<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 Paroxetine and can you explain it in depth? [/INST] Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder, social anxiety disorder, posttraumatic stress disorder, generalized anxiety disorder and premenstrual dysphoric disorder. It has also been used in the treatment of premature ejaculation and hot flashes due to menopause. It is taken by mouth.Common side effects include drowsiness, dry mouth, loss of appetite, sweating, trouble sleeping, and sexual dysfunction. Serious side effects may include suicidal thoughts in those under the age of 25, serotonin syndrome, and mania. While the rate of side effects appears similar compared to other SSRIs and SNRIs, antidepressant discontinuation syndromes may occur more often. Use in pregnancy is not recommended, while use during breastfeeding is relatively safe. It is believed to work by blocking the re-uptake of the chemical serotonin by neurons in the brain.Paroxetine was approved for medical use in the United States in 1992 and initially sold by GlaxoSmithKline. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 78th most commonly prescribed medication in the United States, with more than 9 million prescriptions. In 2018, it was in the top 10 of most prescribed antidepressants in the United States. In 2012, the United States Department of Justice fined GlaxoSmithKline $3 billion for withholding data, unlawfully promoting use in those under 18, and preparing an article that misleadingly reported the effects of paroxetine in adolescents with depression following its clinical trial study 329.

Medical uses
Paroxetine is primarily used to treat major depressive disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder, and panic disorder. It is also occasionally used for agoraphobia, generalized anxiety disorder, premenstrual dysphoric disorder and menopausal hot flashes.

Depression
A variety of meta analyses have been conducted to evaluate the efficacy of paroxetine in depression. They have variously concluded that paroxetine is superior or equivalent to placebo and that it is equivalent or inferior to other antidepressants. Despite this, there was no clear evidence that paroxetine was better or worse compared with other antidepressants at increasing response to treatment at any point in time.

Anxiety disorders
Paroxetine was the first antidepressant approved in the United States for the treatment of panic disorder. Several studies have concluded that paroxetine is superior to placebo in the treatment of panic disorder.Paroxetine has demonstrated efficacy for the treatment of social anxiety disorder in adults and children. It is also beneficial for people with co-occurring social anxiety disorder and alcohol use disorder. It appears to be similar to a number of other SSRIs.Paroxetine is used in the treatment of obsessive-compulsive disorder. Comparative efficacy of paroxetine is equivalent to that of clomipramine and venlafaxine. Paroxetine is also effective for children with obsessive-compulsive disorder.Paroxetine is approved for treatment of PTSD in the United States, Japan and Europe. In the United States it is approved for short-term use.Paroxetine is also FDA-approved for generalized anxiety disorder.

Menopausal hot flashes
In 2013, low-dose paroxetine was approved in the US for the treatment of moderate-to-severe vasomotor symptoms such as hot flashes and night sweats associated with menopause. At the low dose used for menopausal hot flashes, side effects are similar to placebo and dose tapering is not required for discontinuation.

Fibromyalgia
Studies have also shown paroxetine "appears to be well-tolerated and improve the overall symptomatology in patients with fibromyalgia" but is less robust in helping with the pain involved.

Adverse effects
Common side effects include drowsiness, dry mouth, loss of appetite, sweating, trouble sleeping, and sexual dysfunction. Serious side effects may include suicide in those under the age of 25, serotonin syndrome, and mania. While the rate of side effects appears similar compared to other SSRIs and SNRIs, antidepressant discontinuation syndromes may occur more often. Use in pregnancy is not recommended while use during breastfeeding is relatively safe.Paroxetine shares many of the common adverse effects of SSRIs, including (with the corresponding rates seen in people treated with placebo in parentheses):

nausea 26% (9%)
diarrhea 12% (8%)
constipation 14% (9%)
dry mouth 18% (12%)
somnolence 23% (9%)
insomnia 13% (6%)
headache 18% (17%)
hypomania 1% (0.3%)
blurred vision 4% (1%)
loss of appetite 6% (2%)
nervousness 5% (3%)
paraesthesia 4% (2%)
dizziness 13% (6%)
asthenia (weakness; 15% (6%))
tremor 8% (2%)
sweating 11% (2%)
sexual dysfunction (≥10% incidence).Most of these adverse effects are transient and go away with continued treatment. Central and peripheral 5-HT3 receptor stimulation is believed to result in the gastrointestinal effects observed with SSRI treatment. Compared to other SSRIs, it has a lower incidence of diarrhea, but a higher incidence of anticholinergic effects (e.g., dry mouth, constipation, blurred vision, etc.), sedation/somnolence/drowsiness, sexual side effects, and weight gain.Due to reports of adverse withdrawal reactions upon terminating treatment, the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency recommends gradually reducing over several weeks or months if the decision to withdraw is made. See also Discontinuation syndrome (withdrawal).
Mania or hypomania may occur in 1% of patients with depression and up to 12% of patients with bipolar disorder. This side effect can occur in individuals with no history of mania but it may be more likely to occur in those with bipolar or with a family history of mania.

Suicide
Like other antidepressants, paroxetine may increase the risk of suicidal thinking and behaviour in people under the age of 25. The FDA conducted a statistical analysis of paroxetine clinical trials in children and adolescents in 2004 and found an increase in suicidality and ideation as compared to placebo, which was observed in trials for both depression and anxiety disorders. In 2015 a paper published in The BMJ that reanalysed the original case notes argued that in Study 329, assessing paroxetine and imipramine against placebo in adolescents with depression, the incidence of suicidal behavior had been under-reported and the efficacy exaggerated for paroxetine.

Sexual dysfunction
Sexual dysfunction, including loss of libido, anorgasmia, lack of vaginal lubrication, and erectile dysfunction, is one of the most commonly encountered adverse effects of treatment with paroxetine and other SSRIs. While early clinical trials suggested a relatively low rate of sexual dysfunction, more recent studies in which the investigator actively inquires about sexual problems suggest that the incidence is higher than 70%. Symptoms of sexual dysfunction have been reported to persist after discontinuing SSRIs, although this is thought to be occasional.

Pregnancy
Antidepressant exposure (including paroxetine) is associated with shorter duration of pregnancy (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g or 2.6 oz), and lower Apgar scores (by <0.4 points). The American College of Obstetricians and Gynecologists recommends that for pregnant women and women planning to become pregnant, paroxetine "be avoided, if possible", as it may be associated with increased risk of birth defects.Babies born to women who used paroxetine during the first trimester have an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs). Unless the benefits of paroxetine justify continuing treatment, consideration should be given to stopping or switching to another antidepressant. Paroxetine use during pregnancy is associated with about 1.5–1.7-fold increase in congenital birth defects, in particular, heart defects, cleft lip and palate, clubbed feet or any birth defects.

Discontinuation syndrome
Many psychoactive medications can cause withdrawal symptoms upon discontinuation from administration. Evidence has shown that paroxetine has among the highest incidence rates and severity of withdrawal syndrome of any medication of its class. Common withdrawal symptoms for paroxetine include nausea, dizziness, lightheadedness and vertigo; insomnia, nightmares and vivid dreams; feelings of electricity in the body, as well as rebound depression and anxiety. Liquid formulation of paroxetine is available and allows a very gradual decrease of the dose, which may prevent discontinuation syndrome. Another recommendation is to temporarily switch to fluoxetine, which has a longer half-life and thus decreases the severity of discontinuation syndrome.In 2002, the U.S. FDA published a warning regarding "severe" discontinuation symptoms among those terminating paroxetine treatment, including paraesthesia, nightmares, and dizziness. The Agency also warned of case reports describing agitation, sweating, and nausea. In connection with a Glaxo spokespersons statement that withdrawal reactions occur only in 0.2% of patients and are "mild and short-lived", the International Federation of Pharmaceutical Manufacturers Associations said GSK had breached two of the Federations codes of practice.Paroxetine prescribing information posted at GlaxoSmithKline has been updated related to the occurrence of a discontinuation syndrome, including serious discontinuation symptoms.

Overdose
Acute overdosage is often manifested by emesis, lethargy, ataxia, tachycardia, and seizures. Plasma, serum, or blood concentrations of paroxetine may be measured to monitor therapeutic administration, confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities. Plasma paroxetine concentrations are generally in a range of 40–400 μg/L in persons receiving daily therapeutic doses and 200–2,000 μg/L in poisoned patients. Postmortem blood levels have ranged from 1–4 mg/L in acute lethal overdose situations. Along with the other SSRIs, sertraline and fluoxetine, paroxetine is considered a low-risk drug in cases of overdose.

Interactions
Interactions with other drugs acting on the serotonin system or impairing the metabolism of serotonin may increase the risk of serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reaction. Such reactions have been observed with SNRIs and SSRIs alone, but particularly with concurrent use of triptans, MAO inhibitors, antipsychotics, or other dopamine antagonists.
The prescribing information states that paroxetine should "not be used in combination with an MAOI (including linezolid, an antibiotic which is a reversible non-selective MAOI), or within 14 days of discontinuing treatment with an MAOI", and should not be used in combination with pimozide, thioridazine, tryptophan, or warfarin.Paroxetine interacts with the following cytochrome P450 enzymes:
CYP2D6 for which it is both a substrate and a potent inhibitor.
CYP2B6 (strong) inhibitor.
CYP3A4 (weak) inhibitor.
CYP1A2 (weak) inhibitor.
CYP2C9 (weak) inhibitor.
CYP2C19 (weak) inhibitor.Paroxetine has been shown to be an inhibitor of G protein-coupled receptor kinase 2 (GRK2).

