-induced OCD
Many different types of medication can create or induce pure obsessive-compulsive disorder (OCD) in patients who have never had symptoms before. A new chapter about OCD in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (2013) now specifically includes drug-induced OCD.

Metabolic effects
The US Food and Drug Administration (FDA) requires all atypical antipsychotics to include a warning about the risk of developing hyperglycemia and diabetes, both of which are factors in the metabolic syndrome. These effects may be related to the drugs ability to induce weight gain, although some reports have been made of metabolic changes in the absence of weight gain. Studies have indicated that olanzapine carries a greater risk of causing and exacerbating diabetes than another commonly prescribed atypical antipsychotic, risperidone. Of all the atypical antipsychotics, olanzapine is one of the most likely to induce weight gain based on various measures. The effect is dose dependent in humans and animal models of olanzapine-induced metabolic side effects. There are some case reports of olanzapine-induced diabetic ketoacidosis. Olanzapine may decrease insulin sensitivity, though one 3-week study seems to refute this. It may also increase triglyceride levels.Despite weight gain, a large multicenter, randomized National Institute of Mental Health study found that olanzapine was better at controlling symptoms because patients were more likely to remain on olanzapine than the other drugs. One small, open-label, nonrandomized study suggests that taking olanzapine by orally dissolving tablets may induce less weight gain, but this has not been substantiated in a blinded experimental setting.

Post-injection delirium/sedation syndrome
Postinjection delirium/sedation syndrome (PDSS) is a rare syndrome that is specific to the long-acting injectable formulation of olanzapine, olanzapine pamoate. The incidence of PDSS with olanzapine pamoate is estimated to be 0.07% of administrations, and is unique among other second-generation, long-acting antipsychotics (e.g. paliperidone palmitate), which do not appear to carry the same risk. PDSS is characterized by symptoms of delirium (e.g. confusion, difficulty speaking, and uncoordinated movements) and sedation. Most people with PDSS exhibit both delirium and sedation (83%). Although less specific to PDSS, a majority of cases (67%) involved a feeling of general discomfort. PDSS may occur due to accidental injection and absorption of olanzapine pamoate into the bloodstream, where it can act more rapidly, as opposed to slowly distributing out from muscle tissue. Using the proper, intramuscular-injection technique for olanzapine pamoate helps to decrease the risk of PDSS, though it does not eliminate it entirely. This is why the FDA advises that people who are injected with olanzapine pamoate be watched for 3 hours after administration, in the event that PDSS occurs.

Animal toxicology
Olanzapine has demonstrated carcinogenic effects in multiple studies when exposed chronically to female mice and rats, but not male mice and rats. The tumors found were in either the liver or mammary glands of the animals.

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, vertigo, numbness, or muscle pains may occur. Symptoms generally resolve after a short time.Tentative evidence indicates 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 of an overdose include tachycardia, agitation, dysarthria, decreased consciousness, and coma. Death has been reported after an acute overdose of 450 mg, but also survival after an acute overdose of 2000 mg. Fatalities generally have occurred with olanzapine plasma concentrations greater than 1000 ng/mL post mortem, with concentrations up to 5200 ng/mL recorded (though this might represent confounding by dead tissue, which may release olanzapine into the blood upon death). No specific antidote for olanzapine overdose is known, and even physicians are recommended to call a certified poison control center for information on the treatment of such a case.
Olanzapine is considered moderately toxic in overdose, more toxic than quetiapine, aripiprazole, and the SSRIs, and less toxic than the monoamine oxidase inhibitors and tricyclic antidepressants.

Interactions
Drugs or agents that increase the activity of the enzyme CYP1A2, notably tobacco smoke, may significantly increase hepatic first-pass clearance of olanzapine; conversely, drugs that inhibit CYP1A2 activity (examples: ciprofloxacin, fluvoxamine) may reduce olanzapine clearance. Carbamazepine, a known enzyme inducer, has decreased the concentration/dose ration of olanzapine by 33% compared to olanzapine alone. Another enzyme inducer, ritonavir, has also been shown to decrease the bodys exposure to olanzapine, due to its induction of the enzymes CYP1A2 and uridine 5-diphospho-glucuronosyltransferase (UGT).Probenecid increases the total exposure (area under the curve) and maximum plasma concentration of olanzapine. Although olanzapines metabolism includes the minor metabolic pathway of CYP2D6, the presence of the CYP2D6 inhibitor fluoxetine does not have a clinically significant effect on olanzapines clearance.

