<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 Zolpidem and can you explain it in depth? [/INST] Zolpidem, sold under the brand name Ambien, among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and behavioral changes, such as sleep hygiene, have been tried. It decreases the time to sleep onset by about fifteen minutes and at larger doses helps people stay asleep longer. It is taken by mouth and is available in conventional tablets, sublingual tablets, or oral spray.Common side effects include daytime sleepiness, headache, nausea, and diarrhea. More severe side effects include memory problems and hallucinations. The previously recommended dose was decreased in 2013, by the US Food and Drug Administration (FDA), to the immediate-release 10 mg for men, and 5 mg for women, in an attempt to reduce next-day somnolence. Newer extended-release formulations include the 6.25 mg for women, and 12.5 mg or 6.25 mg for men, which also cause next-day somnolence when used in higher doses. Additionally, driving the next morning is not recommended with either higher doses or the long-acting formulation. While flumazenil, a GABAA–receptor antagonist, can reverse zolpidems effects, usually supportive care is all that is recommended in overdose.Zolpidem is a nonbenzodiazepine which acts as a sedative and hypnotic. Zolpidem is a GABAA receptor agonist of the imidazopyridine class. It works by increasing GABA effects in the central nervous system by binding to GABAA receptors at the same location as benzodiazepines. It generally has a half-life of two to three hours. This, however, is increased in those with liver problems.Zolpidem was approved for medical use in the United States in 1992. It became available as a generic medication in 2007. Zolpidem is a Schedule IV controlled substance under the Controlled Substances Act of 1970 (CSA). More than ten million prescriptions are filled each year in the United States, making it one of the most commonly used treatments for sleeping problems. In 2020, it was the 47th most commonly prescribed medication in the United States, with more than 14 million prescriptions.

Medical uses
Zolpidem is labelled for short-term (usually about two to six weeks) treatment of insomnia at the lowest possible dose. It may be used for both improving sleep onset, sleep onset latency, and staying asleep.Guidelines from NICE, the European Sleep Research Society, and the American College of Physicians recommend medication for insomnia (including possibly zolpidem) only as a second line treatment after non-pharmacological treatment options have been tried (e.g. cognitive behavioral therapy for insomnia). This is based in part on a 2012 review which found that zolpidems effectiveness is nearly as much due to psychological effects as to the medication itself.A lower-dose version (3.5 mg for men and 1.75 mg for women) is given as a tablet under the tongue and used for middle-of-the-night awakenings. It can be taken if there are at least 4 hours between the time of administration and when the person must be awake.

Contraindications
Zolpidem should not be taken by people with obstructive sleep apnea, myasthenia gravis, severe liver disease, respiratory depression; or by children, or people with psychotic illnesses.  It should not be taken by people who are or have been addicted to other substances.Use of zolpidem may impair driving skills with a resultant increased risk of road traffic accidents. This adverse effect is not unique to zolpidem, but also occurs with other hypnotic drugs. Caution should be exercised by motor vehicle drivers.  In 2013, the FDA recommended the dose for women be reduced and that prescribers should consider lower doses for men due to impaired function the day after taking the drug.Zolpidem should not be prescribed to older people, who are more sensitive to the effects of hypnotics including zolpidem and are at an increased risk of falls and adverse cognitive effects, such as delirium and neurocognitive disorder.Zolpidem has not been assigned to a pregnancy category by the FDA. Animal studies have revealed evidence of incomplete ossification and increased intrauterine fetal death at doses greater than seven times the maximum recommended human dose or higher; however, teratogenicity was not observed at any dose level. There are no controlled data in human pregnancy. In one case report, zolpidem was found in cord blood at delivery. Zolpidem is recommended for use during pregnancy only when benefits outweigh risks.

Adverse effects
The most common adverse effects of short-term use include headache (reported by 7% of people in clinical trials), drowsiness (2%), dizziness (1%), and diarrhea (1%); the most common side effects of long-term use included
drowsiness (8%),
dizziness (5%),
allergy (4%),
sinusitis (4%),
back pain (3%),
diarrhea (3%),
drugged feeling (3%),
dry mouth (3%),
lethargy (3%),
sore throat (3%),
abdominal pain (2%),
constipation (2%),
heart palpitations (2%),
lightheadedness (2%),
rash (2%),
abnormal dreams (1%),
amnesia (1%),
chest pain (1%),
depression (1%),
flu-like symptoms (1%),
and
sleep disorder (1%).Zolpidem increases risk of depression, falls and bone fracture, poor driving, suppressed respiration, and has been associated with an increased risk of death. Upper and lower respiratory infections are also common (experienced by between 1 and 10% of people).Residual hangover effects, such as sleepiness and impaired psychomotor and cognitive function, may persist into the day following nighttime administration. Such effects may impair the ability of users to drive safely and increase risks of falls and hip fractures. Around 3% of people taking zolpidem are likely to break a bone as a result of a fall due to impaired coordination caused by the drug.Some users have reported unexplained sleepwalking while using zolpidem, as well as sleep driving, night eating syndrome while asleep, and performing other daily tasks while sleeping. Research by Australias National Prescribing Service found these events occur mostly after the first dose taken, or within a few days of starting therapy. In February 2008, the Australian Therapeutic Goods Administration attached a boxed warning concerning this adverse effect.

Tolerance, dependence and withdrawal
As zolpidem is associated with drug tolerance and substance dependence, its prescription guidelines are only for severe insomnia and short periods of use at the lowest effective dose. Tolerance to the effects of zolpidem can develop in some people in just a few weeks. Abrupt withdrawal may cause delirium, seizures, or other adverse effects, especially if used for prolonged periods and at high doses. When drug tolerance and physical dependence to zolpidem develop, treatment usually entails a gradual dose reduction over a period of months to minimize withdrawal symptoms, which can resemble those seen during benzodiazepine withdrawal. Failing that, an alternative method may be necessary for some people, such as a switch to a benzodiazepine equivalent dose of a longer-acting benzodiazepine drug, as for diazepam or chlordiazepoxide, followed by a gradual reduction in dose of the long-acting benzodiazepine. In people who are difficult to treat, an inpatient flumazenil administration allows for rapid competitive binding of flumazenil to GABAA–receptor as an antagonist, thus stopping (and effectively detoxifying) zolpidem from being able to bind as an agonist on GABAA–receptor; slowly drug dependence or addiction to zolpidem will wane.Alcohol has cross tolerance with GABAA receptor positive allosteric modulators, such as the benzodiazepines and the nonbenzodiazepine drugs. For this reason, alcoholics or recovering alcoholics may be at increased risk of physical dependency or abuse of zolpidem. It is not typically prescribed in people with a history of alcoholism, recreational drug use, physical dependency, or psychological dependency on sedative-hypnotic drugs. A 2014 review found evidence of drug-seeking behavior, with prescriptions for zolpidem making up 20% of falsified or forged prescriptions.Rodent studies of the tolerance-inducing properties have shown that zolpidem has less tolerance-producing potential than benzodiazepines, but in primates, the tolerance-producing potential of zolpidem was the same as seen with benzodiazepines.

Overdose
Overdose can lead to coma or death.  When overdose occurs, there are often other drugs in the persons system.Zolpidem overdose can be treated with the GABAA receptor antagonist flumazenil, which displaces zolpidem from its binding site on the GABAA receptor to rapidly reverse the effects of the zolpidem. It is unknown if dialysis is helpful.

Detection in body fluids
Zolpidem may be quantitated in blood or plasma to confirm a diagnosis of poisoning in people who are hospitalized, to provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma zolpidem concentrations are usually in a range of 30–300 μg/L in persons receiving the drug therapeutically, 100–700 μg/L in those arrested for impaired driving, and 1000–7000 μg/L in victims of acute overdosage. Analytical techniques, in general, involve gas or liquid chromatography.

Pharmacology
Mechanism of action
Zolpidem is a ligand of high-affinity positive modulator sites of GABAA receptors, which enhances GABAergic inhibition of neurotransmission in the central nervous system. It selectively binds to α1 subunits of this pentameric ion channel. Accordingly, it has strong hypnotic properties and weak anxiolytic, myorelaxant, and anticonvulsant properties. Opposed to diazepam, zolpidem is able to bind to binary αβ GABA receptors, where it was shown to bind to the α1–α1 subunit interface. Zolpidem has about 10-fold lower affinity for the α2- and α3- subunits than for α1, and no appreciable affinity for α5 subunit-containing receptors. ω1 type GABAA receptors are the α1-containing GABAA receptors and are found primarily in the brain, the ω2 receptors are those that contain the α2-, α3-, α4-, α5-, or α6 subunits, and are found primarily in the spine. Thus, zolpidem favours binding to GABAA receptors located in the brain rather than the spine. Zolpidem has no affinity for γ1 and γ3 subunit-containing receptors and, like the vast majority of benzodiazepine-like drugs, it lacks affinity for receptors containing α4 and α6. Zolpidem modulates the receptor presumably by inducing a receptor conformation that enables an increased binding strength of the orthosteric agonist GABA towards its cognate receptor without affecting desensitization or peak currents.Like zaleplon, zolpidem may increase slow wave sleep but cause no effect on stage 2 sleep. A meta-analysis that compared benzodiazepines against nonbenzodiazepines has shown few consistent differences between zolpidem and benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.