Pharmacology
Pharmacodynamics
Paroxetine is the most potent and one of the most specific selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs). It also binds to the allosteric site of the serotonin transporter, similarly, but less potently, than escitalopram. Paroxetine also inhibits the reuptake of norepinephrine to a lesser extent (<50 nmol/L). Based on evidence from four weeks of administration in rats, the equivalent of 20 mg paroxetine taken once daily occupies approximately 88% of serotonin transporters in the prefrontal cortex.

Pharmacokinetics
Paroxetine is well-absorbed following oral administration. It has an absolute bioavailability of about 50%, with evidence of a saturable first pass effect. When taken orally, it achieves maximum concentration in about 6–10 hours and reaches steady-state in 7–14 days. Paroxetine exhibits significant interindividual variations in volume of distribution and clearance. Less than 2% of an oral dose is excreted in urine unchanged.Paroxetine is a mechanism-based inhibitor of CYP2D6.

Society and culture
GlaxoSmithKline has paid substantial fines, paid settlements in class-action lawsuits, and become the subject of several highly critical books about its marketing of paroxetine, in particular the off-label marketing of paroxetine for children, the suppression of negative research results relating to its use in children, and allegations that it failed to warn consumers of substantial withdrawal effects associated with use of the drug. Paroxetine was approved for medical use in the United States in 1992 and initially sold by GlaxoSmithKline. It is currently available as a generic medication. In 2017, it was the 68th most commonly prescribed medication in the United States, with more than eleven million prescriptions. The United States Department of Justice fined GlaxoSmithKline $3 billion in 2012, for withholding data, unlawfully promoting use in those under 18, and preparing an article that misleadingly reported the effects of paroxetine in adolescents with depression following its clinical trial study 329.

Marketing
In early 2004, GSK agreed to settle charges of consumer fraud for $2.5 million. The legal discovery process also uncovered evidence of deliberate, systematic suppression of unfavorable Paxil research results. One of GSKs internal documents read, "It would be commercially unacceptable to include a statement that efficacy [in children] had not been demonstrated, as this would undermine the profile of paroxetine".In 2012 the U.S. Justice Department announced that GSK agreed to plead guilty and pay a $3 billion fine, in part for promoting the use of Paxil for children.On 12 February 2016, the UK Competition and Markets Authority imposed record fines of £45 million on companies which were found to have infringed European Union and UK Competition law by entering into agreements to delay the market entry of generic versions of the drug in the UK. GlaxoSmithKline received the bulk of the fines, being fined £37,600,757. Other companies, which produce generics, were issued fines which collectively total £7,384,146. UK public health services are likely to claim damages for being overcharged in the period where the generic versions of the drug were illegally blocked from the market, as the generics are over 70% less expensive. GlaxoSmithKline may also face actions from other generics manufacturers who incurred loss as a result of the anticompetitive conduct. On 18 April 2016, appeals were lodged with the Competition Appeal Tribunal by the companies which were fined.GSK marketed paroxetine through television advertisements throughout the late 1990s and early 2000s. Commercials also aired for the CR version of the drug beginning in 2003.

Sales
In 2007, paroxetine was ranked 94th on the list of bestselling drugs, with over $1 billion in sales. In 2006, paroxetine was the fifth-most prescribed antidepressant in the U.S. retail market, with more than 19.7 million prescriptions </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 Ribavirin and can you explain it in depth? [/INST] Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, peginterferon alfa-2b or peginterferon alfa-2a. Among the viral hemorrhagic fevers it is used for Lassa fever, Crimean–Congo hemorrhagic fever, and Hantavirus infection but should not be used for Ebola or Marburg infections. Ribavirin is taken by mouth or inhaled.Common side effects include feeling tired, headache, nausea, fever, muscle pains, and an irritable mood. Serious side effects include red blood cell breakdown, liver problems, and allergic reactions. Use during pregnancy results in harm to the baby. Effective birth control is recommended for both males and females for at least seven months during and after use. The mechanism of action of ribavirin is not entirely clear.Ribavirin was patented in 1971 and approved for medical use in 1986. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication.

Medical uses
Ribavirin is used primarily to treat hepatitis C and viral hemorrhagic fevers (which is an orphan indication in most countries). In this former indication the oral (capsule or tablet) form of ribavirin is used in combination with pegylated interferon alfa, including in people coinfected with hepatitis B, HIV and in the pediatric population. Statins may improve this combinations efficacy in treating hepatitis C. Ribavirin is the only known treatment for a variety of viral hemorrhagic fevers, including Lassa fever, Crimean-Congo hemorrhagic fever, Venezuelan hemorrhagic fever, and Hantavirus infection, although data regarding these infections are scarce and the drug might be effective only in early stages. It is noted by the USAMRIID that "Ribavirin has poor in vitro and in vivo activity against the filoviruses (Ebola and Marburg) and the flaviviruses (dengue, yellow fever, Omsk hemorrhagic fever, and Kyasanur forest disease)" The aerosol form has been used in the past to treat respiratory syncytial virus-related diseases in children, although the evidence to support this is rather weak.It has been used (in combination with ketamine, midazolam, and amantadine) in treatment of rabies.Experimental data indicate that ribavirin may have useful activity against canine distemper and poxviruses. Ribavirin has also been used as a treatment for herpes simplex virus. One small study found that ribavirin treatment reduced the severity of herpes outbreaks and promoted recovery, as compared with placebo treatment. Another study found that ribavirin potentiated the antiviral effect of acyclovir.Some interest has been seen in its possible use as a treatment for cancers, especially acute myeloid leukemia.

Adverse effects
The medication has two FDA "black box" warnings: One raises concerns that use before or during pregnancy by either sex may result in birth defects in the baby, and the other is regarding the risk of red blood cell breakdown.Ribavirin should not be given with zidovudine because of the increased risk of anemia; concurrent use with didanosine should likewise be avoided because of an increased risk of mitochondrial toxicity.

Mechanisms of action
It is a guanosine (ribonucleic) analog used to stop viral RNA synthesis and viral mRNA capping, thus, it is a nucleoside inhibitor. Ribavirin is a prodrug, which when metabolized resembles purine RNA nucleotides. In this form, it interferes with RNA metabolism required for viral replication. Over five direct and indirect mechanisms have been proposed for its mechanism of action. The enzyme inosine triphosphate pyrophosphatase (ITPase) dephosphorylates ribavirin triphosphate in vitro to ribavirin monophosphate, and ITPase reduced enzymatic activity present in 30% of humans potentiates mutagenesis in hepatitis C virus.

RNA viruses
Ribavirins amide group can make the native nucleoside drug resemble adenosine or guanosine, depending on its rotation. For this reason, when ribavirin is incorporated into RNA, as a base analog of either adenine or guanine, it pairs equally well with either uracil or cytosine, inducing mutations in RNA-dependent replication in RNA viruses. Such hypermutation can be lethal to RNA viruses.

DNA viruses
Neither of these mechanisms explains ribavirins effect on many DNA viruses, which is more of a mystery, especially given the complete inactivity of ribavirins 2 deoxyribose analogue, which suggests that the drug functions only as an RNA nucleoside mimic, and never a DNA nucleoside mimic. Ribavirin 5-monophosphate inhibits cellular inosine monophosphate dehydrogenase, thereby depleting intracellular pools of GTP.

History
Ribavirin was first made in 1972 under the national cancer institutes Virus-Cancer program. This was done by researchers from International Chemical and Nuclear Corporation including Roberts A. Smith, Joseph T. Witkovski and Roland K. Robins. It was reported that ribavirin was active against a variety of RNA and DNA viruses in culture and in animals, without undue toxicity in the context of cancer chemotherapies. By the late 1970s, the Virus-Cancer program was widely considered a failure, and the drug development was abandoned.

Names
Ribavirin is the INN and USAN, whereas tribavirin is the BAN. Brand names of generic forms include Copegus, Ribasphere, Rebetol.

Derivatives
Ribavirin is possibly best viewed as a ribosyl purine analogue with an incomplete purine 6-membered ring. This structural resemblance historically prompted replacement of the 2 nitrogen of the triazole with a carbon (which becomes the 5 carbon in an imidazole), in an attempt to partly "fill out" the second ring--- but to no great effect. Such 5 imidazole riboside derivatives show antiviral activity with 5 hydrogen or halide, but the larger the substituent, the smaller the activity, and all proved less active than ribavirin </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 Lonapegsomatropin 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 Dinutuximab and can you explain it in depth? [/INST] Dinutuximab (Ch14.18, tradename Unituxin) and dinutuximab beta (tradename Qarziba) are monoclonal antibodies used as a second-line treatment for children with high-risk neuroblastoma.  Each antibody is made of both mouse and human components and targets glycolipid GD2, expressed on neuroblastoma cells and on normal cells of neuroectodermal origin, including the central nervous system and peripheral nerves.  They differ in that dinutuximab is manufactured using mouse cells, and dinutuximab beta is manufactured using hamster cells.  The dosing regime differs, and dinutuximab is given in combination with granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA), while dinutuximab beta can be given alone.
They both cause severe side effects, including severe pain that must be controlled with morphine, and a high risk of infusion reaction that must be controlled with antihistamines and anti-inflammatory drugs. They both work by binding to neurons and causing the bodys immune system to destroy them.
Dinutuximab received marketing approval in the US and in the European Union in March 2015; the marketing approval was withdrawn in 2017. Dinutuximab beta received marketing approval in Europe in 2017. The antibody was originally called Ch14.18 and was discovered by a group at University of California San Diego led by Alice Yu; this antibody and several others were brought into clinical trials funded by the National Cancer Institute.