Pharmacology
Pharmacodynamics
Olanzapine was first discovered while searching for a chemical analog of clozapine that would not require hematological monitoring. Investigation on a series of thiophene isosteres on 1 of the phenyl rings in clozapine, a thienobenzodiazepine analog (olanzapine) was discovered.Olanzapine has a higher affinity for 5-HT2A serotonin receptors than D2 dopamine receptors, which is a common property of most atypical antipsychotics, aside from the benzamide antipsychotics such as amisulpride along with the nonbenzamides aripiprazole, brexpiprazole, blonanserin, cariprazine, melperone, and perospirone.
Olanzapine had the highest affinity of any second-generation antipsychotic towards the P-glycoprotein in one in vitro study. P-glycoprotein transports a myriad of drugs across a number of different biological membranes (found in numerous body systems) including the blood-brain barrier (a semipermeable membrane that filters the contents of blood prior to it reaching the brain); P-GP inhibition could mean that less brain exposure to olanzapine results from this interaction with the P-glycoprotein. A relatively large quantity of commonly encountered foods and medications inhibit P-GP, and pharmaceuticals fairly commonly are either substrates of P-GP, or inhibit its action; both substrates and inhibitors of P-GP effectively increase the permeability of the blood-brain barrier to P-GP substrates and subsequently increase the central activity of the substrate, while reducing the local effects on the GI tract. The mediation of olanzapine in the central nervous system by P-GP means that any other substance or drug that interacts with P-GP increases the risk for toxic accumulations of both olanzapine and the other drug.Olanzapine is a potent antagonist of the muscarinic M3 receptor, which may underlie its diabetogenic side effects.
Additionally, it also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites.The antagonistic effects of olanzapine at 5-HT2c, histaminergic H1, and muscarinic M3 receptors have been implicated in weight gain.The mode of action of olanzapines antipsychotic activity is unknown. It may involve antagonism of dopamine and serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia (TD), and with therapeutic effects. Antagonism of muscarinic acetylcholine receptors is associated with anticholinergic side effects such as dry mouth and constipation; in addition, it may suppress or reduce the emergence of extrapyramidal effects for the duration of treatment, but it offers no protection against the development of TD. In common with other second-generation (atypical) antipsychotics, olanzapine poses a relatively low risk of extrapyramidal side effects including TD, due to its higher affinity for the 5HT2A receptor over the D2 receptor.Antagonizing H1 histamine receptors causes sedation and may cause weight gain, although antagonistic actions at serotonin 5-HT2C and dopamine D2 receptors have also been associated with weight gain and appetite stimulation.

Pharmacokinetics
Metabolism
Olanzapine is metabolized by the cytochrome P450 (CYP) system; principally by isozyme 1A2 (CYP1A2) and to a lesser extent by CYP2D6. By these mechanisms, more than 40% of the oral dose, on average, is removed by the hepatic first-pass effect. Clearance of olanzapine appears to vary by sex; women have roughly 25% lower clearance than men. Clearance of olanzapine also varies by race; in self-identified African Americans or Blacks, olanzapines clearance was 26% higher. A difference in the clearance is not apparent between individuals identifying as Caucasian, Chinese, or Japanese. Routine, pharmacokinetic monitoring of olanzapine plasma levels is generally unwarranted, though unusual circumstances (e.g. the presence of drug-drug interactions) or a desire to determine if patients are taking their medicine may prompt its use.

Chemistry
Olanzapine is unusual in having four well-characterised crystalline polymorphs and many hydrated forms.

Chemical synthesis
The preparation of olanzapine was first disclosed in a series of patents from Eli Lilly & Co. in the 1990s. In the final two steps, 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile was reduced with stannous chloride in ethanol to give the substituted thienobenzodiazepine ring system, and this was treated with methylpiperazine in a mixture of dimethyl sulfoxide and toluene as solvent to produce the drug.