Pharmokinetics
Microsome studies indicate zolpidem is metabolized by CYP3A4 (61%) CYP2C9 (22%), CYP1A2 (14%), CYP2D6 (<3%), and CYP2C19 (<3%). It is principally metabolized into three metabolites, none of which are believed to be pharmocologically active. The absolute bioavailability of zolpidem is about 70%. The drug reaches peak concentration in about 2 hours and has a half life in healthly adults of about 2-3 hours. Zolpidems half life is decreased in children and increased in the elderly and people with liver issues. While some studies show men metabolize zolipdem faster than women (possibly due to testosterone), others do not. A review found only a 33% lower clearance in women compared to men, suggesting the FDAs dosage reduction of 50% for women may have been too large.

Interactions
People should not consume alcohol while taking zolpidem, and should not be prescribed opioid drugs nor take such illicit drugs recreationally. Opioids can also increase the risk of becoming psychologically dependent on zolpidem. Use of opioids with zolpidem increases the risk of respiratory depression and death. The US Food and Drug Administration (FDA) is advising that the opioid addiction medications buprenorphine and methadone should not be withheld from patients taking benzodiazepines or other drugs that depress the central nervous system (CNS).Next day sedation can be worsened if people take zolpidem while they are also taking antipsychotics, other sedatives, anxiolytics, antidepressant agents, antiepileptic drugs, and antihistamines. Some people taking antidepressants have had visual hallucinations when they also took zolpidem.Cytochrome P450 inhibitors, particularly CYP3A4 and CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, and clarithromycin will increase the effects of a given dose of zolpidem. Cytochrome P450 activators like St. Johns Wort may decrease the activity of zolpidem. One study found that caffeine increases the concentration over time curve of zolpidem by about 20% and furthermore found that caffeine cannot adequately compensate for the impaired cognition caused by zolpidem.

Chemistry
Three syntheses of zolpidem are common. 4-methylacetophenone is used as a common precursor. This is brominated and reacted with 2-amino-5-methylpyridine to give the imidazopyridine. From here the reactions use a variety of reagents to complete the synthesis, either involving thionyl chloride or sodium cyanide. These reagents are challenging to handle and require thorough safety assessments. Though such safety procedures are common in industry, they make clandestine manufacture difficult.
A number of major side-products of the sodium cyanide reaction have been characterised and include dimers and mannich products.

History
Zolpidem was used in Europe starting in 1988, and was brought to market there by Synthelabo.  Synthelabo and Searle collaborated to bring it to market in the US, and it was approved in the United States in 1992 under the brand name "Ambien". It became available as a generic medication in 2007.In 2015, the American Geriatrics Society said that zolpidem, eszopiclone and zaleplon met the Beers criteria and should be avoided in individuals 65 and over "because of their association with harms balanced with their minimal efficacy in treating insomnia." The AGS stated the strength of the recommendation that older adults avoid zolpidem is "strong" and the quality of evidence supporting it is "moderate."

Society and culture
Prescriptions in the US for all sleeping pills (including zolpidem) steadily declined from around 57 million tablets in 2013, to around 47 million in 2017, possibly in relation to concern about prescribing addictive drugs in the midst of the opioid crisis.

Military use
The United States Air Force uses zolpidem as one of the hypnotics approved as a "no-go pill" (with a six-hour restriction on subsequent flight operation) to help aviators and special duty personnel sleep in support of mission readiness. (The other hypnotics used are temazepam and zaleplon.) "Ground tests" are required prior to authorization issued to use the medication in an operational situation.

Recreational use
Zolpidem has potential for either medical misuse when the drug is continued long term without or against medical advice, or for recreational use when the drug is taken to achieve a "high". The transition from medical use of zolpidem to high-dose addiction or drug dependence can occur with use, but some believe it may be more likely when used without a doctors recommendation to continue using it, when physiological drug tolerance leads to higher doses than the usual 5 mg or 10 mg, when consumed through inhalation or injection, or when taken for purposes other than as a sleep aid. Recreational use is more prevalent in those having been dependent on other drugs in the past, but tolerance and drug dependence can still sometimes occur in those without a history of drug dependence. Chronic users of high doses are more likely to develop physical dependence on the drug, which may cause severe withdrawal symptoms, including seizures, if abrupt withdrawal from zolpidem occurs.Other drugs, including benzodiazepines and zopiclone, are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range, suggesting a high degree of excessive-use potential for benzodiazepines, zolpidem and zopiclone.  US Congressman Patrick J. Kennedy says that he was using zolpidem (Ambien) and promethazine (Phenergan) when caught driving erratically at 3 a.m.  "I simply do not remember getting out of bed, being pulled over by the police, or being cited for three driving infractions," Kennedy said.
Nonmedical use of zolpidem is increasingly common in the US, Canada, and the UK. Some users have reported decreased anxiety, mild euphoria, perceptual changes, visual distortions, and hallucinations. Zolpidem was used by Australian Olympic swimmers at the London Olympics in 2012, leading to controversy.

Regulation
For the stated reason of its potential for recreational use and dependence, zolpidem (along with the other benzodiazepine-like Z-drugs) is a Schedule IV substance under the Controlled Substances Act in the US. The United States patent for zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis.

Use in crime
The Z-drugs including zolpidem have been used as date rape drugs. Zolpidem is available legally by prescription, and broadly prescribed unlike other date rape drugs: gamma-hydroxybutyrate (GHB), which is used to treat narcolepsy, or flunitrazepam (Rohypnol), which is only prescribed as a second-line choice for insomnia. Zolpidem can typically be detected in bodily fluids for 36 hours, though it may be possible to detect it by hair testing much later, which is due to the short elimination half-life of 2.5–3 hours </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 Lumasiran and can you explain it in depth? [/INST] Lumasiran, sold under the brand name Oxlumo, is a medication for the treatment of primary hyperoxaluria type 1 (PH1).The most common side effects include injection site reactions and abdominal pain.Lumasiran is a double-stranded small interfering ribonucleic acid (siRNA) that reduces levels of glycolate oxidase (GO) enzyme by targeting the HAO1 messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. Decreased GO enzyme levels reduce the amount of available glyoxylate, a substrate for oxalate production. This results in reduction of urinary and plasma oxalate levels, the underlying cause of disease manifestations in people with PH1. As the GO enzyme is upstream of the deficient alanine:glyoxylate aminotransferase (AGT) enzyme that causes PH1, the mechanism of action of lumasiran is independent of the underlying AGXT gene mutation.Lumasiran was approved for medical use in the European Union and in the United States in November 2020. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.

Medical uses
Lumasiran is indicated for the treatment of primary hyperoxaluria type 1 (PH1) in adults and children of all ages.PH1 is a rare illness that causes the liver to produce an excessive amount of oxalate. Oxalate is removed by the kidneys and through the urine. In people with PH1, the extra oxalate can cause kidney stones and kidney failure. The extra oxalate can also build up, and damage other parts of the body, including eyes, heart, skin, and bone. This is called oxalosis.

History
Lumasiran was evaluated by the U.S. Food and Drug Administration (FDA) in two studies of participants with PH1: a randomized, placebo-controlled trial in participants six years and older and an open-label study in participants younger than six years (NCT03681184 and NCT03905694). Participants ranged in age from four months to 61 years at the first dose. In the first study, 26 participants received a monthly injection of lumasiran followed by a maintenance dose every three months; 13 participants received placebo injections. Neither the patients nor the healthcare providers knew which treatment was being given until after the trial was completed. The primary endpoint was the amount of oxalate measured in the urine over 24 hours. In the lumasiran group, participants had, on average, a 65% reduction of oxalate in the urine, compared to an average 12% reduction in the placebo group </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 Insys Therapeutics and can you explain it in depth? [/INST] Insys Therapeutics was an American specialty pharmaceutical company based in Chandler, Arizona. Its main product was Subsys, a sublingual liquid form of the drug fentanyl. Fentanyl is an extremely fast-acting and powerful opioid used to relieve peaks of pain in cancer patients.Founded in 1990, the company and its executives are facing legal issues related to the opioid crisis and marketing activities by the company, including accusations of bribes and misleading advertising. Several company executives were convicted of racketeering in a jury trial rendered in May 2019.Insys filed for bankruptcy in 2019. The filing came just 10 days after the company agreed to pay $225 million to settle separate criminal and civil cases brought by the U.S. Justice Department.