Medical use
Dinutuximab is used as post-consolidation therapy for children with high-risk neuroblastoma, in combination with granulocyte-macrophage colony-stimulating factor, interleukin-2, 13-cis-retinoic acid. It is given in patients who have completed induction therapy and consolidation therapy (autologous bone marrow transplant and external beam radiation therapy), as part of standard-of-care therapy for newly-diagnosed high-risk neuroblastoma. It is given by intravenous infusion, over ten to twenty hours, four days in a row. It is also used second-line for relapsed/refractory neuroblastoma in combination with chemotherapy and GM-CSF.
Dinutuximab beta is also used as a second line treatment for children with high-risk neuroblastoma; it was tested and is used with a longer and slower dosing regime, and is given on its own, although it may be combined with IL-2 if a stronger immune response is needed.Morphine is administered prior to, during, and for two hours after infusion of dinutuximab and dinutuximab beta to manage the severe pain that this drug causes. An antihistamine and an anti-inflammatory are also given before, during, and after to manage the infusion reaction.Women who are pregnant or who might become pregnant should not take dinutuximab or dinutuximab beta, because it is very likely to cause harm to a fetus.

Adverse effects
The US label for dinutuximab carries black box warnings for life-threatening infusion reactions and neurotoxicity, as it causes severe neuropathic pain, and can cause severe sensory neuropathy and severe peripheral motor neuropathy.  Dinutuximab beta also has these adverse effects.More than 25% of children taking these drugs experienced pain, fever, hives, vomiting, diarrhea, bone marrow suppression causing loss of platelets, red blood cells, white blood cells, and albumin, hypotension, electrolyte imbalance including low sodium, potassium, and calcium, elevated transaminases, infusion reactions, and capillary leak syndrome.Other common adverse effects include retention or urine for weeks to months after receiving the drugs, protein in urine, blurred vision or dilated pupils, infections, edema, high blood pressure, bleeding that wont stop, tachycardia, and weight gain.

Pharmacology
Dinutuximab and dinutuximab beta each work by binding to GD2, a glycolipid found on cells originating from the neuroectoderm during prenatal development, including neurons in the central nervous system and in the peripheral nervous system.   Neuroblastoma cells have this as well.  When dinutuximab binds to any cell that has GD2, that cell is destroyed via cell-mediated cytotoxicity and complement-dependent cytotoxicity.In clinical trials of dinutuximab, the maximum plasma concentration was 11.5 mcg/mL; the mean steady state volume distribution was 5.4 L; the clearance rate was 0.21 L/day; and the average half-life was 10 days.

Chemistry
Ch14.18 is a chimeric monoclonal antibody in which the variable heavy and light chain regions come from a mouse, with a human constant region for the heavy chain IgG1 and light chain kappa.The version of dinutuximab made by United Therapeutics, and marketed under the brand name Unituxin, is manufactured via industrial fermentation using a murine myeloma cell line, SP2/0.  The version marketed by EUSA for Apeiron is called generically dinutuximab beta and is marketed under the brand name Isquette, and is manufactured in Chinese hamster ovary cells.

History
Dinutuximab (originally called Ch14.18) was discovered by a group at University of California San Diego led by Alice Yu; this antibody and several others were brought into clinical trials funded by the National Cancer Institute </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 Zoster vaccine and can you explain it in depth? [/INST] A zoster vaccine is a vaccine that reduces the incidence of herpes zoster (shingles), a disease caused by reactivation of the varicella zoster virus, which is also responsible for chickenpox. Shingles provokes a painful rash with blisters, and can be followed by chronic pain (postherpetic neuralgia), as well as other complications. Older people are more often affected, as are people with weakened immune systems (immunosuppression). Both shingles and postherpetic neuralgia can be prevented by vaccination.Two zoster vaccines have been approved for use in people over 50 years old. Shingrix (GSK) is a recombinant subunit vaccine which has been used in many countries since 2017. Zostavax (Merck), in use since 2006, is an attenuated vaccine which consists of a larger-than-normal dose of chickenpox vaccine. Unlike Shingrix, Zostavax is not suitable for people with immunosuppression or diseases that affect the immune system. Zostavax was discontinued in the United States in November 2020.Shingrix appears to prevent more cases of shingles than Zostavax, although side effects seem to be more frequent.Another vaccine, known as varicella vaccine, is used to prevent diseases caused by the same virus.

Medical uses
Zoster vaccination is used to prevent shingles and its complications, including postherpetic neuralgia. It can be considered a therapeutic vaccine, given that it is used to treat a latent virus that has remained dormant in cells since chicken pox infection earlier in life. The two available zoster vaccines are intended for use in people over the age of 50. As of 2021 it remained to be confirmed whether a booster dose was required, but the Advisory Committee on Immunization Practices (ACIP) in the United States recommends Shingrix for adults over the age of 50, including those who have already received Zostavax.

Shingrix
The ACIP voted that Shingrix is preferred over Zostavax for the prevention of zoster and related complications because data showed vaccine efficacy of more than 90% against shingles across all age groups. Unlike Zostavax, which is given as a single shot, Shingrix is given as two intramuscular doses, two to six months apart. Most of the studies conducted showed efficacy to at least 4 years post-vaccination, but it is possible the vaccine may provide protection for much longer.A large randomized clinical trial showed Shingrix reduced the incidence of shingles 96.6% in the 50–59 age group, and 91.3% in those over age 70. The absolute decrease in risk of herpes zoster following immunization over three and a half years is 3.3% (3.54% down to 0.28%) while the decrease in the risk of postherpetic neuralgia is 0.3% (0.34% down to 0.06%).

Zostavax
A Cochrane review concluded that Zostavax is "effective in preventing herpes zoster disease for up to three years". The duration of protection beyond four years after vaccination with the zoster vaccine is unknown. The need for re-vaccination remains to be confirmed.Zostavax was shown to reduce the incidence of shingles by 51% in a study of 38,000 adults aged 60 and older who received the vaccine. The vaccine also reduced by 67% the number of cases of postherpetic neuralgia (PHN) and reduced the severity and duration of pain and discomfort associated with shingles, by 61%. The FDA originally recommended it for individuals 60 years of age or older who are not severely allergic to any of its components and who meet the following requirements:
do not have a weakened immune system due to HIV/AIDS or another disease or medications (such as steroids, radiation and chemotherapy) that affect the immune system;
do not have a history of cancer affecting the bone marrow or lymphatic system, such as leukemia or lymphoma; and
do not have active, untreated tuberculosis.In 2006, the U.S. Advisory Committee on Immunization Practices (ACIP) recommended that the live vaccine be given to all adults age 60 and over, including those who have had a previous episode of shingles, and those who do not recall having had chickenpox, since more than 99% of Americans ages 40 and older have had chickenpox.

Side effects
Shingrix
Temporary side effects from the Shingrix shots are likely and can be severe enough in one out of six people to affect normal daily activities for up to three days. Mild to moderate pain at the injection site is common, and some may have redness or swelling. Side effects include fatigue, muscle pain, headache, shivering, fever, and nausea. Symptoms usually resolve in two to three days. Side effects with Shingrix are greater than those with Zostavax and occur more frequently in individuals aged 50 to 69 years compared with those 70 years and older.

Zostavax
The live vaccine (Zostavax) is very safe; one to a few percent of people develop a mild form of chickenpox, often with about five or six blisters around the injection site, and without fever. The blisters are harmless and temporary. In one study 64% of the Zostavax group and 14% of the controls had some adverse reaction. However, the rates of serious adverse events were comparable between the Zostavax group (0.6%) and those receiving the placebo (0.5%). A study including children with leukaemia found that the risk of getting shingles after vaccination is much lower than the risk of getting shingles for children with natural chicken pox in their history. Data from healthy children and adults point in the same direction.Zostavax is not used in people with compromised immune function.

Composition
Shingrix
Shingrix is a suspension for intramuscular injection consisting of a lyophilized recombinant varicella zoster virus glycoprotein E antigen that is reconstituted at the time of use with AS01B suspension as an immunological adjuvant. The antigen is a purified truncated form of the glycoprotein, expressed in Chinese hamster ovary cells. The AS01B adjuvant suspension is composed of 3-O-desacyl-4-monophosphoryl lipid A (MPL) from Salmonella (Minnesota strain) and a saponin molecule (QS-21) purified from Quillaja saponaria (soap bark tree) extract, combined in a liposomal formulation consisting of dioleoyl phosphatidylcholine (DOPC) and cholesterol in phosphate-buffered saline solution.

Zostavax
Zostavax contains live attenuated varicella-zoster virus. It is injected subcutaneously (under the skin) in the upper arm. The live vaccine is produced using the MRC-5 line of fetal cells. This has raised religious and ethical concerns for some potential users, since that cell line was derived from an aborted fetus.

Cost effectiveness
A 2007 study found that the live vaccine is likely to be cost-effective in the U.S., projecting an annual savings of US$82 to US$103 million in healthcare costs with cost-effectiveness ratios ranging from US$16,229 to US$27,609 per quality-adjusted life year gained. In 2007, the live vaccine was officially recommended in the U.S. for healthy adults aged 60 and over, but is now is no longer given out in the United States as of 2020, given the likely superiority of Shingrix.In Canada the cost of Shingrix is about CA$300 for the two doses. This likely represents a more cost effective intervention than the live vaccine given its lower cost and increased effectiveness.