Society and culture
Regulatory status
Olanzapine is approved by the US FDA for:

Treatment—in combination with fluoxetine—of depressive episodes associated with bipolar disorder (December 2003).Long-term treatment of bipolar I disorder (January 2004).
Long-term treatment—in combination with fluoxetine—of resistant depression (March 2009)
Oral formulation: acute and maintenance treatment of schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder (monotherapy and in combination with lithium or sodium valproate)
Intramuscular formulation: acute agitation associated with schizophrenia and bipolar I mania in adults
Oral formulation combined with fluoxetine: treatment of acute depressive episodes associated with bipolar I disorder in adults, or treatment of acute, resistant depression in adults
Treatment of the manifestations of psychotic disorders (September 1996 – March 2000).Short-term treatment of acute manic episodes associated with bipolar I disorder (March 2000)
Short-term treatment of schizophrenia instead of the management of the manifestations of psychotic disorders (March 2000)
Maintaining treatment response in schizophrenic patients who had been stable for about eight weeks and were then followed for a period of up to eight months (November 2000)The drug became generic in 2011. Sales of Zyprexa in 2008 were $2.2 billion in the US and $4.7 billion worldwide.

Controversy and litigation
Eli Lilly has faced many lawsuits from people who claimed they developed diabetes or other diseases after taking Zyprexa, as well as by various governmental entities, insurance companies, and others. Lilly produced a large number of documents as part of the discovery phase of this litigation, which started in 2004; the documents were ruled to be confidential by a judge and placed under seal, and later themselves became the subject of litigation.In 2006, Lilly paid $700 million to settle around 8,000 of these lawsuits, and in early 2007, Lilly settled around 18,000 suits for $500 million, which brought the total Lilly had paid to settle suits related to the drug to $1.2 billion.A December 2006 New York Times article based on leaked company documents concluded that the company had engaged in a deliberate effort to downplay olanzapines side effects. The company denied these allegations and stated that the article had been based on cherry-picked documents. The documents were provided to the Times by Jim Gottstein, a lawyer who represented mentally ill patients, who obtained them from a doctor, David Egilman, who was serving as an expert consultant on the case. After the documents were leaked to online peer-to-peer, file-sharing networks by Will Hall and others in the psychiatric survivors movement, who obtained copies, in 2007 Lilly filed a protection order to stop the dissemination of some of the documents, which Judge Jack B. Weinstein of the Brooklyn Federal District Court granted. Judge Weinstein also criticized the New York Times reporter, Gottstein, and Egilman in the ruling. The Times of London also received the documents and reported that as early as 1998, Lilly considered the risk of drug-induced obesity to be a "top threat" to Zyprexa sales. On October 9, 2000, senior Lilly research physician Robert Baker noted that an academic advisory board to which he belonged was "quite impressed by the magnitude of weight gain on olanzapine and implications for glucose."Lilly had threatened Egilman with criminal contempt charges regarding the documents he took and provided to reporters; in September 2007, he agreed to pay Lilly $100,000 in return for the companys agreement to drop the threat of charges.In September 2008, Judge Weinstein issued an order to make public Lillys internal documents about the drug in a different suit brought by insurance companies, pension funds, and other payors.In March 2008, Lilly settled a suit with the state of Alaska, and in October 2008, Lilly agreed to pay $62 million to 32 states and the District of Columbia to settle suits brought under state consumer protection laws.In 2009, Eli Lilly pleaded guilty to a US federal criminal misdemeanor charge of illegally marketing Zyprexa for off-label use and agreed to pay $1.4 billion. The settlement announcement stated "Eli Lilly admits that between September 1999 and March 31, 2001, the company promoted Zyprexa in elderly populations as treatment for dementia, including Alzheimer’s dementia. Eli Lilly has agreed to pay a $515 million criminal fine and to forfeit an additional $100 million in assets."The outcomes described here, and their legal ramifications, were fueled by motions and appeals that were not resolved until 2010. In 2021, Gottstein summarized this tangle of legal activities, and their impact on the political landscape of psychiatry and antipsychiatry in the US, in The Zyprexa Papers.

Trade names
Olanzapine is generic and available under many trade names worldwide.

Dosage forms
Olanzapine is marketed in a number of countries, with tablets ranging from 2.5 to 20 mg. Zyprexa (and generic olanzapine) is available as an orally disintegrating "wafer", which rapidly dissolves in saliva. It is also available in 10-mg vials for intramuscular injection.