Products
In addition to Subsys, Insys Therapeutics marketed Syndros, a synthetic THC product, and was working toward approval of other cannabis derivatives. Despite delta-9 THC being classified as a Schedule I substance by the U.S. Drug Enforcement Administration, Syndros was classified as a Schedule II substance used in adults to treat loss of appetite (anorexia) in people with AIDS who have lost weight, as well as nausea and vomiting caused by anti-cancer medicines (chemotherapy) in people whose nausea and vomiting have not improved with usual anti-nausea medicines. Syndros was the first and only FDA-approved liquid THC formulation, which allows for fast absorption, flexible dosing, and a potential solution for patients who may prefer a liquid medication. The disparity between the US DEA scheduling of THC and of Syndros is pre- and post-formulation, respectively, according to Title 21 United States Code of Controlled Substances Act.

History
The company was founded in 1990 by American multi-millionaire John Kapoor, who served as CEO and president after former CEO Michael Babich was arrested. Kapoor retired from Insys in 2017 due to racketeering conspiracy charges and was ultimately replaced by Saeed Motahari.Insys had a practice of paying doctors speaking fees to promote their products. They had set up the Insys Reimbursement Center, in which Insys workers would call insurers on behalf of doctors’ offices to get them to authorize payment for Subsys. Even tough Subsys was only supposed to be for cancer related patients, the reps would mislead the insurers into paying for it. In 2012, a sales rep for Insys filed a whistleblower lawsuit against the company. He gathered documents, emails and even audio recordings to bolster his case, yet the government declined to intervene.In March 2013, the company had its IPO. The public paid no attention to the lawsuit and accusations, and the company was the best performing IPO that year.In 2016, the company was ranked No. 52 on the Deloitte Fast 500 North America list.In 2017, U.S. Senator Claire McCaskill released a report and audio recording of an Insys representative allegedly falsely claiming to represent a doctors office and lying about a patients diagnosis in order to circumvent prescribing rules for Subsys. The patient later died due to an adverse reaction to her medications.A study done by physician and scientist Scott Hadland, examined the marketing of Insys Therapeutics and found that it was responsible for half of all marketing dollars to doctors. Hadland’s study was cited in a 2017 federal case against the company CEO John Kapoor and several executives, which resulted in their conviction by a federal jury of racketeering conspiracy.

Political advocacy
In 2016, Insys donated $500,000 to Arizonans for Responsible Drug Policy, a group opposing a marijuana legalization ballot initiative in the state of Arizona. Investor filings confirm the company was concerned about the impact of legalization on sales for a cannabis-based drug it was developing. The reason publicly given for opposing the measure was to "protect children". However, medical marijuana advocates have criticized Insys position as hypocritical, profit-driven, and an appeal to emotion, as the company actively developed its own cannabis-derived products. In a September 2016 statement, J.P. Holyoak, a representative from the pro-legalization campaign, commented, "It appears they are trying to kill a non-pharmaceutical market for marijuana in order to line their own pockets." That same month, the opposition campaign defended Insys involvement, stating: "We are grateful that Insys Therapeutics – an Arizona-based company – has chosen to join Governor Ducey, the Arizona Association of County School Superintendents, the Arizona Small Business Association, the Arizona Hospital and Healthcare Association, the Arizona Catholic Conference of Bishops, the Arizona Chamber of Commerce and several other community organizations in defeating Prop. 205 in November." The ballot measure eventually failed to pass, losing 51.32% to 48.68%.

Litigation and bankruptcy
In December 2016, seven former executives and managers employed by Insys were taken into custody, including CEO John Kapoor and charged with conspiracy to bribe medical staff in several states to prescribe a specific pain medication to their patients. The accusations were the topic of an NBC special feature report on Megyn Kellys Sunday Night on June 4, 2017.In August 2017, Insys Therapeutics was sued by Arizona Attorney General Mark Brnovich for misleading patients and doctors about the dangers of the drug Subsys, and for lying to insurers about the condition of the patients in a bid to get payment for the drug. He said the firm deceived insurers and pharmaceutical benefit companies into agreeing to pay for the expensive drug by misleading them to believe that the payment request was coming from a doctors office and not the company making the drug. Brnovich also said those Insys employees misrepresented the medical conditions of the patients, lying that they had breakthrough pain, lying that the patients had tried other medications, and lying that the patients needed the sublingual spray rather than less expensive pills marketed by other firms because they had difficulty swallowing. Insys Therapeutics issued a response to the Arizona filing on their website, stating, in part, that "[t]he allegations contained in the Arizona Attorney Generals complaint relate to former employees and physicians that are no longer associated with our Company or our speaker bureau."In October 2017, Insys founder John Kapoor was arrested in Arizona and charged with RICO conspiracy, conspiracy to commit wire fraud, and conspiracy to violate the anti-kickback law related to Insys effort to secure prescriptions of Subsys. Kapoor is also alleged to have conspired to defraud health insurance providers.In December 2018, former Insys CEO Michael Babich agreed to plead guilty to one count of conspiracy and one count of mail fraud, in connection to bribes paid to doctors and their assistants. In April 2019, Alec Burlakoff, the former vice president of sales for Insys, agreed to pay the State of Arizona $9.5 million in a civil settlement with Attorney General Mark Brnovich for his role in the alleged bribery campaign of doctors to prescribe Insys products to patients. Brnovich had accused Burlakoff of operating a program that paid doctors lucrative "speaking fees" in order to encourage them to prescribe more Subsys, Insys fentanyl-based pain medication. Burlakoff is required to pay the state $5.2 million from the proceeds he made from the operation, as well as $4.3 million in civil penalties. As part of the settlement, Burlakoff agreed to testify against Insys in ongoing litigation and will be permanently banned from advertising or selling any pharmaceutical drugs in Arizona.On May 2, 2019, a federal jury found top executives of Insys Therapeutics guilty of racketeering charges. The jury, after deliberating for 15 days, issued guilty verdicts against the companys founder, the one-time billionaire John Kapoor, and four former executives, finding they had conspired to fuel sales of its highly potent drug, Subsys, by not only bribing doctors to prescribe its product but also by misleading insurers about patients need for the drug. Other Insys employees also found guilty included Richard M. Simon, former national director of sales; Sunrise Lee, regional sales director; Joseph A </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 Bexarotene and can you explain it in depth? [/INST] Bexarotene, sold under the brand Targretin, is an antineoplastic (anti-cancer) agent used for the treatment of cutaneous T cell lymphoma (CTCL). It is a third-generation retinoid.It was approved by the U.S. Food and Drug Administration (FDA) in December 1999, and the European Medicines Agency (EMA) in March 2001. It is available as a generic medication.

Medical uses
Bexarotene is indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in people who are refractory to at least one prior systemic therapy (oral) and for the topical treatment of cutaneous lesions in patients with CTCL who have refractory or persistent disease after other therapies or who have not tolerated other therapies (topical).It has been used off-label for non-small cell lung cancer and breast cancer.

Contraindications
Known contraindications include:

Adverse effects
Overall the most common adverse effects are skin reactions (mostly itchiness and rashes), leucopenia, headache, weakness, thyroid anomalies (which seem to be mediated by RXR-mediated downregulation of thyroid stimulating hormone) and blood lipid anomalies such as hypercholesterolaemia (high blood cholesterol) and hyperlipidaemia, hypothyroidism.

Interactions
Its plasma concentration may be increased by concomitant treatment with CYP3A4 inhibitors such as ketoconazole. It may also induce CYP3A4, and hence CYP3A4 substrates like cyclophosphamide may have their plasma concentrations reduced. Likewise consumption of grapefruit juice might increase bexarotenes plasma concentrations, hence potentially altering its therapeutic effects.

Mechanism
Bexarotene is a retinoid that selectively activates retinoid X receptors (RXRs), as opposed to the retinoic acid receptors, the other major target of retinoic acid (the acid form of vitamin A) </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 Sular 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 Clomifene and can you explain it in depth? [/INST] Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a course of treatment that usually lasts for 5 days.Common side effects include pelvic pain and hot flashes. Other side effects can include changes in vision, vomiting, trouble sleeping, ovarian cancer, and seizures. It is not recommended in people with liver disease or abnormal vaginal bleeding of unknown cause or who are pregnant. Clomifene is in the selective estrogen receptor modulator (SERM) family of medication and is a nonsteroidal medication. It works by causing the release of GnRH by the hypothalamus, and subsequently gonadotropin from the anterior pituitary.Clomifene was approved for medical use in the United States in 1967. It is on the World Health Organizations List of Essential Medicines, under the category "Ovulation inducers" (Complementary List). Its introduction began the era of assisted reproductive technology.Clomifene (particularly the purified enclomiphene isomer) has also been found to have a powerful ability to boost or restore testosterone levels in hypogonadal men.