History
European Union
In 2006, the European Medicines Agency (EMA) issued a marketing authorization for the zoster vaccine to Sanofi Pasteur for routine vaccination in individuals aged 60 and over. In 2007, the EMA updated the marketing authorization for routine vaccination in individuals aged 50 and over.Shingrix was approved for medical use in the European Union in March 2018, with an indication for the prevention of herpes zoster (HZ) and post-herpetic neuralgia (PHN) in adults 50 years of age or older.

United Kingdom
From 2013, the UK National Health Service (NHS) started offering shingles vaccination to elderly people. People aged either 70 or 79 on 1 September 2013, were offered the vaccine. People aged 71 to 78 on that date would only have an opportunity to have the shingles vaccine after reaching the age of 79. The original intention was for people aged between 70 and 79 to be vaccinated, but the NHS later said that the vaccination program was being staggered as it would be impractical to vaccinate everyone in their 70s in a single year.In 2021, vaccination against shingles is available on the NHS to people aged 70 to 79. Vaccination is with single-dose Zostavax, except for people for whom Zostavax is deemed unsuitable, for example, with a condition that affects the immune system, for whom two-dose Shingrix vaccine is recommended. The NHS stated "The shingles vaccine is not available on the NHS to anyone aged 80 or over because it seems to be less effective in this age group".

United States
Zostavax was developed by Merck & Co. and approved and licensed by the U.S. Food and Drug Administration (FDA) in May 2006, In 2011, the FDA approved the live vaccine for use in individuals 50 to 59 years of age. Shingrix is a zoster vaccine developed by GlaxoSmithKline that was approved in the United States in October 2017.On June 30, 2020, Merck discontinued the sale of Zostavax in the U.S. Vaccine already held by practitioners could still be administered up to the expiration date (none expired later than November 2020).The U.S. Centers for Disease Control and Prevention (CDC) recommends that healthy adults 50 years and older get two doses of Shingrix, at least two months apart.  Initial clinical trials only tested a gap of less than six months between doses, but unexpected popularity and resulting shortages caused further testing to validate wider spacing of the two doses. Shingrix, which provides strong protection against shingles and PHN, was preferred over Zostavax before Zostavax was discontinued.The zoster vaccine is covered by Medicare Part D. In 2019, more than 90% of Medicare Part D vaccine spending was for the zoster vaccine. 5.8 million vaccine doses were administered to Part D beneficiaries that year at a cost of $857 million.

References
Further reading
World Health Organization (2014). "Varicella and herpes zoster vaccines : WHO position paper, June 2014" (PDF). Weekly Epidemiological Record. 89 (25): 265–287. hdl:10665/242227. PMID 24983077.
Hamborsky J, Kroger A, Wolfe S, eds. (2015). "Chapter 22: Varicella". Epidemiology and Prevention of Vaccine-Preventable Diseases (13th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC) </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 Azelastine and can you explain it in depth? [/INST] Azelastine, sold under the brand name Optivar among others, is a medication primarily used as a nasal spray to treat allergic rhinitis (hay fever) and as eye drops for allergic conjunctivitis. Other uses may include asthma and skin rashes for which it is taken by mouth. Onset of effects is within minutes when used in the eyes and within an hour when used in the nose. Effects last for up to 12 hours.Common side effects include headache, sleepiness, change in taste, and sore throat. It is unclear if use is safe during pregnancy or breastfeeding. It is a second-generation antihistamine and works by blocking the release of a number of inflammatory mediators including histamine.Azelastine was patented in 1971 and came into medical use in 1986. It is available as a generic medication. In 2019, it was the 167th most commonly prescribed medication in the United States, with more than 3 million prescriptions.

Medical uses
Azelastine nasal spray is indicated for the local treatment of the symptoms of seasonal allergic rhinitis and perennial allergic rhinitis, such as rhinorrhea, sneezing and nasal pruritus in people five years of age and older. In some countries, it is also indicated for the treatment of vasomotor rhinitis in adults and children ≥ 12 years old. Azelastine eye drops are indicated for the local treatment of seasonal and perennial allergic conjunctivitis.

Side effects
Azelastine is safe and well tolerated in both adults and children with allergic rhinitis. Bitter taste, headache, nasal burning and somnolence are the most frequently reported adverse events. US prescribing recommendations warn against the concurrent use of alcohol and/or other central nervous system depressants, but to date there have been no studies to assess the effects of azelastine nasal spray on the CNS in humans. More recent studies have shown similar degrees of somnolence (approx. 2%) compared with placebo treatment.
The most common side effect is a bitter taste (about 20% of people). Due to this, the manufacturer has produced another formulation of azelastine with sucralose. The problem of bitter taste may also be reduced by correct application of the nasal spray (i.e. slightly tipping the head forward and not inhaling the medication too deeply), or alternatively using the azelastine/sucralose formulation.In addition, anosmia (loss in the ability to smell) can occur with nasal spray antihistamines (including both formulations of azelastine).

Pharmacology
Pharmacodynamics
Azelastine has a triple mode of action:
Anti-histamine effect,
Mast-cell stabilizing effect and
Anti-inflammatory effect.

Pharmacokinetics
The systemic bioavailability of azelastine is approximately 40% when administered intranasally. Maximum plasma concentrations (Cmax) are observed within 2–3 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 Ethambutol and can you explain it in depth? [/INST] Ethambutol (EMB, E) is a medication primarily used to treat tuberculosis. It is usually given in combination with other tuberculosis medications, such as isoniazid, rifampicin and pyrazinamide. It may also be used to treat Mycobacterium avium complex, and Mycobacterium kansasii. It is taken by mouth.Common side effects include problems with vision, joint pain, nausea, headaches, and feeling tired. Other side effects include liver problems and allergic reactions. It is not recommended in people with optic neuritis, significant kidney problems, or under the age of five. Use during pregnancy or breastfeeding has not been found to cause harm. In the United States the FDA has raised concerns about eye issues in the baby if used during pregnancy. Ethambutol is believed to work by interfering with the bacterias metabolism.Ethambutol was discovered in 1961. It is on the World Health Organizations List of Essential Medicines and is available as a generic medication.

Chirality and biological activity
(S,S)-(+)-Ethambutol is powerful and selective antitubercular drug. It is a typical example of an old drug that was introduced for clinical use in its unichiral form. Ethambutol contains two constitutionally symmetrical chiral centers in its structure and exists in three stereoisomeric forms. An enantiomeric pair (S,S)- and (R,R)-ethmabutol, along with the achiral stereoisomer called meso-form. The (S,S)-(+)-enantiomer harbors the antitubercular activity. This enantiomer is 500 and 12 fold more potent than the (R,R)-ethmabutol and the meso-form respectively. On the other hand, all the three isomers are equipotent in terms of the major side-effect of the drug, optic neuritis. Toxicity is associated to both dose and duration of treatment </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 Lindane and can you explain it in depth? [/INST] Lindane, also known as gamma-hexachlorocyclohexane (γ-HCH), gammaxene, Gammallin and benzene hexachloride (BHC), is an organochlorine chemical and an isomer of hexachlorocyclohexane that has been used both as an agricultural insecticide and as a pharmaceutical treatment for lice and scabies.Lindane is a neurotoxin that interferes with GABA neurotransmitter function by interacting with the GABAA receptor-chloride channel complex at the picrotoxin binding site. In humans, lindane affects the nervous system, liver, and kidneys, and may well be a carcinogen. Whether lindane is an endocrine disruptor is unclear.The World Health Organization classifies lindane as "moderately hazardous", and its international trade is restricted and regulated under the Rotterdam Convention on Prior Informed Consent. In 2009, the production and agricultural use of lindane was banned under the Stockholm Convention on persistent organic pollutants. A specific exemption to that ban allows it to continue to be used as a second-line pharmaceutical treatment for lice and scabies.

History and use
The chemical was originally synthesized in 1825 by Faraday. It is named after the Dutch chemist Teunis van der Linden (1884–1965), the first to isolate and describe γ-hexachlorcyclohexane in 1912. The fact that mixtures of isomers of hexachlorocyclohexane have insecticidal activity is a case of multiple discovery.  Work in the 1930s at the Jealotts Hill laboratories of Imperial Chemical Industries Ltd (ICI) led in 1942 to the realization that the γ isomer was the key active component in the mixture which had hitherto been tested. Development  work in the UK was accelerated because at that time in World War II imports of derris containing the insecticide rotenone were restricted owing to the Japanese occupation of Malaya and alternatives were urgently needed. In trials in 1943 it was found that a five-fold increase in the yield of oats and wheat was achieved using a dust formulation of the available material, owing to its efficacy against wireworm pests. By the end of 1945, γ-hexachlorcyclohexane of 98% purity became available and ICI commercialised a seed treatment launched in 1949 as Mergamma A, containing 1% mercury and 20% lindane. Subsequently, lindane has been used to treat food crops and forestry products, as a seed or soil treatment, and to treat livestock and pets. It was used as a household pesticide as the active pesticide ingredient of an insecticidal floor wax product called "Freewax".   It has also been used as pharmaceutical treatment for lice and scabies, formulated as a shampoo or lotion. Between 1950 and 2000, an estimated 600,000 tonnes of lindane were produced globally, and the vast majority of which was used in agriculture. It has been manufactured by several countries, including the United States, China, Brazil, and several European countries, but as of 2007, only India and possibly Russia are still producing it.
By November 2006, the use of lindane had been banned in 52 countries and restricted in 33 others. Seventeen countries, including the US and Canada, allowed either limited agricultural or pharmaceutical use. In 2009, an international ban on the use of lindane in agriculture was implemented under the Stockholm Convention on Persistent Organic Pollutants. A specific exemption allows for it to continue to be used in second-line treatments for the head lice and scabies for five more years. The production of the lindane isomers α- and β-hexachlorocyclohexane was also banned. Although the US has not ratified the Convention, it has similarly banned agricultural uses while still allowing its use as a second-line lice and scabies treatment.