Research
Olanzapine has been studied as an antiemetic, particularly for the control of chemotherapy-induced nausea and vomiting (CINV).In general, olanzapine appears to be about as effective as aprepitant for the prevention of CINV, though some concerns remain for its use in this population. For example, concomitant use of metoclopramide or haloperidol increases the risk for extrapyramidal symptoms </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Bazedoxifene/conjugated estrogens and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Amiodarone and can you explain it in depth? [/INST] Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibrillation and paroxysmal supraventricular tachycardia. Evidence in cardiac arrest, however, is poor. It can be given by mouth, intravenously, or intraosseously. When used by mouth, it can take a few weeks for effects to begin.Common side effects include feeling tired, tremor, nausea, and constipation. As amiodarone can have serious side effects, it is mainly recommended only for significant ventricular arrhythmias. Serious side effects include lung toxicity such as interstitial pneumonitis, liver problems, heart arrhythmias, vision problems, thyroid problems, and death. If taken during pregnancy or breastfeeding it can cause problems in the fetus. It is a class III antiarrhythmic medication. It works partly by increasing the time before a heart cell can contract again.Amiodarone was first made in 1961 and came into medical use in 1962 for chest pain believed to be related to the heart. It was pulled from the market in 1967 due to side effects. In 1974 it was found to be useful for arrhythmias and reintroduced. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 183rd most commonly prescribed medication in the United States, with more than 3 million prescriptions.

Medical uses
Amiodarone has been used both in the treatment of acute life-threatening arrhythmias as well as the long term suppression of arrhythmias. It is used both in supraventricular arrhythmias and ventricular arrhythmias.

Cardiac arrest
Defibrillation is the treatment of choice for ventricular fibrillation and pulseless ventricular tachycardia resulting in cardiac arrest. While amiodarone has been used in shock-refractory cases, evidence of benefit is poor. Amiodarone does not appear to improve survival or positive outcomes in those who had a cardiac arrest.

Ventricular tachycardia
Amiodarone may be used in the treatment of ventricular tachycardia in certain instances.  Individuals with hemodynamically unstable ventricular tachycardia should not initially receive amiodarone.  These individuals should be cardioverted.
Amiodarone can be used in individuals with hemodynamically stable ventricular tachycardia.  In these cases, amiodarone can be used regardless of the individuals underlying heart function and the type of ventricular tachycardia; it can be used in individuals with monomorphic ventricular tachycardia, but is contraindicated in individuals with polymorphic ventricular tachycardia as it is associated with a prolonged QT interval which will be made worse with anti-arrhythmic drugs.

Atrial fibrillation
Individuals who have undergone open heart surgery are at an increased risk of developing atrial fibrillation (or AF) in the first few days post-procedure.  In the ARCH trial, intravenous amiodarone (2 g administered over 2 d) has been shown to reduce the incidence of atrial fibrillation after open heart surgery when compared to placebo.  However, clinical studies have failed to demonstrate long-term efficacy and have shown potentially fatal side effects such as pulmonary toxicities.  While amiodarone is not approved for AF by the FDA, it is a commonly prescribed off-label treatment due to the lack of equally effective treatment alternatives.So-called acute onset atrial fibrillation, defined by the North American Society of Pacing and Electrophysiology (NASPE) in 2003, responds well to short duration treatment with amiodarone. This has been demonstrated in seventeen randomized controlled trials, of which five included a placebo arm. The incidence of severe side effects in this group is low.The benefit of amiodarone in the treatment of atrial fibrillation in the critical care population has yet to be determined but it may prove to be the agent of choice where the patient is hemodynamically unstable and unsuitable for DC cardioversion. It is recommended in such a role by the UK governments National Institute for Health and Clinical Excellence (NICE).

Contraindications
Women who are pregnant or may become pregnant are strongly advised to not take amiodarone.  Since amiodarone can be expressed in breast milk, women taking amiodarone are advised to stop nursing.
It is contraindicated in individuals with sinus nodal bradycardia, atrioventricular block, and second or third degree heart block who do not have an artificial pacemaker.
Individuals with baseline depressed lung function should be monitored closely if amiodarone therapy is to be initiated.
Formulations of amiodarone that contain benzyl alcohol should not be given to neonates, because the benzyl alcohol may cause the potentially fatal "gasping syndrome".Amiodarone can worsen the cardiac arrhythmia brought on by digitalis toxicity.

Side effects
At oral doses of 400 mg per day or higher, amiodarone can have serious, varied side effects, including toxicity to thyroid, liver, lung, and retinal functions, requiring clinical surveillance and regular laboratory testing. Allergic reactions to amiodarone may occur. Most individuals administered amiodarone on a chronic basis will experience at least one side effect. In some people, daily use of amiodarone at 100 mg oral doses can be effective for arrhythmia control with no or minimal side effects.