Medical uses
Ovulation induction
Clomifene is one of several alternatives for ovulation induction in those who are infertile due to anovulation or oligoovulation. Evidence is lacking for the use of clomifene in those who are infertile without a known reason. In such cases, studies have observed a clinical pregnancy rate 5.6% per cycle with clomifene treatment vs. 1.3%–4.2% per cycle without treatment.Proper timing of the drug is important; it should be taken starting on about the fifth day of the cycle, and there should be frequent intercourse.The following procedures may be used to monitor induced cycles:
Follicular monitoring with vaginal ultrasound, starting 4–6 days after the last pill. Serial transvaginal ultrasound can reveal the size and number of developing follicles. It can also provide presumptive evidence of ovulation such as the sudden collapse of the preovulatory follicle, and an increase in fluid volume in the rectouterine pouch. After ovulation, it may reveal signs of luteinization such as loss of clearly defined follicular margins and appearance of internal echoes.
Serum estradiol levels, starting 4–6 days after the last pill
Adequacy of LH surge by urine LH surge tests 3 to 4 days after last clomifene pill
Post-coital test 1–3 days before ovulation to check whether there are at least 5 progressive sperm per HPF
Mid-luteal progesterone, with at least 10  ng/ml 7–9 days after ovulation being regarded as adequate.Repeat dosing: This 5-day treatment course can be repeated every 30 days. The dosage may be increased by 50-mg increments in subsequent cycles until ovulation is achieved. It is not recommended by the manufacturer to use clomifene for more than 6 cycles.It is no longer recommended to perform an ultrasound examination to exclude any significant residual ovarian enlargement before each new treatment cycle.

Other uses
Clomifene has also been used with other assisted reproductive technology to increase success rates of these other modalities.Clomifene is sometimes used in the treatment of male hypogonadism as an alternative to testosterone replacement therapy. The medication has been used at a dosage of 20 to 50 mg three times per week to once day for this indication. It has been found to increase testosterone levels by 2- to 2.5-times in hypogonadal men at such dosages. Despite the use of questionnaires in testosterone replacement comparator trials being called into question, clomifenes lower cost, therapeutic benefits, and greater value towards hypogonadism improvement have been noted.Clomifene consists of two stereoisomers in equal proportion: enclomifene and zuclomifene. Zuclomifene has pro-estrogenic properties, whereas enclomifene is pro-androgenic, i.e. it promotes testosterone production through stimulation of the HPG axis. For this reason, purified enclomifene isomer has been found to be twice as effective in boosting testosterone compared to the standard mix of both isomers. Additionally, enclomifene has a half-life of just 10 hours, but zuclomifene has a half-life of 30 days—therefore if the goal is to boost testosterone, taking regular clomifene may produce far longer-lasting pro-estrogenic effects than pro-androgenic effects.
Clomifene has been used in the treatment of gynecomastia. It has been found to be useful in the treatment of some cases of gynecomastia but it is not as effective as tamoxifen or raloxifene for this indication. It has shown variable results for gynecomastia (probably because the zuclomifene isomer is estrogenic), and hence is not recommended for treatment of the condition. Pure enclomifene isomer is likely to be more effective than clomifene at treating gynecomastia, because of the lack of the zuclomifene isomer (as noted above).
Due to its long half-life, zuclomifene can be detected in urine for at least 261 days after discontinuation (261 days after discontinuation with a half-life of 30 days, there is still 0.24% of the peak level of zuclomifene being excreted, whereas with a half-life of 10 hours, enclomifene reaches the same 0.24% level in less than 4 days).
Because of its potential for boosting testosterone, clomifene is listed as banned for use by competitive sportsmen, both in and out of competition, by the World Anti-Doping Agency, absent an organic etiology of primary hypogonadism.

Contraindications
Contraindications include an allergy to the medication, pregnancy, prior liver problems, abnormal vaginal bleeding of unclear cause, ovarian cysts other than those due to polycystic ovarian syndrome, unmanaged adrenal or thyroid problems, and pituitary tumors.

Side effects
The most common adverse drug reaction associated with the use of clomifene (>10% of people) is reversible ovarian enlargement.Less common effects (1–10% of people) include visual symptoms (blurred vision, double vision, floaters, eye sensitivity to light, scotomata), headaches, vasomotor flushes (or hot flashes), light sensitivity and pupil constriction, abnormal uterine bleeding and/or abdominal discomfort.Rare adverse events (<1% of people) include: high blood level of triglycerides, liver inflammation, reversible baldness and/or ovarian hyperstimulation syndrome.Clomifene can lead to multiple ovulation, hence increasing the chance of twins (10% of births instead of ~1% in the general population) and triplets.
Rates of birth defects and miscarriages do not appear to change with the use of clomifene for fertility. Clomifene has been associated with liver abnormalities and a couple of cases of hepatotoxicity.

Cancer risk
Some studies have suggested that clomifene if used for more than a year may increase the risk of ovarian cancer. This may only be the case in those who have never been and do not become pregnant. Subsequent studies have failed to support those findings.Clomifene has been shown to be associated with an increased risk of malignant melanomas and thyroid cancer. Thyroid cancer risk was not associated with the number of pregnancies carried to viability.

Pharmacology
Pharmacodynamics
Selective estrogen receptor modulator activity
Clomifene is a nonsteroidal triphenylethylene derivative that acts as a selective estrogen receptor modulator (SERM). It consists of a racemic mixture of zuclomifene (~38%) and enclomifene (~62%), each of which has unique pharmacologic properties. It is a mixed agonist and antagonist of the estrogen receptor (ER). Clomifene activates the ERα in the setting of low baseline estrogen levels and partially blocks the receptor in the context of high baseline estrogen levels. Conversely, it is an antagonist of the ERβ. Clomifene has antiestrogenic effects in the uterus. There is little clinical research on the influence of clomifene in many target tissues, such as lipids, the cardiovascular system, and the breasts. Positive effects of clomifene on bone have been observed. Clomifene has been found to decrease insulin-like growth factor 1 (IGF-1) levels in women.Clomifene is a long-acting ER ligand, with a nuclear retention of greater than 48 hours. Clomifene is a prodrug being activated via similar metabolic pathways as the related triphenylethylene SERMs tamoxifen and toremifene. The affinity of clomifene for the ER relative to estradiol ranges from 0.1 to 12% in different studies, which is similar to the range for tamoxifen (0.06–16%). 4-Hydroxyclomifene, a major active metabolite of clomifene, and afimoxifene (4-hydroxytamoxifen), a major active metabolite of tamoxifen, show 89–251% and 41–246% of the affinity of estradiol for the ER in human MCF-7 breast cancer cells, respectively. The ER affinities of the isomers of 4-hydroxyclomifene were 285% for (E)-4-hydroxyclomifene and 16% for (Z)-4-hydroxyclomifene relative to estradiol. 4-Hydroxy-N-desmethylclomifene has similar affinity to 4-hydroxyclomifene for the ER. In one study, the affinities of clomifene and its metabolites for the ERα were ~100 nM for clomifene, ~2.4 nM for 4-hydroxyclomifene, ~125 nM for N-desmethylclomifene, and ~1.4 nM for 4-hydroxy-N-desmethylclomifene.Even though clomifene has some estrogenic effect, the antiestrogenic property is believed to be the primary source for stimulating ovulation. Clomifene appears to act mostly in the hypothalamus where it depletes hypothalamic ERs and blocks the negative feedback effect of circulating endogenous estradiol, which in turn results in an increase in hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency and circulating concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
In normal physiologic female hormonal cycling, at 7 days past ovulation, high levels of estrogen and progesterone produced from the corpus luteum inhibit GnRH, FSH, and LH at the hypothalamus and anterior pituitary. If fertilization does not occur in the post-ovulation period the corpus luteum disintegrates due to a lack of human chorionic gonadotropin (hCG). This would normally be produced by the embryo in the effort of maintaining progesterone and estrogen levels during pregnancy.
Therapeutically, clomifene is given early in the menstrual cycle. It is typically prescribed beginning on day 3 and continuing for 5 days. By that time, FSH levels are rising steadily, causing the development of a few follicles. Follicles, in turn, produce the estrogen, which circulates in serum. In the presence of clomifene, the body perceives a low level of estrogen, similar to day 22 in the previous cycle. Since estrogen can no longer effectively exert negative feedback on the hypothalamus, GnRH secretion becomes more rapidly pulsatile, which results in increased pituitary gonadotropin release. (More rapid, lower amplitude pulses of GnRH lead to increased LH and FSH secretion, while more irregular, larger amplitude pulses of GnRH leads to a decrease in the ratio of LH to FSH.) Increased FSH levels cause the growth of more ovarian follicles, and subsequently rupture of follicles resulting in ovulation. Ovulation occurs most often 6 to 7 days after a course of clomifene.
In normal men, 50 mg/day clomifene for 8 months has been found to increase testosterone levels by around 870 ng/dL in younger men and by around 490 ng/dL in elderly men. Estradiol levels increased by 62 pg/mL in younger men and by 40 pg/mL in elderly men. These findings suggest that the progonadotropic effects of clomifene are stronger in younger men than in older men. In men with hypogonadism, clomifene has been found to increase testosterone levels by 293 to 362 ng/dL and estradiol levels by 5.5 to 13 pg/mL. In a large clinical study of men with low testosterone levels (<400 ng/dL), 25 mg/day clomifene increased testosterone levels from 309 ng/dL to 642 ng/dL after 3 months of therapy. No significant changes in HDL cholesterol, triglycerides, fasting glucose, or prolactin levels were observed, although total cholesterol levels decreased significantly.