United States
In the US, lindane pesticide products were regulated by the U.S. Environmental Protection Agency (EPA), while lindane medications are regulated by the Food and Drug Administration (FDA). It was registered as an agricultural insecticide in the 1940s, and as pharmaceutical in 1951. The EPA gradually began restricting its agricultural use in the 1970s due to concerns over its effects on human health and the environment. By 2002, its use was limited to seed treatments for just six crops, and in 2007, these last uses were cancelled.

Pharmaceutical uses
Lindane medications continue to be available in the US, though since 1995, they have been designated "second-line" treatments, meaning they should be prescribed when other "first-line" treatments have failed or cannot be used. In December 2007, the FDA sent a Warning Letter to Morton Grove Pharmaceuticals, the sole U.S. manufacturer of lindane products, requesting that the company correct misleading information on two of its lindane websites. The letter said, in part, that the materials "are misleading in that they omit and/or minimize the most serious and important risk information associated with the use of Lindane Shampoo, particularly in pediatric patients; include a misleading dosing claim; and overstate the efficacy of Lindane Shampoo."California banned the pharmaceutical lindane, effective 2002, and the Michigan House of Representatives passed a bill in 2009 to restrict its use to doctors offices. A recent analysis of the California ban concluded that a majority of pediatricians had not experienced problems treating lice or scabies since that ban took effect. The study also documented a marked decrease in lindane wastewater contamination and a dramatic decline in lindane poisoning incidents reported to poison control centers. The authors concluded, "The California experience suggests elimination of pharmaceutical lindane produced environmental benefits, was associated with a reduction in reported unintentional exposures and did not adversely affect head lice and scabies treatment."The Persistent Organic Pollutants Review Committee of the Stockholm Convention on Persistent Organic Pollutants considers the use of lindane in agriculture as largely redundant, with other, less toxic and less persistent pesticides. In the case of pharmaceutical use, the committee noted, "alternatives for pharmaceutical uses have often failed for scabies and lice treatment and the number of available alternative products for this use is scarce. For this particular case, a reasonable alternative would be to use lindane as a second-line treatment when other treatments fail, while potential new treatments are assessed."

Other uses
Pest repellent
Lindane is a bird repellent. Rudd & Genelly 1954 noticed that bird pests seemed uninterested in treated seeds, specifically pheasants and blackbirds around Davis, CA, US. They tested its repellent effect on pheasants and found it effective, speculating that it may be usable as a general bird repellent.

Preparation
Lindane is prepared by treating chlorine with benzene in the presence of sunlight and in the absence of oxygen as well as substitution catalysts.

Human health effects
The EPA and WHO both classify lindane as "moderately" acutely toxic. It has an oral LD50 of 88 mg/kg in rats and a dermal LD50 of 1000 mg/kg. Most of the adverse human health effects reported for lindane have been related to agricultural uses and chronic, occupational exposure of seed-treatment workers.Exposure to large amounts of lindane can harm the nervous system, producing a range of symptoms from headache and dizziness to seizures, convulsions, and more rarely, death. Lindane has not been shown to affect the immune system in humans, and it is not considered to be genotoxic. Prenatal exposure to β-HCH, an isomer of lindane and production byproduct, has been associated with altered thyroid hormone levels and could affect brain development.The Occupational Safety and Health Administration and National Institute for Occupational Safety and Health have set occupational exposure limits (permissible exposure and recommended exposure, respectively) for lindane at 0.5 mg/m3 at a time-weighted average of eight hours for skin exposure. People can be exposed to lindane in the workplace by inhaling it, absorbing it through their skin, swallowing it, and eye contact. At levels of 50 mg/m3, lindane is immediately dangerous to life and health.It is classified as an extremely hazardous substance in the United States as defined in section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.

Cancer risk
Based primarily on evidence from animal studies, most evaluations of lindane have concluded that it may possibly cause cancer. In 2015, the International Agency for Research on Cancer classified lindane as a known human carcinogen, and in 2001 the EPA concluded there was "suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential." The U.S. Department of Health and Human Services determined that all isomers of hexachlorocyclohexane, including lindane, "may reasonably be anticipated to cause cancer in humans," and in 1999, the EPA characterized the evidence carcinogenicity for lindane as "suggestive ... of carcinogenicity, but not sufficient to assess human carcinogenic potential." Lindane and its isomers have also been on Californias Proposition 65 list of known carcinogens since 1989. In contrast, the World Health Organization concluded in 2004 that "lindane is not likely to pose a carcinogenic risk to humans." Indias BIS considers Lindane a "confirmed carcinogen".

Adverse reactions
A variety of adverse reactions to lindane pharmaceuticals have been reported, ranging from skin irritation to seizures, and, in rare instances, death. The most common side effects are burning sensations, itching, dryness, and rash. While serious effects are rare and have most often resulted from misuse, adverse reactions have occurred when used properly. The FDA, therefore, requires a so-called black box warning on lindane products, which explains the risks of lindane products and their proper use.The black box warning emphasizes that lindane should not be used on premature infants and individuals with known uncontrolled seizure disorders, and should be used with caution in infants, children, the elderly, and individuals with other skin conditions (e.g., dermatitis, psoriasis) and people who weigh less than 110 lb (50 kg), as they may be at risk of serious neurotoxicity.

Environmental contamination
Lindane is a persistent organic pollutant: it is relatively long-lived in the environment, it is transported long distances by natural processes like global distillation, and it can bioaccumulate in food chains, though it is rapidly eliminated when exposure is discontinued.The production and agricultural use of lindane are the primary causes of environmental contamination, and levels of lindane in the environment have been decreasing in the U.S., consistent with decreasing agricultural usage patterns. The production of lindane generates large amounts of waste hexachlorocyclohexane isomers, and "every ton of lindane manufactured produces about nine tons of toxic waste." Modern manufacturing standards for lindane involve the treatment and conversion of waste isomers to less toxic molecules, a process known as "cracking".When lindane is used in agriculture, an estimated 12–30% of it volatilizes into the atmosphere, where it is subject to long-range transport and can be deposited by rainfall. Lindane in soil can leach to surface and even ground water, and can bioaccumulate in the food chain. However, biotransformation and elimination are relatively rapid when exposure is discontinued. Most exposure of the general population to lindane has resulted from agricultural uses and the intake of foods, such as produce, meats, and milk, produced from treated agricultural commodities. Human exposure has decreased significantly since the cancellation of agricultural uses in 2006. Even so, the CDC published in 2005 its Third National Report on Human Exposures to Environmental Chemicals, which found no detectable amounts of lindane in human blood taken from a random sampling of about 5,000 people in the US as part of the NHANES study (National Health and Nutrition Examination Survey at: https://www.cdc.gov/nchs/nhanes/about_nhanes.htm). The lack of detection of lindane in this large human "biomonitoring" study likely reflects the increasingly limited agricultural uses of lindane over the last two decades. The cancellation of agricultural uses in the United States will further reduce the amount of lindane introduced into the environment by more than 99%.Over time, lindane is broken down in soil, sediment, and water into less harmful substances by algae, fungi, and bacteria; however, the process is relatively slow and dependent on ambient environmental conditions. Lindane residues in honey and beeswax are reported to be the highest of any historical or current pesticide and to continue to pose a threat to honeybee health. The ecological impact of lindanes environmental persistence continues to be debated.
The US EPA determined in 2002 that the agency does not believe that lindane contaminates drinking water in excess of levels considered safe. U.S. Geological Survey teams concluded the same in 1999 and 2000. With regard to lindane medications, the EPA conducted "down-the-drain" estimates of the amount of lindane reaching public water supplies and concluded that lindane levels from pharmaceutical sources were "extremely low" and not of concern.Note that the EPA has set the maximum contaminant level or "MCL" for lindane allowed in public water supplies and considered safe for drinking at 200 parts per trillion (ppt). By comparison, the state of California imposes a lower MCL for lindane of 19 ppt. However, the California standard is based on a dated 1988 national water criterion that was subsequently revised by the EPA in 2003 to 980 ppt </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 SPS 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 Cisatracurium besilate and can you explain it in depth? [/INST] Cisatracurium besilate (INN; cisatracurium besylate (USAN); formerly recognized as 51W89; trade name Nimbex) is a bisbenzyltetrahydroisoquinolinium that has effect as a neuromuscular-blocking drug  non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. It shows intermediate duration of action. Cisatracurium is one of the ten isomers of the parent molecule, atracurium. Moreover, cisatracurium represents approximately 15% of the atracurium mixture.