Lung
Side effects of oral amiodarone at doses of 400 mg or higher include various pulmonary effects. The most serious reaction is interstitial lung disease.  Risk factors include high cumulative dose, more than 400 milligrams per day, duration over two months, increased age, and preexisting pulmonary disease.  Some individuals were noted to develop pulmonary fibrosis after a week of treatment, while others did not develop it after years of continuous use.  Common practice is to avoid the agent if possible in individuals with decreased lung function.
The most specific test of pulmonary toxicity due to amiodarone is a dramatically decreased DLCO noted on pulmonary function testing.

Thyroid
Induced abnormalities in thyroid function are common. Both under- and overactivity of the thyroid may occur.
Amiodarone is structurally similar to thyroxine and  also contains iodine. Both of these contribute to the effects of amiodarone on thyroid function. Amiodarone also causes an anti-thyroid action, via Plummer and Wolff–Chaikoff effects, due its large amount of iodine in its molecule, which causes a particular "cardiac hypothyroidism" with bradycardia and arrhythmia.Thyroid function should be checked at least every six months.
Hypothyroidism (slowing of the thyroid) occurs frequently; in the SAFE trial, which compared amiodarone with other medications for the treatment of atrial fibrillation, biochemical hypothyroidism (as defined by a TSH level of 4.5–10 mU/L) occurred in 25.8% of the amiodarone-treated group as opposed to 6.6% of the control group (taking placebo or sotalol). Overt hypothyroidism (defined as TSH >10 mU/L) occurred at 5.0% compared to 0.3%; most of these (>90%) were detected within the first six months of amiodarone treatment.
Amiodarone induced thyrotoxicosis (AIT), can be caused due to the high iodine contebt in the drug via the Jod-Basedow effect. This is known as Type 1 AIT, and usually occurs in patients with an underlying predisposition to hyperthyroidism such as Graves disease, within weeks to months after starting amiodarone. Type 1 AIT is usually treated with anti-thyroid drugs or thyroidectomy. Type 2 AIT is caused by a destructive thyroiditis due to a direct toxic effect of amiodarone on thyroid follicular epithelial cells. Type 2 AIT can occur even years after starting amiodarone, is usually self-limited and responds to anti-inflammatory treatment such as corticosteroids. In practice, often the type of AIT is undetermined or presumed as mixed with both treatments combined. Thyroid uptake measurements (I-123 or I-131), which are used to differentiate causes of hyperthyroidism, are generally unreliable in patients who have been taking amiodarone. Because of the high iodine content of amiodarone, the thyroid gland is effectively saturated, thus preventing further uptake of isotopes of iodine.  However, a positive radioactive iodine can be used to rule in type 1AIT .

Eye
Corneal micro-deposits (cornea verticillata, also called vortex or whorl keratopathy) are almost universally present (over 90%) in individuals taking amiodarone longer than 6 months, especially doses greater than 400 mg/day.  These deposits typically do not cause any symptoms.  About 1 in 10 individuals may complain of a bluish halo.  Anterior subcapsular lens deposits are relatively common (50%) in higher doses (greater than 600 mg/day) after 6 months of treatment.
Optic neuropathy, nonarteritic anterior ischemic optic neuropathy (N-AION), occurs in 1–2% of people and is not dosage dependent. Bilateral optic disc swelling and mild and reversible visual field defects can also occur.
Loss of eyelashes has been linked to amiodarone use.

Liver
Abnormal liver enzyme results are common in people taking amiodarone. Much rarer are jaundice, hepatomegaly (liver enlargement), and hepatitis (inflammation of the liver).Low-dose amiodarone has been reported to cause pseudo-alcoholic cirrhosis.

Skin
Long-term administration of amiodarone (usually more than eighteen months) is associated with a light-sensitive blue-grey discoloration of the skin, sometimes called ceruloderma; such patients should avoid exposure to the sun and use sunscreen that protects against ultraviolet-A  and -B. The discoloration will slowly improve upon cessation of the medication, however, the skin color may not return completely.

Pregnancy and breastfeeding
Use during pregnancy may result in a number of problems in the infant including thyroid problems, heart problems, neurological problems, and preterm birth. Use during breastfeeding is generally not recommended though one dose may be okay.