Other activities
Clomifene is an inhibitor of the conversion of desmosterol into cholesterol by the enzyme 24-dehydrocholesterol reductase. Concerns about possible induction of desmosterolosis and associated symptoms such as cataracts and ichthyosis with extended exposure precluded the use of clomifene in the treatment of breast cancer. Continuous use of clomifene has been found to increase desmosterol levels by 10% and continuous high doses of clomifene (200 mg/day) have been reported to produce visual disturbances.

Pharmacokinetics
Clomifene produces N-desmethylclomifene, clomifenoxide (clomifene N-oxide), 4-hydroxyclomifene, and 4-hydroxy-N-desmethylclomifene as metabolites. Clomifene is a prodrug most importantly of 4-hydroxyclomifene and 4-hydroxy-N-desmethylclomifene, which are the most active of its metabolites. In one study, the peak levels after a single 50 mg dose of clomifene were 20.37 nmol/L for clomifene, 0.95 nmol/L for 4-hydroxyclomifene, and 1.15 nmol/L for 4-hydroxy-N-desmethylclomifene.Clomifene has an onset of action of 5 to 10 days following course of treatment and an elimination half-life about 5 days. In one study, after a single 50 mg dose of clomifene, the half-life of clomifene was 128 hours (5.3 days), of 4-hydroxyclomifene was 13 hours, and of 4-hydroxy-N-desmethylclomifene was 15 hours. Individuals with the CYP2D6*10 allele showed longer half-lives for 4-hydroxyclomifene and 4-hydroxy-N-desmethylclomifene.Most clomifene metabolism occurs in the liver, where it undergoes enterohepatic recirculation. Clomifene and its metabolites are excreted primarily through feces (42%), and excretion can occur up to 6 weeks after discontinuation.

Chemistry
Clomifene is a triphenylethylene derivative. It is a mixture of two geometric isomers, enclomifene ((E)-clomifene) and zuclomifene ((Z)-clomifene). These two isomers have been found to contribute to the mixed estrogenic and antiestrogenic properties of clomifene.

History
A team at William S. Merrell Chemical Company led by Frank Palopoli synthesized clomifene in 1956; after its biological activity was confirmed a patent was filed and issued in November 1959.  Scientists at Merrell had previously synthesized chlorotrianisene and ethamoxytriphetol. Clomifene was studied in the treatment of advanced breast cancer during the period of 1964 to 1974 and was found to be effective but was abandoned due to concerns about desmosterolosis with extended use. Short-term use (e.g. days to months) did not raise the same concerns however and clomifene continued to be studied for other indications.
Clinical studies were conducted under an Investigational New Drug Application; clomifene was third drug for which an IND had been filed under the 1962 Kefauver Harris Amendment to the Federal Food, Drug, and Cosmetic Act that had been passed in response to the thalidomide tragedy.  It was approved for marketing in 1967 under the brand name Clomid </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 Nicardipine 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 Perphenazine and can you explain it in depth? [/INST] Perphenazine is a typical antipsychotic drug.  Chemically, it is classified as a piperazinyl phenothiazine. Originally marketed in the United States as Trilafon, it has been in clinical use for decades.
Perphenazine is roughly ten times as potent as chlorpromazine at the dopamine-2 (D2) receptor; thus perphenazine is considered a medium-potency antipsychotic.

Medical uses
In low doses it is used to treat agitated depression (together with an antidepressant). Fixed combinations of perphenazine and the tricyclic antidepressant amitriptyline in different proportions of weight exist (see Etrafon below). When treating depression, perphenazine is discontinued as fast as the clinical situation allows. Perphenazine has no intrinsic antidepressive activity. Several studies show that the use of perphenazine  with fluoxetine (Prozac) in patients with psychotic depression is most promising, although fluoxetine interferes with the metabolism of perphenazine, causing higher plasma levels of perphenazine and a longer half-life. In this combination the strong antiemetic action of perphenazine attenuates fluoxetine-induced nausea and vomiting (emesis), as well as the initial agitation caused by fluoxetine. Both actions can be helpful for many patients.
Perphenazine has been used in low doses as a normal or minor tranquilizer in patients with a known history of addiction to drugs or alcohol, a practice which is now strongly discouraged.Perphenazine has sedating and anxiolytic properties, making the drug useful for the treatment of agitated psychotic patients.
A valuable off-label indication is the short-time treatment of hyperemesis gravidarum, in which pregnant women experience violent nausea and vomiting. This problem can become severe enough to endanger the pregnancy. As perphenazine has not been shown to be teratogenic and works very well, it is sometimes given orally in the smallest possible dose.

Effectiveness
Perphenazine is used to treat psychosis (e.g. in people with schizophrenia and the manic phases of bipolar disorder). Perphenazine effectively treats the positive symptoms of schizophrenia, such as hallucinations and delusions, but its effectiveness in treating the negative symptoms of schizophrenia, such as flattened affect and poverty of speech, is unclear. Earlier studies found the typical antipsychotics to be ineffective or poorly effective in the treatment of negative symptoms, but two recent, large-scale studies found no difference between perphenazine and the atypical antipsychotics. A 2015 systematic review compared perphenazine with other antipsychotic drugs:

Side effects
As a member of the phenothiazine type of antipsychotics, perphenazine shares in general all allergic and toxic side-effects of chlorpromazine.  A 2015 systematic review of the data on perphenazine conducted by the Cochrane Collaboration concluded that "there were no convincing differences between perphenazine and other antipsychotics" in the incidence of adverse effects. Perphenazine causes early and late extrapyramidal side effects more often than placebo, and at a similar rate to other medium-potency antipsychotics and the atypical antipsychotic risperidone.When used for its strong antiemetic or antivertignosic effects in cases with associated brain injuries, it may obscure the clinical course and interferes with the diagnosis.  High doses of perphenazine can cause temporary dyskinesia.  As with other typical antipsychotics, permanent or lasting tardive dyskinesia is a risk.

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

Pharmacology
Pharmacodynamics
Perphenazine has the following binding profile towards cloned human receptors unless otherwise specified:
Acronyms:
RS — Rat striatum receptor.
RB — Rat brain receptor.

Pharmacokinetics
Perphenazine has an oral bioavailability of approximately 40% and a half-life of 8 to 12 hours (up to 20 hours), and is usually given in 2 or 3 divided doses each day. It is possible to give two-thirds of the daily dose at bedtime and one-third during breakfast to maximize hypnotic activity during the night and to minimize daytime sedation and hypotension without loss of therapeutic activity.

Formulations
It is sold under the brand names Trilafon (single drug) and Etrafon/Triavil/Triptafen (contains fixed dosages of amitriptyline). A brand name in Europe is Decentan pointing to the fact that perphenazine is approximately 10-times more potent than chlorpromazine </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 Metreleptin and can you explain it in depth? [/INST] Metreleptin, sold under the brand name Myalept among others, is a synthetic analog of the hormone leptin used to treat various forms of dyslipidemia </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 Ursodeoxycholic acid and can you explain it in depth? [/INST] Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid, produced in humans and most other species from metabolism by intestinal bacteria. It is synthesized in the liver in some species, and was first identified in bile of bears of genus Ursus, from which its name derived. In purified form, it has been used to treat or prevent several diseases of the liver or bile ducts.
It is available as a generic medication.

Medical uses
UDCA has been used as medical therapy in gallstone disease (cholelithiasis) and for biliary sludge.  UDCA helps reduce the cholesterol saturation of bile and leads to gradual dissolution of cholesterol-rich gallstones.UDCA may be given after bariatric surgery to prevent cholelithiasis, which commonly occurs due to the rapid weight loss producing biliary cholesterol oversaturation and also biliary dyskinesia secondary hormonal changes.

Primary biliary cholangitis
UDCA is used as therapy in primary biliary cholangitis (PBC; previously known as primary biliary cirrhosis) where it can produce an improvement in biomarkers. Meta-analyses have borne out conflicting results on the mortality benefit.  However analyses that exclude trials of short duration (i.e. < 2 years) have demonstrated a survival benefit and are generally considered more clinically relevant. A Cochrane systematic review in 2012 found no significant benefit in reducing mortality, the rate of liver transplantation, pruritus or fatigue. Ursodiol and obeticholic acid are FDA-approved for the treatment of primary biliary cholangitis.

Primary sclerosing cholangitis
UDCA use is associated with improved serum liver tests that do not always correlate with improved liver disease status. WHO Drug Information advises against its use in primary sclerosing cholangitis in unapproved doses beyond 13–15 mg/kg/day.UDCA in a dose of 28-30mg/kg/day increases risk of death and need for liver transplant by 2.3 folds among those with primary sclerosing cholangitis, despite decrease in liver enzymes.