History
The generic name cisatracurium was conceived by scientists at Burroughs Wellcome Co. (now part of GlaxoSmithKline) by combining the name "atracurium" with "cis" [hence cisatracurium] because the molecule is one of the three cis-cis isomers comprising the ten isomers of the parent, atracurium.  Atracurium itself was invented at Strathclyde University and licensed to Burroughs Wellcome Co., Research Triangle Park, NC, for further development and subsequent marketing as Tracrium. As the secondary pharmacology of atracurium was being developed, it became clear that the primary clinical disadvantage of atracurium was likely to be its propensity to elicit histamine release. To address this issue, a program was initiated to investigate the individual isomer constituents of atracurium to identify and isolate the isomer(s) associated with the undesirable histamine effects as well as identify the isomer that might possibly retain the desirable properties without the histamine release. Thus, in 1989, D A Hill and G L Turner, PhD (both chemists at Burroughs Wellcome Co., Dartford, UK) first synthesized cisatracurium as an individual isomer molecule. The pharmacological research of cisatracurium and the other individual isomers was then developed further primarily by R. Brandt Maehr and William B. Wastila, PhD (both of whom were pharmacologists within the Division of Pharmacology at Burroughs Wellcome Co.) in collaboration with John J. Savarese MD (who at the time was an anesthesiologist in the Dept. of Anesthesia, Harvard Medical School at the Massachusetts General Hospital, Boston, MA). Thereafter, the entire clinical development of cisatracurium was completed in a record short period from 1992 to 1994: the team of scientists was led by J. Neal Weakly PhD, Martha M. Abou-Donia PhD, and Steve Quessy PhD, in the Division of Clinical Neurosciences at Burroughs Wellcome Co., Research Triangle Park, NC.  By the time of its approval for human use, in 1995, by the US Food and Drug Administration, Burroughs Wellcome Co. had merged with Glaxo Inc., and cisatracurium was approved to be marketed as Nimbex by GlaxoWellcome Inc. The trade name "Nimbex" was derived from inserting an "i" to the original proposal "Nmbex," which stood for excellent Neuromuscular blocker.

Preclinical pharmacology
In vitro studies using human plasma indicated that cisatracurium spontaneously degrades at physiological pH via Hofmann elimination to yield laudanosine and the quaternary monoacrylate. Subsequent ester hydrolysis of the monoacrylate generates the monoquaternary alcohol, although the rate-limiting step is Hofmann elimination. In rat plasma, cisatracurium is also metabolized by non-specific carboxylesterases (a rate-limiting step) to the monoquaternary alcohol and the monoquaternary acid.

Clinical pharmacology
As is evident with the parent molecule, atracurium, cisatracurium is also susceptible to degradation by Hofmann elimination and ester hydrolysis as components of the in vivo metabolic processes. See the atracurium page for information on Hofmann elimination in vivo versus the Hofmann degradation chemical reaction.
Because Hofmann elimination is a temperature- and plasma pH-dependent process, cisatracuriums rate of degradation in vivo is highly influenced by body pH and temperature just as it is with the parent molecule, atracurium: thus, an increase in body pH favors the elimination process, whereas a decrease in temperature slows down the process.
One of the metabolites of cisatracurium via Hofmann elimination is laudanosine – see the atracurium page for further discussion of the issue regarding this metabolite.  80% of cisatracurium is metabolized eventually to laudanosine and 20% is metabolized hepatically or excreted renally. 10-15% of the dose is excreted unchanged in the urine.Since Hofmann elimination is an organ-independent chemodegradative mechanism, there is little or no risk to the use of cisatracurium in patients with liver or renal disease when compared with other neuromuscular-blocking agents.The two reverse ester linkages in the bridge between the two isoquinolinium groups make atracurium and cisatracurium poor targets for plasma cholinesterase, unlike mivacurium which has two conventional ester linkages.

Adverse effects
Histamine release – hypotension, reflex tachycardia and cutaneous flush
Bronchospasm – Pulmonary compliance
To date, cisatracurium has not been reported to elicit bronchospasm at doses that are clinically prescribed.

Laudanosine – Epileptic foci
Cisatracurium undergoes Hofmann elimination as a primary route of chemodegradation: consequently one of the metabolites from this process is laudanosine, a tertiary amino alkaloid reported to be a modest CNS stimulant with epileptogenic activity and cardiovascular effects such as low blood pressure and a slowed heart rate. As a tertiary amine, Laudanosine is unionised and readily crosses the blood–brain barrier. Presently, there is little evidence that laudanosine accumulation and related toxicity will likely ever be seen with the doses of cisatracurium that are administered in clinical practice especially given that the plasma concentrations of laudanosine generated are lower with cisatracurium than those seen with atracurium.

Research
A recent study showed that cisatracurium pretreatment effectively decreases the incidence and severity of pain induced by propofol general anaesthesia.

Another study showed that hiccups accompanied by vomiting, insomnia, shortness of breath can also be relieved by the nondepolarizing muscle relaxant, cisatracurium, during total intravenous anesthesia.

Synthesis
Treatment of 1,5-Pentanediol with 3-bromopropionyl chloride gives the corresponding ester; dehydrohalogenation of the ester with triethylamine then gives the bis-acrylate (2). Reaction of that unsaturated ester with tetrahydropapaverine (3) leads to conjugate addition of the secondary amine and formation of the intermediate (4). Alkylation with methyl benzenesulfonate forms the bis-quaternary salt, affording cisatracuronium (5).

References
Further reading
Caldwell JE (1995). "New skeletal muscle relaxants". Int Anesthesiol Clin. 33 (1): 39–60. doi:10.1097/00004311-199500000-00003. PMID 7635557.
Hull CJ (1995). "Pharmacokinetics and pharmacodynamics of the benzylisoquinolinium muscle relaxants". Acta Anaesthesiol Scand. 106 Suppl: 13–17. doi:10.1111/j.1399-6576.1995.tb04302.x. PMID 8533537. S2CID 43784865.
Savarese JJ, Wastila WB (1995). "The future of the benzylisoquinolinium relaxants". Acta Anaesthesiol Scand. 106 Suppl: 91–93. doi:10.1111/j.1399-6576.1995.tb04317.x. PMID 8533554. S2CID 39461057.
Esmaoglu A, Akin A, Mizrak A, Turk Y, Boyaci A (2006). "Addition of cisatracurium to lidocaine for intravenous regional anesthesia". J Clin Anesth. 18 (3): 194–7. doi:10.1016/j.jclinane.2005.08.003. PMID 16731321.
Melloni C, De Vivo P, Launo C, Mastronardi P, Novelli G, Romano E (2006). "Cisatracurium versus vecuronium: a comparative, double blind, randomized, multicenter study in adult patients under propofol/fentanyl/N2O anesthesia". Minerva Anestesiol. 72 (5): 299–308. PMID 16675938.
Serra C, Oliveira A (2006). "Cisatracurium: myographical and electrophysiological studies in the isolated rat muscle". Fundam Clin Pharmacol. 20 (3): 291–8. doi:10.1111/j.1472-8206.2006.00395.x. PMID 16671964. S2CID 11980810.
Katzung, Bertram G </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Drospirenone/ethinylestradiol/levomefolic acid and can you explain it in depth? [/INST] Drospirenone/ethinylestradiol/levomefolic acid (EE/DRSP/LMF), sold under the brand names Beyaz among others, is a combination of ethinylestradiol (EE), an estrogen, drospirenone (DRSP), a progestogen, antimineralocorticoid, and antiandrogen, and levomefolic acid (LMF), a form of vitamin B9, which is used as a birth control pill to prevent pregnancy in women. The formulation contains folate as the calcium salt of levomefolic acid to lower the risk of complications such as fetal neural tube defects should the medication fail as a form of birth control. EE/DRSP/LMF was approved for use by the U.S. Food and Drug Administration (FDA) on 24 September 2010.

Medical uses
Studies have shown its uses to be oral contraception, lessening premenstrual dysphoric disorder (PMDD), and treatment of moderate acne in women over 14 years of age who choose an oral contraceptive for contraception. Five clinical trials were carried out for these labeled uses, “including a one-year contraceptive efficacy study, two 3-cycle studies in women with premenstrual dysphoric disorder (PMDD), and two 6-cycle studies in women with moderate acne.” The drug combination will also increase folate levels due to its extra ingredient, levomefolic calcium. This is equivalent to folic acid 0.4 mg and will help prevent neural tube defects in case of accidental pregnancy while taking, or shortly after stopping the drug.

Dosage and use
Each box, as supplied by the manufacturer, contains three blister packs of 28 tablets packaged in individual boxes. Each blister pack of 28 tablets contains 24 pink active pills containing drospirenone 3 mg, ethinylestradiol 20 mcg, and levomefolate calcium 0.451 mg and four light orange inactive pills containing of levomefolate calcium 0.451 mg.One tablet is taken by mouth at the same time every day. The failure rate may increase when pills are missed or taken incorrectly. Single missed pills should be taken as soon as remembered. It is important to know that when experiencing stomach upset in the form of diarrhea or vomiting (within 3–4 hours of taking), backup contraception methods should be utilized to account for possible absorption failure.

Side effects
Adverse reactions commonly reported by combined oral contraceptive users are irregular uterine bleeding, nausea, breast tenderness, and headache.

Interactions
Decreased efficacy
Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Factor IX and can you explain it in depth? [/INST] Factor IX (or Christmas factor) (EC 3.4.21.22) is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes haemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to haemophilia.Coagulation factor IX is on the World Health Organizations List of Essential Medicines.