Other
Long-term use of amiodarone has been associated with peripheral neuropathies.Amiodarone is sometimes responsible for epididymitis. Amiodarone accumulates in the head of the organ and can cause unilateral or bilateral inflammation. It tends to resolve if amiodarone is stopped.Some cases of gynecomastia have been reported with men on amiodarone.A study published in 2013 showed a possible association between amiodarone and an increased risk of cancer, especially in males, with a dose-dependent effect.

Interactions
The pharmacokinetics of numerous drugs, including many that are commonly administered to individuals with heart disease, are affected by amiodarone.  Particularly, doses of digoxin should be halved in individuals taking amiodarone. Amiodarone may also interact with sotalol.Amiodarone potentiates the action of warfarin by inhibiting the clearance of both (S) and (R) warfarin.  Individuals taking both of these medications should have their warfarin doses adjusted based on their dosing of amiodarone, and have their anticoagulation status (measured as prothrombin time (PT) and international normalized ratio (INR)) measured more frequently. Dose reduction of warfarin is as follows: 40% reduction if amiodarone dose is 400 mg daily, 35% reduction if amiodarone dose is 300 mg daily, 30% reduction if amiodarone dose is 200 mg daily, and 25% reduction if amiodarone dose is 100 mg daily.
The effect of amiodarone on the warfarin concentrations can be as early as a few days after initiation of treatment; however, the interaction may not peak for up to seven weeks.
Amiodarone inhibits the action of the cytochrome P450 isozyme family. This reduces the clearance of many drugs, including the following:

Ciclosporin
Digoxin
Flecainide
Procainamide
Quinidine
Sildenafil
Simvastatin
Theophylline
WarfarinIn 2015, Gilead Sciences warned health care providers about people that began taking the hepatitis C drugs ledipasvir/sofosbuvir or sofosbuvir along with amiodarone, who developed abnormally slow heartbeats or died of cardiac arrest.

Metabolism
Amiodarone is extensively metabolized in the liver by cytochrome P450 3A4 and can affect the metabolism of numerous other drugs. It interacts with digoxin, warfarin, phenytoin, and others. The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties.  The metabolism of amiodarone is inhibited by grapefruit juice, leading to elevated serum levels of amiodarone.
On 8 August 2008, the FDA issued a warning of the risk of rhabdomyolysis, which can lead to kidney failure or death, when simvastatin is used with amiodarone. This interaction is dose-dependent with simvastatin doses exceeding 20 mg. This drug combination especially with higher doses of simvastatin should be avoided.

Excretion
Excretion is primarily via the liver and the bile duct with almost no elimination via the kidney and it is not dialyzable. Elimination half-life average of 58 days (ranging from 25 to 100 days [Remington: The Science and Practice of Pharmacy 21st edition]) for amiodarone and 36 days for the active metabolite, desethylamiodarone (DEA). There is 10-50% transfer of amiodarone and DEA in the placenta as well as a presence in breast milk. Accumulation of amiodarone and DEA occurs in adipose tissue and highly perfused organs (i.e. liver, lungs), therefore, if an individual was taking amiodarone on a chronic basis, if it is stopped it will remain in the system for weeks to months.

Pharmacology
Amiodarone is categorized as a class III antiarrhythmic agent, and prolongs phase 3 of the cardiac action potential, the repolarization phase where there is normally decreased calcium permeability and increased potassium permeability.  It has numerous other effects, however, including actions that are similar to those of antiarrhythmic classes Ia, II, and IV.
Amiodarone is a blocker of voltage gated potassium (KCNH2) and voltage gated calcium channels (CACNA2D2).Amiodarone slows conduction rate and prolongs the refractory period of the SA and AV nodes. It also prolongs the refractory periods of the ventricles, bundles of His, and the Purkinje fibres without exhibiting any effects on the conduction rate. Amiodarone has been shown to prolong the myocardial cell action potential duration and refractory period and is a non-competitive β-adrenergic inhibitor.It also shows  beta blocker-like and calcium channel blocker-like actions on the SA and AV nodes, increases the refractory period via sodium- and potassium-channel effects, and slows intra-cardiac conduction of the cardiac action potential, via sodium-channel effects. It is suggested that amiodarone may also exacerbate the phenotype associated with Long QT-3 syndrome causing mutations such as ∆KPQ. This effect is due to a combination of blocking the peak sodium current, but also contributing to an increased persistent sodium current.Amiodarone chemically resembles thyroxine (thyroid hormone), and its binding to the nuclear thyroid receptor might contribute to some of its pharmacologic and toxic actions.