Intrahepatic cholestasis of pregnancy
UDCA has been used for intrahepatic cholestasis of pregnancy. UDCA lessens itching in the mother and may reduce the number of preterm births. Effects on fetal distress and other adverse outcomes are unlikely to be great.

Cholestasis
UDCA use is not licensed in children, as its safety and effectiveness have not been established. Evidence is accumulating that ursodeoxycholic acid is ineffective, unsafe and its use is associated with significant risk of morbidity and mortality in neonatal hepatitis and neonatal cholestasis.

Other conditions
UDCA has been suggested to be an adequate treatment of bile reflux gastritis.In cystic fibrosis there is insufficient evidence to justify routine use of UDCA, especially as there is a lack of available data for long-term outcomes such as death or need for liver transplantation.UDCA has also been in effective in non-alcoholic fatty liver disease, in liver bile duct-paucity syndromes. It is contraindicated in obstruction of biliary tracts such as biliary atresia. Its not effective in liver allograft rejection, and in Graft-versus-host disease involving the liver.

Adverse effects
Diarrhea was the most frequent adverse event seen in trial of UDCA in gallstone dissolution, occurring in 2 to 9%, which is less frequent than with chenodeoxycholic acid therapy. Bacterial conversion of UDCA to chenodeoxycholic acid may be the mechanism for this side effect. Right upper quadrant abdominal pain and exacerbation of pruritus was occasionally reported in trials in patients with PBC.  Additional symptoms may include bloating, weight gain, and occasionally, thinning of hair.

Mechanisms of action
Choleretic effects
Primary bile acids are produced by the liver and stored in the gall bladder. When secreted into the intestine, primary bile acids can be metabolized into secondary bile acids by intestinal bacteria. Primary and secondary bile acids help the body digest fats. Ursodeoxycholic acid helps regulate cholesterol by reducing the rate at which the intestine absorbs cholesterol molecules while breaking up micelles containing cholesterol. The drug reduces cholesterol absorption and is used to dissolve (cholesterol) gallstones in patients who want an alternative to surgery. There are multiple mechanisms involved in cholestatic liver diseases.

Immunomodulating effects
Ursodeoxycholic acid has also been shown experimentally to suppress immune response such as immune cell phagocytosis. Prolonged exposure and/or increased quantities of systemic (throughout the body, not just in the digestive system) ursodeoxycholic acid can be toxic.

Anti-inflammatory effects
Ursodeoxycholic acid has been shown to exert anti-inflammatory and protective effects in human epithelial cells of the gastrointestinal tract. It has been linked to regulation of immunoregulatory responses by regulation of cytokines, antimicrobial peptides defensins, and take an active part in increased restitution of wound in the colon. Moreover, UDCAs effects has been shown to have exert actions outside the epithelial cells.While some bile acids are known to be colon tumor promoters (e.g. deoxycholic acid), others such as ursodeoxycholic acid are thought to be chemopreventive, perhaps by inducing cellular differentiation and/or cellular senescence in colon epithelial cells.

Chemistry
Ursodeoxycholic acid is an epimer of chenodeoxycholic acid, which has similar choleretic effects and a wider species distribution </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 Magnesium citrate and can you explain it in depth? [/INST] Magnesium citrate is a magnesium preparation in salt form with citric acid in a 1:1 ratio (1 magnesium atom per citrate molecule).  The name "magnesium citrate" is ambiguous and sometimes may refer to other salts such as trimagnesium citrate which has a magnesium:citrate ratio of 3:2.
Magnesium citrate is used medicinally as a saline laxative and to completely empty the bowel prior to a major surgery or colonoscopy. It is available without a prescription, both as a generic and under various brand names. It is also used in the pill form as a magnesium dietary supplement. It contains 11.23% magnesium by weight. Compared to trimagnesium citrate, it is much more water-soluble, less alkaline, and contains less magnesium.
As a food additive, magnesium citrate is used to regulate acidity and is known as E number E345.

Mechanism of action
Magnesium citrate works by attracting water through the tissues by a process known as osmosis. Once in the intestine, it can attract enough water into the intestine to induce defecation. The additional water stimulates bowel motility. This means it can also be used to treat rectal and colon problems. Magnesium citrate functions best on an empty stomach, and should always be followed with a full (eight ounce or 250 ml) glass of water or juice to help the magnesium citrate absorb properly and help prevent any complications. Magnesium citrate solutions generally produce bowel movement in one half to three hours.

Use and dosage
The maximum upper tolerance limit (UTL) for magnesium in supplement form for adults is 350 mg of elemental magnesium per day, according to the National Institutes of Health (NIH). In addition, according to the NIH, total dietary requirements for magnesium from all sources (in other words, food and supplements) is 320–420 mg of elemental magnesium per day, though there is no UT for dietary magnesium.

Laxative
Magnesium citrate is used as a laxative agent.As a laxative syrup with a concentration of 1.745 g of magnesium citrate per fluid ounce, a typical dose for adults and children twelve years or older is between 7 and 10 US fluid ounces (210 and 300 ml; 7.3 and 10.4 imp fl oz), followed immediately with a full 8 US fluid ounces (240 ml; 8.3 imp fl oz) glass of water </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 Imiglucerase 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 Moexipril and can you explain it in depth? [/INST] Moexipril an angiotensin converting enzyme inhibitor (ACE inhibitor) used for the treatment of hypertension and congestive heart failure. Moexipril can be administered alone or with other antihypertensives or diuretics.It works by inhibiting the conversion of angiotensin I to angiotensin II.It was patented in 1980 and approved for medical use in 1995. Moexipril is available from Schwarz Pharma under the trade name Univasc.

Side effects
Moexipril is generally well tolerated in elderly patients with hypertension.
Hypotension, dizziness, increased cough, diarrhea, flu syndrome, fatigue, and flushing have been found to affect less than 6% of patients who were prescribed moexipril.

Mechanism of action
As an ACE inhibitor, moexipril causes a decrease in ACE. This blocks the conversion of angiotensin I to angiotensin II. Blockage of angiotensin II limits hypertension within the vasculature. Additionally, moexipril has been found to possess cardioprotective properties. Rats given moexipril one week prior to induction of myocardial infarction, displayed decreased infarct size. The cardioprotective effects of ACE inhibitors are mediated through a combination of angiotensin II inhibition and bradykinin proliferation. Increased levels of bradykinin stimulate in the production of prostaglandin E2 and nitric oxide, which cause vasodilation and continue to exert antiproliferative effects. Inhibition of angiotensin II by moexipril decreases remodeling effects on the cardiovascular system. Indirectly, angiotensin II stimulates of the production of endothelin 1 and 3 (ET1, ET3) and the transforming growth factor beta-1 (TGF-β1), all of which have tissue proliferative effects that are blocked by the actions of moexipril </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 Brolucizumab and can you explain it in depth? [/INST] Brolucizumab (sold, depending on part of the world, under trade names Beovu or Vsiqq), is a humanized single-chain antibody fragment for the treatment of neovascular (wet) age-related macular degeneration (AMD).The most common side effects are reduced visual acuity, cataract (clouding of the lens in the eye), conjunctival haemorrhage (bleeding at the front of the eye) and vitreous floaters (spots in the vision). The most serious side effects are blindness, endophthalmitis (an infection inside the eye), retinal artery occlusion (blockage of the artery in the retina) and retinal detachment (separation of the retina from the back of the eye).Brolucizumab was designed to attach to and block a substance called vascular endothelial growth factor A (VEGF-A). VEGF-A is a protein that makes blood vessels grow and leak fluid and blood, damaging the macula </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 Makena 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 Enfuvirtide and can you explain it in depth? [/INST] Enfuvirtide (INN) is an HIV fusion inhibitor, the first of a class of antiretroviral drugs used in combination therapy for the treatment of HIV-1 infection. It is marketed under the trade name Fuzeon (Roche).

Structural formula
Enfuvirtide is a 36-amino acid peptide with the following sequence:CH3CO-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln-Asn-Gln-Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-NH2 (Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2)

History
Enfuvirtide originated at Duke University, where researchers formed a pharmaceutical company known as Trimeris.  Trimeris began development on enfuvirtide in 1996 and initially designated it T-20. In 1999, Trimeris entered into partnership with Hoffmann-La Roche to complete the development of the drug. It was approved by the U.S. Food and Drug Administration (FDA) on March 13, 2003 as the first HIV fusion inhibitor, a new class of antiretroviral drugs. It was approved on the basis of two studies which compared the effect of optimized regimens of antiretroviral medication with and without the addition of enfuvirtide on serum viral load.