Physiology
Factor IX is produced as a zymogen, an inactive precursor.  It is processed to remove the signal peptide, glycosylated and then cleaved by factor XIa (of the contact pathway) or factor VIIa (of the tissue factor pathway) to produce a two-chain form, where the chains are linked by a disulfide bridge.  When activated into factor IXa, in the presence of Ca2+, membrane phospholipids, and a Factor VIII cofactor, it hydrolyses one arginine-isoleucine bond in factor X to form factor Xa.
Factor IX is inhibited by antithrombin.Factor IX expression increases with age in humans and mice. In mouse models, mutations within the promoter region of factor IX have an age-dependent phenotype.

Domain architecture
Factors VII, IX, and X all play key roles in blood coagulation and also share a common domain architecture. The factor IX protein is composed of four protein domains: the Gla domain, two tandem copies of the EGF domain and a C-terminal trypsin-like peptidase domain which carries out the catalytic cleavage.

The N-terminal EGF domain has been shown to at least in part be responsible for binding tissue factor. Wilkinson et al. conclude that residues 88 to 109 of the second EGF domain mediate binding to platelets and assembly of the factor X activating complex.The structures of all four domains have been solved. A structure of the two EGF domains and the trypsin-like domain was determined for the pig protein. The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR.Several structures of super active mutants have been solved, which reveal the nature of factor IX activation by other proteins in the clotting cascade.

Genetics
The gene for factor IX is located on the X chromosome (Xq27.1-q27.2) and is therefore X-linked recessive: mutations in this gene affect males much more frequently than females. At least 534 disease-causing mutations in this gene have been discovered. The F9 gene was first cloned in 1982 by Kotoku Kurachi and Earl Davie.Polly, a transgenic cloned Poll Dorset sheep carrying the gene for factor IX, was produced by Dr Ian Wilmut at the Roslin Institute in 1997.

Role in disease
Deficiency of factor IX causes Christmas disease (hemophilia B). Over 3000 variants of factor IX have been described, affecting 73% of the 461 residues; some cause no symptoms, but many lead to a significant bleeding disorder. The original Christmas disease mutation was identified by sequencing of Christmas DNA, revealing a mutation which changed a cysteine to a serine.Recombinant factor IX is used to treat Christmas disease. Formulations include:

nonacog alfa (brand name BeneFix)
albutrepenonacog alfa (brand name Idelvion)
eftrenonacog alfa (brand name Alprolix)
nonacog beta pegol (brand name Refixia)Some rare mutations of factor IX result in elevated clotting activity, and can result in clotting diseases, such as deep vein thrombosis. This gain of function mutation renders the protein hyperfunctional and is associated with familial early-onset thrombophilia.Factor IX deficiency is treated by injection of purified factor IX produced through cloning in various animal or animal cell vectors. Tranexamic acid may be of value in patients undergoing surgery who have inherited factor IX deficiency in order to reduce the perioperative risk of bleeding.A list of all the mutations in Factor IX is compiled and maintained by EAHAD.Coagulation factor IX is on the World Health Organizations List of Essential Medicines.

References
Further reading
External links
"Coagulation Factor IX (Recombinant), Fc Fusion Protein". Drug Information Portal. U.S. National Library of Medicine.
"Eftrenonacog alfa". Drug Information Portal. 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 Nafcillin 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 Clofarabine and can you explain it in depth? [/INST] Clofarabine is a purine nucleoside antimetabolite marketed in the United States and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra. It is FDA-approved for treating relapsed or refractory acute lymphoblastic leukaemia (ALL) in children after at least two other types of treatment have failed. Some investigations of effectiveness in cases of  acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out. Ongoing trials are assessing its efficacy for managing other cancers.

Approval
Clolar was Food and Drug Administration (FDA) approved 28 December 2004. (Under accelerated approval regulations requiring further clinical studies.)

Side effects
Tumor lysis syndrome (TLS). Clofarabine quickly kills leukaemia cells in the blood. The body may react to this. Signs include hyperkalemia, hyperuricemia, and hyperphosphatemia.  TLS is very serious and can lead to death if it is not treated right away.
Systemic inflammatory response syndrome (SIRS): symptoms include fast breathing, fast heartbeat, low blood pressure, and fluid in the lungs.
Bone marrow problems (suppression). Clofarabine can stop the bone marrow from making enough red blood cells, white blood cells, and platelets. Serious side effects that can happen because of bone marrow suppression include severe infection (sepsis), bleeding, and anemia.
Effects on pregnancy and breastfeeding. Girls and women should not become pregnant or breastfeed during treatment which may harm the baby.
Dehydration and low blood pressure. Clofarabine can cause vomiting and diarrhea which may lead to low body fluid (dehydration). Signs and symptoms of dehydration include dizziness, lightheadedness, fainting spells, or decreased urination.
Other side effects. The most common side effects are stomach problems (including vomiting, diarrhea, and nausea), and effects on blood cells (including low red blood cells count, low white blood cell count, low platelet count, fever, and infection). Clofarabine can also cause tachycardia and can affect the liver and kidneys.

Contraindications
pregnancy or planned pregnancy
breast-feeding
liver problems
kidney problems

Drug interactions
nephrotoxic drugs
hepatotoxic drugs

Delivery
By intravenous infusion.
Dosage is a 2-hour infusion (52 mg/m2) every day for five days. The cycle is repeated every 2 to 6 weeks.
Regular blood tests to monitor his or her blood cells, kidney function, and liver function.

Biology
Clofarabine is a second-generation purine nucleoside analog designed to overcome biological limitations observed with ara-A and fludarabine. A 2´(S)-fluorine in clofarabine significantly increased the stability of the glycosidic bond in acidic solution and toward phosphorolytic cleavage as compared to fludarabine. A chlorine substitution at the 2-position of the adenine base avoids production of a 2-fluoroadenine analog, a precursor to the toxic 2-fluoro-adenosine-5´-triphosphate and prevents deamination of the base as compared to ara-A.Clofarabine can be administered intravenously or given orally. Clofarabine enters cells via hENT1, hENT2, and hCNT2, where upon it is phosphorylated by deoxycytidine kinase to generate clofarabine-5´-monophosphate </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 Eletriptan and can you explain it in depth? [/INST] Eletriptan, sold under the brand name Relpax and used in the form of eletriptan hydrobromide, is a second generation triptan medication intended for treatment of migraine headaches. It is used as an abortive medication, blocking a migraine attack which is already in progress. Eletriptan is marketed and manufactured by Pfizer Inc.

Approval and availability
Eletriptan was approved by the US Food and Drug Administration (FDA) on December 26, 2002, for the acute treatment of migraine with or without aura in adults. It is available only by prescription in the United States and Canada. It is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. It is available in 20 mg and 40 mg strengths.
Eletriptan was covered by U.S. Patent no. 5545644 and U.S. Patent  no. 6110940;  both now expired.

Mechanism of action
Eletriptan is believed to reduce swelling of the blood vessels surrounding the brain. This swelling is associated with the head pain of a migraine attack. Eletriptan blocks the release of substances from nerve endings that cause more pain and other symptoms like nausea, and sensitivity to light and sound. It is thought that these actions contribute to relief of symptoms by eletriptan.
Eletriptan is a serotonin receptor agonist, specifically an agonist of certain 5-HT1 family receptors. Eletriptan binds with high affinity to the 5-HT[1B, 1D, 1F] receptors. It has a modest affinity to the 5-HT[1A, 1E, 2B, 7] receptors, and little to no affinity at the 5-HT[2A, 2C, 3, 4, 5A, 6] receptors.
Eletriptan has no significant affinity or pharmacological activity at adrenergic α1, α2, or β; dopaminergic D1 or D2; muscarinic; or opioid receptors. Eletriptan could be efficiently co-administrated with nitric oxide synthase (NOSs) inhibitors for the treatment of NOS-dependent diseases (US patent US 2007/0254940).
Two theories have been proposed to explain the efficacy of 5-HT1 receptor agonists in migraine. One theory suggests that activation of 5-HT1 receptors located on intracranial blood vessels, including those on the arteriovenous anastomoses, leads to vasoconstriction, which is correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HT1 receptors on sensory nerve endings in the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.

Side effects
Common side effects include hypertension, tachycardia, headache, dizziness, drowsiness and symptoms similar to angina pectoris </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 Drospirenone/estetrol 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 Meclizine and can you explain it in depth? [/INST] Meclizine, sold under the brand name Bonine, among others, is an antihistamine used to treat motion sickness and dizziness (vertigo). It is taken by mouth. Effects generally begin in an hour and last for up to a day.Common side effects include sleepiness and dry mouth. Serious side effects may include allergic reactions. Use in pregnancy appears safe, but has not been well studied while use in breastfeeding is of unclear safety. It is believed to work in part by anticholinergic and antihistamine mechanisms.Meclizine was patented in 1951 and came into medical use in 1953. It is available as a generic medication and often over the counter. In 2019, it was the 150th most commonly prescribed medication in the United States, with more than 4 million prescriptions.

Medical uses
Meclizine is used to treat symptoms of motion sickness. Safety and efficacy in children younger than twelve years of age has not been established; therefore, use in this population is not recommended. Meclizine should be taken with caution in the elderly due to increased risk of confusion and amnesia.

Motion sickness
Meclizine is effective in inhibiting nausea, vomiting, and dizziness caused by motion sickness.The drug is safe for treating nausea in pregnancy and is a first-line therapy for this use. Doxylamine is similarly safe. Meclizine may not be strong enough for especially sickening motion stimuli and second-line defenses should be tried in those cases.

Vertigo
Meclizine may be used to treat motion sickness or vertigo such as in those with Ménières disease.