History
The original observation that amiodarones progenitor molecule, khellin, had cardioactive properties, was made by the Russian physiologist Gleb von Anrep while working in Cairo in 1946. Khellin is obtained from a plant extract of Khella or Ammi visnaga, a common plant in north Africa. Anrep noticed that one of his technicians had been cured of anginal symptoms after taking khellin, then used for various, non-cardiac ailments.  This led to efforts by European pharmaceutical industries to isolate an active compound. Amiodarone was initially developed in 1961 at the Labaz company, Belgium, by chemists Tondeur and Binon, who were working on preparations derived from khellin. It became popular in Europe as a treatment for angina pectoris.As a doctoral candidate at Oxford University, Bramah Singh determined that amiodarone and sotalol had antiarrhythmic properties and belonged to a new class of antiarrhythmic agents (what would become the class III antiarrhythmic agents). Today the mechanisms of action of amiodarone and sotalol have been investigated in more detail. Both drugs have been demonstrated to prolong the duration of the action potential, prolonging the refractory period, by interacting among other cellular function with K+ channels.
Based on Singhs work, the Argentinian physician Mauricio Rosenbaum began using amiodarone to treat his patients who have supraventricular and ventricular arrhythmias, with impressive results.  Based on papers written by Rosenbaum developing Singhs theories, physicians in the United States began prescribing amiodarone to their patients with potentially life-threatening arrhythmias in the late 1970s.  By 1980, amiodarone was commonly prescribed throughout Europe for the treatment of arrhythmias, but in the U.S. amiodarone remained unapproved by the Food and Drug Administration, and physicians were forced to directly obtain amiodarone from pharmaceutical companies in Canada and Europe.The FDA was reluctant to officially approve the use of amiodarone since initial reports had shown increased incidence of serious pulmonary side-effects of the drug.  In the mid-1980s, the European pharmaceutical companies began putting pressure on the FDA to approve amiodarone by threatening to cut the supply to American physicians if it was not approved.  In December 1985, amiodarone was approved by the FDA for the treatment of arrhythmias. This makes amiodarone one of the few drugs approved by the FDA without rigorous randomized clinical trials.

Name
Amiodarone may be an acronym for its IUPAC name (2-butyl-1-benzofuran-3-yl)-[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone, where ar is a placeholder for phenyl. This is partially supported by dronedarone which is noniodinated benzofuran derivative of amiodarone, where the arylmethanone is conserved.

Dosing
Amiodarone is available in oral and intravenous formulations.
Orally, it is available under the brand names Pacerone (produced by Upsher-Smith Laboratories, Inc.) and Cordarone (produced by Wyeth-Ayerst Laboratories). It is also available under the brand name Aratac (produced by Alphapharm Pty Ltd) in Australia and New Zealand, and further in Australia under the brands Cardinorm and Rithmik as well as a number of generic brands.  Also Arycor in South Africa (Produced by Winthrop Pharmaceuticals.). In South America, it is known as Atlansil and is produced by Roemmers.
In India, amiodarone is marketed (produced by Cipla Pharmaceutical) under the brand name Tachyra. It is also available in intravenous ampules and vials.
The dose of amiodarone administered is tailored to the individual and the dysrhythmia that is being treated.  When administered orally, the bioavailability of amiodarone is quite variable.  Absorption ranges from 22 to 95%, with better absorption when it is given with food.

Administration
Amiodarone IV should be administered via a central venous catheter.  It has a pH of 4.08.  If administered outside of the standard concentration of 900 mg/500mL it should be administered using a 0.22 micron filter to prevent precipitate from reaching the patient.  Amiodarone IV is a known vesicant </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Naxitamab and can you explain it in depth? [/INST] Naxitamab, sold under the brand name Danyelza, is an anti-cancer medication. It is a monoclonal antibody used in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) for people one year of age and older with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow demonstrating a partial response, minor response, or stable disease to prior therapy.The most common adverse reactions include infusion-related reactions, pain, tachycardia (fast heart beats), vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema, and irritability.The U.S </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Levocetirizine and can you explain it in depth? [/INST] Levocetirizine, sold under the brand name Xyzal among others, is a second-generation antihistamine used for the treatment of allergic rhinitis (hay fever) and long term hives of unclear cause. It is less sedating than older antihistamines. It is taken by mouth.Common side effects include sleepiness, dry mouth, cough, vomiting, and diarrhea. Use in pregnancy appears safe but has not been well studied and use when breastfeeding is of unclear safety. It is classified as a second-generation antihistamine and works by blocking histamine H1-receptors.Levocetirizine was approved for medical use in the United States in 2007. It is available as a generic medication. In 2019, it was the 193rd most commonly prescribed medication in the United States, with more than 2 million prescriptions.