Pharmacology
Mechanism of action
Enfuvirtide works by disrupting the HIV-1 molecular machinery at the final stage of fusion with the target cell, preventing uninfected cells from becoming infected. A biomimetic peptide, enfuvirtide was designed to mimic components of the HIV-1 fusion machinery and displace them, preventing normal fusion. Drugs that disrupt fusion of virus and target cell are termed entry inhibitors or fusion inhibitors.HIV binds to the host CD4+ cell receptor via the viral protein gp120; gp41, a viral transmembrane protein, then undergoes a conformational change that assists in the fusion of the viral membrane to the host cell membrane </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 Maribavir and can you explain it in depth? [/INST] Maribavir, sold under the brand name Livtencity, is an antiviral medication that is used to treat post-transplant cytomegalovirus (CMV).The most common side effects include taste disturbance, nausea, diarrhea, vomiting and fatigue.Maribavir is a cytomegalovirus pUL97 kinase inhibitor that works by preventing the activity of human cytomegalovirus enzyme pUL97, thus blocking virus replication.Maribavir was approved for medical use in the United States in November 2021.

Medical uses
Maribavir is indicated to treat people twelve years of age and older and weighing at least 35 kilograms (77 lb) with post-transplant cytomegalovirus infection/disease that does not respond (with or without genetic mutations that cause resistance) to available antiviral treatment for cytomegalovirus.

Adverse effects
Adverse effects of maribavir include taste disturbances, nausea, and vomiting.

Contraindications
Maribavir may reduce the antiviral activity of ganciclovir and valganciclovir, so coadministration with these medications is not recommended.

History
Maribavir is licensed by ViroPharma from GlaxoSmithKline in 2003, for the prevention and treatment of human cytomegalovirus (HCMV) disease in hematopoietic stem cell/bone marrow transplant patients.  The mechanism by which maribavir  inhibits HCMV replication is by inhibition of an HCMV encoded protein kinase enzyme called UL97 or pUL97.  Maribavir showed promise in Phase II clinical trials and was granted fast track status, but failed to meet study goals in a Phase III trial.  However, the dosage used in the Phase III trial may have been too low to be efficacious.A Phase II study with maribavir demonstrated that prophylaxis with maribavir displayed strong antiviral activity, as measured by statistically significant reduction in the rate of reactivation of CMV in recipients of hematopoietic stem cell/bone marrow transplants. In an intent-to-treat analysis of the first 100 days after the transplant, the number of subjects who required pre-emptive anti-CMV therapy was statistically significantly reduced with maribavir compared to placebo.ViroPharma conducted a Phase III clinical study to evaluate the prophylactic use for the prevention of cytomegalovirus disease in recipients of allogeneic stem cell transplant patients </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 Retapamulin 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 Vibegron and can you explain it in depth? [/INST] Vibegron, sold under the brand name Gemtesa, is a medication for the treatment of overactive bladder.Vibegron (other names: RVT-901; MK4618; KRP114V; URO-901) is a selective beta 3 adrenergic receptor agonist.
The most common side effects include headache, urinary tract infection, common cold, diarrhea, nausea, and upper respiratory tract infection.It was approved for medical use in the United States in December 2020.

Medical uses
Vibegron is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults.

History and Discovery
The beta 3 adrenergic receptor was discovered in the late 1980s and initially beta3AR agonists were investigated as treatment for obesity and diabetes. A number of compounds were tested in clinical trials but didnt show sufficient benefits in these areas.Since the 2000s there is evidence that there are beta3AR on the detrusor muscle of the bladder. The detrusor muscle contracts during urination and remains relaxed to allow the bladder to store urine.
Mirabegron was the first FDA approved selective agonist approved to treat overactive bladder (OAB).Vibegron is a selective beta3AR agonist that is developed in Japan by Kyorin Pharmaceutical Co., Ltd and Kissei Pharmaceutical Co.,Ltd and Urovant Sciences to treat overactive bladders  and pain caused by irritable bowel syndrome. It was globally approved on September 21, 2018, in Japan for OAB.Vibegron has been proven effective in 5 key clinical trials.A phase IIb global trial completed in 2013 of 1395 patients, of which 89.7% were women and 63.3% had not been treated previously, demonstrated a significant decrease in daily micturitions and urgent urinary incontinence episodes upon administration of vibegron.An international phase III trial of 506 participants completed in 2019 found statistically significant efficacy of vibegron after 2 weeks of daily administration. The adverse effect rates in patients treated with vibegron were comparable to those in patients who received a placebo.GEMTESA, a drug using vibegron as an active ingredient was approved by the FDA on December 23, 2020, after an additional phase III international trial of 1085 patients.

Society and culture
Legal status
Vibegron was approved for medical use in the United States in December 2020.

Names
Vibegron is the international nonproprietary name (INN).

Mechanism of action
Vibegron is a selective agonist for the beta-3 adrenergic receptor (β3-AR). The receptors are located in the kidneys, urinary tract and bladder tissue. Upon binding, the β3 receptor undergoes a conformational change. This induces the activation of adenylate cyclases via G proteins and thereby promotes the formation of cyclic adenosine monophosphate (cAMP). The consequence of this cascade is an increased intracellular cAMP concentration which triggers activation of cAMP-dependent protein kinase A and causes a reduction of Ca2+ concentration in the cytoplasm. The kinase then phosphorylates myosin chains and thereby inhibits muscle contraction.The final effect of vibegron is muscle relaxation in the bladder. Due to this muscle relaxation, bladder capacity increases and symptoms of overactive bladder are relieved.

Metabolism
The two main metabolic pathways are the oxidation and glucuronidation of vibegron. Two oxidative metabolites and three glucuronide metabolites can be formed. The exact structure of these metabolites have not been studied yet. In vitro, CYP3A4 is the enzyme responsible for the metabolism of vibegron, facilitating oxidative metabolism. Eventually, still a large part of the unmodified drug is excreted through feces and urine.

Indications
Vibegron is indicated for people with OAB. Urgency urinary incontinence (UUI), urgency and urinary frequency in adults are the most common symptoms for this condition.The drug is contraindicated in patients with known hypersensitivity to Vibegron itself or single components of the drug. The inactive components of the drug for which allergic reactions can occur are sodium croscarmellose, hydroxypropyl cellulose, magnesium stearate, mannitol and microcrystalline cellulose. The thin coating of the drug with green color contains FD&C Blue No.2.Vibegron treatment should be discontinued if urinary retention occurs. Use with nonselective muscarinic antagonists may increase the risk of urinary retention. The manufacturer suggests discontinuing vibegron if an elevated digoxin concentration occurs.

Efficacy and side effects
Efficacy
Vibegron was evaluated in patients with overactive bladder (OAB) in several clinical studies. A large active-controlled study, called Empower, showed the beneficial effects of the drug to treat the condition and UUI. Primary outcomes of different clinical trials showed there was an overall increase in efficacy. These outcomes concluded that there was a reduction in urgency to urinate, a decrease in micturitions and a decrease in average volume voided per micturition. There is also an improvement observed of the symptoms when Vibegron is administered over a longer period (52 weeks) concluding that it is effective and safe for longer use. In severe patients, increasing the dose was accompanied by similar beneficial effects when there was first a lack of these. Quality of life of the patients is improved, including a reduction of nocturia.

Adverse effects
The most common side effects of Vibegron are a dry mouth, constipation, headache, nasopharyngitis, diarrhea, nausea, bronchitis, urinary tract infection and upper respiratory tract infection. An indication is made that upon urinary retention development, the patient should stop using the drug. Risk assessment for the drug in pregnant women has yet to be evaluated.

Interactions
Vibegron is in contrast to other OAB drugs very selective and leads to a lesser degree in unwanted side effects. Vibegron is found to be a substrate for CYP3A4 in vivo, but does not actually induce or inhibit any of the cytochrome P450 enzymes and is thus less likely to take part in drug–drug interactions (DDI). Here vibegron differs from the previous overactive bladder drug mirabegron, which was known to be associated in various drug–drug interactions by inhibiting CYP2D6 or inducing CYP3A4, CYP2D6 and CYP2C9 in the liver.Using Vibegron only (monotherapy) has positive effects on OAB and UUI, but a combination with other drugs can have additional effects. In a study with antimuscarinic drugs, more DDIs were investigated using a model of Rhesus monkeys. Dose combinations of vibegron and tolterodine showed increased bladder capacity, the effects of both drugs at low dosis strengthened each other, known as synergism. The addition of darifenacin to vibegron created greater bladder relaxation only when used at high doses. Additionally, co-administration with Imidafenacin shows an increase in bladder capacity and voided volume in comparison to monotherapy </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 Estradiol/drospirenone 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 Alfentanil 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 Maralixibat chloride 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 Pentamidine and can you explain it in depth? [/INST] Pentamidine is an antimicrobial medication used to treat African trypanosomiasis, leishmaniasis, Balamuthia infections, babesiosis, and to prevent and treat pneumocystis pneumonia (PCP) in people with poor immune function. In African trypanosomiasis it is used for early disease before central nervous system involvement, as a second line option to suramin. It is an option for both visceral leishmaniasis and cutaneous leishmaniasis. Pentamidine can be given by injection into a vein or muscle or by inhalation.Common side effects of the injectable form include low blood sugar, pain at the site of injection, nausea, vomiting, low blood pressure, and kidney problems. Common side effects of the inhaled form include wheezing, cough, and nausea. It is unclear if doses should be changed in those with kidney or liver problems. Pentamidine is not recommended in early pregnancy but may be used in later pregnancy. Its safety during breastfeeding is unclear. Pentamidine is in the aromatic diamidine family of medications. While the way the medication works is not entirely clear, it is believed to involve decreasing the production of DNA, RNA, and protein.Pentamidine came into medical use in 1937. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In regions of the world where the disease is common pentamidine is provided for free by the World Health Organization (WHO).