Side effects
Some common side effects such as drowsiness, dry mouth, and tiredness may occur. Meclizine has been shown to have fewer dry mouth side effects than the traditional treatment for motion sickness, transdermal scopolamine. A very serious allergic reaction to this drug is unlikely, but immediate medical attention should be sought if it occurs. Symptoms of a serious allergic reaction may include rash, itching, swelling, severe dizziness, and trouble breathing.

Drowsiness
Drowsiness may result as a side effect of taking meclizine. Users are advised not to operate heavy machinery while under the influence. The consumption of alcohol while under the influence of meclizine may result in additional drowsiness.

Elderly
As with any anticholinergic agent, meclizine may cause confusion or aggravate symptoms in those with dementia in the geriatric population (older than 65 years). Therefore, caution should be used when administering meclizine to the elderly.

Mechanism of action
Meclizine is an antagonist at H1 receptors. It possesses anticholinergic, central nervous system depressant, and local anesthetic effects. Its antiemetic and antivertigo effects are not fully understood, but its central anticholinergic properties are partially responsible. The drug depresses labyrinth excitability and vestibular stimulation, and it may affect the medullary chemoreceptor trigger zone. It has however been suggested that meclizine only has an inhibitory effect under normal viewing-circumstances, as the drug has been shown to enhance an isolated vestibular response. Much like motion-sickness arises from a discrepancy between multiple senses, Meclizine most likely affects a wide array of sensory mechanisms related to self-motion.
Meclizine also is a dopamine antagonist at D1-like and D2-like receptors but does not cause catalepsy in mice, perhaps because of its anticholinergic activity.

Chemistry
Meclizine is a first-generation antihistamine (nonselective H1 antagonist) of the piperazine class. It is structurally and pharmacologically similar to buclizine, cyclizine, and hydroxyzine, but has a shorter half-life of six hours compared to cyclizine and hydroxyzine with about 20 hours (though half-life should not be confused with duration). It is used as an antivertigo/antiemetic agent, specifically in the prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness. Meclizine is sometimes combined with opioids, especially ones of the open-chain class like methadone, dextropropoxyphene, and dipipanone. Similarly, Diconal is a combination drug containing dipipanone and cyclizine.

Synthesis
(4-Chlorphenyl)-phenylmethanol is halogenated with thionyl chloride before adding acetylpiperazine. The acetyl group is cleaved with diluted sulfuric acid. An N-alkylation of the piperazine ring with 3-methylbenzylchloride completes the synthesis.
Alternatively, the last step can be replaced by a reductive N-alkylation with 3-methylbenzaldehyde </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 Cenobamate and can you explain it in depth? [/INST] Cenobamate, sold under the brand names Xcopri (US) and Ontozry (EU), is a medication used for the treatment of partial-onset seizures, a kind of epilepsy, in adults. It is taken by mouth.Cenobamate was approved for medical use in the United States in November 2019 and placed in Schedule V of the Controlled Substances Act in March 2020. Cenobamate was approved for medical use in the European Union in March 2021.

Medical uses
In the United States, cenobamate is indicated for the treatment of partial-onset seizures in adults.In the European Union, it is indicated for the adjunctive treatment of focal-onset seizures with or without secondary generalization in adults with epilepsy who have not been adequately controlled despite a history of treatment with at least two anti-epileptic medications.

Contraindications
Cenobamate shortens the QT interval of the heart rhythm. It is therefore contraindicated in people with familial short QT syndrome, a very rare disease of the electrical system of the heart.

Adverse effects
The most common side effects are drowsiness (in 37% of people taking the drug), dizziness (33%), and fatigue (24%). Sight disorders, headache and elevated potassium levels in the blood (over 5 mmol/L) are also common. Hypersensitivity occurs in fewer than 1% of patients, drug reaction with eosinophilia and systemic symptoms (DRESS) in fewer than 0.1%.

Overdose
There are few data regarding cenobamate overdose. It is expected that the described adverse effects such as drowsiness, dizziness and fatigue would occur, as well as possibly problems with the heart rhythm. No specific antidote exists.

Interactions
Using cenobamate together with other central nervous system depressants such as barbiturates, benzodiazepines or alcohol may result in increased drowsiness and other central nervous system symptoms.Cenobamate induces the enzymes CYP3A4 and CYP2B6 and can therefore decrease blood concentrations of drugs that are metabolized by these enzymes (for example midazolam and bupropion, respectively). Conversely, it inhibits the enzyme CYP2C19, potentially increasing concentrations of drugs metabolized by this enzyme (for example omeprazole).

Pharmacology
Mechanism of action
Cenobamate is a voltage-gated sodium channel (VGSC) blocker. It is a selective blocker of the inactivated state of VGSCs, preferentially inhibiting persistent sodium current. It has been proposed that cenobamate additionally enhances presynaptic release of γ-aminobutyric acid (GABA), thereby increasing inhibitory GABAergic neurotransmission.

Pharmacokinetics
Cenobamate is absorbed from the gut to at least 88% and reaches highest concentrations in the blood plasma after one to four hours. When in the bloodstream, 60% of the substance are bound to plasma proteins, mostly to albumin. Cenobamate is inactivated mainly by glucuronidation via the enzyme UGT2B7 and to a lesser extent UGT2B4. The enzymes CYP2E1, CYP2A6, CYP2B6, CYP2C19 and CYP3A4 play smaller roles in the drugs metabolism.Steady state conditions are reached after 14 days </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 Dexrazoxane and can you explain it in depth? [/INST] Dexrazoxane hydrochloride (Zinecard, Cardioxane) is a cardioprotective agent. It was discovered by Eugene Herman in 1972. The IV administration of dexrazoxane is in acidic condition with HCl adjusting the pH.

Uses
Dexrazoxane has been used to protect the heart against the cardiotoxic side effects of chemotherapeutic drugs such as anthracyclines, such as daunorubicin or doxorubicin or other chemotherapeutic agents. However, in July 2011 the European Medicines Agency (EMA) released a statement restricting use only in adult patients with cancer who have received > 300 mg/m2 doxorubicin or > 540 mg/m2 epirubicin and general approval for use for cardioprotection. That showed a possibly higher rate of secondary malignancies and acute myelogenous leukemia in pediatric patients treated for different cancers with both dexrazoxane and other chemotherapeutic agents that are associated with secondary malignancies.  On July 19, 2017, based on evaluation of the currently available data the European Commission issued  an EU-wide legally binding decision to implement the recommendations of the Committee for Medicinal Products for Human Use (CHMP) on dexrazoxane and lifted its 2011-contraindication for primary prevention of anthracycline-induced cardiotoxicity with dexrazoxane in children and adolescents where high doses (≥ 300 mg/m3) of anthracyclines are anticipated.
Dexrazoxane was designated by the US FDA as an orphan drug for "prevention of cardiomyopathy for children and adults 0 through 16 years of age treated with anthracyclines".  This  decision allows virtually all children to receive dexrazoxane starting with the first dose of anthracycline at the discretion of the treating provider. The label change by the agency announcing dexrazoxane as an approved cardio-oncology protectant has been followed by a review by the agency </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 Tasimelteon and can you explain it in depth? [/INST] Tasimelteon, sold under the brand name Hetlioz, is a medication approved by the U.S. Food and Drug Administration (FDA) in January 2014, for the treatment of non-24-hour sleep–wake disorder (also called non-24, N24 and N24HSWD). In June 2014, the European Medicines Agency (EMA) accepted an EU filing application for tasimelteon and in July 2015, the drug was approved in the European Union for the treatment of non-24-hour sleep-wake rhythm disorder in totally blind adults, but not in the rarer case of non-24 in sighted people.
The most common side effects include headache, somnolence, nausea (feeling sick) and dizziness.

Medical uses
In the United States, tasimelteon capsules are indicated for the treatment of non-24-hour sleep–wake disorder (Non-24) in adults and for the treatment of nighttime sleep disturbances in Smith-Magenis Syndrome (SMS) in people sixteen years of age and older. Tasimelteon oral suspension is indicated for the treatment of nighttime sleep disturbances in SMS in children from 3 to 15 years of age.In the European Union, tasimelteon capsules are indicated for the treatment of non-24-hour sleep–wake disorder (Non-24) in totally blind adults.The capsule and liquid suspension forms of tasimelteon are not interchangeable.Tasimelteon is a selective agonist for the melatonin receptors MT1 and MT2, similar to other members of the melatonin receptor agonist class of which ramelteon (2005), melatonin (2007), and agomelatine (2009) were the first approved. As a treatment for N24HSWD, as with melatonin or other melatonin derivatives, the patient may experience improved sleep timing while taking the drug. Reversion to baseline sleep performance occurs within a month of discontinuation.

Development
Tasimelteon (previously known as BMS-214,778) was developed for the treatment of insomnia and other sleep disorders. A phase II trial on circadian rhythm sleep disorders was concluded in March 2005.  A phase III insomnia trial was conducted in 2006. A second phase III trial on insomnia, this time concerning primary insomnia, was completed in June 2008. In 2010, the FDA granted orphan drug status to tasimelteon, then regarded as an investigational medication, for use in totally blind adults with N24HSWD.  (Through mechanisms such as easing the approval process and extending exclusivity periods, orphan drug status encourages development of drugs for rare conditions that otherwise might lack sufficient commercial incentive.)
On completion of Phase III trials, interpretations of the clinical trials by the research team concluded that the drug may have therapeutic potential for transient insomnia in circadian rhythm sleep disorders </s>