Medical uses
Levocetirizine is used for allergic rhinitis. This includes allergy symptoms such as watery eyes, runny nose, sneezing, hives, and itching.

Side effects
Levocetirizine is referred to as a non-sedating antihistamine as it does not enter the brain in significant amounts and is therefore unlikely to cause drowsiness. Cardiac safety with repolarization may be better than some other antihistamines, as levocetirizine does not significantly prolong the QT interval in healthy individuals. However, some people may still experience some slight sleepiness, headache, mouth dryness, lightheadedness, vision problems (mainly blurred vision), palpitations and fatigue.

Pharmacology
Levocetirizine is an antihistamine. It acts as an inverse agonist that decreases activity at histamine H1 receptors. This in turn prevents the release of other allergy chemicals and increases the blood supply to the area, providing relief from the typical symptoms of hay fever. Levocetirizine, (R)-(-)-cetirizine, is essentially a chiral switch of (±)-cetirizine. This enantiomer, the eutomer, is more selective and less sedative and the (S)-counterpart, the distomer, is inactive.

Chemistry
Chemically, levocetirizine is the active levorotary enantiomer of cetirizine, also called the l-enantiomer of cetirizine </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Daunorubicin and can you explain it in depth? [/INST] Daunorubicin, also known as daunomycin, is a chemotherapy medication used to treat cancer. Specifically it is used for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and Kaposis sarcoma. It is administeted by injection into a vein. A liposomal formulation known as liposomal daunorubicin also exists.Common side effects include hair loss, vomiting, bone marrow suppression, and inflammation of the inside of the mouth. Other severe side effects include heart disease and tissue death at the site of injection. Use in pregnancy may harm the fetus. Daunorubicin is in the anthracycline family of medication. It works in part by blocking the function of topoisomerase II.Daunorubicin was approved for medical use in the United States in 1979. It is on the World Health Organizations List of Essential Medicines.  It was originally isolated from bacteria of the Streptomyces type.

Medical uses
It slows or stops the growth of cancer cells in the body. Treatment is usually performed together with other chemotherapy drugs (such as cytarabine), and its administration depends on the type of tumor and the degree of response.
In addition to its major use in treating AML, daunorubicin is also used to treat neuroblastoma. Daunorubicin has been used with other chemotherapy agents to treat the blastic phase of chronic myelogenous leukemia.
Daunorubicin is also used as the starting material for semi-synthetic manufacturing of doxorubicin, epirubicin and idarubicin.

Mechanism of action
Similar to doxorubicin, daunorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis. This inhibits the progression of the enzyme topoisomerase II, which relaxes supercoils in DNA for transcription. Daunorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thereby stopping the process of replication.
On binding to DNA, daunomycin intercalates, with its daunosamine residue directed toward the minor groove. It has the highest preference for two adjacent G/C base pairs flanked on the 5 side by an A/T base pair.  Crystallography shows that daunomycin induces a local unwinding angle of 8°, and other conformational disturbances of adjacent and second-neighbour base pairs.
It can also induce histone eviction from chromatin upon intercalation.

History
In the 1950s, an Italian research company, Farmitalia Research Laboratories, began an organized effort to isolate anticancer compounds from soil-based microbes. A soil sample was isolated from the area surrounding the Castel del Monte, a 13th-century castle in Apulia </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Alitretinoin and can you explain it in depth? [/INST] Alitretinoin, or 9-cis-retinoic acid, is a form of vitamin A. It is also used in medicine as an antineoplastic (anti-cancer) agent developed by Ligand Pharmaceuticals. It is a first generation retinoid. Ligand gained Food and Drug Administration (FDA) approval for alitretinoin in February 1999.

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

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

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

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

Uncommon (0.1-1% frequency):

Rare (<0.1% frequency):

Benign intracranial hypertension
VasculitisUnknown frequency:

Topical use
Very common (>10% frequency):

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

Exfoliative dermatitis
Oedema
Skin changes
Paraesthesia

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