Medical uses
Treatment of PCP caused by Pneumocystis jirovecii
Prevention of PCP in adults with HIV who have one or both of the following:
History of PCP
CD4+ count ≤ 200mm³
Treatment of leishmaniasis
Treatment of African trypanosomiasis caused by Trypanosoma brucei gambiense
Balamuthia infections
Pentamidine is classified as an orphan drug by the U.S. Food and Drug Administration

Other uses
Use as an antitumor drug has also been proposed.
Pentamidine is also identified as a potential small molecule antagonist that disrupts this interaction between S100P and RAGE receptor.

Special Populations
Pregnancy
It has not been shown to cause birth defects in animal studies when given intravenously. There are no controlled studies to show if pentamidine can harm the fetus in pregnant women. It is only recommended if the drug of choice trimethoprim-sulfamethoxazole is contraindicated.

Breastfeeding
There is no information regarding the excretion of pentamidine in breast milk, but since the adverse effects on breastfed infants are unknown currently, it is recommended by the manufacturer for the infant to not be breastfed or for the mother to stop the drug. Risks versus benefits for the mother should be considered when making this decision.

Children
Pentamidine can be used in the prevention of PCP in children with HIV who cannot tolerate Trimethoprim/Sulfamethoxazole and can use a nebulizer. Intranvenous solutions of pentamidine should only be used in children with HIV older than 2 years old when other treatments are unavailable

Elderly
There is no data for the use of pentamidine in this specific population.

Contraindications
Patients with a history of anaphylaxis or hypersensitivity to pentamidine isethionate

Side effects
Common
Burning pain, dryness, or sensation of lump in throat
Chest pain
Coughing
difficulty in breathing
difficulty in swallowing
skin rash
wheezing

Rare
Nausea and vomiting
Pain in upper abdomen, possibly radiating to the back
Severe pain in side of chest
Shortness of breath

Others
Blood: Pentamidine frequently causes leukopenia and less often thrombopenia, which may cause symptomatic bleeding. Some cases of anemia, possibly related to folic acid deficiency, have been described.
Cardiovascular: Hypotension, which may be severe. Severe or fatal arrhythmias and heart failure are quite frequent.
Kidney: 25 percent develop signs of nephrotoxicity ranging from mild, asymptomatic azotemia (increased serum creatinine and urea) to irreversible renal failure. Ample fluids or intravenous hydration may prevent some nephrotoxicity.
Liver: Elevated liver enzymes are associated with intravenous use of pentamidine. Hepatomegaly and hepatitis have been encountered with long term prophylactic use of pentamidine inhalation.
Neurological:  Dizziness, drowsiness, neuralgia, confusion, hallucinations, seizures and other central side effects are reported.
Pancreas: Hypoglycemia that requires symptomatic treatment is frequently seen. On the other hand, pentamidine may cause or worsen diabetes mellitus.
Respiratory: Cough and bronchospasm, most frequently seen with inhalation.
Skin: Severe local reactions after extravasculation of intravenous solutions or following intramuscular injection treatment have been seen. Pentamidine itself may cause rash, or rarely Stevens–Johnson syndrome or Lyell syndrome.
Eye discomfort, conjunctivitis, throat irritation, splenomegaly, Herxheimer reaction, electrolyte imbalances (e.g. hypocalcemia).

Drug interactions
The additional or sequential use of other nephrotoxic drugs like aminoglycosides, amphotericin B, capreomycin, colistin, polymyxin B, vancomycin, foscarnet, or cisplatin should be closely monitored, or whenever possible completely avoided.

Mechanism of action
The mechanism seems to vary with different organisms and is not well understood. However, pentamidine is suspected to work through various methods of interference of critical functions in DNA, RNA, phospholipid and protein synthesis. Pentamidine binds to adenine-thymine-rich regions of the Trypanosoma parasite DNA, forming a cross-link between two adenines four to five base pairs apart. The drug also inhibits topoisomerase enzymes in the mitochondria of Pneumocystis jirovecii. Similarly, pentamidine inhibits type II topoisomerase in the mitochondria of the Trypanosoma parasite, resulting in a broken and unreadable mitochondrial genome.

Resistance
Strains of the Trypanosoma brucei parasite that are resistant to pentamidine have been discovered. Pentamidine is brought into the mitochondria through carrier proteins, and the absence of these carriers prevents the drug from reaching its site of action.

Pharmacokinetics
Absorption: Pentamidine is completely absorbed when given intravenously or intramuscularly. When inhaled through a nebulizer, pentamidine accumulates in the bronchoalveolar fluid of the lungs at a higher concentration compared to injections. The inhaled form is minimally absorbed in the blood. Absorption is unreliable when given orally.Distribution: When injected, pentamidine binds to tissues and proteins in the plasma. It accumulates in the kidney, liver, lungs, pancreas, spleen, and adrenal glands. Additionally, pentamidine does not reach curative levels in the cerebrospinal fluid. It has a volume of distribution of 286-1356 liters when given intravenously and 1658-3790 liters when given intramuscularly. Inhaled pentamidine is mainly deposited into the bronchoalveolar lavage fluid of the lungs.Metabolism: Pentamidine is primarily metabolized by Cytochrome P450 enzymes in the liver. Up to 12% of pentamidine is eliminated in the urine unchanged.Elimination: Pentamidine has an average half-life of 5–8 hours when given intravenously and 7–11 hours when given intramuscularly. However, these may increase with severe kidney problems </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 Omadacycline and can you explain it in depth? [/INST] Omadacycline, sold under the brand name Nuzyra,  is a broad spectrum antibiotic medication belonging to the aminomethylcycline subclass of tetracycline antibiotics. In the United States, it was approved in October 2018, for the treatment of community-acquired bacterial pneumonia and acute skin and skin structure infections.

In vitro studies
In vitro studies have shown that omadacycline has activity against a broad range of Gram-positive and select Gram-negative pathogens.  Omadacycline has potent in vitro activity against Gram-positive aerobic bacteria including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant and multi-drug resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus.  Omadacycline also has antimicrobial activity against common Gram-negative aerobes, some anaerobes, and atypical bacteria such as Legionella and Chlamydia. This activity translated to potent efficacy for omadacycline in an in vivo systemic infection model in mice.Additional in vitro and in vivo studies of omadacycline metabolism, disposition, and drug interactions show that omadacycline is metabolically stable (i.e., it does not undergo significant biotransformation) and neither inhibits nor interacts with metabolizing enzymes or transporters.

Mechanism of action
The mechanism of action of omadacycline is similar to that of other tetracyclines – inhibition of bacterial protein synthesis.  Omadacycline has activity against bacterial strains expressing the two main forms of tetracycline resistance (efflux and ribosomal protection).

Clinical trials
A phase II study was conducted comparing the safety and efficacy of omadacycline to linezolid for the treatment of complicated skin and skin structure infections.  Patients were randomized at 11 sites in the US to receive either omadacycline 100 mg intravenously once daily with an option to transition to 200 mg orally once daily or linezolid 600 mg intravenously twice daily with an option to transition to 600 mg orally twice daily.  The results indicated that omadacycline is well tolerated and has the potential to be an effective treatment in patients with complicated skin and skin structure infections.In June 2013, the US Food and Drug Administration (FDA) designated the intravenous and oral formulations of omadacycline as a qualified infectious disease product in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia.A 650-patient phase III registration study comparing omadacycline to linezolid for the treatment of acute bacterial skin and skin structure infections began in June 2015. Omadacycline met the primary efficacy endpoint of early clinical response with statistical non-inferiority (10% margin) compared to linezolid, and was generally safe and well tolerated.  The most common treatment-emergent adverse events were gastrointestinal side effects (18.0% for omadacycline vs. 15.8% for linezolid).A 750-patient phase III study comparing omadacycline to moxifloxacin for the treatment of community-acquired bacterial pneumonia began in November 2015.  Omadacycline was statistically non-inferior to moxifloxacin at the early clinical response, 72 to 120 hours after therapy was initiated.In May 2016, a phase Ib study of omadacycline in urinary tract infection was initiated.In August 2016, a second phase III study of omadacycline was initiated in patients with acute bacterial skin and skin structure infections, comparing the efficacy and safety of once-daily, oral omadacycline to that of twice-daily, oral linezolid. In July 2017, analysis of the data showed that all of the primary and secondary endpoints required for submission to the FDA and EMA were met </s>